Patients with diabetes benefit from aggressive cardiovascular (CV) risk factor management.[161]Kelsey MD, Nelson AJ, Green JB, et al. Guidelines for cardiovascular risk reduction in patients with type 2 diabetes: JACC guideline comparison. J Am Coll Cardiol. 2022 May 10;79(18):1849-57.
https://www.sciencedirect.com/science/article/pii/S0735109722009408
http://www.ncbi.nlm.nih.gov/pubmed/35512864?tool=bestpractice.com
One large prospective cohort study showed that patients with diabetes who met target ranges for hemoglobin A1c (HbA1c), low-density lipoproteins (LDLs), blood pressure (BP), albuminuria, and smoking had the same or only slightly increased long-term mortality compared with those without diabetes.[162]Rawshani A, Rawshani A, Franzén S, et al. Risk factors, mortality, and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2018 Aug 16;379(7):633-44.
https://www.nejm.org/doi/10.1056/NEJMoa1800256
http://www.ncbi.nlm.nih.gov/pubmed/30110583?tool=bestpractice.com
However, in a large US cohort study of patients with diabetes and known cardiovascular disease (CVD), only 6.9% received guideline-recommended medical therapies for CV risk reduction.[163]Arnold SV, de Lemos JA, Rosenson RS, et al; GOULD Investigators. Use of guideline-recommended risk-reduction strategies among patients with diabetes and atherosclerotic cardiovascular disease. Circulation. 2019 Aug 13;140(7):618-20.
https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.119.041730
http://www.ncbi.nlm.nih.gov/pubmed/31174429?tool=bestpractice.com
Therapeutic lifestyle interventions such as medical nutrition therapy and aerobic exercise have been shown in large clinical trials to improve glycemic, lipid, and BP control, in addition to insulin sensitivity and markers of inflammation. They are also effective in achieving sustained weight loss and improvements in fitness.[47]Joseph JJ, Deedwania P, Acharya T, et al. Comprehensive management of cardiovascular risk factors for adults with type 2 diabetes: a scientific statement from the American Heart Association. Circulation. 2022 Mar;145(9):e722-59.
https://www.ahajournals.org/doi/full/10.1161/CIR.0000000000001040
http://www.ncbi.nlm.nih.gov/pubmed/35000404?tool=bestpractice.com
[71]Colberg SR, Sigal RJ, Yardley JE, et al. Physical activity/exercise and diabetes: a position statement of the American Diabetes Association. Diabetes Care. 2016 Nov;39(11):2065-79.
http://care.diabetesjournals.org/content/39/11/2065.long
http://www.ncbi.nlm.nih.gov/pubmed/27926890?tool=bestpractice.com
[164]Evert AB, Dennison M, Gardner CD, et al. Nutrition therapy for adults with diabetes or prediabetes: a consensus report. Diabetes Care. 2019 Apr 18;42(5):731-54.
http://care.diabetesjournals.org/content/42/5/731.long
http://www.ncbi.nlm.nih.gov/pubmed/31000505?tool=bestpractice.com
[165]Wing RR; Look AHEAD Research Group. Long-term effects of a lifestyle intervention on weight and cardiovascular risk factors in individuals with type 2 diabetes mellitus: four-year results of the Look AHEAD trial. Arch Intern Med. 2010 Sep 27;170(17):1566-75.
https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/226013
http://www.ncbi.nlm.nih.gov/pubmed/20876408?tool=bestpractice.com
[166]Elhayany A, Lustman A, Abel R, et al. A low carbohydrate Mediterranean diet improves cardiovascular risk factors and diabetes control among overweight patients with type 2 diabetes mellitus: a 1-year prospective randomized intervention study. Diabetes Obes Metab. 2010 Mar;12(3):204-9.
http://www.ncbi.nlm.nih.gov/pubmed/20151996?tool=bestpractice.com
[167]Wormgoor SG, Dalleck LC, Zinn C, et al. Effects of high-intensity interval training on people living with type 2 diabetes: a narrative review. Can J Diabetes. 2017 Oct;41(5):536-47.
http://www.ncbi.nlm.nih.gov/pubmed/28366674?tool=bestpractice.com
The US Preventive Services Task Force recommends behavioral counseling interventions to improve diet and increase physical activity for people with cardiometabolic risk factors to prevent longer term CV events.[168]O'Connor EA, Evans CV, Rushkin MC, et al. Behavioral counseling to promote a healthy diet and physical activity for cardiovascular disease prevention in adults with cardiovascular risk factors: updated evidence report and systematic review for the US Preventive Services Task Force. JAMA. 2020 Nov 24;324(20):2076-94.
https://jamanetwork.com/journals/jama/fullarticle/2773279
http://www.ncbi.nlm.nih.gov/pubmed/33231669?tool=bestpractice.com
Recommendations for the management of CVD and risk reduction in patients with diabetes include:[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
[169]Samson SL, Vellanki P, Blonde L, et al. American Association of Clinical Endocrinology consensus statement: comprehensive type 2 diabetes management algorithm - 2023 update. Endocr Pract. 2023 May;29(5):305-40.
https://www.endocrinepractice.org/article/S1530-891X(23)00034-4/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/37150579?tool=bestpractice.com
Therapeutic lifestyle interventions (medical nutrition therapy/dietary advice, physical activity, and smoking cessation)
Treatment for overweight or obesity
Glycemic control
BP control
Dyslipidemia treatment
Antiplatelet therapy
There is substantial evidence to support the benefit of CV risk factor management in people with type 2 diabetes; however, robust evidence to support a comparable benefit in people with type 1 diabetes is lacking. Current treatment guidelines extrapolate clinical trial evidence obtained in people with type 2 diabetes to provide similar treatment recommendations for people with both type 1 and type 2 diabetes. There is evidence, however, to support the more aggressive treatment of CV risk factors in people with type 1 diabetes, who would likely benefit from early risk stratification and comprehensive risk factor management, including aggressive lipid-lowering therapy.[170]Karmali R, Sipko J, Majid M, et al. Hyperlipidemia and cardiovascular disease in people with type 1 diabetes: review of current guidelines and evidence. Curr Cardiol Rep. 2023 May;25(5):435-42.
http://www.ncbi.nlm.nih.gov/pubmed/37052761?tool=bestpractice.com
Medical nutrition therapy
There is no ideal amount of macronutrients that people with diabetes should consume, and studies suggest that such recommendations should be decided on an individual basis.[164]Evert AB, Dennison M, Gardner CD, et al. Nutrition therapy for adults with diabetes or prediabetes: a consensus report. Diabetes Care. 2019 Apr 18;42(5):731-54.
http://care.diabetesjournals.org/content/42/5/731.long
http://www.ncbi.nlm.nih.gov/pubmed/31000505?tool=bestpractice.com
[171]Wheeler ML, Dunbar SA, Jaacks LM, et al. Macronutrients, food groups, and eating patterns in the management of diabetes: a systematic review of the literature, 2010. Diabetes Care. 2012 Feb;35(2):434-45.
http://care.diabetesjournals.org/content/35/2/434.full
http://www.ncbi.nlm.nih.gov/pubmed/22275443?tool=bestpractice.com
The Mediterranean diet, Dietary Approaches to Stop Hypertension (DASH), vegetarian, and vegan diets have all demonstrated some efficacy in people with diabetes.[164]Evert AB, Dennison M, Gardner CD, et al. Nutrition therapy for adults with diabetes or prediabetes: a consensus report. Diabetes Care. 2019 Apr 18;42(5):731-54.
http://care.diabetesjournals.org/content/42/5/731.long
http://www.ncbi.nlm.nih.gov/pubmed/31000505?tool=bestpractice.com
[172]Esposito K, Maiorino MI, Ciotola M, et al. Effects of a Mediterranean-style diet on the need for antihyperglycemic drug therapy in patients with newly diagnosed type 2 diabetes: a randomized trial. Ann Intern Med. 2009 Sep 1;151(5):306-14.
http://www.ncbi.nlm.nih.gov/pubmed/19721018?tool=bestpractice.com
[173]Azadbakht L, Fard NR, Karimi M, et al. Effects of the Dietary Approaches to Stop Hypertension (DASH) eating plan on cardiovascular risks among type 2 diabetic patients: a randomized crossover clinical trial. Diabetes Care. 2011 Jan;34(1):55-7.
http://care.diabetesjournals.org/content/34/1/55.full
http://www.ncbi.nlm.nih.gov/pubmed/20843978?tool=bestpractice.com
[174]Barnard ND, Cohen J, Jenkins DJ, et al. A low-fat vegan diet improves glycemic control and cardiovascular risk factors in a randomized clinical trial in individuals with type 2 diabetes. Diabetes Care. 2006 Aug;29(8):1777-83.
http://care.diabetesjournals.org/content/29/8/1777.long
http://www.ncbi.nlm.nih.gov/pubmed/16873779?tool=bestpractice.com
[175]Wang T, Kroeger CM, Cassidy S, et al. Vegetarian dietary patterns and cardiometabolic risk in people with or at high risk of cardiovascular disease: a systematic review and meta-analysis. JAMA Netw Open. 2023 Jul 3;6(7):e2325658.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10369207
http://www.ncbi.nlm.nih.gov/pubmed/37490288?tool=bestpractice.com
European guidelines recommend a Mediterranean or plant-based diet with high unsaturated fat content for lowering CV risk in people with diabetes.[6]Marx N, Federici M, Schütt K, et al. 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. Eur Heart J. 2023 Oct 14;44(39):4043-140.
https://academic.oup.com/eurheartj/article/44/39/4043/7238227
http://www.ncbi.nlm.nih.gov/pubmed/37622663?tool=bestpractice.com
One meta-analysis found that red meat consumption was associated with higher risk of CVD and diabetes, while another reported moderate certainty evidence that a shift from animal-based to plant-based foods is beneficially associated with cardiometabolic health and all-cause mortality.[176]Shi W, Huang X, Schooling CM, et al. Red meat consumption, cardiovascular diseases, and diabetes: a systematic review and meta-analysis. Eur Heart J. 2023 Jul 21;44(28):2626-35.
https://academic.oup.com/eurheartj/article/44/28/2626/7188739
http://www.ncbi.nlm.nih.gov/pubmed/37264855?tool=bestpractice.com
[177]Neuenschwander M, Stadelmaier J, Eble J, et al. Substitution of animal-based with plant-based foods on cardiometabolic health and all-cause mortality: a systematic review and meta-analysis of prospective studies. BMC Med. 2023 Nov 16;21(1):404.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10652524
http://www.ncbi.nlm.nih.gov/pubmed/37968628?tool=bestpractice.com
Reducing overall carbohydrate intake has demonstrated some evidence for improving glycemia and one study found that among people with type 2 diabetes, greater adherence to low-carbohydrate diet patterns was associated with significantly lower all-cause mortality.[178]Hu Y, Liu G, Yu E, et al. Low-carbohydrate diet scores and mortality among adults with incident type 2 diabetes. Diabetes Care. 2023 Apr 1;46(4):874-84.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10090909
http://www.ncbi.nlm.nih.gov/pubmed/36787923?tool=bestpractice.com
While the American Diabetes Association (ADA) suggests that adults with diabetes may consider reducing their overall carbohydrate intake to improve glycemia, it cautions that the optimal level of restriction and the long-term impact on CVD are not yet fully understood.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
Both World Health Organization (WHO) and European guidelines emphasize that carbohydrate quality, rather than quantity, is key.[179]Diabetes and Nutrition Study Group (DNSG) of the European Association for the Study of Diabetes (EASD). Evidence-based European recommendations for the dietary management of diabetes. Diabetologia. 2023 Jun;66(6):965-85.
https://link.springer.com/article/10.1007/s00125-023-05894-8
http://www.ncbi.nlm.nih.gov/pubmed/37069434?tool=bestpractice.com
[180]World Health Organization. Carbohydrate intake for adults and children: WHO guideline. Jul 2023 [internet publication].
https://www.who.int/publications/i/item/9789240073593
The concept of carbohydrate quality refers to the nature and composition of carbohydrates in a food or in the diet, including the proportion of sugars, how quickly polysaccharides are metabolized and release glucose into the body (i.e., digestibility), and the amount of dietary fiber. It is recommended that carbohydrate intake should come primarily from high-fiber foods, such as whole grains, vegetables, whole fruits, and pulses.[179]Diabetes and Nutrition Study Group (DNSG) of the European Association for the Study of Diabetes (EASD). Evidence-based European recommendations for the dietary management of diabetes. Diabetologia. 2023 Jun;66(6):965-85.
https://link.springer.com/article/10.1007/s00125-023-05894-8
http://www.ncbi.nlm.nih.gov/pubmed/37069434?tool=bestpractice.com
[180]World Health Organization. Carbohydrate intake for adults and children: WHO guideline. Jul 2023 [internet publication].
https://www.who.int/publications/i/item/9789240073593
Diets high in naturally occurring fiber have been shown to be protective against cardiometabolic disease and premature mortality.[179]Diabetes and Nutrition Study Group (DNSG) of the European Association for the Study of Diabetes (EASD). Evidence-based European recommendations for the dietary management of diabetes. Diabetologia. 2023 Jun;66(6):965-85.
https://link.springer.com/article/10.1007/s00125-023-05894-8
http://www.ncbi.nlm.nih.gov/pubmed/37069434?tool=bestpractice.com
When choosing high-fiber foods, focus should be on minimally processed and largely intact whole grains, rather than products with finely milled whole grains that may also have added sugars, sodium, and saturated fats.[179]Diabetes and Nutrition Study Group (DNSG) of the European Association for the Study of Diabetes (EASD). Evidence-based European recommendations for the dietary management of diabetes. Diabetologia. 2023 Jun;66(6):965-85.
https://link.springer.com/article/10.1007/s00125-023-05894-8
http://www.ncbi.nlm.nih.gov/pubmed/37069434?tool=bestpractice.com
[180]World Health Organization. Carbohydrate intake for adults and children: WHO guideline. Jul 2023 [internet publication].
https://www.who.int/publications/i/item/9789240073593
Fiber-enriched foods and fiber supplements can be considered when sufficient intake cannot be obtained from diet alone.[179]Diabetes and Nutrition Study Group (DNSG) of the European Association for the Study of Diabetes (EASD). Evidence-based European recommendations for the dietary management of diabetes. Diabetologia. 2023 Jun;66(6):965-85.
https://link.springer.com/article/10.1007/s00125-023-05894-8
http://www.ncbi.nlm.nih.gov/pubmed/37069434?tool=bestpractice.com
Some evidence suggests that reducing intake of high-glycemic index foods and lowering overall glycemic load may help prevent CVD. However, WHO guidelines do not currently recommend this approach, citing inconsistent findings from observational studies and little to no improvement in cardiometabolic risk factors in randomized controlled trials of lower-glycemic index or lower-glycemic load diets.[180]World Health Organization. Carbohydrate intake for adults and children: WHO guideline. Jul 2023 [internet publication].
https://www.who.int/publications/i/item/9789240073593
[181]Jenkins DJA, Willett WC, Yusuf S, et al. Association of glycaemic index and glycaemic load with type 2 diabetes, cardiovascular disease, cancer, and all-cause mortality: a meta-analysis of mega cohorts of more than 100 000 participants. Lancet Diabetes Endocrinol. 2024 Feb;12(2):107-18.
http://www.ncbi.nlm.nih.gov/pubmed/38272606?tool=bestpractice.com
Replacing saturated fats and trans-fats with unsaturated fats and carbohydrates from foods containing naturally occurring dietary fiber (such as whole grains, vegetables, fruits, and pulses) reduces LDL-cholesterol (LDL-C) and also benefits CVD risk.[164]Evert AB, Dennison M, Gardner CD, et al. Nutrition therapy for adults with diabetes or prediabetes: a consensus report. Diabetes Care. 2019 Apr 18;42(5):731-54.
http://care.diabetesjournals.org/content/42/5/731.long
http://www.ncbi.nlm.nih.gov/pubmed/31000505?tool=bestpractice.com
[182]Schwab U, Reynolds AN, Sallinen T, et al. Dietary fat intakes and cardiovascular disease risk in adults with type 2 diabetes: a systematic review and meta-analysis. Eur J Nutr. 2021 Sep;60(6):3355-63.
http://www.ncbi.nlm.nih.gov/pubmed/33611616?tool=bestpractice.com
[183]World Health Organization. Saturated fatty acid and trans-fatty acid intake for adults and children: WHO guideline. Jul 2023 [internet publication].
https://www.who.int/publications/i/item/9789240073630
Saturated fat should comprise <10% of total energy intake and trans-fats <1%.[179]Diabetes and Nutrition Study Group (DNSG) of the European Association for the Study of Diabetes (EASD). Evidence-based European recommendations for the dietary management of diabetes. Diabetologia. 2023 Jun;66(6):965-85.
https://link.springer.com/article/10.1007/s00125-023-05894-8
http://www.ncbi.nlm.nih.gov/pubmed/37069434?tool=bestpractice.com
[183]World Health Organization. Saturated fatty acid and trans-fatty acid intake for adults and children: WHO guideline. Jul 2023 [internet publication].
https://www.who.int/publications/i/item/9789240073630
Dietary fats should mainly come from plant-based foods high in mono- and poly-unsaturated fats, such as nuts, seeds, and nonhydrogenated, nontropical vegetable oils (e.g., olive oil, rapeseed/canola oil, soybean oil, sunflower oil, linseed oil).[179]Diabetes and Nutrition Study Group (DNSG) of the European Association for the Study of Diabetes (EASD). Evidence-based European recommendations for the dietary management of diabetes. Diabetologia. 2023 Jun;66(6):965-85.
https://link.springer.com/article/10.1007/s00125-023-05894-8
http://www.ncbi.nlm.nih.gov/pubmed/37069434?tool=bestpractice.com
People with diabetes who have overweight or obesity should be supported with evidence-based nutritional support to achieve and maintain weight loss.[179]Diabetes and Nutrition Study Group (DNSG) of the European Association for the Study of Diabetes (EASD). Evidence-based European recommendations for the dietary management of diabetes. Diabetologia. 2023 Jun;66(6):965-85.
https://link.springer.com/article/10.1007/s00125-023-05894-8
http://www.ncbi.nlm.nih.gov/pubmed/37069434?tool=bestpractice.com
European guidelines recommend that a variety of weight-loss diets can be used equally effectively, provided they can be followed and meet recommendations for protein, fat, micronutrient, and fiber intake. Neither extreme high-carbohydrate, nor very-low-carbohydrate ketogenic diets are recommended, however.[179]Diabetes and Nutrition Study Group (DNSG) of the European Association for the Study of Diabetes (EASD). Evidence-based European recommendations for the dietary management of diabetes. Diabetologia. 2023 Jun;66(6):965-85.
https://link.springer.com/article/10.1007/s00125-023-05894-8
http://www.ncbi.nlm.nih.gov/pubmed/37069434?tool=bestpractice.com
One systematic umbrella review of published meta-analyses of studies comparing hypoenergetic diets for weight management in people with type 2 diabetes did not find evidence for any particular weight-loss diet over others (e.g., low-carbohydrate, high-protein, low-glycemic index, Mediterranean, high-monounsaturated fatty acid, or vegetarian diets).[184]Churuangsuk C, Hall J, Reynolds A, et al. Diets for weight management in adults with type 2 diabetes: an umbrella review of published meta-analyses and systematic review of trials of diets for diabetes remission. Diabetologia. 2022 Jan;65(1):14-36.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8660762
http://www.ncbi.nlm.nih.gov/pubmed/34796367?tool=bestpractice.com
Intermittent fasting or time-restricted eating as strategies for weight and glucose management have gained popularity.[185]Tagde P, Tagde S, Bhattacharya T, et al. Multifaceted effects of intermittent fasting on the treatment and prevention of diabetes, cancer, obesity or other chronic diseases. Curr Diabetes Rev. 2022;18(9):e131221198789.
http://www.ncbi.nlm.nih.gov/pubmed/34961463?tool=bestpractice.com
They have been shown to result in mild to moderate weight loss (3% to 8% loss from baseline) over 8-12 weeks, but no significant difference in weight loss when compared with continuous calorie restriction.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
The ADA advises that due to its simplicity, intermittent fasting may lend itself as a useful strategy for people with diabetes who are looking for practical eating management tools.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
People with diabetes who are on insulin and/or secretagogues should be medically monitored during the fasting period.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
Evidence indicates that low- and very-low-energy diets (<3500 kJ/day [<840 kcal/day]), using total diet replacement formula diet products (replacing all meals) or partial liquid meal replacement products (replacing 1-2 meals per day) for the weight-loss phase, are most effective for weight loss and reduction of other cardiometabolic risk factors when compared with the results from self-administered food-based weight-loss diets.[179]Diabetes and Nutrition Study Group (DNSG) of the European Association for the Study of Diabetes (EASD). Evidence-based European recommendations for the dietary management of diabetes. Diabetologia. 2023 Jun;66(6):965-85.
https://link.springer.com/article/10.1007/s00125-023-05894-8
http://www.ncbi.nlm.nih.gov/pubmed/37069434?tool=bestpractice.com
[186]Lean ME, Leslie WS, Barnes AC, et al. Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial. Lancet. 2018 Feb 10;391(10120):541-51.
http://www.ncbi.nlm.nih.gov/pubmed/29221645?tool=bestpractice.com
Low-energy nutritionally complete formula diets with a total diet replacement induction phase also appear to be the most effective dietary approach for achieving type 2 diabetes remission.[179]Diabetes and Nutrition Study Group (DNSG) of the European Association for the Study of Diabetes (EASD). Evidence-based European recommendations for the dietary management of diabetes. Diabetologia. 2023 Jun;66(6):965-85.
https://link.springer.com/article/10.1007/s00125-023-05894-8
http://www.ncbi.nlm.nih.gov/pubmed/37069434?tool=bestpractice.com
One population-based cohort study found that those who achieved remission from diabetes, even for a short time, had a much lower risk of CVD events, including myocardial infarction (MI) and stroke, as well macrovascular and microvascular complications.[187]Dambha-Miller H, Hounkpatin HO, Stuart B, et al. Type 2 diabetes remission trajectories and variation in risk of diabetes complications: a population-based cohort study. PLoS One. 2023 Aug 29;18(8):e0290791.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10464964
http://www.ncbi.nlm.nih.gov/pubmed/37643199?tool=bestpractice.com
Physical activity
A sedentary lifestyle is a major risk factor for CVD.[68]Wahid A, Manek N, Nichols M, et al. Quantifying the association between physical activity and cardiovascular disease and diabetes: a systematic review and meta-analysis. J Am Heart Assoc. 2016 Sep 14;5(9):e002495.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5079002
http://www.ncbi.nlm.nih.gov/pubmed/27628572?tool=bestpractice.com
[69]Vasankari V, Husu P, Vähä-Ypyä H, et al. Association of objectively measured sedentary behaviour and physical activity with cardiovascular disease risk. Eur J Prev Cardiol. 2017 Aug;24(12):1311-8.
https://academic.oup.com/eurjpc/article/24/12/1311/5926905
http://www.ncbi.nlm.nih.gov/pubmed/28530126?tool=bestpractice.com
Many individuals with type 2 diabetes do not meet the recommended exercise level per week.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
[70]Bazargan-Hejazi S, Arroyo JS, Hsia S, et al. A racial comparison of differences between self-reported and objectively measured physical activity among US adults with diabetes. Ethn Dis. 2017 Fall;27(4):403-10.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5720950
http://www.ncbi.nlm.nih.gov/pubmed/29225441?tool=bestpractice.com
Physical activity improves glycemic control, lipids, BP, insulin sensitivity, and markers of inflammation in type 2 diabetes.[47]Joseph JJ, Deedwania P, Acharya T, et al. Comprehensive management of cardiovascular risk factors for adults with type 2 diabetes: a scientific statement from the American Heart Association. Circulation. 2022 Mar;145(9):e722-59.
https://www.ahajournals.org/doi/full/10.1161/CIR.0000000000001040
http://www.ncbi.nlm.nih.gov/pubmed/35000404?tool=bestpractice.com
[71]Colberg SR, Sigal RJ, Yardley JE, et al. Physical activity/exercise and diabetes: a position statement of the American Diabetes Association. Diabetes Care. 2016 Nov;39(11):2065-79.
http://care.diabetesjournals.org/content/39/11/2065.long
http://www.ncbi.nlm.nih.gov/pubmed/27926890?tool=bestpractice.com
[167]Wormgoor SG, Dalleck LC, Zinn C, et al. Effects of high-intensity interval training on people living with type 2 diabetes: a narrative review. Can J Diabetes. 2017 Oct;41(5):536-47.
http://www.ncbi.nlm.nih.gov/pubmed/28366674?tool=bestpractice.com
[188]Batty GD, Shipley MJ, Marmot M, et al. Physical activity and cause-specific mortality in men with type 2 diabetes/impaired glucose tolerance: evidence from the Whitehall study. Diabet Med. 2002 Jul;19(7):580-8.
http://www.ncbi.nlm.nih.gov/pubmed/12099962?tool=bestpractice.com
Increased physical activity is associated with lower risk of CVD and reduced all-cause mortality in both type 1 and type 2 diabetes.[47]Joseph JJ, Deedwania P, Acharya T, et al. Comprehensive management of cardiovascular risk factors for adults with type 2 diabetes: a scientific statement from the American Heart Association. Circulation. 2022 Mar;145(9):e722-59.
https://www.ahajournals.org/doi/full/10.1161/CIR.0000000000001040
http://www.ncbi.nlm.nih.gov/pubmed/35000404?tool=bestpractice.com
[72]Rietz M, Lehr A, Mino E, et al. Physical activity and risk of major diabetes-related complications in individuals with diabetes: a systematic review and meta-analysis of observational studies. Diabetes Care. 2022 Dec 1;45(12):3101-11.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9862380
http://www.ncbi.nlm.nih.gov/pubmed/36455117?tool=bestpractice.com
[123]Rahman H, Khan SU, Lone AN, et al. Sodium-glucose cotransporter-2 inhibitors and primary prevention of atherosclerotic cardiovascular disease: a meta-analysis of randomized trials and systematic review. J Am Heart Assoc. 2023 Aug 15;12(16):e030578.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10492958
http://www.ncbi.nlm.nih.gov/pubmed/37581396?tool=bestpractice.com
[189]Tikkanen-Dolenc H, Wadén J, Forsblom C, et al. Physical activity reduces risk of premature mortality in patients with type 1 diabetes with and without kidney disease. Diabetes Care. 2017 Dec;40(12):1727-32.
http://www.ncbi.nlm.nih.gov/pubmed/29038314?tool=bestpractice.com
At least 150 minutes per week of moderate- to vigorous-intensity aerobic physical activity is recommended for adults with diabetes.[6]Marx N, Federici M, Schütt K, et al. 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. Eur Heart J. 2023 Oct 14;44(39):4043-140.
https://academic.oup.com/eurheartj/article/44/39/4043/7238227
http://www.ncbi.nlm.nih.gov/pubmed/37622663?tool=bestpractice.com
[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
The physical activity should be spread over at least 3 days per week, with no more than 2 consecutive days without exercise.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
Shorter durations (minimum 75 minutes per week) of vigorous-intensity or interval training may be sufficient for more physically fit individuals.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
In the absence of contraindications, resistance training 2 to 3 times per week on nonconsecutive days is also recommended.[6]Marx N, Federici M, Schütt K, et al. 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. Eur Heart J. 2023 Oct 14;44(39):4043-140.
https://academic.oup.com/eurheartj/article/44/39/4043/7238227
http://www.ncbi.nlm.nih.gov/pubmed/37622663?tool=bestpractice.com
[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
The ADA recommends interrupting sedentary activity every 30 minutes with short bouts of physical activity.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
Older adults may also benefit from flexibility and balance exercise 2 to 3 times per week.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
The ADA recommends assessment of the following prior to starting an exercise program: age, physical condition, BP (uncontrolled hypertension or orthostatic hypotension), and presence or absence of autonomic neuropathy or peripheral neuropathy, balance impairment, history of foot ulcers or Charcot foot, or untreated proliferative retinopathy.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
The European Society of Cardiology (ESC) recommends that any exercise interventions be tailored according to a patient’s frailty and diabetes-associated comorbidities such as retinopathy.[6]Marx N, Federici M, Schütt K, et al. 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. Eur Heart J. 2023 Oct 14;44(39):4043-140.
https://academic.oup.com/eurheartj/article/44/39/4043/7238227
http://www.ncbi.nlm.nih.gov/pubmed/37622663?tool=bestpractice.com
The European Association of Preventive Cardiology recommends testing for silent myocardial ischemia prior to initiating an exercise program in patients with type 2 diabetes and CVD, whereas the ADA states that clinical judgment should be used in determining whether to screen asymptomatic individuals for coronary artery disease (CAD) prior to recommending an exercise program.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
[190]Kemps H, Kränkel N, Dörr M, et al. Exercise training for patients with type 2 diabetes and cardiovascular disease: what to pursue and how to do it – position paper of the European Association of Preventive Cardiology (EAPC). Eur J Prev Cardiol. 2019 May;26(7):709-27.
https://academic.oup.com/eurjpc/article/26/7/709/5925108
http://www.ncbi.nlm.nih.gov/pubmed/30642190?tool=bestpractice.com
Smoking cessation
All patients with diabetes should be advised not to smoke or to quit smoking.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
Smoking counseling and other forms of smoking cessation therapy should be incorporated into routine diabetes care.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
Varenicline combined with nicotine replacement therapy may be more effective than varenicline alone and the ADA recommends referring patients for combination treatment consisting of both tobacco/smoking cessation counseling and pharmacologic therapy.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
[191]Koegelenberg CF, Noor F, Bateman ED, et al. Efficacy of varenicline combined with nicotine replacement therapy vs varenicline alone for smoking cessation: a randomized clinical trial. JAMA. 2014 Jul;312(2):155-61.
https://jamanetwork.com/journals/jama/fullarticle/1886188
http://www.ncbi.nlm.nih.gov/pubmed/25005652?tool=bestpractice.com
The ADA does not support e-cigarettes as an alternative to smoking or to facilitate smoking cessation.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
Patients who quit smoking are prone to weight gain; therefore, it is important to have weight management strategies in place to maximize the CV benefits of smoking cessation.[47]Joseph JJ, Deedwania P, Acharya T, et al. Comprehensive management of cardiovascular risk factors for adults with type 2 diabetes: a scientific statement from the American Heart Association. Circulation. 2022 Mar;145(9):e722-59.
https://www.ahajournals.org/doi/full/10.1161/CIR.0000000000001040
http://www.ncbi.nlm.nih.gov/pubmed/35000404?tool=bestpractice.com
See Smoking cessation.
Weight management
Modest and sustained weight loss of at least 3% to 7% is recommended for most patients with type 2 diabetes who have overweight or obesity.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
This degree of weight reduction significantly improves glycemia, blood pressure, and lipids and may reduce the need for disease-specific drugs.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
Sustained loss of >10% of body weight usually confers greater benefits, including disease-modifying effects and possible remission of type 2 diabetes, and may improve long-term CV outcomes and mortality.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
People with diabetes and overweight or obesity should be informed of the potential benefits of both modest and more substantial weight loss and supported in exploring the full range of available treatment options.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
Pharmacotherapy
Obesity pharmacotherapy should be considered as an adjunct to lifestyle interventions and behavioral counseling to improve CV risk factors in people with type 2 diabetes who have overweight or obesity.[6]Marx N, Federici M, Schütt K, et al. 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. Eur Heart J. 2023 Oct 14;44(39):4043-140.
https://academic.oup.com/eurheartj/article/44/39/4043/7238227
http://www.ncbi.nlm.nih.gov/pubmed/37622663?tool=bestpractice.com
[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
[169]Samson SL, Vellanki P, Blonde L, et al. American Association of Clinical Endocrinology consensus statement: comprehensive type 2 diabetes management algorithm - 2023 update. Endocr Pract. 2023 May;29(5):305-40.
https://www.endocrinepractice.org/article/S1530-891X(23)00034-4/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/37150579?tool=bestpractice.com
When choosing glucose-lowering drugs for this patient group, the ADA recommends that healthcare professionals should prioritize those with a beneficial effect on weight; this includes glucagon-like peptide-1 (GLP-1) receptor agonists (e.g., semaglutide) and the dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist tirzepatide.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
Two phase 3 trials in adults with obesity demonstrated mean losses of 15% to 21% of body weight with the highest dose of tirzepatide, with adverse effects similar to those seen with GLP-1 receptor agonists.[192]Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022 Jul 21;387(3):205-16.
https://www.nejm.org/doi/10.1056/NEJMoa2206038
http://www.ncbi.nlm.nih.gov/pubmed/35658024?tool=bestpractice.com
[193]Garvey WT, Frias JP, Jastreboff AM, et al. Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2023 Aug 19;402(10402):613-26.
http://www.ncbi.nlm.nih.gov/pubmed/37385275?tool=bestpractice.com
In the larger of the two trials, over 80% of participants in all tirzepatide treatment groups lost ≥5% of body weight, compared with 35% of those assigned to placebo.[192]Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022 Jul 21;387(3):205-16.
https://www.nejm.org/doi/10.1056/NEJMoa2206038
http://www.ncbi.nlm.nih.gov/pubmed/35658024?tool=bestpractice.com
With higher body weight reduction, there were greater reductions in HbA1c, triglycerides, waist circumference, and BP.[194]Małecki MT, Batterham RL, Sattar N, et al. Predictors of ≥15% weight reduction and associated changes in cardiometabolic risk factors with tirzepatide in adults with type 2 diabetes in SURPASS 1-4. Diabetes Care. 2023 Dec 1;46(12):2292-9.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10698219
http://www.ncbi.nlm.nih.gov/pubmed/37824793?tool=bestpractice.com
If these drugs are not tolerated or contraindicated, the ADA advises that other obesity treatment approaches may be considered, including phentermine, orlistat, phentermine/topiramate, or naltrexone/bupropion.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
The ESC recommends a GLP-1 receptor agonist or sodium-glucose cotransporter-2 (SGLT2) inhibitor as the agents of choice for glucose-lowering in patients with type 2 diabetes and overweight and obesity, in view of their proven CV benefits for these patients.[6]Marx N, Federici M, Schütt K, et al. 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. Eur Heart J. 2023 Oct 14;44(39):4043-140.
https://academic.oup.com/eurheartj/article/44/39/4043/7238227
http://www.ncbi.nlm.nih.gov/pubmed/37622663?tool=bestpractice.com
[195]Palmer SC, Tendal B, Mustafa RA, et al. Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials. BMJ. 2021 Jan 13;372:m4573.
https://www.bmj.com/content/372/bmj.m4573.long
http://www.ncbi.nlm.nih.gov/pubmed/33441402?tool=bestpractice.com
When initiating chronic weight management treatment, continuation should be considered if a patient achieves >5% weight loss after 3 months, provided there are no limiting factors such as poor tolerability, financial cost, or patient preference.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
If <5% weight loss is achieved at 3 months, the decision to continue treatment should carefully weigh potential benefits against glycemic response, alternative treatment options, treatment tolerance, and overall treatment burden.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
Ongoing monitoring of weight management goals is recommended.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
The ADA recommends that weight management pharmacotherapy should be continued beyond reaching weight loss goals to maintain the health benefits and avoid weight regain.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
Sudden discontinuation of drugs like semaglutide and tirzepatide can lead to regaining up to two-thirds of the weight lost within one year.[196]Wilding JPH, Batterham RL, Davies M, et al. Weight regain and cardiometabolic effects after withdrawal of semaglutide: the STEP 1 trial extension. Diabetes Obes Metab. 2022 Aug;24(8):1553-64.
https://dom-pubs.pericles-prod.literatumonline.com/doi/10.1111/dom.14725
http://www.ncbi.nlm.nih.gov/pubmed/35441470?tool=bestpractice.com
[197]Rubino D, Abrahamsson N, Davies M, et al. Effect of continued weekly subcutaneous semaglutide vs placebo on weight loss maintenance in adults with overweight or obesity: the STEP 4 randomized clinical trial. JAMA. 2021 Apr 13;325(14):1414-25.
http://www.ncbi.nlm.nih.gov/pubmed/33755728?tool=bestpractice.com
[198]Aronne LJ, Sattar N, Horn DB, et al. Continued treatment with tirzepatide for maintenance of weight reduction in adults with obesity: the SURMOUNT-4 randomized clinical trial. JAMA. 2024 Jan 2;331(1):38-48.
http://www.ncbi.nlm.nih.gov/pubmed/38078870?tool=bestpractice.com
Shared decision-making is crucial to determine the best long-term approach, which could include continuing the lowest effective dose, using intermittent therapy, or discontinuing the drug with close weight monitoring.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
For those not reaching goals, the ADA recommends evaluation of weight management therapies and intensification of treatment with additional approaches (e.g., metabolic surgery, additional pharmacologic agents, and structured lifestyle management programs).[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
As well as considering specific drugs to treat obesity, healthcare professionals should carefully review the individual’s other drug treatments and, whenever possible, minimize or provide alternatives for drugs that promote weight gain. Examples of drugs associated with weight gain include antipsychotics (e.g., clozapine, olanzapine, risperidone), some antidepressants (e.g., tricyclic antidepressants, some selective serotonin-reuptake inhibitors [SSRIs], monoamine oxidase inhibitors), glucocorticoids, injectable progestins, some anticonvulsants (e.g., gabapentin, pregabalin), beta-blockers, and possibly sedating antihistamines and anticholinergics.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
Metabolic (bariatric) surgery
A large number of studies have demonstrated that metabolic surgery achieves superior glycemic management and reduction of CV risk in people with type 2 diabetes and obesity compared with nonsurgical intervention.[9]Cosentino F, Verma S, Ambery P, et al. Cardiometabolic risk management: insights from a European Society of Cardiology Cardiovascular Round Table. Eur Heart J. 2023 Oct 14;44(39):4141-56.
https://academic.oup.com/eurheartj/article/44/39/4141/7224026
http://www.ncbi.nlm.nih.gov/pubmed/37448181?tool=bestpractice.com
[199]Courcoulas AP, Patti ME, Hu B, et al. Long-term outcomes of medical management vs bariatric surgery in type 2 diabetes. JAMA. 2024 Feb 27;331(8):654-64.
https://jamanetwork.com/journals/jama/fullarticle/2815401
http://www.ncbi.nlm.nih.gov/pubmed/38411644?tool=bestpractice.com
It has also been shown to reduce microvascular complications, cancer risk, and all-cause mortality in people with obesity and type 2 diabetes.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
[200]Hussain S, Khan MS, Jamali MC, et al. Impact of bariatric surgery in reducing macrovascular complications in severely obese T2DM patients. Obes Surg. 2021 May;31(5):1929-36.
http://www.ncbi.nlm.nih.gov/pubmed/33409981?tool=bestpractice.com
[201]Cohen R, Sforza NS, Clemente RG. Impact of metabolic surgery on type 2 diabetes mellitus, cardiovascular risk factors, and mortality: a review. Curr Hypertens Rev. 2021;17(2):159-69.
http://www.ncbi.nlm.nih.gov/pubmed/32753020?tool=bestpractice.com
[202]Cui B, Wang G, Li P, et al. Disease-specific mortality and major adverse cardiovascular events after bariatric surgery: a meta-analysis of age, sex, and BMI-matched cohort studies. Int J Surg. 2023 Mar 1;109(3):389-400.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10389244
http://www.ncbi.nlm.nih.gov/pubmed/36928139?tool=bestpractice.com
Of note, one meta-analysis reported a 50% reduction in macrovascular complications following metabolic surgery in patients with type 2 diabetes and extreme obesity (BMI ≥40 kg/m²).[200]Hussain S, Khan MS, Jamali MC, et al. Impact of bariatric surgery in reducing macrovascular complications in severely obese T2DM patients. Obes Surg. 2021 May;31(5):1929-36.
http://www.ncbi.nlm.nih.gov/pubmed/33409981?tool=bestpractice.com
Another meta-analysis found that metabolic surgery reduced the risk of any CV event by 44% and yielded a risk reduction of over 55% in overall mortality and 69% in CV mortality in patients with type 2 diabetes.[203]Obeso-Fernández J, Millan-Alanis JM, Sáenz-Flores M, et al. Benefits of metabolic surgery on macrovascular outcomes in adult patients with type 2 diabetes: a systematic review and meta-analysis. Surg Obes Relat Dis. 2024 Feb;20(2):202-12.
http://www.ncbi.nlm.nih.gov/pubmed/37845131?tool=bestpractice.com
Vertical sleeve gastrectomy (VSG) and Roux-en-Y gastric bypass (RYGB) are the most commonly performed procedures. Both result in an anatomically smaller stomach pouch; in VSG, approximately 80% of the stomach is removed, leaving behind a long, thin sleeve-shaped pouch, whereas RYGB creates a much smaller stomach pouch (roughly the size of a walnut), which is then attached to the distal small intestine, thereby bypassing the duodenum and jejunum.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
The ADA recommends metabolic surgery to treat type 2 diabetes in adults with BMI ≥30 kg/m² (≥27.5 kg/m² for Asian-Americans) who are otherwise good surgical candidates.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
The ESC recommends that metabolic surgery be considered for all patients with type 2 diabetes and BMI ≥35 kg/m² who have not achieved sufficient weight loss through lifestyle interventions and drug treatment.[6]Marx N, Federici M, Schütt K, et al. 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. Eur Heart J. 2023 Oct 14;44(39):4043-140.
https://academic.oup.com/eurheartj/article/44/39/4043/7238227
http://www.ncbi.nlm.nih.gov/pubmed/37622663?tool=bestpractice.com
Metabolic surgery is best done in a high-volume, specialized center to reduce the risk of perioperative and longer-term complications.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
For more comprehensive information, see Obesity in adults.
Long-term glycemic control - general principles
Increasing severity of hyperglycemia correlates with increasing CV risk.[47]Joseph JJ, Deedwania P, Acharya T, et al. Comprehensive management of cardiovascular risk factors for adults with type 2 diabetes: a scientific statement from the American Heart Association. Circulation. 2022 Mar;145(9):e722-59.
https://www.ahajournals.org/doi/full/10.1161/CIR.0000000000001040
http://www.ncbi.nlm.nih.gov/pubmed/35000404?tool=bestpractice.com
[204]Cavero-Redondo I, Peleteiro B, Álvarez-Bueno C, et al. Glycated haemoglobin A1c as a risk factor of cardiovascular outcomes and all-cause mortality in diabetic and non-diabetic populations: a systematic review and meta-analysis. BMJ Open. 2017 Jul 31;7(7):e015949.
https://bmjopen.bmj.com/content/7/7/e015949.long
http://www.ncbi.nlm.nih.gov/pubmed/28760792?tool=bestpractice.com
One meta-analysis found that antihyperglycemic therapies reduce major adverse cardiac events in an HbA1c-dependent manner.[205]Hasebe M, Yoshiji S, Keidai Y, et al. Efficacy of antihyperglycemic therapies on cardiovascular and heart failure outcomes: an updated meta-analysis and meta-regression analysis of 35 randomized cardiovascular outcome trials. Cardiovasc Diabetol. 2023 Mar 19;22(1):62.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10024854
http://www.ncbi.nlm.nih.gov/pubmed/36935489?tool=bestpractice.com
However, three large studies, Action to Control Cardiovascular Risk in Diabetes (ACCORD), Action in Diabetes and Vascular Disease (ADVANCE), and Veterans Administration Diabetes Trial (VADT), found that very intensive glucose control (goal HbA1c <6.0% to 6.5% over 3-5 years) did not reduce macrovascular events in adults with type 2 diabetes.[6]Marx N, Federici M, Schütt K, et al. 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. Eur Heart J. 2023 Oct 14;44(39):4043-140.
https://academic.oup.com/eurheartj/article/44/39/4043/7238227
http://www.ncbi.nlm.nih.gov/pubmed/37622663?tool=bestpractice.com
[206]Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009 Jan 8;360(2):129-39.
https://www.nejm.org/doi/full/10.1056/NEJMoa0808431
http://www.ncbi.nlm.nih.gov/pubmed/19092145?tool=bestpractice.com
[207]Reaven PD, Emanuele NV, Wiitala WL, et al; VADT Investigators. Intensive glucose control in patients with type 2 diabetes - 15-year follow-up. N Engl J Med. 2019 Jun 6;380(23):2215-24.
http://www.ncbi.nlm.nih.gov/pubmed/31167051?tool=bestpractice.com
[208]ACCORD Study Group. Nine-year effects of 3.7 years of intensive glycemic control on cardiovascular outcomes. Diabetes Care. 2016 Jan 28;39(5):701-8.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4839177
http://www.ncbi.nlm.nih.gov/pubmed/26822326?tool=bestpractice.com
[209]Zoungas S, Chalmers J, Ninomiya T, et al; ADVANCE Collaborative Group. Association of HbA1c levels with vascular complications and death in patients with type 2 diabetes: evidence of glycaemic thresholds. Diabetologia. 2011 Dec 21;55(3):636-43.
https://link.springer.com/article/10.1007%2Fs00125-011-2404-1
http://www.ncbi.nlm.nih.gov/pubmed/22186981?tool=bestpractice.com
In contrast, intensive glycemic control appeared to have long-term beneficial effects on the risk of CVD in patients with type 1 diabetes.[210]Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular outcomes in type 1 diabetes: the DCCT/EDIC Study 30-year follow-up. Diabetes Care. 2016 Feb 9;39(5):686-93.
http://care.diabetesjournals.org/content/39/5/686.long
http://www.ncbi.nlm.nih.gov/pubmed/26861924?tool=bestpractice.com
One meta-analysis found that intensive versus standard glycemic control in patients with type 2 diabetes was associated with a reduced risk of nonfatal MI but no significant difference in the risk of major adverse CV events or other adverse CV outcomes.[211]Kunutsor SK, Balasubramanian VG, Zaccardi F, et al. Glycaemic control and macrovascular and microvascular outcomes: a systematic review and meta-analysis of trials investigating intensive glucose-lowering strategies in people with type 2 diabetes. Diabetes Obes Metab. 2024 Jun;26(6):2069-81.
https://dom-pubs.pericles-prod.literatumonline.com/doi/10.1111/dom.15511
http://www.ncbi.nlm.nih.gov/pubmed/38409644?tool=bestpractice.com
A long-term follow-up study of intensive glycemic control (median HbA1c 6.9% vs. 8.4%) in type 2 diabetes did show fewer major CV events per 1000 person-years, but there was no improvement in overall survival.[212]Hayward RA, Reaven PD, Wiitala WL, et al; VADT Investigators. Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015 Jun 4;372(23):2197-206.
https://www.nejm.org/doi/full/10.1056/NEJMoa1414266
http://www.ncbi.nlm.nih.gov/pubmed/26039600?tool=bestpractice.com
Furthermore, a follow-up of the ACCORD trial, which studied intensive versus standard glycemic control (<6.0% vs. 7.0% to 7.9%), showed that MI, coronary revascularization, and unstable angina were less frequent in the intensive group than the standard therapy group.[213]Gerstein HC, Miller ME, Ismail-Beigi F, et al; ACCORD Study Group. Effects of intensive glycaemic control on ischaemic heart disease: analysis of data from the randomised, controlled ACCORD trial. Lancet. 2014 Nov 29;384(9958):1936-41.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4397008
http://www.ncbi.nlm.nih.gov/pubmed/25088437?tool=bestpractice.com
The reasons for the discrepancy in study findings are unclear. It appears that there may be a lag period before a benefit of glycemic control on CV risk is realized.[214]Holman R, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008 Oct 9;359(15):1577-89.
https://www.nejm.org/doi/full/10.1056/NEJMoa0806470
http://www.ncbi.nlm.nih.gov/pubmed/18784090?tool=bestpractice.com
Other possibilities that may have influenced results include the magnitude or rapidity of reductions in HbA1c in intensively treated patients; effect of specific antihyperglycemic drugs or drug interactions; treatment-related hypoglycemia; or age at which therapy is begun.[215]Gerstein HC, Miller ME, et al; Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008 Jun 6;358(24):2545-59.
https://www.nejm.org/doi/full/10.1056/NEJMoa0802743
http://www.ncbi.nlm.nih.gov/pubmed/18539917?tool=bestpractice.com
The ADA recommends a general HbA1c goal of <7% (<53 mmol/mol) for nonpregnant adults with diabetes to optimize clinical outcomes, although this should be individualized by the physician following patient discussion.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
If using a continuous glucose monitoring (CGM) device to assess glycemia, a parallel goal is time in range >70%, with time below range <4% and time below 54 mg/dL (<3 mmol/L) <1%.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
Less stringent goals may be appropriate for: older adults; people with a history of severe hypoglycemia; and those with limited life expectancies, advanced microvascular or macrovascular complications, or comorbid conditions.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
If using CGM, the ADA recommends a target of >50% time in range with <1% time below range for those with frailty or at high risk of hypoglycemia.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
A person-centered shared decision-making approach should guide the choice of pharmacologic agents for adults with type 2 diabetes, considering the effects on CV and renal comorbidities, effectiveness, hypoglycemia risk, impact on weight, cost and access, risk of adverse reactions and tolerability, and individual preferences.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
The treatment plan and drug-taking behavior should be reevaluated at regular intervals (the ADA suggests 3-6 monthly) and treatment intensification, deintensification, or modification - as appropriate - for people not meeting individualized treatment goals should not be delayed.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
Metformin is a commonly used first-line drug for type 2 diabetes due to its effectiveness, safety, and low cost.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
Evidence for the CV benefit of metformin is limited; however, it does not cause weight gain or hypoglycemia, and is widely available relative to other agents.[47]Joseph JJ, Deedwania P, Acharya T, et al. Comprehensive management of cardiovascular risk factors for adults with type 2 diabetes: a scientific statement from the American Heart Association. Circulation. 2022 Mar;145(9):e722-59.
https://www.ahajournals.org/doi/full/10.1161/CIR.0000000000001040
http://www.ncbi.nlm.nih.gov/pubmed/35000404?tool=bestpractice.com
People who are unable to take metformin due to contraindications or intolerance can either use an alternative noninsulin agent or start insulin therapy. The ADA recommends a GLP-1 receptor agonist over insulin when possible.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
Early combination therapy can be considered in adults with type 2 diabetes at treatment initiation to shorten time to attainment of individualized treatment goals.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
When selecting an additional therapy, clinicians should consider the evidence of benefits, harms, patient burden, and cost of drugs in addition to performing an individualized assessment of each patient’s preferences, glycemic control target, comorbid conditions, and risk for symptomatic hypoglycemia.[216]Qaseem A, Obley AJ, Shamliyan T, et al. Newer pharmacologic treatments in adults with type 2 diabetes: a clinical guideline from the American College of Physicians. Ann Intern Med. 2024 May;177(5):658-66.
https://www.acpjournals.org/doi/full/10.7326/M23-2788
http://www.ncbi.nlm.nih.gov/pubmed/38639546?tool=bestpractice.com
The American College of Physicians (ACP) now recommends that SGLT2 inhibitors or GLP-1 receptor agonists should be the add-on therapy of choice for patients with inadequate glycemic control, noting that sulfonylureas and long-acting insulins are inferior to these drugs in reducing all-cause mortality and morbidity, but may still have some limited value for glycemic control.[216]Qaseem A, Obley AJ, Shamliyan T, et al. Newer pharmacologic treatments in adults with type 2 diabetes: a clinical guideline from the American College of Physicians. Ann Intern Med. 2024 May;177(5):658-66.
https://www.acpjournals.org/doi/full/10.7326/M23-2788
http://www.ncbi.nlm.nih.gov/pubmed/38639546?tool=bestpractice.com
The ACP specifically recommends against dipeptidyl peptidase-4 (DPP-4) inhibitors as an add-on to metformin and lifestyle modifications in light of high-certainty evidence showing that this does not reduce morbidity or all-cause mortality.[216]Qaseem A, Obley AJ, Shamliyan T, et al. Newer pharmacologic treatments in adults with type 2 diabetes: a clinical guideline from the American College of Physicians. Ann Intern Med. 2024 May;177(5):658-66.
https://www.acpjournals.org/doi/full/10.7326/M23-2788
http://www.ncbi.nlm.nih.gov/pubmed/38639546?tool=bestpractice.com
When considering glycemic control in patients who have overweight or obesity, the ADA recommends that healthcare professionals should prioritize glucose-lowering drugs with a beneficial effect on weight.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
One meta-analysis found that when glucose-lowering therapies were associated with weight loss, the risk of mortality was reduced by 22% for each 1% reduction in HbA1c.[217]Diallo A, Villard O, Carlos-Bolumbu M, et al. Effects of hypoglycaemic agents on reducing surrogate metabolic parameters for the prevention of cardiovascular events and death in patients with type 2 diabetes: a systematic review and meta-analysis. Diabetes Obes Metab. 2024 Feb;26(2):495-502.
http://www.ncbi.nlm.nih.gov/pubmed/37869934?tool=bestpractice.com
In addition, concomitant reductions in HbA1c and body weight were associated with a significantly lower risk of mortality and vascular events.
Agents associated with clinically meaningful weight loss include GLP-1 receptor agonists, tirzepatide, SGLT2 inhibitors, metformin, and amylin analogs.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
One network meta-analysis of 531 trials with 279,118 participants confirmed that tirzepatide is the most effective drug for reducing body weight (mean reduction 8.57 kg), followed by GLP-1 receptor agonists, SGLT2 inhibitors, and metformin.[218]Shi Q, Nong K, Vandvik PO, et al. Benefits and harms of drug treatment for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials. BMJ. 2023 Apr 6;381:e074068.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10077111
http://www.ncbi.nlm.nih.gov/pubmed/37024129?tool=bestpractice.com
DPP-4 inhibitors, bromocriptine (a centrally acting dopamine agonist), alpha-glucosidase inhibitors, and bile acid sequestrants are considered weight neutral.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
Insulin secretagogues (such as sulfonylureas and meglitinides), thiazolidinediones, and insulin are often associated with weight gain.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
See Type 2 diabetes mellitus in adults and Type 1 diabetes mellitus for further information.
Choice of glucose-lowering agents for patients with, or at high risk of, atherosclerotic cardiovascular disease (ASCVD) or with heart failure (HF)
For patients with established ASCVD, significant ASCVD risk factors, HF or CKD, addition of a GLP-1 receptor agonist or a SGLT2 inhibitor with demonstrated CV benefit is strongly recommended (independent of HbA1c) to reduce the risk of adverse CV or kidney events.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
[153]Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association joint committee on clinical practice guidelines. Circulation. 2022 May 3;145(18):e895-1032.
https://www.ahajournals.org/doi/full/10.1161/CIR.0000000000001063
http://www.ncbi.nlm.nih.gov/pubmed/35363499?tool=bestpractice.com
[219]Das SR, Everett BM, Birtcher KK, et al. 2020 Expert consensus decision pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2020 Sep 1;76(9):1117-45.
https://www.jacc.org/doi/full/10.1016/j.jacc.2020.05.037
http://www.ncbi.nlm.nih.gov/pubmed/32771263?tool=bestpractice.com
The ADA and European Association for the Study of Diabetes (EASD) advise that for patients in whom ASCVD predominates (e.g., previous MI, unstable angina, ischemic stroke, or indicators of high CV risk present) either a GLP-1 receptor agonist or an SGLT2 inhibitor should be used for glycemic management and CV event reduction.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
[220]Davies MJ, Aroda VR, Collins BS, et al. Management of hyperglycemia in type 2 diabetes, 2022. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2022 Nov 1;45(11):2753-86.
https://diabetesjournals.org/care/article/45/11/2753/147671/Management-of-Hyperglycemia-in-Type-2-Diabetes
http://www.ncbi.nlm.nih.gov/pubmed/36148880?tool=bestpractice.com
Although definitions of what constitutes high CV risk vary, most comprise ≥55 years of age with two or more additional risk factors such as obesity, hypertension, smoking, dyslipidemia, or albuminuria.[220]Davies MJ, Aroda VR, Collins BS, et al. Management of hyperglycemia in type 2 diabetes, 2022. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2022 Nov 1;45(11):2753-86.
https://diabetesjournals.org/care/article/45/11/2753/147671/Management-of-Hyperglycemia-in-Type-2-Diabetes
http://www.ncbi.nlm.nih.gov/pubmed/36148880?tool=bestpractice.com
While the ADA and EASD do not specify different treatments based on specific ASCVD manifestations, the ACP and American Heart Association (AHA)/American Stroke Association specify that GLP-1 receptor agonists should be prioritized in patients with an increased risk for stroke.[119]Bushnell C, Kernan WN, Sharrief AZ, et al. 2024 guideline for the primary prevention of stroke: a guideline from the American Heart Association/American Stroke Association. Stroke. 2024 Dec;55(12):e344-424.
https://www.ahajournals.org/doi/full/10.1161/STR.0000000000000475
http://www.ncbi.nlm.nih.gov/pubmed/39429201?tool=bestpractice.com
[216]Qaseem A, Obley AJ, Shamliyan T, et al. Newer pharmacologic treatments in adults with type 2 diabetes: a clinical guideline from the American College of Physicians. Ann Intern Med. 2024 May;177(5):658-66.
https://www.acpjournals.org/doi/full/10.7326/M23-2788
http://www.ncbi.nlm.nih.gov/pubmed/38639546?tool=bestpractice.com
For patients in whom HF (with either reduced ejection fraction [HFrEF] or preserved ejection fraction [HFpEF]) predominates, SGLT2 inhibitors should usually be favored for both glycemic management and prevention of HF hospitalization.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
[220]Davies MJ, Aroda VR, Collins BS, et al. Management of hyperglycemia in type 2 diabetes, 2022. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2022 Nov 1;45(11):2753-86.
https://diabetesjournals.org/care/article/45/11/2753/147671/Management-of-Hyperglycemia-in-Type-2-Diabetes
http://www.ncbi.nlm.nih.gov/pubmed/36148880?tool=bestpractice.com
[216]Qaseem A, Obley AJ, Shamliyan T, et al. Newer pharmacologic treatments in adults with type 2 diabetes: a clinical guideline from the American College of Physicians. Ann Intern Med. 2024 May;177(5):658-66.
https://www.acpjournals.org/doi/full/10.7326/M23-2788
http://www.ncbi.nlm.nih.gov/pubmed/38639546?tool=bestpractice.com
However, in patients with symptomatic HFpEF and obesity, a GLP-1 receptor agonist with demonstrated benefits for both glycemic management and reduction of HF-related symptoms is recommended.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
Combination therapy with a GLP-1 receptor agonist and an SGLT2 inhibitor may be appropriate for some patients to provide additive reduction in risk of adverse CV and kidney outcomes (e.g., if HbA1c remains above target and the patient is taking either an SGLT2 inhibitor or a GLP-1 receptor agonist).[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
SGLT2 inhibitors and GLP-1 receptor agonists have been shown to reduce CV events and mortality in outcome trials and real-world studies, regardless of baseline HbA1c values and concurrent use of CV drugs.[47]Joseph JJ, Deedwania P, Acharya T, et al. Comprehensive management of cardiovascular risk factors for adults with type 2 diabetes: a scientific statement from the American Heart Association. Circulation. 2022 Mar;145(9):e722-59.
https://www.ahajournals.org/doi/full/10.1161/CIR.0000000000001040
http://www.ncbi.nlm.nih.gov/pubmed/35000404?tool=bestpractice.com
[221]Sattar N, Lee MMY, Kristensen SL, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials. Lancet Diabetes Endocrinol. 2021 Oct;9(10):653-62.
http://www.ncbi.nlm.nih.gov/pubmed/34425083?tool=bestpractice.com
[222]Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet. 2018 Nov 10;393(10166):31-9.
http://www.ncbi.nlm.nih.gov/pubmed/30424892?tool=bestpractice.com
[223]Zerovnik S, Kos M, Locatelli I. Cardiovascular morbidity and mortality in patients with type 2 diabetes using novel antidiabetic medicines as add-on therapy: an observational real-world study. BMJ Open. 2021 Sep 13;11(9):e051549.
https://bmjopen.bmj.com/content/11/9/e051549.long
http://www.ncbi.nlm.nih.gov/pubmed/34518273?tool=bestpractice.com
[224]Kunutsor SK, Zaccardi F, Balasubramanian VG, et al. Glycaemic control and macrovascular and microvascular outcomes in type 2 diabetes: systematic review and meta-analysis of cardiovascular outcome trials of novel glucose-lowering agents. Diabetes Obes Metab. 2024 May;26(5):1837-49.
https://dom-pubs.pericles-prod.literatumonline.com/doi/10.1111/dom.15500
http://www.ncbi.nlm.nih.gov/pubmed/38379094?tool=bestpractice.com
[225]Mellbin LG, Bhatt DL, David JP, et al. Semaglutide and cardiovascular outcomes by baseline HbA1c in diabetes: the SUSTAIN 6 and PIONEER 6 trials. Eur Heart J. 2024 Apr 14;45(15):1371-4.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11015952
[226]Huang X, Dannya E, Liu X, et al. Effect of sodium-glucose cotransporter-2 inhibitors on myocardial infarction incidence: a systematic review and meta-analysis of randomized controlled trials and cohort studies. Diabetes Obes Metab. 2024 Mar;26(3):1040-9.
http://www.ncbi.nlm.nih.gov/pubmed/38086546?tool=bestpractice.com
[227]Yoshihara F, Imazu M, Sakuma I, et al. DAPagliflozin for the attenuation of albuminuria in Patients with hEaRt failure and type 2 diabetes (DAPPER study): a multicentre, randomised, open-label, parallel-group, standard treatment-controlled trial. EClinicalMedicine. 2023 Dec;66:102334.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10772256
http://www.ncbi.nlm.nih.gov/pubmed/38192595?tool=bestpractice.com
[228]Sohn M, Frias JP, Lim S. Cardiovascular efficacy and safety of antidiabetic agents: a network meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2023 Dec;25(12):3560-77.
http://www.ncbi.nlm.nih.gov/pubmed/37649320?tool=bestpractice.com
[229]Xie Y, Bowe B, Xian H, et al. Comparative effectiveness of SGLT2 inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, and sulfonylureas on risk of major adverse cardiovascular events: emulation of a randomised target trial using electronic health records. Lancet Diabetes Endocrinol. 2023 Sep;11(9):644-56.
http://www.ncbi.nlm.nih.gov/pubmed/37499675?tool=bestpractice.com
In one Cochrane meta-analysis, high-certainty evidence supported use of SGLT2 inhibitors to reduce risk of hospitalization for HF, while moderate-certainty evidence supported use of GLP-1 receptor agonists to reduce fatal and nonfatal stroke.[230]Kanie T, Mizuno A, Takaoka Y, et al. Dipeptidyl peptidase-4 inhibitors, glucagon-like peptide 1 receptor agonists and sodium-glucose co-transporter-2 inhibitors for people with cardiovascular disease: a network meta-analysis. Cochrane Database Syst Rev. 2021 Oct 25;10(10):CD013650.
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD013650.pub2/full
http://www.ncbi.nlm.nih.gov/pubmed/34693515?tool=bestpractice.com
Another meta-analysis found that in patients with type 2 diabetes, the hypotensive effects of SGLT2 inhibitors and GLP-1 receptor agonists were significantly associated with a reduction in mortality and cardiorenal events, suggesting that this BP-lowering effect could be seen as an additive indicator of the CV protective effects of these agents.[231]Diallo A, Carlos-Bolumbu M, Galtier F. Blood pressure-lowering effects of SGLT2 inhibitors and GLP-1 receptor agonists for preventing of cardiovascular events and death in type 2 diabetes: a systematic review and meta-analysis. Acta Diabetol. 2023 Dec;60(12):1651-62.
https://www.doi.org/10.1007/s00592-023-02154-4
http://www.ncbi.nlm.nih.gov/pubmed/37439858?tool=bestpractice.com
SGLT inhibitors
SGLT2 inhibitors reduce the risk for all-cause mortality, major adverse CV events, progression of CKD, and hospitalization due to congestive HF.[216]Qaseem A, Obley AJ, Shamliyan T, et al. Newer pharmacologic treatments in adults with type 2 diabetes: a clinical guideline from the American College of Physicians. Ann Intern Med. 2024 May;177(5):658-66.
https://www.acpjournals.org/doi/full/10.7326/M23-2788
http://www.ncbi.nlm.nih.gov/pubmed/38639546?tool=bestpractice.com
[232]Eraikhuemen N, Leung S, Warren SB, et al. Effects of the sodium-glucose cotransporter inhibitors on cardiovascular death and all-cause mortality: a systematic review and meta-analysis of randomized placebo-controlled clinical trials. Am J Cardiovasc Drugs. 2023 Mar;23(2):113-26.
http://www.ncbi.nlm.nih.gov/pubmed/36572841?tool=bestpractice.com
[233]Hinton W, Ansari AS, Whyte MB, et al. Sodium-glucose co-transporter-2 inhibitors in type 2 diabetes: are clinical trial benefits for heart failure reflected in real-world clinical practice? a systematic review and meta-analysis of observational studies. Diabetes Obes Metab. 2023 Feb;25(2):501-15.
http://www.ncbi.nlm.nih.gov/pubmed/36239122?tool=bestpractice.com
They have been shown to improve CV outcomes in patients with HF regardless of left ventricular ejection fraction, and irrespective of type 2 diabetes status.[218]Shi Q, Nong K, Vandvik PO, et al. Benefits and harms of drug treatment for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials. BMJ. 2023 Apr 6;381:e074068.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10077111
http://www.ncbi.nlm.nih.gov/pubmed/37024129?tool=bestpractice.com
[234]Braunwald E. Gliflozins in the management of cardiovascular disease. N Engl J Med. 2022 May 26;386(21):2024-34.
http://www.ncbi.nlm.nih.gov/pubmed/35613023?tool=bestpractice.com
[235]Jhalani NB. Clinical Considerations for use of SGLT2 inhibitor therapy in patients with heart failure and reduced ejection fraction: a review. Adv Ther. 2022 Aug;39(8):3472-87.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9309138
http://www.ncbi.nlm.nih.gov/pubmed/35699903?tool=bestpractice.com
[236]Anker SD, Butler J, Filippatos G, et al. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med. 2021 Oct 14;385(16):1451-61.
https://www.nejm.org/doi/10.1056/NEJMoa2107038
http://www.ncbi.nlm.nih.gov/pubmed/34449189?tool=bestpractice.com
[237]Solomon SD, McMurray JJV, Claggett B, et al. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med. 2022 Sep 22;387(12):1089-98.
https://www.nejm.org/doi/10.1056/NEJMoa2206286
http://www.ncbi.nlm.nih.gov/pubmed/36027570?tool=bestpractice.com
[238]Usman MS, Siddiqi TJ, Anker SD, et al. Effect of SGLT2 inhibitors on cardiovascular outcomes across various patient populations. J Am Coll Cardiol. 2023 Jun 27;81(25):2377-87.
https://www.sciencedirect.com/science/article/pii/S0735109723055055
http://www.ncbi.nlm.nih.gov/pubmed/37344038?tool=bestpractice.com
[239]Chen J, Jiang C, Guo M, et al. Effects of SGLT2 inhibitors on cardiac function and health status in chronic heart failure: a systematic review and meta-analysis. Cardiovasc Diabetol. 2024 Jan 3;23(1):2.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10765651
http://www.ncbi.nlm.nih.gov/pubmed/38172861?tool=bestpractice.com
[240]De Marzo V, Savarese G, Porto I, et al. Efficacy of SGLT2-inhibitors across different definitions of heart failure with preserved ejection fraction. J Cardiovasc Med (Hagerstown). 2023 Aug 1;24(8):537-43.
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[241]Vaduganathan M, Docherty KF, Claggett BL, et al. SGLT-2 inhibitors in patients with heart failure: a comprehensive meta-analysis of five randomised controlled trials. Lancet. 2022 Sep 3;400(10354):757-67.
http://www.ncbi.nlm.nih.gov/pubmed/36041474?tool=bestpractice.com
The SGLT2 inhibitors with the strongest evidence for CVD risk reduction are dapagliflozin, canagliflozin, and empagliflozin.[121]Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019 Jan 24;380(4):347-57.
https://www.nejm.org/doi/10.1056/NEJMoa1812389
http://www.ncbi.nlm.nih.gov/pubmed/30415602?tool=bestpractice.com
[220]Davies MJ, Aroda VR, Collins BS, et al. Management of hyperglycemia in type 2 diabetes, 2022. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2022 Nov 1;45(11):2753-86.
https://diabetesjournals.org/care/article/45/11/2753/147671/Management-of-Hyperglycemia-in-Type-2-Diabetes
http://www.ncbi.nlm.nih.gov/pubmed/36148880?tool=bestpractice.com
[242]McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019 Nov 21;381(21):1995-2008.
https://www.nejm.org/doi/10.1056/NEJMoa1911303
http://www.ncbi.nlm.nih.gov/pubmed/31535829?tool=bestpractice.com
[243]Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019 Jun 13;380(24):2295-306.
https://www.nejm.org/doi/10.1056/NEJMoa1811744
http://www.ncbi.nlm.nih.gov/pubmed/30990260?tool=bestpractice.com
[244]Mahaffey KW, Jardine MJ, Bompoint S, et al. Canagliflozin and cardiovascular and renal outcomes in type 2 diabetes mellitus and chronic kidney disease in primary and secondary cardiovascular prevention groups. Circulation. 2019 Aug 27;140(9):739-50.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6727954
http://www.ncbi.nlm.nih.gov/pubmed/31291786?tool=bestpractice.com
[245]Inzucchi SE, Kosiborod M, Fitchett D, et al. Improvement in cardiovascular outcomes with empagliflozin is independent of glycemic control. Circulation. 2018 Oct 23;138(17):1904-7.
https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.118.035759
http://www.ncbi.nlm.nih.gov/pubmed/30354665?tool=bestpractice.com
[246]Ali AE, Mazroua MS, ElSaban M, et al. Effect of dapagliflozin in patients with heart failure: a systematic review and meta-analysis. Glob Heart. 2023 Aug 22;18(1):45.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10453961
http://www.ncbi.nlm.nih.gov/pubmed/37636033?tool=bestpractice.com
[247]Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015 Nov 26;373(22):2117-28.
https://www.nejm.org/doi/10.1056/NEJMoa1504720
http://www.ncbi.nlm.nih.gov/pubmed/26378978?tool=bestpractice.com
[248]Neal B, Perkovic V, Matthews DR. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017 Nov 23;377(21):2099. Only empagliflozin and canagliflozin have shown reduction in major adverse cardiac events (MACE) in patients with type 2 diabetes.[249]Davies MJ, Drexel H, Jornayvaz FR, et al. Cardiovascular outcomes trials: a paradigm shift in the current management of type 2 diabetes. Cardiovasc Diabetol. 2022 Aug 4;21(1):144.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9351217
http://www.ncbi.nlm.nih.gov/pubmed/35927730?tool=bestpractice.com
CV outcome trials in patients with type 2 diabetes:
The EMPA-REG OUTCOME trial evaluated CV outcomes with empagliflozin in patients with established CVD. Empagliflozin was superior to placebo in reducing the risk of the primary composite outcome of 3-point MACE (nonfatal MI, nonfatal stroke, and CV mortality; MACE-3) and unexpectedly yielded a 35% relative risk reduction in hospitalization for HF. All-cause mortality was also significantly reduced by 32% compared with placebo.[247]Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015 Nov 26;373(22):2117-28.
https://www.nejm.org/doi/10.1056/NEJMoa1504720
http://www.ncbi.nlm.nih.gov/pubmed/26378978?tool=bestpractice.com
Similar findings were seen for canagliflozin in the CANVAS Program trial.[248]Neal B, Perkovic V, Matthews DR. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017 Nov 23;377(21):2099.[250]Rådholm K, Figtree G, Perkovic V, et al. Canagliflozin and heart failure in type 2 diabetes mellitus: results from the CANVAS program. Circulation. 2018 Jul 31;138(5):458-68.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6075881
http://www.ncbi.nlm.nih.gov/pubmed/29526832?tool=bestpractice.com
The DECLARE-TIMI 58 trial found that dapagliflozin did not significantly reduce MACE-3, but resulted in a 27% reduction in HF-related hospitalization compared with placebo.[121]Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019 Jan 24;380(4):347-57.
https://www.nejm.org/doi/10.1056/NEJMoa1812389
http://www.ncbi.nlm.nih.gov/pubmed/30415602?tool=bestpractice.com
However, it decreased CV outcomes in a subanalysis of the primary trial confined to participants with prior MI.[251]Furtado RHM, Bonaca MP, Raz I, et al. Dapagliflozin and cardiovascular outcomes in patients with type 2 diabetes mellitus and previous myocardial infarction. Circulation. 2019 May 28;139(22):2516-27.
https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.119.039996
http://www.ncbi.nlm.nih.gov/pubmed/30882239?tool=bestpractice.com
In the VERTIS-CV trial, ertugliflozin was not found to be superior to placebo in reducing MACE-3 or CV mortality; however, a significant reduction in HF hospitalizations was reported in the ertugliflozin arm.[252]Cannon CP, Pratley R, Dagogo-Jack S, et al. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med. 2020 Oct 8;383(15):1425-35.
https://www.nejm.org/doi/10.1056/NEJMoa2004967
http://www.ncbi.nlm.nih.gov/pubmed/32966714?tool=bestpractice.com
[253]Cosentino F, Cannon CP, Cherney DZI, et al. Efficacy of ertugliflozin on heart failure-related events in patients with type 2 diabetes mellitus and established atherosclerotic cardiovascular disease: results of the VERTIS CV trial. Circulation. 2020 Dec 8;142(23):2205-15.
https://www.doi.org/10.1161/CIRCULATIONAHA.120.050255
http://www.ncbi.nlm.nih.gov/pubmed/33026243?tool=bestpractice.com
The CREDENCE trial primarily evaluated kidney-related outcomes with canagliflozin and found a significant 31% reduction in the secondary composite outcome of CV death and HF hospitalizations with canagliflozin compared to placebo.[243]Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019 Jun 13;380(24):2295-306.
https://www.nejm.org/doi/10.1056/NEJMoa1811744
http://www.ncbi.nlm.nih.gov/pubmed/30990260?tool=bestpractice.com
One pooled meta-analysis of these trials revealed a significant reduction in MACE (most apparent in patients with established ASCVD), all-cause mortality, CV deaths, and HF hospitalizations. The greatest magnitude of benefit was for reduction in risk for hospitalization for HF and kidney disease progression.[254]McGuire DK, Shih WJ, Cosentino F, et al. Association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes: a meta-analysis. JAMA Cardiol. 2021 Feb 1;6(2):148-58.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542529
http://www.ncbi.nlm.nih.gov/pubmed/33031522?tool=bestpractice.com
On the basis of these findings, SGLT2 inhibitors are recommended in the management of HF, regardless of diabetes status.[153]Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association joint committee on clinical practice guidelines. Circulation. 2022 May 3;145(18):e895-1032.
https://www.ahajournals.org/doi/full/10.1161/CIR.0000000000001063
http://www.ncbi.nlm.nih.gov/pubmed/35363499?tool=bestpractice.com
[255]McDonagh TA, Metra M, Adamo M, et al. 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021 Sep 21;42(36):3599-726.
https://academic.oup.com/eurheartj/article/42/36/3599/6358045
[256]McDonagh TA, Metra M, Adamo M, et al. 2023 focused update of the 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2023 Oct 1;44(37):3627-39.
https://academic.oup.com/eurheartj/article/44/37/3627/7246292
SGLT inhibitors, particularly empagliflozin, have been shown to significantly reverse cardiac remodeling in patients with HF.[257]Fan G, Guo DL. The effect of sodium-glucose cotransporter-2 inhibitors on cardiac structure remodeling and function: a meta-analysis of randomized controlled trials. Eur J Intern Med. 2023 Aug;114:49-57.
https://www.ejinme.com/article/S0953-6205(23)00115-2/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/37062643?tool=bestpractice.com
[258]Huang YL, Xu XZ, Liu J, et al. Effects of new hypoglycemic drugs on cardiac remodeling: a systematic review and network meta-analysis. BMC Cardiovasc Disord. 2023 Jun 9;23(1):293.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10251583
http://www.ncbi.nlm.nih.gov/pubmed/37296380?tool=bestpractice.com
[259]Zhang N, Wang Y, Tse G, et al. Effect of sodium-glucose cotransporter-2 inhibitors on cardiac remodelling: a systematic review and meta-analysis. Eur J Prev Cardiol. 2022 Feb 3;28(17):1961-73.
https://academic.oup.com/eurjpc/article/28/17/1961/6430917
http://www.ncbi.nlm.nih.gov/pubmed/34792124?tool=bestpractice.com
[260]Wang Y, Zhong Y, Zhang Z, et al. Effect of sodium-glucose cotransporter protein-2 inhibitors on left ventricular hypertrophy in patients with type 2 diabetes: a systematic review and meta-analysis. Front Endocrinol (Lausanne). 2023 Jan 9;13:1088820.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9868415
http://www.ncbi.nlm.nih.gov/pubmed/36699027?tool=bestpractice.com
[261]Theofilis P, Antonopoulos AS, Katsimichas T, et al. The impact of SGLT2 inhibition on imaging markers of cardiac function: a systematic review and meta-analysis. Pharmacol Res. 2022 Jun;180:106243.
http://www.ncbi.nlm.nih.gov/pubmed/35523389?tool=bestpractice.com
One meta-analysis looked at the efficacy of SGLT2 inhibitors in older people with type 2 diabetes and HF and found they were associated with a significant reduction in all-cause mortality, cardiac death, and hospitalization for HF, confirming that their cardioprotective advantages extend to the frail/older population. However, they did not demonstrate a significant effect in reducing the risk of macrovascular events (acute coronary syndrome [ACS] or stroke).[262]Aldafas R, Crabtree T, Alkharaiji M, et al. Sodium-glucose cotransporter-2 inhibitors (SGLT2) in frail or older people with type 2 diabetes and heart failure: a systematic review and meta-analysis. Age Ageing. 2024 Jan 2;53(1):afad254.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10825241
http://www.ncbi.nlm.nih.gov/pubmed/38287703?tool=bestpractice.com
The ESC now recommends dapagliflozin or empagliflozin for all patients with type 2 diabetes and CKD to reduce risk of HF hospitalization or CV death, regardless of whether they have a preexisting HF diagnosis.[256]McDonagh TA, Metra M, Adamo M, et al. 2023 focused update of the 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2023 Oct 1;44(37):3627-39.
https://academic.oup.com/eurheartj/article/44/37/3627/7246292
SGLT2 inhibitors also reduce the risk of serious hyperkalemia in people with type 2 diabetes at high CV risk without increasing the risk of hypokalemia, allowing the titration of guideline-directed medical therapy in patients with HF.[263]Neuen BL, Oshima M, Agarwal R, et al. Sodium-glucose cotransporter 2 inhibitors and risk of hyperkalemia in people with type 2 diabetes: a meta-analysis of individual participant data from randomized, controlled trials. Circulation. 2022 May 10;145(19):1460-70.
https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.121.057736
http://www.ncbi.nlm.nih.gov/pubmed/35394821?tool=bestpractice.com
An initial decline in estimated glomerular filtration rate (eGFR) is commonly observed after initiating an SGLT2 inhibitor but this decline is not associated with subsequent risk of CV or kidney events.[264]Mc Causland FR, Claggett BL, Vaduganathan M, et al. Decline in estimated glomerular filtration rate after dapagliflozin in heart failure with mildly reduced or preserved ejection fraction: a prespecified secondary analysis of the DELIVER randomized clinical trial. JAMA Cardiol. 2024 Feb 1;9(2):144-52.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10641768
http://www.ncbi.nlm.nih.gov/pubmed/37952176?tool=bestpractice.com
Thus, SGLT2 inhibitors should not be interrupted or discontinued in response to an initial eGFR decline.
SGLT2 inhibitors are generally well-tolerated; however, some serious adverse reactions have been documented, including a higher rate of diabetic ketoacidosis (DKA), acute kidney injury, fracture, and/or amputation. The European Medicines Agency (EMA) warns of the potential increased risk of toe amputation.[265]European Medicines Agency. SGLT2 inhibitors: information on potential risk of toe amputation to be included in prescribing information. Feb 2017 [internet publication].
https://www.ema.europa.eu/en/documents/press-release/sglt2-inhibitors-information-potential-risk-toe-amputation-be-included-prescribing-information_en.pdf
The Food and Drug Administration (FDA) states that the risk of amputation, while increased with canagliflozin, is lower than previously described, particularly when appropriately monitored.[266]US Food and Drug Administration. FDA removes boxed warning about risk of leg and foot amputations for the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR). August 2020 [internet publication]
https://www.fda.gov/drugs/drug-safety-and-availability/fda-removes-boxed-warning-about-risk-leg-and-foot-amputations-diabetes-medicine-canagliflozin
One large network meta-analysis estimated that treatment with SGLT2 inhibitors in 1000 patients for 5 years probably results in three additional amputations.[218]Shi Q, Nong K, Vandvik PO, et al. Benefits and harms of drug treatment for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials. BMJ. 2023 Apr 6;381:e074068.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10077111
http://www.ncbi.nlm.nih.gov/pubmed/37024129?tool=bestpractice.com
The FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA) warn of cases of necrotizing fasciitis of the perineum (also known as Fournier gangrene) observed in post-marketing surveillance of SGLT2 inhibitors.[267]US Food and Drug Administration. FDA drug safety communication: FDA warns about rare occurrences of a serious infection of the genital area with SGLT2 inhibitors for diabetes. August 2018 [internet publication].
https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-rare-occurrences-serious-infection-genital-area-sglt2-inhibitors-diabetes
[268]Medicines and Healthcare products Regulatory Agency. SGLT2 inhibitors: reports of Fournier’s gangrene (necrotising fasciitis of the genitalia or perineum). Feb 2019 [internet publication].
https://www.gov.uk/drug-safety-update/sglt2-inhibitors-reports-of-fournier-s-gangrene-necrotising-fasciitis-of-the-genitalia-or-perineum
Thus, SGLT2 inhibitors should be avoided in patients with conditions that increase the risk for limb amputations, and in patients prone to urinary tract or genital infections.
Sotagliflozin is the first dual SGLT1/SGLT2 inhibitor.[269]Cefalo CMA, Cinti F, Moffa S, et al. Sotagliflozin, the first dual SGLT inhibitor: current outlook and perspectives. Cardiovasc Diabetol. 2019 Feb 28;18(1):20.
https://cardiab.biomedcentral.com/articles/10.1186/s12933-019-0828-y
http://www.ncbi.nlm.nih.gov/pubmed/30819210?tool=bestpractice.com
It inhibits both renal SGLT2 (promoting significant excretion of glucose in the urine, in the same way as other already available SGLT2 selective inhibitors) and intestinal SGLT1 (delaying glucose absorption and therefore reducing postprandial glucose).[269]Cefalo CMA, Cinti F, Moffa S, et al. Sotagliflozin, the first dual SGLT inhibitor: current outlook and perspectives. Cardiovasc Diabetol. 2019 Feb 28;18(1):20.
https://cardiab.biomedcentral.com/articles/10.1186/s12933-019-0828-y
http://www.ncbi.nlm.nih.gov/pubmed/30819210?tool=bestpractice.com
It has been approved in people with HF (both with and without diabetes) and in patients with type 2 diabetes who have CKD or high risk of/established ASCVD, to reduce the risk of hospitalization for HF.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
The approval was based on two randomized, double-blind, placebo-controlled phase 3 CV outcome trials: SOLOIST-WHF (Effects of Sotagliflozin on Clinical Outcomes in Hemodynamically Stable Patients with Type 2 Diabetes Post Worsening Heart Failure) and SCORED (Effects of Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes Mellitus, Cardiovascular Risk Factors and Moderately Impaired Renal Function).[270]Bhatt DL, Szarek M, Pitt B, et al. Sotagliflozin in patients with diabetes and chronic kidney disease. N Engl J Med. 2021 Jan 14;384(2):129-39.
https://www.nejm.org/doi/10.1056/NEJMoa2030186
http://www.ncbi.nlm.nih.gov/pubmed/33200891?tool=bestpractice.com
[271]Bhatt DL, Szarek M, Steg PG, et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med. 2021 Jan 14;384(2):117-28.
https://www.nejm.org/doi/10.1056/NEJMoa2030183
http://www.ncbi.nlm.nih.gov/pubmed/33200892?tool=bestpractice.com
It is not currently approved for glycemic management of type 1 or type 2 diabetes.
One concern with expanded use of SGLT inhibition is the infrequent but serious risk of DKA, including the atypical presentation of euglycemic ketoacidosis.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
Of note, the studies that led to the approved indication of sotagliflozin for HF excluded individuals with type 1 diabetes or a history of DKA.[270]Bhatt DL, Szarek M, Pitt B, et al. Sotagliflozin in patients with diabetes and chronic kidney disease. N Engl J Med. 2021 Jan 14;384(2):129-39.
https://www.nejm.org/doi/10.1056/NEJMoa2030186
http://www.ncbi.nlm.nih.gov/pubmed/33200891?tool=bestpractice.com
[271]Bhatt DL, Szarek M, Steg PG, et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med. 2021 Jan 14;384(2):117-28.
https://www.nejm.org/doi/10.1056/NEJMoa2030183
http://www.ncbi.nlm.nih.gov/pubmed/33200892?tool=bestpractice.com
In clinical trials of sotagliflozin in people with type 1 diabetes, results showed improvements in HbA1c and body weight; however, its use was associated with an eightfold increase in DKA compared with placebo.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
[272]Chen MB, Xu RJ, Zheng QH, et al. Efficacy and safety of sotagliflozin adjuvant therapy for type 1 diabetes mellitus: a systematic review and meta-analysis. Medicine (Baltimore). 2020 Aug 14;99(33):e20875.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437859
http://www.ncbi.nlm.nih.gov/pubmed/32871972?tool=bestpractice.com
The risks and benefits of SGLT inhibitors in this population continue to be evaluated, with guidelines and consensus statements providing direction on patient selection and precautions.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
[273]Danne T, Garg S, Peters AL, et al. International consensus on risk management of diabetic ketoacidosis in patients with type 1 diabetes treated with sodium-glucose cotransporter (SGLT) inhibitors. Diabetes Care. 2019 Jun;42(6):1147-54.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6973545
http://www.ncbi.nlm.nih.gov/pubmed/30728224?tool=bestpractice.com
GLP-1 receptor agonists
Reduce the risk for all-cause mortality and MACE.[216]Qaseem A, Obley AJ, Shamliyan T, et al. Newer pharmacologic treatments in adults with type 2 diabetes: a clinical guideline from the American College of Physicians. Ann Intern Med. 2024 May;177(5):658-66.
https://www.acpjournals.org/doi/full/10.7326/M23-2788
http://www.ncbi.nlm.nih.gov/pubmed/38639546?tool=bestpractice.com
[274]Giugliano D, Scappaticcio L, Longo M, et al. GLP-1 receptor agonists and cardiorenal outcomes in type 2 diabetes: an updated meta-analysis of eight CVOTs. Cardiovasc Diabetol. 2021 Sep 15;20(1):189.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8442438
http://www.ncbi.nlm.nih.gov/pubmed/34526024?tool=bestpractice.com
The GLP-1 receptor agonists with the strongest evidence for ASCVD risk reduction are injectable semaglutide, liraglutide, and dulaglutide.[220]Davies MJ, Aroda VR, Collins BS, et al. Management of hyperglycemia in type 2 diabetes, 2022. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2022 Nov 1;45(11):2753-86.
https://diabetesjournals.org/care/article/45/11/2753/147671/Management-of-Hyperglycemia-in-Type-2-Diabetes
http://www.ncbi.nlm.nih.gov/pubmed/36148880?tool=bestpractice.com
[275]Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019 Jul 13;394(10193):121-30.
http://www.ncbi.nlm.nih.gov/pubmed/31189511?tool=bestpractice.com
[276]Husain M, Birkenfeld AL, Donsmark M, et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2019 Aug 29;381(9):841-51.
https://www.nejm.org/doi/10.1056/NEJMoa1901118
http://www.ncbi.nlm.nih.gov/pubmed/31185157?tool=bestpractice.com
[277]Guo X, Sang C, Tang R, et al. Effects of glucagon-like peptide-1 receptor agonists on major coronary events in patients with type 2 diabetes. Diabetes Obes Metab. 2023 Apr;25 Suppl 1:53-63.
https://dom-pubs.pericles-prod.literatumonline.com/doi/10.1111/dom.15043
http://www.ncbi.nlm.nih.gov/pubmed/36864658?tool=bestpractice.com
[278]Green JB, Everett BM, Ghosh A, et al. Cardiovascular outcomes in GRADE (glycemia reduction approaches in type 2 diabetes: a comparative effectiveness study). Circulation. 2024 Mar 26;149(13):993-1003.
http://www.ncbi.nlm.nih.gov/pubmed/38344820?tool=bestpractice.com
[279]Wang L, Xin Q, Wang Y, et al. Efficacy and safety of liraglutide in type 2 diabetes mellitus patients complicated with coronary artery disease: a systematic review and meta-analysis of randomized controlled trials. Pharmacol Res. 2021 Sep;171:105765.
http://www.ncbi.nlm.nih.gov/pubmed/34252552?tool=bestpractice.com
In addition to their beneficial effects on coronary artery disease, GLP-1 receptor agonists are the only drug class that has been shown to convincingly reduce non-fatal stroke.[216]Qaseem A, Obley AJ, Shamliyan T, et al. Newer pharmacologic treatments in adults with type 2 diabetes: a clinical guideline from the American College of Physicians. Ann Intern Med. 2024 May;177(5):658-66.
https://www.acpjournals.org/doi/full/10.7326/M23-2788
http://www.ncbi.nlm.nih.gov/pubmed/38639546?tool=bestpractice.com
[218]Shi Q, Nong K, Vandvik PO, et al. Benefits and harms of drug treatment for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials. BMJ. 2023 Apr 6;381:e074068.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10077111
http://www.ncbi.nlm.nih.gov/pubmed/37024129?tool=bestpractice.com
[280]Rodriguez-Valadez JM, Tahsin M, Fleischmann KE, et al. Cardiovascular and renal benefits of novel diabetes drugs by baseline cardiovascular risk: a systematic review, meta-analysis, and meta-regression. Diabetes Care. 2023 Jun 1;46(6):1300-10.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10234755
http://www.ncbi.nlm.nih.gov/pubmed/37220263?tool=bestpractice.com
[281]Banerjee M, Pal R, Mukhopadhyay S, et al. GLP-1 receptor agonists and risk of adverse cerebrovascular outcomes in type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. J Clin Endocrinol Metab. 2023 Jun 16;108(7):1806-12.
https://academic.oup.com/jcem/article/108/7/1806/7044761
http://www.ncbi.nlm.nih.gov/pubmed/36800286?tool=bestpractice.com
[282]Li J, Ji C, Zhang W, et al. Effect of new glucose-lowering drugs on stroke in patients with type 2 diabetes: a systematic review and Meta-analysis. J Diabetes Complications. 2023 Jan;37(1):108362.
http://www.ncbi.nlm.nih.gov/pubmed/36462459?tool=bestpractice.com
[283]Wei J, Yang B, Wang R, et al. Risk of stroke and retinopathy during GLP-1 receptor agonist cardiovascular outcome trials: an eight RCTs meta-analysis. Front Endocrinol (Lausanne). 2022 Dec 5:13:1007980.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9760859
http://www.ncbi.nlm.nih.gov/pubmed/36545339?tool=bestpractice.com
The addition of semaglutide to standard care has been shown to be associated with an important gain in life-years free of new/recurrent CVD events and a decrease in 10-year CVD risk.[284]Westerink J, Matthiessen KS, Nuhoho S, et al. Estimated life-years gained free of new or recurrent major cardiovascular events with the addition of semaglutide to standard of care in people with type 2 diabetes and high cardiovascular risk. Diabetes Care. 2022 May 1;45(5):1211-8.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9174968
http://www.ncbi.nlm.nih.gov/pubmed/35263432?tool=bestpractice.com
It is the only GLP-1 receptor agonist that is available in both oral and injectable formulations.[276]Husain M, Birkenfeld AL, Donsmark M, et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2019 Aug 29;381(9):841-51.
https://www.nejm.org/doi/10.1056/NEJMoa1901118
http://www.ncbi.nlm.nih.gov/pubmed/31185157?tool=bestpractice.com
For information on oral semaglutide, see Emerging treatments.
Unlike for SGLT2 inhibitors, the evidence for GLP-1 receptor agonists in reducing HF or improving CV outcomes in patients with HF has been inconsistent across trials.[285]Merza N, Akram M, Mengal A, et al. The safety and efficacy of GLP-1 receptor agonists in heart failure patients: a systematic review and meta-analysis. Curr Probl Cardiol. 2023 May;48(5):101602.
http://www.ncbi.nlm.nih.gov/pubmed/36682393?tool=bestpractice.com
One meta-analysis found that they may prevent new-onset HF and mortality in patients with type 2 diabetes; however, they did not reduce HF hospitalizations and mortality in patients with preexisting HF.[286]Ferreira JP, Saraiva F, Sharma A, et al. Glucagon-like peptide 1 receptor agonists in patients with type 2 diabetes with and without chronic heart failure: a meta-analysis of randomized placebo-controlled outcome trials. Diabetes Obes Metab. 2023 Jun;25(6):1495-502.
http://www.ncbi.nlm.nih.gov/pubmed/36722252?tool=bestpractice.com
Data from retrospective studies and meta-analyses have shown superiority of GLP-1 receptor agonists over other glucose-lowering drugs such as SGLT2 inhibitors and DPP-4 inhibitors in terms of peripheral arterial disease (PAD).[287]Liarakos AL, Tentolouris A, Kokkinos A, et al. Impact of glucagon-like peptide 1 receptor agonists on peripheral arterial disease in people with diabetes mellitus: a narrative review. J Diabetes Complications. 2023 Feb;37(2):108390.
http://www.ncbi.nlm.nih.gov/pubmed/36610322?tool=bestpractice.com
However, data from CV outcome trials regarding the impact of GLP-1 receptor agonists on PAD are scarce and further prospective studies are needed.
The most common adverse effects of GLP-1 receptor agonists are gastrointestinal, particularly nausea, vomiting, and diarrhea; these are frequent but tend to reduce over time.[288]Brown E, Heerspink HJL, Cuthbertson DJ, et al. SGLT2 inhibitors and GLP-1 receptor agonists: established and emerging indications. Lancet. 2021 Jul 17;398(10296):262-76.
http://www.ncbi.nlm.nih.gov/pubmed/34216571?tool=bestpractice.com
Slowed titration can improve tolerability.
As these agents delay gastric emptying, patients may retain gastric contents despite standard preoperative fasting, increasing the risk of pulmonary aspiration during procedures involving general anesthesia or deep sedation. Anesthesiologists should perform an individualized assessment of aspiration risk, particularly in patients with diabetic gastroparesis, obesity, or GORD.[289]Medicines and Healthcare products Regulatory Agency. GLP-1 and dual GIP/GLP-1 receptor agonists: potential risk of pulmonary aspiration during general anaesthesia or deep sedation. Jan 2025 [internet publication].
https://www.gov.uk/drug-safety-update/glp-1-and-dual-gip-slash-glp-1-receptor-agonists-potential-risk-of-pulmonary-aspiration-during-general-anaesthesia-or-deep-sedation
Patients should also be counseled about the potential for ileus.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
An association with pancreatitis and pancreatic cancer has been reported in clinical trials, but causality has not been established.[220]Davies MJ, Aroda VR, Collins BS, et al. Management of hyperglycemia in type 2 diabetes, 2022. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2022 Nov 1;45(11):2753-86.
https://diabetesjournals.org/care/article/45/11/2753/147671/Management-of-Hyperglycemia-in-Type-2-Diabetes
http://www.ncbi.nlm.nih.gov/pubmed/36148880?tool=bestpractice.com
One meta-analysis of 43 randomized controlled trials (RCTs) found no clear evidence for an increased risk of pancreatitis.[290]Nreu B, Dicembrini I, Tinti F, et al. Pancreatitis and pancreatic cancer in patients with type 2 diabetes treated with glucagon-like peptide-1 receptor agonists: an updated meta-analysis of randomized controlled trials. Minerva Endocrinol (Torino). 2023 Jun;48(2):206-13.
https://www.minervamedica.it/en/journals/minerva-endocrinology/article.php?cod=R07Y2023N02A0206
http://www.ncbi.nlm.nih.gov/pubmed/32720500?tool=bestpractice.com
After a review of available data, the FDA and the EMA agreed that there was insufficient evidence to confirm an increased risk of pancreatic cancer with use of GLP-1-based therapies.[291]Egan AG, Blind E, Dunder K, et al. Pancreatic safety of incretin-based drugs--FDA and EMA assessment. N Engl J Med. 2014 Feb 27;370(9):794-7.
https://www.nejm.org/doi/10.1056/NEJMp1314078
Nonetheless, GLP-1 receptor agonists should be used with caution in patients with a history of pancreatitis.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
[288]Brown E, Heerspink HJL, Cuthbertson DJ, et al. SGLT2 inhibitors and GLP-1 receptor agonists: established and emerging indications. Lancet. 2021 Jul 17;398(10296):262-76.
http://www.ncbi.nlm.nih.gov/pubmed/34216571?tool=bestpractice.com
GLP-1 receptor agonists have been associated with increased risk of gallbladder and biliary diseases including cholelithiasis and cholecystitis.[288]Brown E, Heerspink HJL, Cuthbertson DJ, et al. SGLT2 inhibitors and GLP-1 receptor agonists: established and emerging indications. Lancet. 2021 Jul 17;398(10296):262-76.
http://www.ncbi.nlm.nih.gov/pubmed/34216571?tool=bestpractice.com
Hypoglycemia risk is increased with concomitant sulfonylureas and insulin use. Treatment deintensification of these agents or of diuretics, particularly in older and frail individuals, is recommended to avoid hypoglycemia and hypovolemia.[288]Brown E, Heerspink HJL, Cuthbertson DJ, et al. SGLT2 inhibitors and GLP-1 receptor agonists: established and emerging indications. Lancet. 2021 Jul 17;398(10296):262-76.
http://www.ncbi.nlm.nih.gov/pubmed/34216571?tool=bestpractice.com
DKA has been reported in patients on a combination of a GLP-1 receptor agonists and insulin, when concomitant insulin was either rapidly reduced or discontinued; insulin reductions should therefore be undertaken in a cautious stepwise manner, with capillary blood glucose monitoring.[288]Brown E, Heerspink HJL, Cuthbertson DJ, et al. SGLT2 inhibitors and GLP-1 receptor agonists: established and emerging indications. Lancet. 2021 Jul 17;398(10296):262-76.
http://www.ncbi.nlm.nih.gov/pubmed/34216571?tool=bestpractice.com
In rodent studies, GLP-1 receptor agonists were associated with medullary thyroid cancer, resulting in a black box warning for these agents in patients with a personal or family history of multiple endocrine neoplasia type 2 or medullary thyroid cancer; however, there is conflicting evidence as to whether this risk applies in humans.[288]Brown E, Heerspink HJL, Cuthbertson DJ, et al. SGLT2 inhibitors and GLP-1 receptor agonists: established and emerging indications. Lancet. 2021 Jul 17;398(10296):262-76.
http://www.ncbi.nlm.nih.gov/pubmed/34216571?tool=bestpractice.com
[292]Bjerre Knudsen L, Madsen LW, Andersen S, et al. Glucagon-like Peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation. Endocrinology. 2010 Apr;151(4):1473-86.
https://academic.oup.com/endo/article/151/4/1473/2456651
http://www.ncbi.nlm.nih.gov/pubmed/20203154?tool=bestpractice.com
[293]Hu W, Song R, Cheng R, et al. Use of GLP-1 Receptor agonists and occurrence of thyroid disorders: a meta-analysis of randomized controlled trials. Front Endocrinol (Lausanne). 2022 Jul 11;13:927859.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9309474
http://www.ncbi.nlm.nih.gov/pubmed/35898463?tool=bestpractice.com
[294]Bezin J, Gouverneur A, Pénichon M, et al. GLP-1 receptor agonists and the risk of thyroid cancer. Diabetes Care. 2023 Feb 1;46(2):384-90.
https://diabetesjournals.org/care/article/46/2/384/147888/GLP-1-Receptor-Agonists-and-the-Risk-of-Thyroid
http://www.ncbi.nlm.nih.gov/pubmed/36356111?tool=bestpractice.com
[295]Thompson CA, Stürmer T. Putting GLP-1 RAs and thyroid cancer in context: additional evidence and remaining doubts. Diabetes Care. 2023 Feb 1;46(2):249-51.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9887624
The EMA and FDA are reviewing data on the risk of suicidal thoughts and thoughts of self-harm with GLP-1 receptor agonists, following reports of such occurrences in people using liraglutide and semaglutide.[296]European Medicines Agency. EMA statement on ongoing review of GLP-1 receptor agonists. Jul 2023 [internet publication].
https://www.ema.europa.eu/en/news/ema-statement-ongoing-review-glp-1-receptor-agonists
[297]U.S. Food & Drug Administration. Update on FDA’s ongoing evaluation of reports of suicidal thoughts or actions in patients taking a certain type of medicines approved for type 2 diabetes and obesity. Jan 2024 [internet publication].
https://www.fda.gov/drugs/drug-safety-and-availability/update-fdas-ongoing-evaluation-reports-suicidal-thoughts-or-actions-patients-taking-certain-type
[298]Schoretsanitis G, Weiler S, Barbui C, et al. Disproportionality analysis from World Health Organization data on semaglutide, liraglutide, and suicidality. JAMA Netw Open. 2024 Aug 1;7(8):e2423385.
https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2822453
http://www.ncbi.nlm.nih.gov/pubmed/39163046?tool=bestpractice.com
Notably, real-world data from a US nationwide retrospective cohort study using electronic health records showed no increased risk of suicidal ideation with semaglutide compared with non-GLP-1 receptor agonist antiobesity or antihyperglycemic drugs.[299]Wang W, Volkow ND, Berger NA, et al. Association of semaglutide with risk of suicidal ideation in a real-world cohort. Nat Med. 2024 Jan;30(1):168-76.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11034947
http://www.ncbi.nlm.nih.gov/pubmed/38182782?tool=bestpractice.com
This aligns with a meta-analysis of 27 RCTs, which also found no significant increase in suicide or self-harm events in adults with diabetes or obesity receiving GLP-1 receptor agonists versus placebo.[300]Ebrahimi P, Batlle JC, Ayati A, et al. Suicide and self-harm events with GLP-1 receptor agonists in adults with diabetes or obesity: a systematic review and meta-analysis. JAMA Psychiatry. 2025 Mar 19:e250091.
http://www.ncbi.nlm.nih.gov/pubmed/40105856?tool=bestpractice.com
The EMA has identified nonarteritic anterior ischemic optic neuropathy (NAION) as a very rare adverse effect of semaglutide, following evidence of a small increased risk in adults with type 2 diabetes. Patients should be advised to report sudden or worsening vision loss, and treatment should be discontinued if NAION is confirmed.[301]European Medicines Agency. PRAC concludes eye condition NAION is a very rare side effect of semaglutide medicines Ozempic, Rybelsus and Wegovy. Jun 2025 [internet publication].
https://www.ema.europa.eu/en/news/prac-concludes-eye-condition-naion-very-rare-side-effect-semaglutide-medicines-ozempic-rybelsus-wegovy
There is also some concern that GLP1-receptor agonists, through their rapid glucose-lowering effects, may increase the risk of transient worsening of preexisting diabetic retinopathy.[302]Albert SG, Wood EM, Ahir V. Glucagon-like peptide 1-receptor agonists and A1c: good for the heart but less so for the eyes? Diabetes Metab Syndr. 2023 Jan;17(1):102696.
http://www.ncbi.nlm.nih.gov/pubmed/36596264?tool=bestpractice.com
[303]Qian W, Liu F, Yang Q. Effect of glucagon-like peptide-1 receptor agonists in subjects with type 2 diabetes mellitus: a meta-analysis. J Clin Pharm Ther. 2021 Dec;46(6):1650-8.
https://www.doi.org/10.1111/jcpt.13502
http://www.ncbi.nlm.nih.gov/pubmed/34355405?tool=bestpractice.com
[304]Yoshida Y, Joshi P, Barri S, et al. Progression of retinopathy with glucagon-like peptide-1 receptor agonists with cardiovascular benefits in type 2 diabetes - a systematic review and meta-analysis. J Diabetes Complications. 2022 Aug;36(8):108255.
http://www.ncbi.nlm.nih.gov/pubmed/35817678?tool=bestpractice.com
Further studies are required to elucidate this relationship.
One Swedish nationwide study found that the proportion of patients with type 2 diabetes who were eligible for treatment with an SGLT2 inhibitor or a GLP-1 receptor agonist was approximately 80% according to the 2019 ESC guidelines and around 50% according to the 2019 ADA/EASD consensus report.[305]Lim CE, Pasternak B, Eliasson B, et al. Use of sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide-1 receptor agonists according to the 2019 ESC guidelines and the 2019 ADA/EASD consensus report in a national population of patients with type 2 diabetes. Eur J Prev Cardiol. 2023 Jun 1;30(8):634-43.
https://academic.oup.com/eurjpc/article/30/8/634/6965376
http://www.ncbi.nlm.nih.gov/pubmed/36582120?tool=bestpractice.com
Uptake of these recommendations in routine clinical practice was limited, however, indicating that many eligible patients are missing out on the therapeutic benefits of these drugs.[305]Lim CE, Pasternak B, Eliasson B, et al. Use of sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide-1 receptor agonists according to the 2019 ESC guidelines and the 2019 ADA/EASD consensus report in a national population of patients with type 2 diabetes. Eur J Prev Cardiol. 2023 Jun 1;30(8):634-43.
https://academic.oup.com/eurjpc/article/30/8/634/6965376
http://www.ncbi.nlm.nih.gov/pubmed/36582120?tool=bestpractice.com
Glycemic control during acute critical illness (CVD events or interventions)
Trials of tight glycemic control in critically ill patients have yielded mixed results.[306]Griesdale DE, de Souza RJ, van Dam RM, et al. Intensive insulin therapy and mortality among critically ill patients: a meta-analysis including NICE-SUGAR study data. CMAJ. 2009 Mar 24;180(8):821-7.
http://www.cmaj.ca/content/180/8/821.long
http://www.ncbi.nlm.nih.gov/pubmed/19318387?tool=bestpractice.com
[307]Sathya B, Davis R, Taveira T, et al. Intensity of peri-operative glycemic control and postoperative outcomes in patients with diabetes: a meta-analysis. Diabetes Res Clin Pract. 2013 Jun 6;102(1):8-15.
http://www.ncbi.nlm.nih.gov/pubmed/23746852?tool=bestpractice.com
In one study of patients with acute coronary syndrome who presented with hyperglycemia, intensive glucose control was associated with harm and did not reduce infarct size.[308]de Mulder M, Umans VA, Cornel JH, et al. Intensive glucose regulation in hyperglycemic acute coronary syndrome: results of the randomized BIOMarker study to identify the acute risk of a coronary syndrome-2 (BIOMArCS-2) glucose trial. JAMA Intern Med. 2013 Nov 11;173(20):1896-904.
https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/1735896
http://www.ncbi.nlm.nih.gov/pubmed/24018647?tool=bestpractice.com
A large RCT also raised questions about the value of intensive inpatient blood glucose targets, reporting lower mortality in intensive care unit (ICU) patients treated to a conventional blood glucose target of ≤180 mg/dL (≤10 mmol/L) compared with those treated to a much tighter target range of 81 to 108 mg/dL (4.5 to 6.0 mmol/L).[309]Finfer S, Chittock DR, Su SY, et al; NICE-SUGAR Study Investigators. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009 Mar 26;360(13):1283-97.
https://www.nejm.org/doi/full/10.1056/NEJMoa0810625
http://www.ncbi.nlm.nih.gov/pubmed/19318384?tool=bestpractice.com
These findings have raised concern about whether lowering blood glucose levels below approximately 140 to 180 mg/dL (7.8 to 10 mmol/L) offers any additional benefit in the ICU setting.[310]Inzucchi SE, Siegel MD. Glucose control in the ICU: how tight is too tight? N Engl J Med. 2009 Mar 26;360(13):1346-9.
http://www.ncbi.nlm.nih.gov/pubmed/19318385?tool=bestpractice.com
The ADA recommends that in critically ill patients, insulin therapy should be started for persistent hyperglycemia ≥180 mg/dL (≥10 mmol/L) (confirmed on two occasions within 24 hours).[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
Once insulin is started, a target glucose range of 140 to 180 mg/dL (7.8 to 10 mmol/L) is recommended for most patients.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
More stringent goals may be appropriate for selected patients, as long as they can be achieved without significant hypoglycemia.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
Management should be guided by an intravenous insulin protocol with proven efficacy and safety in achieving glucose targets without increasing the risk of severe hypoglycemia.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
In critically ill patients, intravenous insulin infusion provides more reliable absorption and allows for rapid titration compared with subcutaneous injection. In the perioperative setting for coronary artery bypass grafting (CABG), effective glucose control may reduce the risk of infectious complications (including sternal wound infection and mediastinitis), lower cardiac mortality due to pump failure, and decrease the incidence of supraventricular tachycardia.[311]Kirdemir P, Yildirim V, Kiris I, et al. Does continuous insulin therapy reduce postoperative supraventricular tachycardia incidence after coronary artery bypass operations in diabetic patients? J Cardiothorac Vasc Anesth. 2008 Jun;22(3):383-7.
http://www.ncbi.nlm.nih.gov/pubmed/18503925?tool=bestpractice.com
[312]Lazar HL, Chipkin SR, Fitzgerald CA, et al. Tight glycemic control in diabetic coronary artery bypass graft patients improves perioperative outcomes and decreases recurrent ischemic events. Circulation. 2004 Mar 30;109(12):1497-502.
http://circ.ahajournals.org/content/109/12/1497.full
http://www.ncbi.nlm.nih.gov/pubmed/15006999?tool=bestpractice.com
[313]Wang YY, Hu SF, Ying HM, et al. Postoperative tight glycemic control significantly reduces postoperative infection rates in patients undergoing surgery: a meta-analysis. BMC Endocr Disord. 2018 Jun 22;18(1):42.
https://bmcendocrdisord.biomedcentral.com/articles/10.1186/s12902-018-0268-9
http://www.ncbi.nlm.nih.gov/pubmed/29929558?tool=bestpractice.com
ACE inhibitor or angiotensin-II receptor agonist therapy
ESC and AHA/American College of Cardiology (ACC) guidelines recommend use of an ACE inhibitor (or an angiotensin-II receptor antagonist if ACE inhibitors are not tolerated or contraindicated) in patients with chronic coronary disease and diabetes, even in the absence of hypertension, to reduce CV risk, particularly in those with HF or CKD.[6]Marx N, Federici M, Schütt K, et al. 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. Eur Heart J. 2023 Oct 14;44(39):4043-140.
https://academic.oup.com/eurheartj/article/44/39/4043/7238227
http://www.ncbi.nlm.nih.gov/pubmed/37622663?tool=bestpractice.com
[314]Virani SS, Newby LK, Arnold SV, et al. 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA guideline for the management of patients with chronic coronary disease: a report of the American Heart Association/American College of Cardiology Joint Committee on clinical practice guidelines. Circulation. 2023 Aug 29;148(9):e9-119.
https://www.ahajournals.org/doi/10.1161/CIR.0000000000001168
http://www.ncbi.nlm.nih.gov/pubmed/37471501?tool=bestpractice.com
[315]Vrints C, Andreotti F, Koskinas KC, et al. 2024 ESC guidelines for the management of chronic coronary syndromes. Eur Heart J. 2024 Sep 29;45(36):3415-537.
https://academic.oup.com/eurheartj/article/45/36/3415/7743115
In contrast, the ADA adopts a more targeted strategy, recommending ACE inhibitors or angiotensin-II receptor antagonists primarily for patients with diabetes and hypertension who either have established ASCVD or are age ≥55 years with additional CV risk factors.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
The ADA also strongly recommends ACE inhibitors or angiotensin-II receptor antagonists for the treatment of hypertension in patients with diabetes and CKD, particularly those with albuminuria (urinary albumin-to-creatinine ratio ≥30 mg/g), to reduce the risk of CKD progression and CV events.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
It also recommends that one of these drugs should be offered to patients with diabetes and symptomatic (stage C) HF to reduce morbidity and mortality, and to those with asymptomatic (stage B) HF to reduce the risk of progression to symptomatic HF.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
BP management
It is well accepted that good BP management reduces CV risk in patients with diabetes; however, certain pivotal studies investigating the benefits of intensive versus standard BP control yielded discordant results:
The UK Prospective Diabetes Study (UKPDS) found that tight BP control (<150 mmHg) led to a greater reduction in CV events than less tight BP control (<180 mmHg).[58]UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ. 1998 Sep 12;317(7160):703-13.
https://www.bmj.com/content/317/7160/703.long
http://www.ncbi.nlm.nih.gov/pubmed/9732337?tool=bestpractice.com
The Systolic Blood Pressure Intervention Trial (SPRINT) had similar findings, with intensive BP control (<120 mmHg) significantly reducing risk of CV events compared with standard control (<140 mmHg), although patients with diabetes were excluded from enrollment.[57]Wright JT Jr, Williamson JD, Whelton PK, et al; SPRINT Research Group. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015 Nov 26;373(22):2103-16.
https://www.nejm.org/doi/full/10.1056/NEJMoa1511939
http://www.ncbi.nlm.nih.gov/pubmed/26551272?tool=bestpractice.com
Conversely, the ACCORD-BP trial demonstrated that intensive BP control to a goal of <120 mmHg compared with a standard BP goal of <140 mmHg did not change CV outcomes in patients with diabetes.[56]Cushman WC, Evans GW, Byington RP, et al; ACCORD Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010 Apr 29;362(17):1575-85.
https://www.nejm.org/doi/full/10.1056/NEJMoa1001286
http://www.ncbi.nlm.nih.gov/pubmed/20228401?tool=bestpractice.com
The 2021 STEP trial found that, in older adults ages 60-80 years with hypertension, intensive BP control (target 110 to <130 mmHg) was associated with a 26% reduction in CV events compared with less intensive BP control (target 130 to <150 mmHg).[59]Zhang W, Zhang S, Deng Y, et al. Trial of intensive blood-pressure control in older patients with hypertension. N Engl J Med. 2021 Sep 30;385(14):1268-79.
https://www.nejm.org/doi/10.1056/NEJMoa2111437
http://www.ncbi.nlm.nih.gov/pubmed/34491661?tool=bestpractice.com
The reason for the difference in findings between SPRINT and ACCORD-BP remains under debate. However, a post-hoc analysis of ACCORD-BP found that although dual intensive therapy for BP and glycemic control was detrimental, intensive BP control conferred modest CV benefits for patients on standard glycemic control.[316]Shi S, Gouskova N, Najafzadeh M, et al. Intensive versus standard blood pressure control in type 2 diabetes: a restricted mean survival time analysis of a randomised controlled trial. BMJ Open. 2021 Sep 13;11(9):e050335.
https://bmjopen.bmj.com/content/11/9/e050335.long
http://www.ncbi.nlm.nih.gov/pubmed/34518266?tool=bestpractice.com
There is a lack of high-quality evidence regarding optimal treatment of hypertension in people with diabetes.[60]Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2018 May 15;71(19):e127-248.
http://www.onlinejacc.org/content/71/19/e127
http://www.ncbi.nlm.nih.gov/pubmed/29146535?tool=bestpractice.com
However, guidelines recommend a BP treatment goal of <130/80 mmHg, providing this can be safely attained.[6]Marx N, Federici M, Schütt K, et al. 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. Eur Heart J. 2023 Oct 14;44(39):4043-140.
https://academic.oup.com/eurheartj/article/44/39/4043/7238227
http://www.ncbi.nlm.nih.gov/pubmed/37622663?tool=bestpractice.com
[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
[60]Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2018 May 15;71(19):e127-248.
http://www.onlinejacc.org/content/71/19/e127
http://www.ncbi.nlm.nih.gov/pubmed/29146535?tool=bestpractice.com
[61]Blonde L, Umpierrez GE, Reddy SS, et al. American Association of Clinical Endocrinology clinical practice guideline: developing a diabetes mellitus comprehensive care plan-2022 update. Endocr Pract. 2022 Oct;28(10):923-1049.
https://www.sciencedirect.com/science/article/pii/S1530891X22005766
http://www.ncbi.nlm.nih.gov/pubmed/35963508?tool=bestpractice.com
The departure in the guidelines from the previous BP target of <140/90 mmHg was in response to studies like the meta-analysis of data from the ACCORD-BP and SPRINT trials, which showed a reduction in a composite of unstable angina, MI, acute HF, stroke, and CV death with intensive systolic BP targets of <120 mmHg compared with the traditional target of <140 mmHg.[317]Brouwer TF, Vehmeijer JT, Kalkman DN, et al. Intensive blood pressure lowering in patients with and patients without type 2 diabetes: a pooled analysis from two randomized trials. Diabetes Care. 2018 Jun;41(6):1142-8.
http://www.ncbi.nlm.nih.gov/pubmed/29212825?tool=bestpractice.com
Notably, the ADA recommends an individualized approach to BP targets, emphasizing shared decision-making between patients and clinicians to determine individual BP targets, and acknowledging the uncertainty surrounding the benefits and risks of intensive BP targets.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
People with diabetes plus hypertension should monitor their BP at home in addition to having it checked at regular intervals in the clinic setting, both to ensure accuracy of readings and to encourage adherence to treatment regimens.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
Guidelines emphasize the importance of therapeutic lifestyle interventions in the management of hypertension; these include increased physical activity, weight management, a DASH-style eating pattern (including reduced sodium intake and increased potassium intake), moderation of alcohol intake, smoking cessation, and education to support long-term behavior change.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
[61]Blonde L, Umpierrez GE, Reddy SS, et al. American Association of Clinical Endocrinology clinical practice guideline: developing a diabetes mellitus comprehensive care plan-2022 update. Endocr Pract. 2022 Oct;28(10):923-1049.
https://www.sciencedirect.com/science/article/pii/S1530891X22005766
http://www.ncbi.nlm.nih.gov/pubmed/35963508?tool=bestpractice.com
These lifestyle interventions should be initiated alongside pharmacologic therapy when hypertension is diagnosed, and are also recommended for individuals with diabetes and mildly elevated blood pressure (systolic >120 mmHg or diastolic >80 mmHg).[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
The ADA recommends starting one antihypertensive agent for patients with initial BP ≥130/80 mmHg and <150/90 mmHg, and starting two antihypertensive agents for those with initial BP ≥150/90 mmHg.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
ACE inhibitors, angiotensin-II receptor antagonists, dihydropyridine calcium-channel blockers, or thiazide diuretics are all options for initial antihypertensive therapy.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
[60]Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2018 May 15;71(19):e127-248.
http://www.onlinejacc.org/content/71/19/e127
http://www.ncbi.nlm.nih.gov/pubmed/29146535?tool=bestpractice.com
[61]Blonde L, Umpierrez GE, Reddy SS, et al. American Association of Clinical Endocrinology clinical practice guideline: developing a diabetes mellitus comprehensive care plan-2022 update. Endocr Pract. 2022 Oct;28(10):923-1049.
https://www.sciencedirect.com/science/article/pii/S1530891X22005766
http://www.ncbi.nlm.nih.gov/pubmed/35963508?tool=bestpractice.com
For patients with diabetes who have CAD or CKD and/or albuminuria (eGFR <60 mL/minute/1.73 m², urinary albumin-to-creatinine ratio ≥30 mg/g), initial antihypertensive therapy should be with an ACE inhibitor, or an angiotensin-II receptor antagonist if an ACE inhibitor is not tolerated (a dose reduction may be required in patients with renal impairment).[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
[60]Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2018 May 15;71(19):e127-248.
http://www.onlinejacc.org/content/71/19/e127
http://www.ncbi.nlm.nih.gov/pubmed/29146535?tool=bestpractice.com
For those whose BP is >150/90 mmHg, a calcium-channel blocker or thiazide diuretic should be considered in addition at treatment initiation.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
Combining ACE inhibitors and angiotensin-II receptor antagonists is not recommended because of an increased risk for acute kidney injury and hyperkalemia.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
[318]Palmer SC, Mavridis D, Navarese E, et al. Comparative efficacy and safety of blood pressure-lowering agents in adults with diabetes and kidney disease: a network meta-analysis. Lancet. 2015 May 23;385(9982):2047-56.
http://www.ncbi.nlm.nih.gov/pubmed/26009228?tool=bestpractice.com
ACE inhibitors have also shown increased risk for hypoglycemia in conjunction with insulin or insulin secretagogues (such as sulfonylureas or meglitinides).[319]Scheen AJ. Drug interactions of clinical importance with antihyperglycaemic agents: an update. Drug Saf. 2005;28(7):601-31.
http://www.ncbi.nlm.nih.gov/pubmed/15963007?tool=bestpractice.com
One meta-analysis found that ACE inhibitors reduced mortality and MACE in patients with diabetes, while angiotensin-II receptor antagonists did not improve these outcomes. Neither ACE inhibitors or angiotensin-II receptor antagonists were found to reduce the risk of stroke.[320]Cheng J, Zhang W, Zhang X, et al. Effect of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on all-cause mortality, cardiovascular deaths, and cardiovascular events in patients with diabetes mellitus: a meta-analysis. JAMA Intern Med. 2014 May;174(5):773-85.
https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/1847572
http://www.ncbi.nlm.nih.gov/pubmed/24687000?tool=bestpractice.com
Another meta-analysis showed that in patients with diabetes and kidney disease, no antihypertensive regimen improved survival.[318]Palmer SC, Mavridis D, Navarese E, et al. Comparative efficacy and safety of blood pressure-lowering agents in adults with diabetes and kidney disease: a network meta-analysis. Lancet. 2015 May 23;385(9982):2047-56.
http://www.ncbi.nlm.nih.gov/pubmed/26009228?tool=bestpractice.com
However, ACE inhibitors and angiotensin-II receptor antagonists were effective in preventing end-stage renal disease.[318]Palmer SC, Mavridis D, Navarese E, et al. Comparative efficacy and safety of blood pressure-lowering agents in adults with diabetes and kidney disease: a network meta-analysis. Lancet. 2015 May 23;385(9982):2047-56.
http://www.ncbi.nlm.nih.gov/pubmed/26009228?tool=bestpractice.com
Some antihyperglycemic agents have demonstrated modest BP-lowering effects in clinical trials, including SGLT2 inhibitors and GLP-1 receptor agonists.[321]Liakos CI, Papadopoulos DP, Sanidas EA, et al. Blood pressure-lowering effect of newer antihyperglycemic agents (SGLT-2 inhibitors, GLP-1 receptor agonists, and DPP-4 inhibitors). Am J Cardiovasc Drugs. 2021 Mar;21(2):123-37.
http://www.ncbi.nlm.nih.gov/pubmed/32780214?tool=bestpractice.com
Further studies are warranted to investigate the effects of these agents on BP as the primary outcome measure.[321]Liakos CI, Papadopoulos DP, Sanidas EA, et al. Blood pressure-lowering effect of newer antihyperglycemic agents (SGLT-2 inhibitors, GLP-1 receptor agonists, and DPP-4 inhibitors). Am J Cardiovasc Drugs. 2021 Mar;21(2):123-37.
http://www.ncbi.nlm.nih.gov/pubmed/32780214?tool=bestpractice.com
Based on the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE) trial, the FDA recommends that combination of the renin inhibitor aliskiren with ACE inhibitors or angiotensin-II receptor antagonists is contraindicated in patients with diabetes due to the risk of renal impairment, hypotension, and hyperkalemia.
FDA: new warning and contraindication for blood pressure medicines containing aliskiren (Tekturna)
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Beta-blockers may be appropriate to improve outcomes as antihypertensive agents in patients with prior MI, active angina, atrial fibrillation with rapid ventricular response, or HFrEF.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
These patients are typically started on beta-blockers alone, with other antihypertensive therapies added as needed. If a beta-blocker is indicated, an agent should be selected that has concomitant vasodilatory effects to reduce potential for adverse metabolic impact.[115]Arnold SV, Bhatt DL, Barsness GW, et al. Clinical management of stable coronary artery disease in patients with type 2 diabetes mellitus: a scientific statement from the American Heart Association. Circulation. 2020 May 12;141(19):e779-806.
https://www.ahajournals.org/doi/full/10.1161/CIR.0000000000000766
http://www.ncbi.nlm.nih.gov/pubmed/32279539?tool=bestpractice.com
Beta-blockers may mask symptoms of hypoglycemia and also have the potential to exacerbate hypoglycemic episodes, particularly when used concurrently with sulfonylureas.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
[322]Carnovale C, Gringeri M, Battini V, et al. Beta-blocker-associated hypoglycaemia: new insights from a real-world pharmacovigilance study. Br J Clin Pharmacol. 2021 Aug;87(8):3320-31.
https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bcp.14754
http://www.ncbi.nlm.nih.gov/pubmed/33506522?tool=bestpractice.com
[323]Dimakos J, Cui Y, Platt RW, et al. Concomitant use of sulfonylureas and β-blockers and the risk of severe hypoglycemia among patients with type 2 diabetes: a population-based cohort study. Diabetes Care. 2023 Feb 1;46(2):377-83.
https://diabetesjournals.org/care/article/46/2/377/148065/Concomitant-Use-of-Sulfonylureas-and-Blockers-and
http://www.ncbi.nlm.nih.gov/pubmed/36525638?tool=bestpractice.com
Multiple drug therapy is often required to achieve antihypertensive targets.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
If BP remains uncontrolled on monotherapy, add an agent from a different first-line class.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
If BP remains uncontrolled despite combination therapy with first-line agents (i.e., three classes of antihypertensive drugs [including a diuretic] plus lifestyle modifications), discontinue or minimize interfering substances such as nonsteroidal anti-inflammatory drugs (NSAIDs), evaluate for secondary causes of hypertension (including obstructive sleep apnea), and consider the addition of an aldosterone antagonist (e.g., spironolactone, eplerenone).[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
[115]Arnold SV, Bhatt DL, Barsness GW, et al. Clinical management of stable coronary artery disease in patients with type 2 diabetes mellitus: a scientific statement from the American Heart Association. Circulation. 2020 May 12;141(19):e779-806.
https://www.ahajournals.org/doi/full/10.1161/CIR.0000000000000766
http://www.ncbi.nlm.nih.gov/pubmed/32279539?tool=bestpractice.com
Referral to a hypertension specialist may also be necessary.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
[115]Arnold SV, Bhatt DL, Barsness GW, et al. Clinical management of stable coronary artery disease in patients with type 2 diabetes mellitus: a scientific statement from the American Heart Association. Circulation. 2020 May 12;141(19):e779-806.
https://www.ahajournals.org/doi/full/10.1161/CIR.0000000000000766
http://www.ncbi.nlm.nih.gov/pubmed/32279539?tool=bestpractice.com
To ensure safety, serum creatinine/eGFR and potassium levels require monitoring within 7-14 days of starting an ACE inhibitor, angiotensin-II receptor antagonist, aldosterone antagonist, or diuretic, and again 7-14 days after any dose adjustment.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
Regular checks should also be performed at subsequent routine appointments.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
Dyslipidemia therapy
Lifestyle modification focusing on weight loss (if indicated), application of a Mediterranean or DASH eating pattern, reduction of saturated fat and trans-fat, increase of dietary omega-3 fatty acids, viscous fiber, and plant stanol/sterol intake, and increased physical activity should be recommended to improve the lipid profile and reduce the risk of developing CVD in people with diabetes.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
LDL-C is the most extensively studied modifiable risk factor associated with ASCVD. There is strong evidence that LDL-C is a causal factor in the pathophysiology of CVD, and CVD risk reduction is proportional to the absolute and relative LDL-C reduction achieved.[113]Ference BA, Ginsberg HN, Graham I, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2017 Aug 21;38(32):2459-72.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837225
http://www.ncbi.nlm.nih.gov/pubmed/28444290?tool=bestpractice.com
One meta-analysis, which included data from over 18,000 people with diabetes from 14 randomized trials of statin therapy (mean follow-up 4.3 years), demonstrated a 9% proportional reduction in all-cause mortality and 13% reduction in vascular mortality for each 39 mg/dL (1 mmol/L) reduction in LDL-C.[125]Cholesterol Treatment Trialists' (CTT) Collaborators, Kearney PM, Blackwell L, et al. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet. 2008 Jan 12;371(9607):117-25.
http://www.ncbi.nlm.nih.gov/pubmed/18191683?tool=bestpractice.com
The CV benefit did not depend on baseline LDL-C levels and was linearly related to the LDL-C reduction without a low threshold beyond which there was no benefit observed. Lowering of LDL-C has also been shown to have a significant positive impact on long-term outcomes for patients with diabetes and coronary heart disease undergoing percutaneous coronary intervention (PCI).[324]Farkouh ME, Godoy LC, Brooks MM, et al. Influence of LDL-cholesterol lowering on cardiovascular outcomes in patients with diabetes mellitus undergoing coronary revascularization. J Am Coll Cardiol. 2020 Nov 10;76(19):2197-207.
https://www.sciencedirect.com/science/article/pii/S0735109720372120
http://www.ncbi.nlm.nih.gov/pubmed/33153578?tool=bestpractice.com
For patients with diabetes and established ASCVD, both European and US guidelines recommend an LDL-C goal of <55 mg/dL (<1.42 mmol/L) and at least a 50% reduction from baseline.[6]Marx N, Federici M, Schütt K, et al. 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. Eur Heart J. 2023 Oct 14;44(39):4043-140.
https://academic.oup.com/eurheartj/article/44/39/4043/7238227
http://www.ncbi.nlm.nih.gov/pubmed/37622663?tool=bestpractice.com
[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
[114]Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol. Circulation. 2019 Jun 18;139(25):e1082-143.
https://www.ahajournals.org/doi/full/10.1161/CIR.0000000000000625
http://www.ncbi.nlm.nih.gov/pubmed/30586774?tool=bestpractice.com
Statins
Statins are the first-line drug for LDL-C lowering and cardioprotection.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
Moderate-intensity statin therapy has been defined by the ACC/AHA as therapy that generally lowers LDL-C level by 30% to 50%, while high-intensity statin therapy lowers it by ≥50%.[114]Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol. Circulation. 2019 Jun 18;139(25):e1082-143.
https://www.ahajournals.org/doi/full/10.1161/CIR.0000000000000625
http://www.ncbi.nlm.nih.gov/pubmed/30586774?tool=bestpractice.com
Guidelines recommend high-intensity statin therapy in adults of all ages with diabetes and ASCVD, to target an LDL-C reduction of ≥50% from baseline and an LDL-C goal of <55 mg/dL (<1.42 mmol/L).[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
[114]Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol. Circulation. 2019 Jun 18;139(25):e1082-143.
https://www.ahajournals.org/doi/full/10.1161/CIR.0000000000000625
http://www.ncbi.nlm.nih.gov/pubmed/30586774?tool=bestpractice.com
Low-dose statin therapy is generally not recommended in people with diabetes, but it is sometimes the only dose of statin that an individual can tolerate; for individuals who do not tolerate the intended intensity of statin, the maximum tolerated statin dose should be used.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
Ezetimibe
If target LDL-C is not achieved with a statin alone, addition of ezetimibe can be considered.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
Ezetimibe works by reducing cholesterol absorption from the ileum.[6]Marx N, Federici M, Schütt K, et al. 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. Eur Heart J. 2023 Oct 14;44(39):4043-140.
https://academic.oup.com/eurheartj/article/44/39/4043/7238227
http://www.ncbi.nlm.nih.gov/pubmed/37622663?tool=bestpractice.com
One large RCT of 18,144 individuals compared the addition of ezetimibe to simvastatin therapy versus simvastatin alone in people ages ≥50 years who had experienced a recent acute coronary syndrome.[325]Giugliano RP, Cannon CP, Blazing MA, et al; IMPROVE-IT Investigators. Benefit of adding ezetimibe to statin therapy on cardiovascular outcomes and safety in patients with versus without diabetes mellitus: results from IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial). Circulation. 2017 Dec 20;137(15):1571-82.
https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.117.030950
http://www.ncbi.nlm.nih.gov/pubmed/29263150?tool=bestpractice.com
Overall, over an average treatment period of 6 years, addition of ezetimibe led to a 6.4% relative benefit and a 2% absolute reduction in MACE, with the degree of benefit being directly proportional to the change in LDL-C. Subgroup analysis showed that the benefit of adding ezetimibe to statin therapy was enhanced in patients with diabetes.[325]Giugliano RP, Cannon CP, Blazing MA, et al; IMPROVE-IT Investigators. Benefit of adding ezetimibe to statin therapy on cardiovascular outcomes and safety in patients with versus without diabetes mellitus: results from IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial). Circulation. 2017 Dec 20;137(15):1571-82.
https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.117.030950
http://www.ncbi.nlm.nih.gov/pubmed/29263150?tool=bestpractice.com
Another RCT showed that among patients with diabetes and ASCVD, moderate-intensity statin with ezetimibe combined therapy was noninferior to high-intensity statin monotherapy with respect to the primary endpoint of CV death, MACE, or nonfatal stroke.[326]Lee YJ, Cho JY, You SC, et al. Moderate-intensity statin with ezetimibe vs. high-intensity statin in patients with diabetes and atherosclerotic cardiovascular disease in the RACING trial. Eur Heart J. 2023 Mar 14;44(11):972-83.
https://academic.oup.com/eurheartj/article/44/11/972/6931821
http://www.ncbi.nlm.nih.gov/pubmed/36529993?tool=bestpractice.com
Notably, the patients treated with moderate-intensity statin and ezetimibe had lower rates of drug discontinuation or dose reduction than patients receiving high-intensity statin. This study supports moderate-intensity statin with ezetimibe combination therapy as a suitable alternative to high-intensity statins if the latter cannot be tolerated, or if further reduction in LDL-C is required in patients with diabetes and ASCVD.[326]Lee YJ, Cho JY, You SC, et al. Moderate-intensity statin with ezetimibe vs. high-intensity statin in patients with diabetes and atherosclerotic cardiovascular disease in the RACING trial. Eur Heart J. 2023 Mar 14;44(11):972-83.
https://academic.oup.com/eurheartj/article/44/11/972/6931821
http://www.ncbi.nlm.nih.gov/pubmed/36529993?tool=bestpractice.com
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors
If target LDL-C is not achieved with a statin alone, addition of a PCSK9 inhibitor (e.g., alirocumab, evolocumab) can be considered as an alternative to ezetimibe (or in addition to ezetimibe if LDL-C is not at goal). PCSK9 inhibitors can also be used as monotherapy in patients who are statin-intolerant.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
In placebo-controlled RCTs, alirocumab and evolocumab achieved a >50% reduction in LDL-C levels compared with placebo, with a 15% lower risk of ischemic CV events over a 2- to 3-year follow-up.[327]Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018 Nov 29;379(22):2097-107.
https://www.zora.uzh.ch/id/eprint/162737
http://www.ncbi.nlm.nih.gov/pubmed/30403574?tool=bestpractice.com
[328]Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017 May 4;376(18):1713-22.
https://www.nejm.org/doi/10.1056/NEJMoa1615664
http://www.ncbi.nlm.nih.gov/pubmed/28304224?tool=bestpractice.com
Bempedoic acid
Bempedoic acid, an adenosine triphosphate citrate lyase inhibitor, is a novel, oral LDL-C-lowering drug that works by inhibiting cholesterol synthesis.[6]Marx N, Federici M, Schütt K, et al. 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. Eur Heart J. 2023 Oct 14;44(39):4043-140.
https://academic.oup.com/eurheartj/article/44/39/4043/7238227
http://www.ncbi.nlm.nih.gov/pubmed/37622663?tool=bestpractice.com
It is approved in the US as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with established ASCVD who require additional lowering of LDL-C. The ADA advises that it may be considered for patients who cannot use, or tolerate, other evidence-based LDL-C-lowering approaches, or for whom those other therapies are inadequately effective.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
Bempedoic acid is also approved for this indication in Europe.[329]Kulshreshtha M. An update on new cholesterol inhibitor: bempedoic acid. Curr Cardiol Rev. 2022;18(2):e141221198875.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9413737
http://www.ncbi.nlm.nih.gov/pubmed/34906059?tool=bestpractice.com
One meta-analysis found that bempedoic acid therapy lowered LDL-C levels by about 23% compared with placebo, while an RCT found that it was associated with a reduction in risk of MACE in statin-intolerant patients, providing some evidence for its use in this group.[330]Dai L, Zuo Y, You Q, et al. Efficacy and safety of bempedoic acid in patients with hypercholesterolemia: a systematic review and meta-analysis of randomized controlled trials. Eur J Prev Cardiol. 2021 Jul 23;28(8):825-33.
https://academic.oup.com/eurjpc/article/28/8/825/6327121
http://www.ncbi.nlm.nih.gov/pubmed/34298558?tool=bestpractice.com
[331]Nissen SE, Lincoff AM, Brennan D, et al. Bempedoic acid and cardiovascular outcomes in statin-intolerant patients. N Engl J Med. 2023 Apr 13;388(15):1353-64.
http://www.ncbi.nlm.nih.gov/pubmed/36876740?tool=bestpractice.com
Inclisiran
Inclisiran, a small interfering ribonucleic acid (siRNA) that inhibits hepatic synthesis of PCSK9, is now recommended by the ADA as an alternative lipid-lowering treatment for people who are intolerant of statins (off-label use).[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
In the ORION-10 and ORION-11 phase 3 trials, individuals with established ASCVD or at high risk of ASCVD were randomized to receive inclisiran or placebo.[332]Ray KK, Wright RS, Kallend D, et al. Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol. N Engl J Med. 2020 Apr 16;382(16):1507-19.
https://www.nejm.org/doi/10.1056/NEJMoa1912387
http://www.ncbi.nlm.nih.gov/pubmed/32187462?tool=bestpractice.com
Inclisiran allows less frequent administration compared with monoclonal antibodies and was administered on day 1, day 90, and every 6 months thereafter over a period of 540 days. Reductions in LDL-C levels of approximately 50% were obtained with inclisiran.[332]Ray KK, Wright RS, Kallend D, et al. Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol. N Engl J Med. 2020 Apr 16;382(16):1507-19.
https://www.nejm.org/doi/10.1056/NEJMoa1912387
http://www.ncbi.nlm.nih.gov/pubmed/32187462?tool=bestpractice.com
Adverse events were generally similar in the inclisiran and placebo groups, although injection-site adverse events were more frequent with inclisiran (2.6% vs. 0.9% in ORION-10 and 4.7% vs. 0.5% in ORION-11); such reactions were generally mild.[332]Ray KK, Wright RS, Kallend D, et al. Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol. N Engl J Med. 2020 Apr 16;382(16):1507-19.
https://www.nejm.org/doi/10.1056/NEJMoa1912387
http://www.ncbi.nlm.nih.gov/pubmed/32187462?tool=bestpractice.com
A CV outcome trial using inclisiran in people with established ASCVD is ongoing.[333]ClinicalTrials.gov. A randomized trial assessing the effects of inclisiran on clinical outcomes among people with cardiovascular disease (ORION-4). ClinicalTrials.gov Identifier: NCT03705234. Dec 2024 [internet publication].
https://clinicaltrials.gov/study/NCT03705234
Summary of ADA recommendations for lipid-lowering pharmacotherapy in patients with diabetes with established ASCVD:[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
High-intensity statin therapy for adults of all ages, to target an LDL-C reduction of ≥50% from baseline and an LDL-C goal of <55 mg/dL (<1.42 mmol/L). For people who do not tolerate the intended statin intensity, the maximum tolerated statin dose should be used.
Addition of ezetimibe or a PCSK9 inhibitor if this goal is not achieved on maximum tolerated statin therapy.
For people intolerant of statin therapy, a PCSK9 inhibitor, bempedoic acid, or inclisiran should be considered as alternative cholesterol-lowering therapies.
For certain patients at intermediate or borderline risk, coronary artery calcium (CAC) measurement may be useful to support shared decision-making for statin therapy.[76]Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease. Circulation. 2019 Sep 10;140(11):e596-646.
https://www.ahajournals.org/doi/10.1161/CIR.0000000000000678
http://www.ncbi.nlm.nih.gov/pubmed/30879355?tool=bestpractice.com
A CAC score ≥100 Agatston units or in the ≥75th age/sex/race percentile can reclassify CV risk as being increased.[76]Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease. Circulation. 2019 Sep 10;140(11):e596-646.
https://www.ahajournals.org/doi/10.1161/CIR.0000000000000678
http://www.ncbi.nlm.nih.gov/pubmed/30879355?tool=bestpractice.com
A lipid profile should be checked: at time of diagnosis of diabetes or prediabetes; at initiation of statins or other lipid-lowering therapy; 4-12 weeks after initiation or a change in dose; and annually thereafter.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
Role of other lipid-lowering pharmacotherapies
Icosapent ethyl can be considered in patients with ASCVD or other CV risk factors who are on a statin (at maximal dose) and have controlled LDL-C but elevated triglycerides (150 to 499 mg/dL [1.7 to 5.6 mmol/L]).[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
It has been shown to modestly reduce MACE.[115]Arnold SV, Bhatt DL, Barsness GW, et al. Clinical management of stable coronary artery disease in patients with type 2 diabetes mellitus: a scientific statement from the American Heart Association. Circulation. 2020 May 12;141(19):e779-806.
https://www.ahajournals.org/doi/full/10.1161/CIR.0000000000000766
http://www.ncbi.nlm.nih.gov/pubmed/32279539?tool=bestpractice.com
[116]Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019 Jan 3;380(1):11-22.
https://www.nejm.org/doi/10.1056/NEJMoa1812792
http://www.ncbi.nlm.nih.gov/pubmed/30415628?tool=bestpractice.com
There have been some concerns about the use of mineral oil as the control treatment in pivotal clinical trials of icosapent ethyl; however, evaluation of whether this had an impact on trial outcomes remains inconclusive.[334]Doi T, Langsted A, Nordestgaard BG. A possible explanation for the contrasting results of REDUCE-IT vs. STRENGTH: cohort study mimicking trial designs. Eur Heart J. 2021 Dec 14;42(47):4807-17.
https://academic.oup.com/eurheartj/article/42/47/4807/6358478
http://www.ncbi.nlm.nih.gov/pubmed/34455435?tool=bestpractice.com
[335]Olshansky B, Chung MK, Budoff MJ, et al. Mineral oil: safety and use as placebo in REDUCE-IT and other clinical studies. Eur Heart J Suppl. 2020 Oct;22(suppl j):J34-J48.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537802
http://www.ncbi.nlm.nih.gov/pubmed/33061866?tool=bestpractice.com
Fibrates are effective for lowering very high triglyceride levels (i.e., >500 mg/dL [>5.65 mmol/L]) to reduce the risk of pancreatitis.[115]Arnold SV, Bhatt DL, Barsness GW, et al. Clinical management of stable coronary artery disease in patients with type 2 diabetes mellitus: a scientific statement from the American Heart Association. Circulation. 2020 May 12;141(19):e779-806.
https://www.ahajournals.org/doi/full/10.1161/CIR.0000000000000766
http://www.ncbi.nlm.nih.gov/pubmed/32279539?tool=bestpractice.com
They are most often added to statin therapy, although the ADA notes that this approach is generally not recommended due to a lack of evidence for improvement in CVD outcomes.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
Furthermore, caution is recommended as combination statin and fibrate therapy can increase the risk of myositis and rhabdomyolysis. To lower the risk, fenofibrate is recommended over gemfibrozil.[47]Joseph JJ, Deedwania P, Acharya T, et al. Comprehensive management of cardiovascular risk factors for adults with type 2 diabetes: a scientific statement from the American Heart Association. Circulation. 2022 Mar;145(9):e722-59.
https://www.ahajournals.org/doi/full/10.1161/CIR.0000000000001040
http://www.ncbi.nlm.nih.gov/pubmed/35000404?tool=bestpractice.com
Supplementation with omega-3 fatty acids has not been found to reduce the rate of CV events in patients with diabetes at high risk for these events.[117]Bosch J, Gerstein HC, Dagenais GR, et al; ORIGIN Trial Investigators. n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med. 2012 Jul 26;367(4):309-18.
https://www.nejm.org/doi/full/10.1056/NEJMoa1203859
http://www.ncbi.nlm.nih.gov/pubmed/22686415?tool=bestpractice.com
Antiplatelet therapy
Aspirin is recommended for secondary prevention in those with a history of ASCVD.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
Clopidogrel (a P2Y12 inhibitor) should be used in patients who have an aspirin allergy or intolerance.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
In people with stable CAD and/or PAD and low bleeding risk, the ADA and ESC recommend combination treatment with aspirin and low-dose rivaroxaban (a direct oral anticoagulant [DOAC]) for secondary prevention.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
[336]Ajjan RA, Kietsiriroje N, Badimon L, et al. Antithrombotic therapy in diabetes: which, when, and for how long? Eur Heart J. 2021 Jun 14;42(23):2235-59.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203081
http://www.ncbi.nlm.nih.gov/pubmed/33764414?tool=bestpractice.com
Rivaroxaban, when combined with aspirin, provides complementary antithrombotic effects and may also improve endothelial function.[337]Pistrosch F, Matschke JB, Schipp D, et al. Rivaroxaban compared with low-dose aspirin in individuals with type 2 diabetes and high cardiovascular risk: a randomised trial to assess effects on endothelial function, platelet activation and vascular biomarkers. Diabetologia. 2021 Dec;64(12):2701-12.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8563606
http://www.ncbi.nlm.nih.gov/pubmed/34495376?tool=bestpractice.com
Following acute coronary syndrome (ACS), dual antiplatelet therapy with a combination of aspirin and a P2Y12 receptor antagonist (clopidogrel, ticagrelor, or prasugrel) is indicated.[338]Rao SV, O'Donoghue ML, Ruel M, et al. 2025 ACC/AHA/ACEP/NAEMSP/SCAI guideline for the management of patients with acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Joint Committee on clinical practice guidelines. Circulation. 2025 Apr;151(13):e771-862.
https://www.ahajournals.org/doi/10.1161/CIR.0000000000001309
http://www.ncbi.nlm.nih.gov/pubmed/40014670?tool=bestpractice.com
Evidence supports use of either ticagrelor or clopidogrel if no PCI was performed, and clopidogrel, ticagrelor, or prasugrel if PCI was performed.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
[339]Writing Committee Members; Lawton JS, Tamis-Holland JE, Bangalore S, et al. 2021 ACC/AHA/SCAI guideline for coronary artery revascularization: a report of the American College of Cardiology/American Heart Association joint committee on clinical practice guidelines. J Am Coll Cardiol. 2022 Jan 18;79(2):e21-129.
https://www.jacc.org/doi/10.1016/j.jacc.2021.09.006
http://www.ncbi.nlm.nih.gov/pubmed/34895950?tool=bestpractice.com
Generally, prasugrel and ticagrelor have better efficacy in patients with diabetes and are preferred to clopidogrel for patients who undergo PCI.[336]Ajjan RA, Kietsiriroje N, Badimon L, et al. Antithrombotic therapy in diabetes: which, when, and for how long? Eur Heart J. 2021 Jun 14;42(23):2235-59.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203081
http://www.ncbi.nlm.nih.gov/pubmed/33764414?tool=bestpractice.com
[339]Writing Committee Members; Lawton JS, Tamis-Holland JE, Bangalore S, et al. 2021 ACC/AHA/SCAI guideline for coronary artery revascularization: a report of the American College of Cardiology/American Heart Association joint committee on clinical practice guidelines. J Am Coll Cardiol. 2022 Jan 18;79(2):e21-129.
https://www.jacc.org/doi/10.1016/j.jacc.2021.09.006
http://www.ncbi.nlm.nih.gov/pubmed/34895950?tool=bestpractice.com
Short-term dual antiplatelet therapy is also recommended after high-risk transient ischemic attack (TIA) and minor stroke.[340]Kleindorfer DO, Towfighi A, Chaturvedi S, et al. 2021 guideline for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline from the American Heart Association/American Stroke Association. Stroke. 2021 Jul;52(7):e364-467.
https://www.ahajournals.org/doi/full/10.1161/STR.0000000000000375
Extending dual antiplatelet therapy beyond 1 year may reduce long-term risk of recurrent atherosclerotic events.[336]Ajjan RA, Kietsiriroje N, Badimon L, et al. Antithrombotic therapy in diabetes: which, when, and for how long? Eur Heart J. 2021 Jun 14;42(23):2235-59.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203081
http://www.ncbi.nlm.nih.gov/pubmed/33764414?tool=bestpractice.com
However, recommendations regarding length of treatment are rapidly evolving and should be determined by an interprofessional team approach that includes a cardiologist following ACS or a neurologist following TIA/stroke.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
The benefits versus risks of bleeding and thrombosis should be evaluated based on the coronary anatomy and extent of CAD, PCI complexity, bleeding risk, age, and patient’s medical comorbidities such as anemia or renal failure.[341]Angiolillo DJ, Bhatt DL, Cannon CP, et al. Antithrombotic therapy in patients with atrial fibrillation treated with oral anticoagulation undergoing percutaneous coronary intervention: a North American perspective – 2021 update. Circulation. 2021 Feb 9;143(6):583-96.
https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.050438
http://www.ncbi.nlm.nih.gov/pubmed/33555916?tool=bestpractice.com
To reduce risk of gastrointestinal bleeding, a proton-pump inhibitor is recommended for all patients on a combination of antiplatelet or anticoagulant therapy, and the ESC recommends that one should be considered for those on a single agent depending on their individual bleeding risk.[6]Marx N, Federici M, Schütt K, et al. 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. Eur Heart J. 2023 Oct 14;44(39):4043-140.
https://academic.oup.com/eurheartj/article/44/39/4043/7238227
http://www.ncbi.nlm.nih.gov/pubmed/37622663?tool=bestpractice.com
ST-elevation myocardial infarction (STEMI)
For people with STEMI and ischemic symptoms for <12 hours, primary PCI is recommended to improve survival.[339]Writing Committee Members; Lawton JS, Tamis-Holland JE, Bangalore S, et al. 2021 ACC/AHA/SCAI guideline for coronary artery revascularization: a report of the American College of Cardiology/American Heart Association joint committee on clinical practice guidelines. J Am Coll Cardiol. 2022 Jan 18;79(2):e21-129.
https://www.jacc.org/doi/10.1016/j.jacc.2021.09.006
http://www.ncbi.nlm.nih.gov/pubmed/34895950?tool=bestpractice.com
Primary PCI is superior to fibrinolytic therapy, and fibrinolytic therapy is therefore only recommended if PCI is not immediately available (i.e., within 120 minutes).[339]Writing Committee Members; Lawton JS, Tamis-Holland JE, Bangalore S, et al. 2021 ACC/AHA/SCAI guideline for coronary artery revascularization: a report of the American College of Cardiology/American Heart Association joint committee on clinical practice guidelines. J Am Coll Cardiol. 2022 Jan 18;79(2):e21-129.
https://www.jacc.org/doi/10.1016/j.jacc.2021.09.006
http://www.ncbi.nlm.nih.gov/pubmed/34895950?tool=bestpractice.com
An analysis of data from 11 clinical trials compared PCI with fibrinolytic therapy in 2725 patients with STEMI, including 367 patients with diabetes.[342]Grines C, Patel A, Zijlstra F, et al. Primary coronary angioplasty compared with intravenous thrombolytic therapy for acute myocardial infarction: six-month follow up and analysis of individual patient data from randomized trials. Am Heart J. 2003 Jan;145(1):47-57.
http://www.ncbi.nlm.nih.gov/pubmed/12514654?tool=bestpractice.com
Among the patients with diabetes, 30-day mortality or nonfatal reinfarction rate was 19.3% for those treated with fibrinolytics and 9.2% for those who underwent primary PCI. If onset of ischemic symptoms is ≥12 hours and the patient is in cardiogenic shock or experiencing hemodynamic instability, primary PCI is indicated, or CABG if PCI is not feasible.[339]Writing Committee Members; Lawton JS, Tamis-Holland JE, Bangalore S, et al. 2021 ACC/AHA/SCAI guideline for coronary artery revascularization: a report of the American College of Cardiology/American Heart Association joint committee on clinical practice guidelines. J Am Coll Cardiol. 2022 Jan 18;79(2):e21-129.
https://www.jacc.org/doi/10.1016/j.jacc.2021.09.006
http://www.ncbi.nlm.nih.gov/pubmed/34895950?tool=bestpractice.com
PCI may also be reasonable in patients who are stable and presenting 12 to 24 hours after symptom onset, as well as in those whose STEMI is complicated by ongoing ischemia, acute severe HF, or life-threatening arrhythmia.[339]Writing Committee Members; Lawton JS, Tamis-Holland JE, Bangalore S, et al. 2021 ACC/AHA/SCAI guideline for coronary artery revascularization: a report of the American College of Cardiology/American Heart Association joint committee on clinical practice guidelines. J Am Coll Cardiol. 2022 Jan 18;79(2):e21-129.
https://www.jacc.org/doi/10.1016/j.jacc.2021.09.006
http://www.ncbi.nlm.nih.gov/pubmed/34895950?tool=bestpractice.com
For more comprehensive information on the acute management of this condition, see ST-elevation myocardial infarction.
Uncontrolled blood glucose levels in the perioperative or periprocedural period are associated with adverse outcomes for patients with diabetes. Benefits of good control include reductions in length of hospital stay and likelihood of readmission, as well as improved postoperative survival rates.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
One RCT examining the effects of periprocedural intensive glycemic control during early PCI on the rate of restenosis in hyperglycemic (glucose ≥140 mg/dL [7.8 mmol/L]) patients with a STEMI showed that intensive control led to a 50% reduction in restenosis at 6 months compared with conventional glycemic control.[343]Marfella R, Sasso FC, Siniscalchi M, et al. Peri-procedural tight glycemic control during early percutaneous coronary intervention is associated with a lower rate of in-stent restenosis in patients with acute ST-elevation myocardial infarction. J Clin Endocrinol Metab. 2012 Aug;97(8):2862-71.
http://www.ncbi.nlm.nih.gov/pubmed/22639289?tool=bestpractice.com
Non-ST-elevation acute coronary syndrome
Non-ST-elevation acute coronary syndrome (NSTE-ACS) most commonly manifests as non-STEMI (NSTEMI) but may also present as unstable angina.[144]Byrne RA, Rossello X, Coughlan JJ, et al. 2023 ESC guidelines for the management of acute coronary syndromes. Eur Heart J. 2023 Oct 12;44(38):3720-826.
https://academic.oup.com/eurheartj/article/44/38/3720/7243210
http://www.ncbi.nlm.nih.gov/pubmed/37622654?tool=bestpractice.com
Immediate invasive strategy (coronary angiography with intent of revascularization) is required in patients with NSTEMI and cardiogenic shock, refractory angina, or hemodynamic/electrical instability.[339]Writing Committee Members; Lawton JS, Tamis-Holland JE, Bangalore S, et al. 2021 ACC/AHA/SCAI guideline for coronary artery revascularization: a report of the American College of Cardiology/American Heart Association joint committee on clinical practice guidelines. J Am Coll Cardiol. 2022 Jan 18;79(2):e21-129.
https://www.jacc.org/doi/10.1016/j.jacc.2021.09.006
http://www.ncbi.nlm.nih.gov/pubmed/34895950?tool=bestpractice.com
Early invasive strategy (usually within 24 hours) is recommended for patients at high risk for CV events: for example, those with a high Global Registry of Acute Coronary Events (GRACE) score. Patients with low- or intermediate-risk NSTEMI should undergo coronary angiography before discharge with the intent of revascularization. Invasive strategy is important in NSTEMI as it will help determine the suitability for revascularization and the appropriate mode (PCI vs. CABG).[339]Writing Committee Members; Lawton JS, Tamis-Holland JE, Bangalore S, et al. 2021 ACC/AHA/SCAI guideline for coronary artery revascularization: a report of the American College of Cardiology/American Heart Association joint committee on clinical practice guidelines. J Am Coll Cardiol. 2022 Jan 18;79(2):e21-129.
https://www.jacc.org/doi/10.1016/j.jacc.2021.09.006
http://www.ncbi.nlm.nih.gov/pubmed/34895950?tool=bestpractice.com
For more comprehensive information on the acute management of these conditions, see Non-ST-elevation myocardial infarction and Unstable angina.
Revascularization for left main or multivessel disease
Recommendations on the mode of revascularization in patients with diabetes differ slightly from those for the general population, particularly for patients with diabetes and multivessel disease.[344]Neumann FJ, Sousa-Uva M, Ahlsson A, et al. 2018 ESC/EACTS guidelines on myocardial revascularization. Eur Heart J. 2019 Jan 7;40(2):87-165.
https://academic.oup.com/eurheartj/article/40/2/87/5079120
http://www.ncbi.nlm.nih.gov/pubmed/30165437?tool=bestpractice.com
Patients with diabetes and complex multivessel CAD should undergo a heart-team approach to revascularization, inclusive of an interventional cardiologist and a cardiac surgeon.[339]Writing Committee Members; Lawton JS, Tamis-Holland JE, Bangalore S, et al. 2021 ACC/AHA/SCAI guideline for coronary artery revascularization: a report of the American College of Cardiology/American Heart Association joint committee on clinical practice guidelines. J Am Coll Cardiol. 2022 Jan 18;79(2):e21-129.
https://www.jacc.org/doi/10.1016/j.jacc.2021.09.006
http://www.ncbi.nlm.nih.gov/pubmed/34895950?tool=bestpractice.com
CABG is generally recommended in preference to PCI to improve survival in patients with diabetes and multivessel CAD in whom mechanical revascularization is likely to improve survival.[339]Writing Committee Members; Lawton JS, Tamis-Holland JE, Bangalore S, et al. 2021 ACC/AHA/SCAI guideline for coronary artery revascularization: a report of the American College of Cardiology/American Heart Association joint committee on clinical practice guidelines. J Am Coll Cardiol. 2022 Jan 18;79(2):e21-129.
https://www.jacc.org/doi/10.1016/j.jacc.2021.09.006
http://www.ncbi.nlm.nih.gov/pubmed/34895950?tool=bestpractice.com
[345]Patel MR, Calhoon JH, Dehmer GJ, et al. ACC/AATS/AHA/ASE/ASNC/SCAI/SCCT/STS 2017 appropriate use criteria for coronary revascularization in patients with stable ischemic heart disease: a report of the American College of Cardiology Appropriate Use Criteria Task Force, American Association for Thoracic Surgery, American Heart Association, American Society of Echocardiography, American Society of Nuclear Cardiology, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2017 May 2;69(17):2212-41.
http://www.onlinejacc.org/content/69/17/2212
http://www.ncbi.nlm.nih.gov/pubmed/28291663?tool=bestpractice.com
[346]Farkouh ME, Domanski M, Dangas GD, et al; FREEDOM Follow-On Study Investigators. Long-term survival following multivessel revascularization in patients with diabetes: the FREEDOM follow-on study. J Am Coll Cardiol. 2019 Feb 19;73(6):629-38.
http://www.ncbi.nlm.nih.gov/pubmed/30428398?tool=bestpractice.com
This is particularly recommended if a left internal mammary artery to left anterior descending artery (LIMA-LAD) graft is used and the patient is a good surgical candidate. In patients with diabetes and multivessel CAD who are poor surgical candidates, meet the criteria for revascularization, and have anatomy that is amenable to PCI, PCI can be beneficial to improve ischemic outcomes.[339]Writing Committee Members; Lawton JS, Tamis-Holland JE, Bangalore S, et al. 2021 ACC/AHA/SCAI guideline for coronary artery revascularization: a report of the American College of Cardiology/American Heart Association joint committee on clinical practice guidelines. J Am Coll Cardiol. 2022 Jan 18;79(2):e21-129.
https://www.jacc.org/doi/10.1016/j.jacc.2021.09.006
http://www.ncbi.nlm.nih.gov/pubmed/34895950?tool=bestpractice.com
The survival benefit associated with CABG compared with PCI may be greater in patients with diabetes receiving insulin therapy than in those not receiving insulin therapy.[347]Wang R, Serruys PW, Gao C, et al. Ten-year all-cause death after percutaneous or surgical revascularization in diabetic patients with complex coronary artery disease. Eur Heart J. 2021 Dec 28;43(1):56-67.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8720143
http://www.ncbi.nlm.nih.gov/pubmed/34405232?tool=bestpractice.com
The 2021 ACC/AHA/Society for Cardiovascular Angiography and Interventions (SCAI) guidelines recommend CABG for left main disease.[339]Writing Committee Members; Lawton JS, Tamis-Holland JE, Bangalore S, et al. 2021 ACC/AHA/SCAI guideline for coronary artery revascularization: a report of the American College of Cardiology/American Heart Association joint committee on clinical practice guidelines. J Am Coll Cardiol. 2022 Jan 18;79(2):e21-129.
https://www.jacc.org/doi/10.1016/j.jacc.2021.09.006
http://www.ncbi.nlm.nih.gov/pubmed/34895950?tool=bestpractice.com
However, they recognize that PCI might be considered in patients with low- or intermediate-complexity CAD in the rest of the coronary anatomy.[339]Writing Committee Members; Lawton JS, Tamis-Holland JE, Bangalore S, et al. 2021 ACC/AHA/SCAI guideline for coronary artery revascularization: a report of the American College of Cardiology/American Heart Association joint committee on clinical practice guidelines. J Am Coll Cardiol. 2022 Jan 18;79(2):e21-129.
https://www.jacc.org/doi/10.1016/j.jacc.2021.09.006
http://www.ncbi.nlm.nih.gov/pubmed/34895950?tool=bestpractice.com
One trial (EXCEL; about 30% participants with diabetes) found that PCI was noninferior to CABG for the end point of MI, stroke, or mortality at 3 years.[348]Stone GW, Sabik JF, Serruys PW, et al. Everolimus-eluting stents or bypass surgery for left main coronary artery disease. N Engl J Med. 2016 Dec 8;375(23):2223-35.
http://www.ncbi.nlm.nih.gov/pubmed/27797291?tool=bestpractice.com
Mortality after CABG is higher in people with diabetes than in those without diabetes. Nevertheless, among people with diabetes, survival after indicated CABG is superior to survival after medical therapy or PCI.[339]Writing Committee Members; Lawton JS, Tamis-Holland JE, Bangalore S, et al. 2021 ACC/AHA/SCAI guideline for coronary artery revascularization: a report of the American College of Cardiology/American Heart Association joint committee on clinical practice guidelines. J Am Coll Cardiol. 2022 Jan 18;79(2):e21-129.
https://www.jacc.org/doi/10.1016/j.jacc.2021.09.006
http://www.ncbi.nlm.nih.gov/pubmed/34895950?tool=bestpractice.com
[349]Kapur A, Hall RJ, Malik IS, et al. Randomized comparison of percutaneous coronary intervention with coronary artery bypass grafting in diabetic patients: 1-year results of the CARDia (Coronary Artery Revascularization in Diabetes) trial. J Am Coll Cardiol. 2010 Feb 2;55(5):432-40.
http://www.ncbi.nlm.nih.gov/pubmed/20117456?tool=bestpractice.com
The pivotal trials are summarized as follows:
In patients with diabetes with left main coronary disease and/or 3-vessel CAD, the SYNTAX trial found that PCI resulted in higher rates of repeat revascularization and major adverse CV or cerebrovascular events compared with patients who underwent CABG.[350]Mohr FW, Morice MC, Kappetein AP, et al. Coronary artery bypass graft surgery versus percutaneous coronary intervention in patients with three-vessel disease and left main coronary disease: 5-year follow-up of the randomised, clinical SYNTAX trial. Lancet. 2013 Feb 23;381(9867):629-38.
http://www.ncbi.nlm.nih.gov/pubmed/23439102?tool=bestpractice.com
[351]Kappetein AP, Head SJ, Morice MC, et al; SYNTAX Investigators. Treatment of complex coronary artery disease in patients with diabetes: 5-year results comparing outcomes of bypass surgery and percutaneous coronary intervention in the SYNTAX trial. Eur J Cardiothorac Surg. 2013 May;43(5):1006-13.
https://academic.oup.com/ejcts/article/43/5/1006/441451
http://www.ncbi.nlm.nih.gov/pubmed/23413014?tool=bestpractice.com
However, there was no difference in rates of all-cause death, stroke, or MI. A long-term follow-up study of the SYNTAX cohort found the risk of mortality to be greater with PCI than with CABG at 5 years (19.6% vs. 13.3%), with the opposite observed between 5 and 10 years (20.8% vs. 24.4%).[347]Wang R, Serruys PW, Gao C, et al. Ten-year all-cause death after percutaneous or surgical revascularization in diabetic patients with complex coronary artery disease. Eur Heart J. 2021 Dec 28;43(1):56-67.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8720143
http://www.ncbi.nlm.nih.gov/pubmed/34405232?tool=bestpractice.com
The FREEDOM trial evaluated patients with diabetes with multivessel coronary disease (defined as stenosis of >70% in at least two epicardial vessels without left main disease) and found that CABG was superior to PCI in terms of reducing death and MI, but CABG patients had an increased rate of stroke.[352]Farkouh ME, Domanski M, Sleeper LA, et al; FREEDOM Trial Investigators. Strategies for multivessel revascularization in patients with diabetes. N Engl J Med. 2012 Dec 20;367(25):2375-84.
https://www.nejm.org/doi/full/10.1056/NEJMoa1211585
http://www.ncbi.nlm.nih.gov/pubmed/23121323?tool=bestpractice.com
In an extended follow-up study, the all-cause mortality rate was lower in the CABG group (18.7%) compared with the PCI group (23.7%).[346]Farkouh ME, Domanski M, Dangas GD, et al; FREEDOM Follow-On Study Investigators. Long-term survival following multivessel revascularization in patients with diabetes: the FREEDOM follow-on study. J Am Coll Cardiol. 2019 Feb 19;73(6):629-38.
http://www.ncbi.nlm.nih.gov/pubmed/30428398?tool=bestpractice.com
In the Bypass Angioplasty Revascularization Investigation (BARI) trial, when comparing CABG versus balloon-only PCI (percutaneous transluminal coronary balloon angioplasty, PTCA) for 3-vessel disease, 7-year survival was 76.4% for patients with diabetes treated with CABG compared with 55.7% for those treated with PCI.[353]Bypass Angioplasty Revascularization Investigators. Seven-year outcome in the Bypass Angioplasty Revascularization Investigation (BARI) by treatment and diabetic status. J Am Coll Cardiol. 2000 Apr;35(5):1122-9.
http://www.ncbi.nlm.nih.gov/pubmed/10758950?tool=bestpractice.com
At 10 years, patients with diabetes who were assigned to the CABG group had higher survival than the PTCA-assigned group (PTCA 45.5% vs. CABG 57.8%).[354]BARI Investigators. The final 10-year follow-up results from the BARI randomized trial. J Am Coll Cardiol. 2007 Apr 2;49(15):1600-6.
http://www.onlinejacc.org/content/49/15/1600
http://www.ncbi.nlm.nih.gov/pubmed/17433949?tool=bestpractice.com
This trial was performed prior to stents, aggressive statin therapy, and dual antiplatelet therapy.
Subgroup analyses of the Emory Angioplasty versus Surgery Trial (EAST) and the Coronary Angioplasty versus Bypass Revascularization (CABRI) trials showed that CABG tended to be associated with better long-term survival over balloon-only PCI for 3-vessel disease.[355]Flaherty JD, Davidson CJ. Diabetes and coronary revascularization. JAMA. 2005 Mar 23;293(12):1501-8.
https://jamanetwork.com/journals/jama/fullarticle/200563
http://www.ncbi.nlm.nih.gov/pubmed/15784875?tool=bestpractice.com
The Arterial Revascularization Trial (ART) compared CABG with PCI with bare-metal stents in patients with multivessel disease.[356]Berry C, Tardif JC, Bourassa MG. Coronary heart disease in patients with diabetes: part II: recent advances in coronary revascularization. J Am Coll Cardiol. 2007 Feb 13;49(6):643-56.
http://www.ncbi.nlm.nih.gov/pubmed/17291929?tool=bestpractice.com
Subgroup analysis of patients with diabetes showed 1-year event-free survival of 84.4% for CABG and 63.4% for PCI.[356]Berry C, Tardif JC, Bourassa MG. Coronary heart disease in patients with diabetes: part II: recent advances in coronary revascularization. J Am Coll Cardiol. 2007 Feb 13;49(6):643-56.
http://www.ncbi.nlm.nih.gov/pubmed/17291929?tool=bestpractice.com
Multiple studies comparing CABG versus PCI with drug-eluting stents have shown that diabetes is an independent predictor of target lesion restenosis.[355]Flaherty JD, Davidson CJ. Diabetes and coronary revascularization. JAMA. 2005 Mar 23;293(12):1501-8.
https://jamanetwork.com/journals/jama/fullarticle/200563
http://www.ncbi.nlm.nih.gov/pubmed/15784875?tool=bestpractice.com
[357]Banning AP, Westaby S, Morice MC, et al. Diabetic and nondiabetic patients with left main and/or 3-vessel coronary artery disease: comparison of outcomes with cardiac surgery and paclitaxel-eluting stents. J Am Coll Cardiol. 2010 Mar 16;55(11):1067-75.
http://www.ncbi.nlm.nih.gov/pubmed/20079596?tool=bestpractice.com
Drug-eluting stents appear to be superior to bare-metal stents in people with diabetes, with regard to major adverse cardiac events such as death, MI, or need for repeat revascularization.[358]Maresta A, Varani E, Balducci M, et al. Comparison of effectiveness and safety of sirolimus-eluting stents versus bare-metal stents in patients with diabetes mellitus (from the Italian Multicenter Randomized DESSERT Study). Am J Cardiol. 2008 Jun 1;101(11):1560-6.
http://www.ncbi.nlm.nih.gov/pubmed/18489933?tool=bestpractice.com
[359]Mahmud E, Bromberg-Marin G, Palakodeti V, et al. Clinical efficacy of drug-eluting stents in diabetic patients: a meta-analysis. J Am Coll Cardiol. 2008 Jun 24;51(25):2385-95.
http://www.ncbi.nlm.nih.gov/pubmed/18565394?tool=bestpractice.com
[360]Garg P, Normand SL, Silbaugh TS, et al. Drug-eluting or bare-metal stenting in patients with diabetes mellitus: results from the Massachusetts Data Analysis Center Registry. Circulation. 2008 Nov 25;118(22):2277-85.
http://www.ncbi.nlm.nih.gov/pubmed/19001019?tool=bestpractice.com
[361]Frye RL, August P, Brooks MM, et al; BARI 2D Study Group. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med. 2009 Jun 11;360(24):2503-15.
https://www.nejm.org/doi/full/10.1056/NEJMoa0805796
http://www.ncbi.nlm.nih.gov/pubmed/19502645?tool=bestpractice.com
[362]De Luca G, Dirksen MT, Spaulding C, et al; DESERT Cooperation. Meta-analysis comparing efficacy and safety of first generation drug-eluting stents to bare-metal stents in patients with diabetes mellitus undergoing primary percutaneous coronary intervention. Am J Cardiol. 2013 May 1;111(9):1295-304.
http://www.ncbi.nlm.nih.gov/pubmed/23490029?tool=bestpractice.com
The International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trials investigated the effects of an invasive approach (medical therapy plus revascularization) versus a conservative approach (medical therapy alone) in patients with chronic coronary disease.[363]Newman JD, Anthopolos R, Mancini GBJ, et al. Outcomes of participants with diabetes in the ISCHEMIA trials. Circulation. 2021 Oct 26;144(17):1380-95.
https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.121.054439
http://www.ncbi.nlm.nih.gov/pubmed/34521217?tool=bestpractice.com
Overall, no benefit was observed for invasive versus conservative management in patients with diabetes (43% of total cohort).[363]Newman JD, Anthopolos R, Mancini GBJ, et al. Outcomes of participants with diabetes in the ISCHEMIA trials. Circulation. 2021 Oct 26;144(17):1380-95.
https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.121.054439
http://www.ncbi.nlm.nih.gov/pubmed/34521217?tool=bestpractice.com
Medical management, with or without revascularization, for single-vessel disease
In stable patients with single-vessel disease and no recent ACS or left ventricular dysfunction, initial treatment is conservative and involves guideline-directed medical therapy for CAD. This may include antihypertensive agents, lipid-lowering agents, and antiplatelet therapy.[314]Virani SS, Newby LK, Arnold SV, et al. 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA guideline for the management of patients with chronic coronary disease: a report of the American Heart Association/American College of Cardiology Joint Committee on clinical practice guidelines. Circulation. 2023 Aug 29;148(9):e9-119.
https://www.ahajournals.org/doi/10.1161/CIR.0000000000001168
http://www.ncbi.nlm.nih.gov/pubmed/37471501?tool=bestpractice.com
When optimized, medical therapy has demonstrated similar outcomes to revascularization.[364]Boden WE, O'Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 2007 Apr 12;356(15):1503-16.
https://www.nejm.org/doi/10.1056/NEJMoa070829
http://www.ncbi.nlm.nih.gov/pubmed/17387127?tool=bestpractice.com
[365]Maron DJ, Hochman JS, Reynolds HR, et al. Initial invasive or conservative strategy for stable coronary disease. N Engl J Med. 2020 Apr 9;382(15):1395-407.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263833
http://www.ncbi.nlm.nih.gov/pubmed/32227755?tool=bestpractice.com
This approach needs patient-physician discussion to tailor therapy based on symptoms, response to therapy, available expertise, and patient’s preferences.
The usefulness of coronary revascularization in improving survival is uncertain in patients with single-vessel disease involving the proximal left anterior descending artery with normal left ventricular function.[339]Writing Committee Members; Lawton JS, Tamis-Holland JE, Bangalore S, et al. 2021 ACC/AHA/SCAI guideline for coronary artery revascularization: a report of the American College of Cardiology/American Heart Association joint committee on clinical practice guidelines. J Am Coll Cardiol. 2022 Jan 18;79(2):e21-129.
https://www.jacc.org/doi/10.1016/j.jacc.2021.09.006
http://www.ncbi.nlm.nih.gov/pubmed/34895950?tool=bestpractice.com
Revascularization may be considered after patient-physician discussion as well as heart-team discussion with respect to utility and timing.[339]Writing Committee Members; Lawton JS, Tamis-Holland JE, Bangalore S, et al. 2021 ACC/AHA/SCAI guideline for coronary artery revascularization: a report of the American College of Cardiology/American Heart Association joint committee on clinical practice guidelines. J Am Coll Cardiol. 2022 Jan 18;79(2):e21-129.
https://www.jacc.org/doi/10.1016/j.jacc.2021.09.006
http://www.ncbi.nlm.nih.gov/pubmed/34895950?tool=bestpractice.com
Coronary revascularization also has an important role in patients who are symptomatic with angina refractory to maximal medical therapy. If revascularization is indicated, and the anatomy is amenable to PCI, PCI is preferred over CABG for single-vessel CAD.[339]Writing Committee Members; Lawton JS, Tamis-Holland JE, Bangalore S, et al. 2021 ACC/AHA/SCAI guideline for coronary artery revascularization: a report of the American College of Cardiology/American Heart Association joint committee on clinical practice guidelines. J Am Coll Cardiol. 2022 Jan 18;79(2):e21-129.
https://www.jacc.org/doi/10.1016/j.jacc.2021.09.006
http://www.ncbi.nlm.nih.gov/pubmed/34895950?tool=bestpractice.com
[345]Patel MR, Calhoon JH, Dehmer GJ, et al. ACC/AATS/AHA/ASE/ASNC/SCAI/SCCT/STS 2017 appropriate use criteria for coronary revascularization in patients with stable ischemic heart disease: a report of the American College of Cardiology Appropriate Use Criteria Task Force, American Association for Thoracic Surgery, American Heart Association, American Society of Echocardiography, American Society of Nuclear Cardiology, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2017 May 2;69(17):2212-41.
http://www.onlinejacc.org/content/69/17/2212
http://www.ncbi.nlm.nih.gov/pubmed/28291663?tool=bestpractice.com
Considerations for patients with specific comorbidities
HF
HF is common in patients with diabetes, and in many patients can be the initial presentation of ASCVD.[6]Marx N, Federici M, Schütt K, et al. 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. Eur Heart J. 2023 Oct 14;44(39):4043-140.
https://academic.oup.com/eurheartj/article/44/39/4043/7238227
http://www.ncbi.nlm.nih.gov/pubmed/37622663?tool=bestpractice.com
[132]Pop-Busui R, Januzzi JL, Bruemmer D, et al. Heart failure: an underappreciated complication of diabetes – a consensus report of the American Diabetes Association. Diabetes Care. 2022 Jul 7;45(7):1670-90.
https://diabetesjournals.org/care/article/45/7/1670/147048/Heart-Failure-An-Underappreciated-Complication-of
http://www.ncbi.nlm.nih.gov/pubmed/35796765?tool=bestpractice.com
Patients with diabetes and HFrEF or HFpEF should receive HF therapy as per current HF guidelines.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
[153]Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association joint committee on clinical practice guidelines. Circulation. 2022 May 3;145(18):e895-1032.
https://www.ahajournals.org/doi/full/10.1161/CIR.0000000000001063
http://www.ncbi.nlm.nih.gov/pubmed/35363499?tool=bestpractice.com
[255]McDonagh TA, Metra M, Adamo M, et al. 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021 Sep 21;42(36):3599-726.
https://academic.oup.com/eurheartj/article/42/36/3599/6358045
Presence of HF in patients with type 2 diabetes influences choice of antihyperglycemic agent. SGLT2 inhibitors are recommended in all patients with HF and type 2 diabetes, as they reduce risk of HF-related hospitalization and mortality. Thiazolidinediones (e.g., pioglitazone) and saxagliptin (a DPP-4 inhibitor) have been associated with an increased risk of HF hospitalizations and are not recommended in patients with or at risk of HF.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
[153]Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association joint committee on clinical practice guidelines. Circulation. 2022 May 3;145(18):e895-1032.
https://www.ahajournals.org/doi/full/10.1161/CIR.0000000000001063
http://www.ncbi.nlm.nih.gov/pubmed/35363499?tool=bestpractice.com
[255]McDonagh TA, Metra M, Adamo M, et al. 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021 Sep 21;42(36):3599-726.
https://academic.oup.com/eurheartj/article/42/36/3599/6358045
Metformin, insulin, and sitagliptin and linagliptin (DPP-4 inhibitors) are considered neutral in terms of their effect on HF outcomes.[6]Marx N, Federici M, Schütt K, et al. 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. Eur Heart J. 2023 Oct 14;44(39):4043-140.
https://academic.oup.com/eurheartj/article/44/39/4043/7238227
http://www.ncbi.nlm.nih.gov/pubmed/37622663?tool=bestpractice.com
In patients with obesity and HFpEF, semaglutide (a GLP-1 receptor agonist) has been shown to reduce HF-related symptoms, improve exercise function, and result in greater weight loss compared with placebo.[366]Kosiborod MN, Abildstrøm SZ, Borlaug BA, et al. Semaglutide in patients with heart failure with preserved ejection fraction and obesity. N Engl J Med. 2023 Sep 21;389(12):1069-84.
https://www.doi.org/10.1056/NEJMoa2306963
http://www.ncbi.nlm.nih.gov/pubmed/37622681?tool=bestpractice.com
In patients with symptomatic HFpEF and obesity, a GLP-1 receptor agonist with demonstrated benefits for both glycemic management and reduction of HF-related symptoms is therefore recommended.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
Screening for HF in patients with diabetes is important for starting therapy early and optimizing prognosis. The ADA recommends annual screening of asymptomatic adults with diabetes for HF.[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
See Heart failure with reduced ejection fraction and Heart failure with preserved ejection fraction.
CKD
CKD is both a risk factor for CVD and a consequence of it. Worsening kidney function (reflected by declining glomerular filtration rate [GFR] or increasing albuminuria) is associated with progressively higher risk of coronary disease.[80]Sarnak MJ, Levey AS, Schoolwerth AC, et al. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Hypertension. 2003 Nov;42(5):1050-65.
https://www.doi.org/10.1161/01.HYP.0000102971.85504.7c
http://www.ncbi.nlm.nih.gov/pubmed/14604997?tool=bestpractice.com
Conversely, CVD (alongside diabetes) increases the risk of CKD progression and eventual kidney failure requiring dialysis or transplantation.[367]Mark PB, Carrero JJ, Matsushita K, et al. Major cardiovascular events and subsequent risk of kidney failure with replacement therapy: a CKD Prognosis Consortium study. Eur Heart J. 2023 Apr 1;44(13):1157-66.
https://academic.oup.com/eurheartj/article/44/13/1157/7000222
http://www.ncbi.nlm.nih.gov/pubmed/36691956?tool=bestpractice.com
Patients with diabetes should therefore be screened for CKD at least annually.[6]Marx N, Federici M, Schütt K, et al. 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. Eur Heart J. 2023 Oct 14;44(39):4043-140.
https://academic.oup.com/eurheartj/article/44/39/4043/7238227
http://www.ncbi.nlm.nih.gov/pubmed/37622663?tool=bestpractice.com
[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
Reducing the risk of both CV and kidney complications is central to management. Standard lifestyle and risk factor interventions remain essential (e.g., BP, lipid, glycemic, and weight control). Additionally, specific pharmacologic interventions are recommended:[6]Marx N, Federici M, Schütt K, et al. 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. Eur Heart J. 2023 Oct 14;44(39):4043-140.
https://academic.oup.com/eurheartj/article/44/39/4043/7238227
http://www.ncbi.nlm.nih.gov/pubmed/37622663?tool=bestpractice.com
[29]American Diabetes Association. Standards of care in diabetes - 2025. Diabetes Care. 2025 Jan 1;48(suppl 1):S14-352.
https://diabetesjournals.org/care/issue/48/Supplement_1
[368]Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group. KDIGO 2022 clinical practice guideline for diabetes management in chronic kidney disease. Kidney Int. 2022 Nov;102(5s):S1-27.
https://www.kidney-international.org/article/S0085-2538(22)00507-5/fulltext
[369]Bakris GL, Agarwal R, Anker SD, et al. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med. 2020 Dec 3;383(23):2219-29.
https://www.nejm.org/doi/10.1056/NEJMoa2025845
http://www.ncbi.nlm.nih.gov/pubmed/33264825?tool=bestpractice.com
[370]Pitt B, Filippatos G, Agarwal R, et al. Cardiovascular events with finerenone in kidney disease and type 2 diabetes. N Engl J Med. 2021 Dec 9;385(24):2252-63.
https://www.nejm.org/doi/10.1056/NEJMoa2110956
http://www.ncbi.nlm.nih.gov/pubmed/34449181?tool=bestpractice.com
Either an SGLT2 inhibitor or GLP-1 receptor agonist with demonstrated benefit in this population should be used to improve glycemic control, slow CKD progression, and reduce CV events. In advanced CKD (eGFR <30 mL/min/1.73 m²), a GLP-1 receptor agonist is preferred due to lower hypoglycemia risk and established CV benefit.
The ADA strongly recommends ACE inhibitor or angiotensin-II receptor antagonist therapy for the treatment of hypertension in patients with diabetes and CKD - particularly those with albuminuria (urinary albumin-to-creatinine ratio ≥30 mg/g) - to reduce the risk of CKD progression and CV events. Kidney Disease: Improving Global Outcomes (KDIGO) guidelines make the same recommendation, but also recommend considering one of these agents in patients with albuminuria and normal blood pressure.
For people with type 2 diabetes and CKD with albuminuria who are already on maximum tolerated doses of ACE inhibitors or angiotensin-II receptor antagonists, the addition of finerenone, a nonsteroidal mineralocorticoid receptor antagonist, is recommended. These patients are at increased risk of CV events and CKD progression, and finerenone has been shown to mitigate these risks in randomized trials.
In patients with diabetes, CKD, and stable moderate or severe CAD, either an intensive medical strategy or an initial invasive strategy may be considered.
Referral to a nephrologist should be considered.
See Diabetic kidney disease.