Diabetes Mellitus Type 2 in Adults

Background

• Diabetes mellitus type 2 is a common endocrine disorder characterized by variable degrees of insulin resistance and deficiency, resulting in hyperglycemia.
• Potential complications of diabetes mellitus include cardiovascular disease, neuropathy, nephropathy, retinopathy, and increased mortality.
• It is often identified through routine screening beginning in middle age, or through targeted screening of adults of any age with overweight or obesity and with risk factors such as metabolic syndrome, polycystic ovary syndrome, a history of gestational diabetes, or other concerning familial, clinical, or demographic characteristics.

Evaluation

• Type 2 diabetes is frequently asymptomatic, but may present with symptoms typical of hyperglycemia, such as polyuria, polydipsia, and polyphagia.
• Perform blood testing to diagnose diabetes (Strong recommendation).
  • Diagnostic criteria for diabetes is any of:
    • random plasma glucose ≥ 200 mg/dL (11.1 mmol/L) with symptoms of hyperglycemia (such as polyuria or polydipsia) or hyperglycemic crisis
    • no unequivocal hyperglycemia, but 2 abnormal test results from either 2 separate test samples or same sample, including
      • fasting plasma glucose ≥ 126 mg/dL (7 mmol/L) (no caloric intake for ≥ 8 hours)
      • 2-hour plasma glucose ≥ 200 mg/dL (11.1 mmol/L) during 75 g oral glucose tolerance test (OGTT)
      • HbA1c ≥ 6.5% (48 mmol/mol) (HbA1c may not be accurate for diagnosis with pregnancy, hemoglobinopathy, certain anemias, or abnormal erythrocyte loss or replacement)
• Assess HbA1c (or other glycemic measurement) to determine glycemic control.
  • For patients who have stable glycemic control and who are meeting treatment goals, consider testing at least 2 times per year (Weak recommendation).
  • For patients not meeting treatment goals or if therapy changes, consider testing at least every 3 months (quarterly) and as needed (Weak recommendation).
• Additional testing for diabetic complications
  • In adults < 40 years old who are not taking statins or other lipid-lowering therapy, consider measuring lipid levels at time of diabetes diagnosis, at initial medical evaluation, and at 5-year intervals, or more frequently if indicated (Weak recommendation).
  • Assess liver transaminases (alanine aminotransferase and aspartate aminotransferase) at diagnosis and annually thereafter to assess for nonalcoholic fatty liver disease (Strong recommendation).
  • Assess urinary albumin (for example, spot urinary albumin-to-creatinine ratio) and estimated glomerular filtration rate (GFR) at least annually (calculated from serum creatinine) in all patients with type 2 diabetes, regardless of treatment (Strong recommendation).
  • Perform a dilated and comprehensive eye examination at the time of diabetes diagnosis (Strong recommendation).
    • If there is no evidence of retinopathy at ≥ 1 annual eye exam in patients with well-controlled glycemia, consider screening every 1-2 years.
    • If any evidence of retinopathy is detected, subsequent dilated retinal exams should be repeated at least annually.
    • More frequent eye exams are required if the retinopathy is progressive or sight-threatening.
  • Test for distal symmetric polyneuropathy and the loss of a protective sensation with a 10-g monofilament and ≥ 1 of the following tests at the time of diagnosis and annually to identify feet at risk of ulceration and amputation (Strong recommendation):
    • temperature discrimination or pinprick sensation (for small-fiber function)
    • vibration sensation using a 128 hertz (Hz) tuning fork (for large-fiber function)
• Testing in specific populations
  • For patients taking metformin, consider periodic measurement of vitamin B12, particularly in patients with peripheral neuropathy or anemia, since long-term use of metformin might be associated with vitamin B12 deficiency (Weak recommendation).
  • For patients taking angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or diuretics, measure serum creatinine/estimated GFR and serum potassium levels at least annually (Strong recommendation).

Management

Glycemic Goals

• Individualize glycemic goals.
  • HbA1c < 7% (53 mmol/mol) is a reasonable goal for many nonpregnant adults without significant hypoglycemia (Weak recommendation).
  • More stringent target, such as HbA1c < 6.5% (48 mmol/mol), may be reasonable if it can be achieved without significant hypoglycemia or other adverse effects of treatment (such as polypharmacy) for selected patients (Weak recommendation), such as those with:
    • short duration of diabetes
    • long life expectancy
    • no significant cardiovascular disease
  • Less stringent target, such as HbA1c < 8% (64 mmol/mol), may be appropriate for patients with (Weak recommendation):
    • limited life expectancy
    • harms of treatment likely to outweigh the benefits
    • history of severe hypoglycemia

Lifestyle Modification

• Provide support for dietary management, maintaining physical activity, and diabetes self-management education and support (Strong recommendation).
• This can be done individually (by the clinician, certified diabetes educators, and nurses), in a group setting, or via telemedicine.

Glucose-lowering Medications

• Prescribe glucose-lowering medications if hyperglycemia is inadequately controlled with lifestyle modifications.
• Use a patient-centered approach to guide the choice of pharmacologic agents for type 2 diabetes, considering factors such as cardiovascular and kidney comorbidities, hypoglycemia risk, cost and access, risk for adverse events, and patient preferences.
• Choice of first-line therapy depends on patient comorbidities, patient-centered treatment factors, and management needs. Other management factors to consider include healthy lifestyle behaviors, education and support for diabetes self-management, avoidance of clinical inertia, and social determinants of health (Strong recommendation).
  • While metformin has traditionally been recommended as the first-line pharmacologic agent for adults with type 2 diabetes, and is one of the most cost-effective agents, other agents may be used first or in addition to metformin to reduce blood glucose while also addressing specific comorbidities, such as atherosclerotic cardiovascular disease, heart failure, and/or chronic kidney disease.
  • Pharmacologic approaches, including metformin and/or other agents, should provide adequate efficacy to achieve and maintain treatment goals (Strong recommendation).
  • For patients with type 2 diabetes with or at high risk for atherosclerotic cardiovascular disease, heart failure, and/or chronic kidney disease, management strategy should incorporate medications that reduce cardiorenal risk (Strong recommendation).
  • Medications that reduce cardiorenal risk can be used with or without metformin.
  • Choice of glucose-lowering medication regimens should take into account and support weight management goals (Strong recommendation).
• If reduction of cardiorenal risk is the primary treatment goal (in addition to overall cardiovascular risk management), use a sodium-glucose cotransporter-2 (SGLT2) inhibitor and/or a glucagon-like peptide-1 (GLP-1) receptor agonist with demonstrated cardiovascular disease benefit for glucose-lowering and comprehensive cardiovascular risk reduction, regardless of HbA1c and in consideration of patient-specific factors, in patients with type 2 diabetes and any of the following (Strong recommendation):
  • established atherosclerotic cardiovascular disease or indicators of high cardiovascular risk
  • heart failure (SGLT2 inhibitors with proven benefit in this population are preferred)
  • established kidney disease (medication selection depends on estimated GFR)
• If glycemic control is the primary treatment goal, choose approaches with higher efficacy to achieve glycemic goals (while avoiding hypoglycemia in high-risk patients).
  • Agents/regimens with very high efficacy include:
    • GLP-1 agonists dulaglutide (high-dose), semaglutide, and tirzepatide
    • insulin
    • oral combinations
    • injectable combinations (GLP-1 receptor agonist plus insulin)
  • Agents/regimens with high efficacy include:
    • GLP-1 agonists not listed above
    • metformin
    • SGLT2 inhibitors
    • sulfonylureas
    • thiazolidinediones
  • Agents with intermediate efficacy include dipeptidyl peptidase IV (DPP-4) inhibitors.
• If weight management is the primary treatment goal:
  • Consider the medication’s effect on weight when selecting glucose-lowering medications for patients with type 2 diabetes and overweight or obesity (Weak recommendation).
  • Consider an agent with high-to-very-high glucose-lowering and weight management efficacy.
    • Agents with very high weight-loss efficacy include GLP-1 agonists semaglutide or tirzepatide.
    • Agents with high weight-loss efficacy include GLP-1 agonists dulaglutide or liraglutide.
    • Agents with intermediate efficacy include GLP-1 receptor agonists not listed above and SGLT2 inhibitors.
    • Agents with neutral efficacy include DPP-4 inhibitors and metformin.
• Many patients with type 2 diabetes and HbA1c ≥ 1.5% above glycemic target will require combination therapy (≥ 2 agents) to achieve their glycemic target.
  • In adults with type 2 diabetes and HbA1c ≥ 1.5%-2% above the glycemic target, consider early combination therapy at treatment initiation to prolong the time to treatment failure (Weak recommendation).
  • The choice of additional medication should be based on the presence of comorbidities, risk of adverse drug effects, safety, tolerability, and cost.
  • In selected patients, consider other agents such as an alpha-glucosidase inhibitor, colesevelam, dopamine agonist, or pramlintide.
• Injectable therapy (such as GLP-1 receptor agonists and/or insulin) is often eventually needed due to greater potency compared to oral medications, especially in patients with a longer duration of diabetes.
  • For patients who require greater glucose lowering than can be achieved with oral agents alone, GLP-1 receptor agonists are preferred over insulin when possible due to their favorable effects on weight and hypoglycemia risk (Strong recommendation).
  • Consider early introduction of insulin (as the first injectable therapy) in patients with:
    • weight loss or other evidence of ongoing catabolism (Weak recommendation)
    • symptomatic hyperglycemia (such as polyuria or polydipsia) (Weak recommendation)
    • HbA1c > 10% (86 mmol/mol) or blood glucose levels ≥ 300 mg/dL (16.7 mmol/L) (Weak recommendation)
  • If insulin is used, combination therapy with a GLP-1 receptor agonist is recommended to improve efficacy, durability of treatment effect, and benefits for weight and hypoglycemia (Strong recommendation).
  • Continue metformin upon initiation of insulin therapy for ongoing glycemic and metabolic benefit unless metformin is contraindicated or not tolerated (Strong recommendation).
  • Clinical findings that should prompt evaluation for possible overbasalization with insulin therapy (requiring reevaluation to further individualize therapy) include (Weak recommendation):
    • basal insulin dose > 0.5 units/kg/day
    • high bedtime-morning or postpreprandial glucose differential
    • aware or unaware hypoglycemia
    • high glycemic variability
• Do not delay intensification of treatment if the patient is not achieving glycemic goals (Strong recommendation).
• Evaluate the medication regimen every 3-6 months and adjust as needed to account for new patient factors and glycemic control.
• Considerations in older adults (≥ 65 years old):
  • Metformin is the preferred initial pharmacologic agent for older adults with type 2 diabetes.
  • For older adults with diabetes, assess and manage episodes of hypoglycemia at routine office visits (Weak recommendation).
  • Older adults who are cognitively and functionally intact and have few existing chronic illnesses should have an HbA1c goal < 7%-7.5% (53-58 mmol/mol) (Weak recommendation).
  • Less stringent glycemic goals, such as HbA1c < 8% (64 mmol/mol) should be used for adults with multiple coexisting chronic illnesses, cognitive impairment, or functional dependence (Weak recommendation).
  • Treatment goals must consider the patient's capability for glucose monitoring and insulin dose adjustment when diabetes-related complications and comorbidities occur. Consider medication classes with a low risk of hypoglycemia in those at an increased risk for hypoglycemia.
  • Glycemic goals might reasonably be relaxed using individual criteria, but hyperglycemia leading to symptoms or a risk of acute hyperglycemic complications should be avoided (Weak recommendation).
• In hospitalized patients:
  • Avoid the sole use of sliding-scale insulin (Strong recommendation).
  • For noncritically ill patients, insulin therapy is recommended in those with persistent hyperglycemia ≥ 180 mg/dL (10 mmol/L) (Strong recommendation).
    • For patients with poor oral intake or those who are taking nothing by mouth, use basal insulin or a basal plus bolus correction insulin regimen (Strong recommendation).
    • For patients with good nutritional intake, use an insulin regimen with basal, prandial, and correction components (Strong recommendation).
    • A target glucose of 140-180 mg/dL (7.8-10 mmol/L) is recommended for most patients (Strong recommendation).
  • For critically ill patients, continuous IV insulin is the preferred route of insulin. Frequent glucose monitoring (every 30 minutes to 2 hours) is required while using IV insulin.
    • A target glucose of 140-180 mg/dL (7.8-10 mmol/L) is recommended for most patients (Strong recommendation).
    • More stringent targets, such as 110-140 mg/dL (6.1-7.8 mmol/L), may be appropriate for selected patients if significant hypoglycemia can be avoided (Weak recommendation).

Management of Comorbidities

• Statins are recommended as the preferred medication for lowering low-density lipoprotein (LDL) cholesterol.
  • Prescribe a moderate-intensity statin (in addition to lifestyle therapy) for most adults aged 40-75 years with diabetes and without cardiovascular risk factors (Strong recommendation).
  • Consider prescribing a statin (in addition to lifestyle therapy) in patients aged 20-39 years with cardiovascular risk factors (Weak recommendation).
  • Consider high-intensity statin therapy to reduce LDL cholesterol by ≥ 50% of baseline with a target LDL goal of < 70 mg/dL in patients aged 40-75 years at increased cardiovascular risk (including patients with ≥ 1 cardiovascular risk factor) (Weak recommendation).
• Preventative angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs):
  • For nonpregnant patients with diabetes and hypertension
    • Either an ACE inhibitor or an ARB is recommended for those with modestly elevated urinary albumin-to-creatinine ratio (30–299 mg/g creatinine) (Weak recommendation).
    • Either an ACE inhibitor or an ARB is strongly recommended for those with urinary albumin-to-creatinine ratio ≥ 300 mg/g creatinine and/or estimated GFR < 60 mL/minute/1.73 m² (Strong recommendation).
  • ACE inhibitors or ARBs are not recommended for the primary prevention of chronic kidney disease in patients with diabetes who have (Strong recommendation):
    • normal blood pressure
    • normal urinary albumin-to-creatinine ratio (< 30 mg/g creatinine)
    • normal estimated GFR
• Consider aspirin 75-162 mg/day in patients with diabetes and increased cardiovascular risk, such as most patients ≥ 50 years old with no increased risk of bleeding and with ≥ 1 additional major risk factor (Weak recommendation).
• Metabolic (bariatric) surgery is recommended to improve glycemic control in appropriate surgical candidates with either of the following (Strong recommendation):
  • body mass index (BMI) ≥ 40 kg/m² (BMI ≥ 37.5 kg/m² in Asian American patients)
  • BMI 35-39.9 kg/m² (32.5-37.4 kg/m² in Asian American patients) who do not achieve sustainable weight loss and improvement in comorbidities (including hyperglycemia) with nonoperative management.