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Diabetes Mellitus Type 2Published by: Domus Medica | SSMGLast published: 2017Diabète sucré de type 2Published by: SSMG | Domus MedicaLast published: 2017Up to 34% of people with diabetes will develop a diabetic foot ulcer, and at least half of these wounds will develop some form of infection, increasing the risk for hospitalization and amputation.[434]
Incidence of lower extremity amputation (LEA) is between 2.5 and 4 per 1000 people with diabetes per year, with significant geographic variation in LEA rates within countries.[435] Incidence rates of major LEA, defined as loss of lower limb through or above the ankle, are declining in patients with diabetes; however, there is some evidence that minor LEA (loss of lower limb below the level of the ankle) incidence rates are increasing, with about half being toe or metatarsal amputations.[28]
Risk is aggravated by neuropathy and by peripheral vascular disease, and can be reduced by smoking cessation; aggressive management of glucose, blood pressure, and lipids; use of customized footwear in patients with known neuropathy or foot deformity; and prompt and aggressive management of lower extremity infections.
In people with type 2 diabetes, even those with normal or above average bone mineral density, hip fracture risk is increased by 1.79 times, and risk throughout life is 40% to 70% higher than in individuals without diabetes.[2] According to one meta-analysis, people with type 2 diabetes have a 35% higher incidence of vertebral fractures, causing increased risk of mortality (HR 2.11, 95% confidence interval [CI] 1.72 to 2.59).[466] Fracture risk is also increased in the upper limbs and ankle.[2]
Glycemic management significantly impacts fracture risk.[2] One meta-analysis found an 8% increased fracture risk per 1% rise in hemoglobin A1c level (RR 1.08, 95% CI 1.03 to 1.14).[467] Longer disease duration further elevates fracture risk; data indicate that individuals who have had type 2 diabetes for >10 years face significantly higher fracture risks, which are largely attributed to ensuing microvascular and macrovascular damage affecting the skeleton.[468] Additionally, high fracture risk is seen in people with cardiovascular disease, nephropathy, retinopathy, neuropathy, poor physical function, and frequent falls.[2]
Certain glucose-lowering drugs also factor into fracture risk. Studies have reported increased fracture incidence in women using thiazolidinediones, with the risk doubling with 1-2 years of thiazolidinedione use compared with placebo or other glucose-lowering drugs (HR 2.23, 95% CI 1.65 to 3.01).[287][469] Reduced risk is reported in women who discontinued thiazolidendiones for 1-2 years (HR 0.57, 95% CI 0.35 to 0.92) or >2 years (HR 0.42, 95% CI 0.24 to 0.74) compared with current users.[470] Individuals with type 2 diabetes on insulin (RR 1.49, 95% CI 1.29 to 1.73) or sulfonylurea (RR 1.30, 95% CI 1.18 to 1.43) treatment also exhibit a heightened fracture risk.[471]
Fracture risk should be assessed as part of routine care of people with type 2 diabetes.[2] Bone mineral density should be monitored by dual-energy x-ray absorptiometry scan in all older adults (age ≥65 years) and in younger individuals (age >50 years) with bone or diabetes-related risk factors, such as insulin use or diabetes duration >10 years.[2] Reassessment is recommended every 2-3 years, depending on the screening evaluation and the presence of additional risk factors.[2]
Care plans for type 2 diabetes treatment should consider individual fracture risk and the potential effect of drugs on bone metabolism. In particular, drugs other than thiazolidinediones are advisable for postmenopausal women or older men with type 2 diabetes due to their safer bone health profiles.[2] Aggressive therapeutic approaches should be avoided in those who are frail and in older adults to prevent hypoglycemic events and falls.[2] People with diabetes should be offered advice on their intake of calcium and vitamin D to ensure it meets the recommended daily allowance for their age, either through their diet or supplemental means.[2] Antiresorptive drugs and osteoanabolic agents should be recommended for older adults with diabetes who are at higher risk of fracture, including those with low bone mineral density with a T-score ≤−2.0, history of fragility fracture, or elevated Fracture Risk Assessment Tool score (≥3% for hip fracture or ≥20% for major osteoporotic fracture).[2]
Chronic kidney disease (CKD) occurs in about 40% of patients with type 2 diabetes over time. Prevalence of end-stage renal disease is about 1% in those with type 2 diabetes (cross-sectional data).[410] CKD is driven by uncontrolled blood pressure and glucose, and increases the risk of cardiovascular disease at least fourfold. Diabetic kidney disease is usually a clinical diagnosis made based on the presence of albuminuria and/or reduced estimated glomerular filtration rate (eGFR) <60 mL/1.73m²/minute in the absence of signs or symptoms of other primary causes of kidney damage.[2] Either of these findings should prompt increased efforts to aggressively manage systolic blood pressure, avoid nonsteroidal anti-inflammatory drugs (NSAIDs), and consider use of antihyperglycemic drugs with low risk of hypoglycemia and pronounced renal benefits (e.g., sodium-glucose cotransporter-2 [SGLT2] inhibitors and glucagon-like peptide-1 [GLP-1] receptor agonists).[230][429]
Also important are use of an ACE inhibitor or angiotensin-II receptor antagonist, and optimization of glucose control.[2] Patients with type 2 diabetes and CKD with persistent albuminuria (≥30 mg/g [≥3 mg/mmol]) despite maximum tolerated doses of an ACE inhibitor or angiotensin-II receptor antagonist should be started on finerenone, a nonsteroidal mineralocorticoid receptor antagonist that has been shown to reduce CKD progression and cardiovascular events.[2]
Refer to a nephrologist all patients with continuously increasing urinary albumin levels and/or continuously decreasing eGFR, as well as those with eGFR <30 mL/minute/1.73m².[2]
Renal failure predisposes patients to anemia and hypoglycemia; insulin doses may therefore need to be reduced.
In the US, approximately 25% of patients with type 2 diabetes have retinopathy at diagnosis, presumably as a consequence of unrecognized disease.[430] In a global study, prevalence of diabetic retinopathy in newly diagnosed type 2 diabetes varied from 1.5% to 31%, with higher prevalence observed in developing countries.[431] Risk of vision loss is increased by poor blood pressure and glucose control, and by failure to regularly screen for retinopathy, macular degeneration, glaucoma, and cataracts.[432][433] One study found that patients with type 2 diabetes who took metformin for over 10 years were less likely to develop age-related macular degeneration (AMD) and early AMD compared with nonusers. In addition, metformin significantly reduces AMD risk when the cumulative duration is >5 years.[184] The risk of all of these eye conditions is increased in diabetes.
Hyperglycemia and hypoglycemia have both been associated with higher risk of cognitive dysfunction.[35] Type 2 diabetes has been shown to be associated with marked cognitive deficits, particularly in executive functioning and processing speed, as well as structural changes, particularly gray matter atrophy.[450] People with type 2 diabetes have a dementia risk 1.5 to 2.5 times greater than individuals without type 2 diabetes.[451][452][453] Findings from the Swedish National Diabetes Register found that the association of type 2 diabetes with dementia varies by dementia subtype. The strongest association is observed for vascular dementia, but patients with type 2 diabetes with poor glycemic control have an increased risk of developing both vascular and nonvascular dementia.[454] A large UK-based cohort study found that higher or unstable HbA1c levels and the presence of diabetic complications in patients with type 2 diabetes were associated with increased dementia risk.[455]
CVD and CVD-associated mortality is declining in patients with diabetes, particularly in high-income countries, coinciding with markedly increased use of prophylactic cardiovascular (CV) drugs.[28][402] However, CVD is still the leading cause of death in people with diabetes.[403] Mortality from myocardial infarction is about 1.5- to 2-fold greater in people with diabetes than in those without diabetes.[412]
To reduce CV risk, blood pressure, lipids, and tobacco use should be adequately managed. Use of statins, ACE inhibitors, metformin, aspirin, sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, ezetimibe, and bempedoic acid may reduce CV mortality or all-cause mortality in selected patients with type 2 diabetes.[2][85] In the ACCORD and ADVANCE randomized trials, near-normal glucose control failed to decrease CV mortality or all-cause mortality in type 2 diabetes, and in one of those studies, increased all-cause mortality. However, ACCORD and ADVANCE did not use the SGLT2 or GLP-1 classes of drugs, or PCSK9 inhibitors. Many studies suggest that HbA1c ≥8% (≥64 mmol/mol) increases the risk of major CV events.[21][168]
Increased fatigability may be an early warning sign of progressive CVD; clinicians should have a low threshold for cardiac evaluation of any symptoms that are potentially cardiac-related in patients with type 2 diabetes.
Diabetes is a risk factor for HF, with poor glycemic control associated with greater risk for the development of HF and worsening of clinical outcomes for patients with HF and diabetes.[413] HF occurs in up to 22% of patients with diabetes.[414] HF in type 2 diabetes is often related to uncontrolled hypertension or ischemic coronary disease, but may also occur as a microvascular complication of diabetes.[414] HF may be the first presentation of cardiovascular disease in many people with diabetes.[414]
The American Diabetes Association recommends that measurement of B-type natriuretic peptide (BNP) or N-terminal prohormone B-type natriuretic peptide (NT-proBNP) should be considered on at least a yearly basis to screen asymptomatic adults with diabetes for HF.[2] If abnormal natriuretic peptide levels are detected, echocardiography is recommended.[2] Identification, risk stratification, and early treatment of risk factors in people with diabetes and asymptomatic stages of HF reduce the risk for progression to symptomatic HF.[2]
Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been shown to significantly reduce the risk of hospitalization with HF in individuals with a history of HF both with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF), and should be considered as an adjunct to therapy in individuals with type 2 diabetes and a history of HF.[191][415]
Beyond therapy with SGLT2 inhibitors, optimized therapy for HFrEF requires management with ACE inhibitor/angiotensin-II receptor antagonists, beta-blockers, and aldosterone antagonists, often with additional management with diuretics and other drugs.
In patients with symptomatic HFpEF and obesity, a glucagon-like peptide-1 receptor agonist with demonstrated benefits for both glycemic management and reduction of HF-related symptoms is recommended.[2]
It is important to rule out underlying causes such as myocardial infarction, atrial fibrillation, thyroid disorders, anemia, or structural heart disease.
Related to uncontrolled blood pressure, glucose, and lipids. Lifetime risk is higher in women than in men with diabetes.[416]
Prompt hospitalization and neurologic evaluation, with possible emergency use of tissue plasminogen activator or other therapeutic strategies, may minimize damage and maximize potential for recovery of function.
Diabetes is a risk factor for development and progression of PAD. The risk is proportional to the severity and duration of diabetes. The UK Prospective Diabetes Study Group showed that each 1% increase in hemoglobin A1c is associated with a 28% increased risk of incident PAD and a 28% increased risk of death, independent of other variables, such as blood pressure, serum cholesterol, age, or smoking status.[19][166] Thus, aggressive control of hyperglycemia is essential to reduce PAD risk and prevent disease progression.
Hyperglycemia compromises defense against bacterial infections by several mechanisms including impaired phagocytosis.
As with many other infections, patients with type 2 diabetes are at higher risk for severe illness from COVID-19.[417] They are more likely to need intensive care and mechanical ventilation if they develop COVID-19 compared with patients who do not have diabetes, and have a higher case fatality rate and increased odds of in-hospital death with COVID-19.[418][419][420][421] Poor glycemic control, hypertension, previous stroke, previous heart failure, renal impairment, cancer, body mass index <20 kg/m² or ≥40 kg/m², male sex, older age, nonwhite ethnicity, and socioeconomic deprivation are associated with increased mortality from COVID-19.[420][422][423] See Coronavirus disease 2019 (COVID-19) (Management).
Normalization of blood glucose reduces the risk of infections, especially cystitis, cellulitis, and pneumonia. Immunization reduces the risk of serious pneumococcal, Haemophilus influenzae, COVID-19, and influenza infections.
Aggressive infection-specific therapy and supportive therapy including adequate glucose control are key to successful treatment.
Type 2 diabetes is associated with periodontal disease, but causality is not established.[424] In one large epidemiologic survey, periodontal disease was an independent predictor of incident diabetes.[424] Bidirectional risk has been postulated.[425]
Control of periodontal disease and hyperglycemia are mutually beneficial. Routine preventive dental care is important for people with type 2 diabetes, who should be referred for a dental exam at least once per year.[2][424] The American Diabetes Association recommends that dental health professionals should be included in the diabetes care team, and that early detection of oral health problems by clinicians may be helpful to promote prompt referral to dental care and mitigate the expensive and extensive procedures needed to treat advanced oral disease.[2] Clinical assessment of people with diabetes should include a dental history, and dental professionals should be informed about key aspects of the person’s health and diabetes treatment plan, including glycemic goals, drugs, and comorbid conditions. It is important for dental professionals to know when people with diabetes have high HbA1c levels, as this population may have lower oral healing capacity.[2]
Coordination between dental professionals and the diabetes care team is especially important for people treated with insulin, who are at risk of hypoglycemia during dental procedures, especially if fasting.[2] The risk of hypoglycemia can be mitigated by coordination between the dentist and treating clinician prior to the procedure to make a hypoglycemia prevention plan, which may include drug adjustment, blood glucose monitoring before and during the procedure, and treatment of hypoglycemia if appropriate.[2] Dental professionals caring for people with diabetes should have access to blood glucose monitors during procedures as well as carbohydrates and glucagon to treat any hypoglycemia that occurs.[2]
Related to treatment with insulin and/or insulin secretagogues (sulfonylureas or meglitinides), alone or in combination with other drugs.[2]
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Can also be a complication of metabolic surgery.[426]
A glucose alert value (or level 1 hypoglycemia) is defined as <70 mg/dL (<3.9 mmol/L), requiring treatment with fast-acting carbohydrate and dose adjustment of glucose-lowering therapy.[2] Level 2 hypoglycemia is defined as <54 mg/dL (<3.0 mmol/L), indicating serious, clinically important hypoglycemia.[2] Hypoglycemia is usually associated with warning signs, such as rapid heartbeat, perspiration, shakiness, anxiety, confusion, and hunger.[2] Hypoglycemia unawareness (absence of symptoms during hypoglycemia) and severe (level 3) hypoglycemia, defined as a blood sugar so low that it affects mental and/or physical status and assistance from another person or medical personnel is required to treat it, occurs in 1% to 3% of type 2 diabetes patients per year.[2] Hypoglycemic unawareness can occur due to recurrent hypoglycemic episodes and in turn increases risk of future episodes as it is harder for individuals to recognize and prevent them.[133] Continuous glucose monitoring is preferred over self-monitoring of blood glucose in patients with type 2 diabetes who have, or are at risk of, recurrent hypoglycemia, including those with hypoglycemia unawareness.[2]
Patients who experience severe hypoglycemia have increased 5-year mortality and are at higher risk of further hypoglycemic events.[133] Prolonged severe episodes can result in significant adverse effects and can even be fatal.[133] Older people and those with comorbid heart disease, heart failure, chronic kidney disease, hepatic dysfunction or depression are at substantially increased risk for severe hypoglycemia.[35][133][427] Hypoglycemia is associated with reduced quality of life, increased hospital attendance, and can result in reduced compliance with treatment (with resultant uncontrolled glycemia and higher risk of diabetes sequelae).[133]
Patients should be counseled on the recognition, prevention, and treatment of hypoglycemia and should carry with them glucose tablets or a comparable 15-20 g fast-acting carbohydrate product.[2]
When glycemic goals or adherence to treatment plan are difficult to achieve, the presence of depression should be considered. Screening with a validated tool such as the Patient Health Questionnaire (PHQ)-9 may help with identification and diagnosis. The cross-sectional prevalence of depression is 10% to 25% in people with diabetes.[439] Adults with type 2 diabetes diagnosed before age 40 years have excess hospitalizations across their lifespan, which includes a large burden of mental illness in young adulthood.[440] If left untreated, depression can have a major detrimental impact on both physical and mental wellbeing, including cognitive function and self-management of diabetes. Moreover, people with type 2 diabetes and depression are at increased risk of cardiovascular mortality and morbidity.[174]
The American Diabetes Association recommends assessment for symptoms of depression and other mental health comorbidities at diagnosis and at periodic intervals thereafter.[2] Timely recognition and treatment, either in the form of psychotherapy, group therapy, lifestyle intervention, or pharmacotherapy, are crucial to reducing the growing burden of depression in people with type 2 diabetes.[174] Ideally, qualified mental health professionals with specialized training and experience in diabetes should be integrated with or provide collaborative care as part of diabetes care teams.[2]
There exists significant overlap between depression and diabetes distress, a common psychological disorder related to the burden of managing diabetes.[2] One large systematic review and meta-analysis found a prevalence of 36% for diabetes distress, with the disorder more common among women than men.[441] Interventions that enhance self-management can significantly reduce diabetes distress.[134]
OSA is common among adults with overweight and obesity, and has been associated with insulin resistance and altered glucose metabolism. Nearly 50% of people with type 2 diabetes have OSA.[442]
One meta-analysis found that continuous positive airway pressure (CPAP) therapy significantly improved hemoglobin A1c levels in patients with type 2 diabetes and OSA. The amount of improvement was dependent on the hours of usage of CPAP; thus, the authors concluded that optimal concordance with CPAP should be a primary goal in these patients.[443] Further studies are needed to assess the effect of CPAP on glycemic control, however, as results have varied.[444][445][446]
The SURMOUNT-OSA trial showed that in patients with obesity and moderate-to-severe OSA treated with or without CPAP therapy, tirzepatide was associated with a significant improvement in patients’ apnea-hypopnea index (AHI; a measure of sleep apnea severity) compared with placebo.[447] There was also a significant improvement in secondary outcomes including blood pressure, weight, C-reactive protein levels, and patient-reported symptoms. Similarly, liraglutide has shown significant improvement in the AHI.[442]
Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been shown to reduce the incidence of OSA.[448][449] As weight loss with SGLT2 inhibitors is only modest, it is thought that other factors, including decrease in cardiac preload and beneficial effects on respiratory dynamics, might also be responsible.[174]
The American Diabetes Association recommends that assessment of sleep pattern and duration should be considered as part of a comprehensive approach to lifestyle and glycemic control.[2]
Prepregnancy diabetes is associated with preeclampsia, preterm birth, and intrauterine fetal demise.[56] Optimal control of diabetes before and during pregnancy is associated with lower risk of adverse maternal and neonatal outcomes. Low-dose aspirin reduces the risk and severity of preeclampsia for individuals with type 2 diabetes.[56]
Diabetes and insulin resistance are important risk factors for the development and progression of MASLD (previously known as nonalcoholic fatty liver disease). Among adults with type 2 diabetes, it is estimated that the prevalence of MASLD exceeds 70%.[2] Metabolic dysfunction-associated steatohepatitis (MASH; previously known as nonalcoholic steatohepatitis) is the more severe form of MASLD, defined histologically by the presence of lobular inflammation and hepatocyte ballooning.[456] The American Diabetes Association (ADA) recommends screening all patients with type 2 diabetes (or prediabetes) for clinically significant fibrosis (defined as moderate fibrosis to cirrhosis) secondary to MASLD using a calculated fibrosis-4 (FIB-4) index (derived from age, alanine aminotransferase, aspartate aminotransferase, and platelet count).[2] Patients with a FIB-4 score ≥1.3 should have additional risk stratification by liver stiffness measurement with transient elastography, or by measurement of enhanced liver fibrosis (ELF), a blood biomarker.[2] Those at higher risk for significant liver fibrosis (i.e., as indicated by FIB-4, liver stiffness measurement, or ELF) should be referred to a gastroenterologist or hepatologist for further evaluation and management.[2]
For patients with type 2 diabetes or prediabetes and MASLD, lifestyle changes, particularly weight loss, are crucial and should be facilitated through structured nutrition and physical activity programs, ideally within an interprofessional care model.[2] In addition, optimizing the pharmacologic management of hyperglycemia and obesity in these patients could serve the dual purpose of addressing these comorbidities while simultaneously treating the liver disease.[2] In phase 2 trials, pioglitazone (a thiazolidinedione) and some glucagon-like peptide-1 (GLP-1) receptor agonists and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonists have been shown to be potentially effective in treating MASH and slowing fibrosis progression.[457][458][459][460][461] They may also reduce the risk of cardiovascular disease, the leading cause of death in people with type 2 diabetes and MASLD.[2] No glucose-lowering or weight management drug is currently approved in the US for the treatment of MASH. However, based on the evidence available, the ADA has issued a recommendation to choose pioglitazone, a GLP-1 receptor agonist, or a dual GIP/GLP-1 receptor agonist for glycemic management in patients with type 2 diabetes and biopsy-proven MASH or those at high risk for liver fibrosis based on noninvasive tests.[2] Due to their additional benefit of weight loss, GLP-1 receptor agonists or dual GIP/GLP-1 receptor agonists should be prioritized in patients who also have overweight or obesity.[2] Combination therapy with pioglitazone plus a GLP-1 receptor agonist or dual GLP-1/GIP receptor agonist can also be considered.[2] Use of other glucose-lowering therapies may be continued as clinically indicated, but these therapies lack evidence of benefit in MASH.[2] Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been shown to reduce hepatic steatosis, but their impact on liver histology has not fully been established.[214][215][462][463][464][465] Insulin is the preferred agent for the treatment of hyperglycemia in patients with decompensated cirrhosis.[2] Metabolic surgery may be considered in appropriate candidates as an option for treating MASH and improving cardiovascular outcomes.[2]
Resmetirom, a thyroid hormone receptor-beta agonist, is approved in the US for adults with MASLD with moderate (F2) or advanced (F3) liver fibrosis (diagnosed by liver histology or a validated imaging- or blood-based test).[2] Due to the complexities of patient selection, cost, and monitoring, resmetirom therapy requires individualization and should be initiated by a hepatologist or gastroenterologist experienced in managing MASH within a multidisciplinary team.[2]
Around one third of male patients with type 2 diabetes and/or obesity have low levels of testosterone.[73] Mean levels of testosterone are lower in men with diabetes compared with age-matched controls without diabetes. The relationship between low testosterone levels and type 2 diabetes is not completely understood and is thought to be bidirectional: low testosterone is associated with an increased risk of developing obesity and/or type 2 diabetes, and type 2 diabetes and/or obesity may lead to secondary hypogonadism.[74] Use of testosterone replacement therapy is an area of active research; studies have shown that long-term testosterone replacement therapy in patients with type 2 diabetes and hypogonadism can result in sustained remission of diabetes.[75]
The American Diabetes Association recommends checking a morning serum testosterone level in men with diabetes who have symptoms or signs of hypogonadism (e.g., decreased libido or activity or erectile dysfunction).[2]
More commonly associated with type 1 diabetes; however, can occur in type 2 diabetes and a less common type of diabetes known as ketosis-prone diabetes. Infection and poor adherence to glucose-lowering drugs are the most common reasons for developing DKA, but no precipitating factors may be apparent.[428]
Criteria for diagnosis of DKA are the same, regardless of type of diabetes, and it is potentially fatal if not properly treated.
Hydration, parenteral insulin therapy, intensive monitoring and careful management of electrolyte imbalances and acidosis are important for successful therapy.
Occurs most commonly in older people with type 2 diabetes with a precipitating infection or acute illness (e.g., myocardial infarction, cerebrovascular accident) and usually evolves insidiously over days to weeks.[3] Certain drugs, particularly antipsychotic agents, may precipitate hyperosmolar hyperglycemic state.[105]
Characterized by severe hyperglycemia, hyperosmolality, and volume depletion, in the absence of severe ketoacidosis. Delayed recognition of hyperglycemic symptoms may lead to severe dehydration and progressive decline in mental status.[105]
Hydration, insulin therapy, and careful clinical and laboratory monitoring are the basis of successful therapy.
Diabetic peripheral neuropathy is the most common chronic complication of diabetes, characterized by the presence of peripheral nerve dysfunction, diagnosed after the exclusion of other causes.[436] Pain is the outstanding complaint in most patients, but many patients are completely asymptomatic.
Manifestations of autonomic neuropathy may include erectile dysfunction, diarrhea, gastroparesis, or orthostatic hypotension.
The relationship between glycemic control and the progression of peripheral or autonomic neuropathy in type 2 diabetes is less clear compared with type 1 diabetes. However, some studies in type 2 diabetes have demonstrated that improved glycemic management may modestly slow the progression of neuropathy, albeit without evidence of neuronal recovery, and indicate that specific glucose-lowering strategies may exert different effects.[437][438]
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