Approach

Patients with diabetes benefit from aggressive cardiovascular (CV) risk factor management.[161] 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] 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]

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][71][164][165][166][167] 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]

Recommendations for the management of CVD and risk reduction in patients with diabetes include:[29]​​[169]

  • 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]

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][171] The Mediterranean diet, Dietary Approaches to Stop Hypertension (DASH), vegetarian, and vegan diets have all demonstrated some efficacy in people with diabetes.[164][172][173][174][175] European guidelines recommend a Mediterranean or plant-based diet with high unsaturated fat content for lowering CV risk in people with diabetes.[6] 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][177]

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] 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]​ Both World Health Organization (WHO) and European guidelines emphasize that carbohydrate quality, rather than quantity, is key.[179][180]​ 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][180]​ Diets high in naturally occurring fiber have been shown to be protective against cardiometabolic disease and premature mortality.[179] 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][180]​ Fiber-enriched foods and fiber supplements can be considered when sufficient intake cannot be obtained from diet alone.[179]

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][181]

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][182][183] Saturated fat should comprise <10% of total energy intake and trans-fats <1%.[179][183] 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]

People with diabetes who have overweight or obesity should be supported with evidence-based nutritional support to achieve and maintain weight loss.[179] 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] 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]

Intermittent fasting or time-restricted eating as strategies for weight and glucose management have gained popularity.[185] 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]​ 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]​ People with diabetes who are on insulin and/or secretagogues should be medically monitored during the fasting period.[29]​​

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][186] 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] 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]

Physical activity

A sedentary lifestyle is a major risk factor for CVD.[68][69] Many individuals with type 2 diabetes do not meet the recommended exercise level per week.[29]​​[70]

Physical activity improves glycemic control, lipids, BP, insulin sensitivity, and markers of inflammation in type 2 diabetes.[47][71][167][188] Increased physical activity is associated with lower risk of CVD and reduced all-cause mortality in both type 1 and type 2 diabetes.[47][72][123][189]

At least 150 minutes per week of moderate- to vigorous-intensity aerobic physical activity is recommended for adults with diabetes.[6][29]​​​ The physical activity should be spread over at least 3 days per week, with no more than 2 consecutive days without exercise.[29]​ Shorter durations (minimum 75 minutes per week) of vigorous-intensity or interval training may be sufficient for more physically fit individuals.[29]​ In the absence of contraindications, resistance training 2 to 3 times per week on nonconsecutive days is also recommended.[6][29]​​​ The ADA recommends interrupting sedentary activity every 30 minutes with short bouts of physical activity.[29]​ Older adults may also benefit from flexibility and balance exercise 2 to 3 times per week.[29]​​

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]​ 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] 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]​​[190]

Smoking cessation

All patients with diabetes should be advised not to smoke or to quit smoking.[29]​ Smoking counseling and other forms of smoking cessation therapy should be incorporated into routine diabetes care.[29]​ 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][191] The ADA does not support e-cigarettes as an alternative to smoking or to facilitate smoking cessation.[29]​​

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]

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] This degree of weight reduction significantly improves glycemia, blood pressure, and lipids and may reduce the need for disease-specific drugs.[29]​ 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] 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]

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][29]​​[169]​ 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]​ 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][193]​ 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] With higher body weight reduction, there were greater reductions in HbA1c, triglycerides, waist circumference, and BP.[194] 

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]​​

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][195]

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] 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]

Ongoing monitoring of weight management goals is recommended.[29] 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] Sudden discontinuation of drugs like semaglutide and tirzepatide can lead to regaining up to two-thirds of the weight lost within one year.[196][197][198]​ 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]

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]​​

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]​​

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][199]​ It has also been shown to reduce microvascular complications, cancer risk, and all-cause mortality in people with obesity and type 2 diabetes.[29]​​[200][201][202]​ 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] 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]

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]​​

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]​ 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] Metabolic surgery is best done in a high-volume, specialized center to reduce the risk of perioperative and longer-term complications.[29]​ For more comprehensive information, see Obesity in adults.

Long-term glycemic control - general principles

Increasing severity of hyperglycemia correlates with increasing CV risk.[47][204] One meta-analysis found that antihyperglycemic therapies reduce major adverse cardiac events in an HbA1c-dependent manner.[205] 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][206][207][208][209] In contrast, intensive glycemic control appeared to have long-term beneficial effects on the risk of CVD in patients with type 1 diabetes.[210]

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] 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] 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] 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] 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]

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]​ 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]​ 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]​ 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]​​

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]​ 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]​​

Metformin is a commonly used first-line drug for type 2 diabetes due to its effectiveness, safety, and low cost.[29]​​ 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] 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]​​

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]​ 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] 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]​ 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]

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]​ 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] 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]​ 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] DPP-4 inhibitors, bromocriptine (a centrally acting dopamine agonist), alpha-glucosidase inhibitors, and bile acid sequestrants are considered weight neutral.[29]​​

  • Insulin secretagogues (such as sulfonylureas and meglitinides), thiazolidinediones, and insulin are often associated with weight gain.[29]​​

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]​​[153][219]

  • 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]​​[220]​​ 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] 

    • 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][216]​​​​

  • 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]​​[220][216] 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]

  • 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]​​

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][221][222][223][224][225][226][227][228][229]​ 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] 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]

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][232][233] 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][234][235][236][237][238][239][240][241]

  • The SGLT2 inhibitors with the strongest evidence for CVD risk reduction are dapagliflozin, canagliflozin, and empagliflozin.[121][220][242][243][244][245][246][247][248] Only empagliflozin and canagliflozin have shown reduction in major adverse cardiac events (MACE) in patients with type 2 diabetes.[249]

  • 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]

    • Similar findings were seen for canagliflozin in the CANVAS Program trial.[248][250]

    • 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] However, it decreased CV outcomes in a subanalysis of the primary trial confined to participants with prior MI.[251]

    • 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][253]

    • 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]

    • 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]

  • On the basis of these findings, SGLT2 inhibitors are recommended in the management of HF, regardless of diabetes status.[153][255][256]​​ SGLT inhibitors, particularly empagliflozin, have been shown to significantly reverse cardiac remodeling in patients with HF.[257][258][259][260][261]

  • 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]

  • 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]​​

  • 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]

  • 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] 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] 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] One large network meta-analysis estimated that treatment with SGLT2 inhibitors in 1000 patients for 5 years probably results in three additional amputations.[218] 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][268]​ 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] 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] 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]​ 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][271]​ 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]​ 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][271]​​ 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]​​[272]​​ 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]​​[273]

GLP-1 receptor agonists

  • Reduce the risk for all-cause mortality and MACE.[216][274] The GLP-1 receptor agonists with the strongest evidence for ASCVD risk reduction are injectable semaglutide, liraglutide, and dulaglutide.[220][275][276][277][278][279]

  • 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][218][280][281][282][283]

  • 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] It is the only GLP-1 receptor agonist that is available in both oral and injectable formulations.[276] 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] 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]

  • 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] 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]​ 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]​ Patients should also be counseled about the potential for ileus.[29]

  • An association with pancreatitis and pancreatic cancer has been reported in clinical trials, but causality has not been established.[220] One meta-analysis of 43 randomized controlled trials (RCTs) found no clear evidence for an increased risk of pancreatitis.[290]​ ​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] Nonetheless, GLP-1 receptor agonists should be used with caution in patients with a history of pancreatitis.[29]​​[288]

  • GLP-1 receptor agonists have been associated with increased risk of gallbladder and biliary diseases including cholelithiasis and cholecystitis.[288]

  • 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]

  • 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]

  • 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][292][293][294][295]

  • 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][297][298]​ 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]​ 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]

  • 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]​ 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][303][304]​ 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]​ 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]

Glycemic control during acute critical illness (CVD events or interventions)

Trials of tight glycemic control in critically ill patients have yielded mixed results.[306][307] ​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]​ 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] 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]

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]​ 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]​ More stringent goals may be appropriate for selected patients, as long as they can be achieved without significant hypoglycemia.[29]​ 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]​​

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][312][313]

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][314][315]​ 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] 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] 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]

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]

  • 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]

  • 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]

  • 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]

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]

There is a lack of high-quality evidence regarding optimal treatment of hypertension in people with diabetes.[60] However, guidelines recommend a BP treatment goal of <130/80 mmHg, providing this can be safely attained.[6][29]​​​​​[60][61]​ 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] 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]​​

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]​​

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]​​[61]​ 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]​​

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]​ ACE inhibitors, angiotensin-II receptor antagonists, dihydropyridine calcium-channel blockers, or thiazide diuretics are all options for initial antihypertensive therapy.[29]​​[60][61]

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]​​[60]

For those whose BP is >150/90 mmHg, a calcium-channel blocker or thiazide diuretic should be considered in addition at treatment initiation.[29]​ Combining ACE inhibitors and angiotensin-II receptor antagonists is not recommended because of an increased risk for acute kidney injury and hyperkalemia.[29]​​[318]​ ACE inhibitors have also shown increased risk for hypoglycemia in conjunction with insulin or insulin secretagogues (such as sulfonylureas or meglitinides).[319]

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] Another meta-analysis showed that in patients with diabetes and kidney disease, no antihypertensive regimen improved survival.[318]​​ However, ACE inhibitors and angiotensin-II receptor antagonists were effective in preventing end-stage renal disease.[318] Some antihyperglycemic agents have demonstrated modest BP-lowering effects in clinical trials, including SGLT2 inhibitors and GLP-1 receptor agonists.[321] Further studies are warranted to investigate the effects of these agents on BP as the primary outcome measure.[321]

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) Opens in new window

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]​ 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] Beta-blockers may mask symptoms of hypoglycemia and also have the potential to exacerbate hypoglycemic episodes, particularly when used concurrently with sulfonylureas.[29]​​[322][323]

Multiple drug therapy is often required to achieve antihypertensive targets.[29]​ If BP remains uncontrolled on monotherapy, add an agent from a different first-line class.[29]​ 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]​​[115]​ Referral to a hypertension specialist may also be necessary.[29]​​[115]

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] Regular checks should also be performed at subsequent routine appointments.[29]

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]​​

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] 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] 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]

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][29]​​[114]

Statins

Statins are the first-line drug for LDL-C lowering and cardioprotection.[29]​ 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] 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]​​[114]​​ 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]​​

Ezetimibe

If target LDL-C is not achieved with a statin alone, addition of ezetimibe can be considered.[29]​ Ezetimibe works by reducing cholesterol absorption from the ileum.[6] 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] 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] 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] 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]

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]​ 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][328]

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] 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]​ Bempedoic acid is also approved for this indication in Europe.[329] 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][331]

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]​ 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] 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] 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] A CV outcome trial using inclisiran in people with established ASCVD is ongoing.[333]

Summary of ADA recommendations for lipid-lowering pharmacotherapy in patients with diabetes with established ASCVD:[29]​​

  • 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] A CAC score ≥100 Agatston units or in the ≥75th age/sex/race percentile can reclassify CV risk as being increased.[76]

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]​​

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]​ It has been shown to modestly reduce MACE.[115][116]​ 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][335]

  • 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] 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]​ 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]

  • 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]

Antiplatelet therapy

  • Aspirin is recommended for secondary prevention in those with a history of ASCVD.[29]​​

  • Clopidogrel (a P2Y12 inhibitor) should be used in patients who have an aspirin allergy or intolerance.[29]​​

  • 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]​​[336]​ Rivaroxaban, when combined with aspirin, provides complementary antithrombotic effects and may also improve endothelial function.[337]

  • 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]​ Evidence supports use of either ticagrelor or clopidogrel if no PCI was performed, and clopidogrel, ticagrelor, or prasugrel if PCI was performed.[29]​​[339]​ Generally, prasugrel and ticagrelor have better efficacy in patients with diabetes and are preferred to clopidogrel for patients who undergo PCI.[336][339]

  • Short-term dual antiplatelet therapy is also recommended after high-risk transient ischemic attack (TIA) and minor stroke.[340]

  • Extending dual antiplatelet therapy beyond 1 year may reduce long-term risk of recurrent atherosclerotic events.[336] 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]​ 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]

  • 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]

ST-elevation myocardial infarction (STEMI)

For people with STEMI and ischemic symptoms for <12 hours, primary PCI is recommended to improve survival.[339] 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] An analysis of data from 11 clinical trials compared PCI with fibrinolytic therapy in 2725 patients with STEMI, including 367 patients with diabetes.[342] 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] 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]

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]​ 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]

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]

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] 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]

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] 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]

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][345][346] 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] 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]

The 2021 ACC/AHA/Society for Cardiovascular Angiography and Interventions (SCAI) guidelines recommend CABG for left main disease.[339] However, they recognize that PCI might be considered in patients with low- or intermediate-complexity CAD in the rest of the coronary anatomy.[339] 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] 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][349]

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][351] 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]

  • 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] 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]

  • 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] 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] 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]

  • The Arterial Revascularization Trial (ART) compared CABG with PCI with bare-metal stents in patients with multivessel disease.[356] Subgroup analysis of patients with diabetes showed 1-year event-free survival of 84.4% for CABG and 63.4% for PCI.[356] Multiple studies comparing CABG versus PCI with drug-eluting stents have shown that diabetes is an independent predictor of target lesion restenosis.[355][357] 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][359][360][361][362]

  • 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] Overall, no benefit was observed for invasive versus conservative management in patients with diabetes (43% of total cohort).[363]

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]​ When optimized, medical therapy has demonstrated similar outcomes to revascularization.[364][365] 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] Revascularization may be considered after patient-physician discussion as well as heart-team discussion with respect to utility and timing.[339]

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][345]

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][132]

  • Patients with diabetes and HFrEF or HFpEF should receive HF therapy as per current HF guidelines.[29]​​[153][255]

  • 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][153][255]​​​ Metformin, insulin, and sitagliptin and linagliptin (DPP-4 inhibitors) are considered neutral in terms of their effect on HF outcomes.[6] 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] 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]

  • 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]​​

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] Conversely, CVD (alongside diabetes) increases the risk of CKD progression and eventual kidney failure requiring dialysis or transplantation.[367] Patients with diabetes should therefore be screened for CKD at least annually.[6][29]​​​

  • 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][29]​​​​[368][369][370]

    • 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.

    • Combination therapy with a GLP-1 receptor agonist and an SGLT2 inhibitor may be appropriate for some patients to provide additive risk reduction (e.g., if HbA1c remains above target while on one agent).

    • 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.

    • Low-dose aspirin is recommended in patients with diabetes, CKD, and ASCVD.

  • 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. 

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