What is the recommended treatment approach for an adult with type 2 diabetes mellitus, including lifestyle modification, first‑line metformin dosing, criteria for adding second‑line agents based on comorbidities and renal function, and indications for initiating insulin therapy?

Treatment of Type 2 Diabetes Mellitus in Adults

Start metformin immediately at diagnosis alongside lifestyle modifications, titrate to ≥2 g daily, then add an SGLT-2 inhibitor or GLP-1 receptor agonist based on comorbidities—not glycemic control alone—and initiate insulin promptly when HbA1c ≥10% or glucose ≥300 mg/dL with symptoms. 1

Lifestyle Modifications (Foundation for All Patients)

• Prescribe ≥150 minutes per week of moderate-intensity aerobic activity combined with resistance training at least 2 days per week to improve insulin sensitivity and cardiovascular health. 2, 1
• Target 5–10% weight loss from baseline through a plant-forward dietary pattern that is low in saturated fat and refined carbohydrates, emphasizing whole grains, vegetables, legumes, and fruits. 1, 3
• Limit sodium intake to <2 g/day (approximately 5 g salt) to support blood pressure management and reduce cardiovascular risk. 2, 1
• Counsel patients to avoid prolonged sedentary periods and incorporate regular movement throughout the day. 2, 1

First-Line Pharmacotherapy: Metformin

• Initiate metformin 500–850 mg once or twice daily at the time of diagnosis, not after a trial of lifestyle modification alone. 1, 4
• Titrate gradually to a target dose of ≥2 g daily (e.g., 1 g twice daily) or use extended-release formulation once daily to minimize gastrointestinal side effects while maximizing efficacy. 1, 5
• Continue metformin indefinitely while tolerated; it reduces cardiovascular events and mortality, is weight-neutral, does not cause hypoglycemia, and is low-cost. 1, 6, 7

Metformin Dosing by Renal Function

• Use full dose when eGFR ≥60 mL/min/1.73 m²; reduce to 50% of maximum dose when eGFR 45–59; limit to 1 g/day when eGFR 30–44; discontinue when eGFR <30. 2, 1
• Screen for vitamin B12 deficiency periodically, especially in patients with anemia or peripheral neuropathy, as long-term metformin use can cause biochemical deficiency. 1

Second-Line Agent Selection: Comorbidity-Driven, Not Glycemic-Driven

The critical paradigm shift: Add SGLT-2 inhibitors or GLP-1 receptor agonists based on cardiovascular and renal comorbidities regardless of current HbA1c, not solely for glucose lowering. 1, 4

Atherosclerotic Cardiovascular Disease (ASCVD) or High ASCVD Risk

• Add a GLP-1 receptor agonist (preferably semaglutide or tirzepatide) to metformin for patients with established ASCVD (prior MI, stroke, peripheral artery disease) or very high ASCVD risk. 1, 4
• GLP-1 receptor agonists primarily reduce atherosclerotic events, stroke risk, and provide substantial weight loss; liraglutide reduced cardiovascular death by 22% (HR 0.78,95% CI 0.66–0.93) and all-cause mortality by 15% (HR 0.85,95% CI 0.74–0.97) in the LEADER trial. 1
• Prefer GLP-1 receptor agonists over insulin when feasible in patients with ASCVD to maximize cardiovascular protection. 1

Heart Failure (HF) or Chronic Kidney Disease (CKD)

• Add an SGLT-2 inhibitor (empagliflozin, dapagliflozin, or canagliflozin) to metformin for patients with heart failure or CKD, independent of glycemic level. 2, 1, 4
• SGLT-2 inhibitors reduce CKD progression by 24–39%, lower heart failure hospitalizations, and decrease cardiovascular and all-cause mortality; empagliflozin reduced cardiovascular death by 38% (HR 0.62,95% CI 0.49–0.77) in EMPA-REG OUTCOME. 1, 4
• Initiate SGLT-2 inhibitors when eGFR ≥30 mL/min/1.73 m² for glucose lowering; evidence supports use down to eGFR ≥20 mL/min/1.73 m² for renal and cardiovascular protection, continuing even if eGFR falls below the start threshold. 2, 1

Patients with Both ASCVD and HF/CKD

• Employ triple therapy: metformin + SGLT-2 inhibitor + GLP-1 receptor agonist when both atherosclerotic and heart-failure/renal protection are required. 1
• Prioritize SGLT-2 inhibitors when HF or CKD dominates; prioritize GLP-1 agonists when ASCVD or weight loss is the primary goal. 1, 4

Glycemic Targets

• Target HbA1c 7%–8% for most adults to balance efficacy with hypoglycemia risk. 1
• Consider a stricter target (<6.5%) for younger patients with early disease and no significant comorbidities, provided hypoglycemia is unlikely. 1
• Adopt less stringent targets (7.5%–8.5%) for older adults, those with limited life expectancy, advanced complications, extensive comorbidities, or prior severe hypoglycemia. 1

Treatment Intensification Timeline

• Measure HbA1c every 3 months until target is reached, then continue quarterly monitoring. 1, 4
• Do not postpone therapeutic intensification beyond 3 months of inadequate control; treatment inertia increases microvascular complication risk. 1, 4
• Add a third agent (preferably GLP-1 receptor agonist) when HbA1c remains above target on metformin + SGLT-2 inhibitor after 3 months. 2, 1

Third-Line and Additional Agents

• Add a GLP-1 receptor agonist as the preferred third agent for patients whose HbA1c remains above target on metformin + SGLT-2 inhibitor, owing to superior glycemic efficacy, weight loss, and cardiovascular benefit. 2, 1
• Consider DPP-4 inhibitors (sitagliptin, linagliptin) when GLP-1 agonists are unsuitable, recognizing modest glucose lowering and no proven cardiovascular advantage. 2, 1
• Avoid sulfonylureas in older adults or those at high hypoglycemia risk; if required, select agents with lower hypoglycemia potential and use the minimal effective dose. 1
• Thiazolidinediones (pioglitazone) may be used selectively, but weigh risks of weight gain, fluid retention, and possible heart failure exacerbation. 2, 1

Insulin Initiation Criteria

Insulin is indicated immediately—not after prolonged oral agent trials—in specific high-risk scenarios. 1

Absolute Indications for Prompt Insulin Initiation

• Start basal insulin (glargine, degludec, or detemir) immediately when HbA1c ≥10% (or plasma glucose ≥300 mg/dL) and the patient is symptomatic or catabolic to prevent metabolic decompensation and preserve β-cell function. 2, 1
• For marked hyperglycemia (blood glucose ≥250 mg/dL or HbA1c ≥8.5%) with symptoms (polyuria, polydipsia, nocturia, weight loss), begin basal insulin while initiating and titrating metformin. 2, 1
• In ketosis or ketoacidosis, administer immediate subcutaneous or intravenous insulin, then add metformin once acidosis resolves. 2, 1

Insulin Dosing and Titration

• Prefer long-acting insulin analogs (glargine, degludec, detemir) for their lower weight-gain and hypoglycemia profiles compared to NPH insulin. 1, 3
• Titrate basal insulin by 2–4 units every 3–4 days until fasting glucose reaches 100–130 mg/dL (5.6–7.2 mmol/L). 5
• Continue metformin and the selected SGLT-2 inhibitor or GLP-1 receptor agonist when adding insulin to preserve cardiovascular and renal protection. 1
• Watch for over-basalization (basal dose >0.5 U/kg/day, large bedtime-to-morning glucose gap, frequent hypoglycemia, or high glycemic variability) and modify therapy accordingly. 1

Special Scenario: Newly Diagnosed with Very High HbA1c

• Initiate dual therapy immediately (metformin plus SGLT-2 inhibitor or GLP-1 agonist) rather than sequential monotherapy in newly diagnosed patients with HbA1c ≥9%. 4
• Consider initiating insulin therapy (with or without additional agents) from the outset in newly diagnosed patients with HbA1c ≥10% or glucose ≥300 mg/dL, especially if symptomatic. 4

Critical Pitfalls to Avoid

• Never discontinue metformin when adding second-line agents; continue at maximum tolerated dose unless contraindicated (eGFR <30) or not tolerated. 1, 4
• Do not delay adding SGLT-2 inhibitors or GLP-1 agonists in patients with established ASCVD, HF, or CKD while waiting for HbA1c to rise; these agents provide mortality and morbidity benefits independent of glycemic control. 1, 4
• When adding SGLT-2 inhibitors or GLP-1 agonists to patients on sulfonylureas or insulin, immediately reduce or discontinue the hypoglycemia-causing agents to prevent severe hypoglycemia. 4
• Avoid sulfonylureas as second-line agents due to significant hypoglycemia risk, weight gain, and lack of cardiovascular or renal protection. 1
• Do not use metformin in patients with eGFR <30 mL/min/1.73 m² due to lactic acidosis risk. 2, 1

Adjunctive Cardiovascular Risk Management

• Prescribe moderate-to-high intensity statin therapy for all adults aged 40–75 years with diabetes, independent of baseline LDL or calculated risk. 1
• Target blood pressure <130/80 mmHg using renin-angiotensin system inhibitors as first-line agents. 1
• Recommend low-dose aspirin (75–162 mg daily) for secondary prevention in patients with established ASCVD, unless contraindicated. 1