What is the recommended initial treatment plan for a patient with type 2 diabetes, including lifestyle modification, metformin dosing, target HbA1c, and second‑line therapy options if targets are not achieved?

Initial Treatment Plan for Type 2 Diabetes

Start Metformin Immediately at Diagnosis

Begin metformin 500–850 mg once or twice daily with meals at the time of diagnosis, titrate by 500 mg weekly to a minimum of 2 g/day (or equivalent extended-release formulation once daily), and continue indefinitely while tolerated. 1, 2, 3

• Metformin lowers cardiovascular events and all-cause mortality, is inexpensive, and has a long safety record 1, 2
• Extended-release formulations provide comparable efficacy with fewer gastrointestinal side effects 2
• Continue metformin when eGFR is 30–45 mL/min/1.73 m² with dose reduction; discontinue only when eGFR falls below 30 mL/min/1.73 m² 1, 2

Implement Lifestyle Modifications Concurrently

• Prescribe ≥150 minutes per week of moderate-intensity aerobic activity plus resistance training on ≥2 non-consecutive days 1, 2
• Target 5–10% body-weight reduction through a plant-forward, low-saturated-fat dietary pattern 2
• Limit sodium intake to <2 g/day (≈5 g salt) 1, 2
• Interrupt sedentary periods lasting ≥30 minutes with brief standing or walking 2

Set Glycemic Target

Aim for HbA1c between 7% and 8% for most adults to balance efficacy with hypoglycemia risk 2

• Consider HbA1c <6.5% for younger patients with early disease and no significant comorbidities when achievable without hypoglycemia 2
• Adopt less stringent targets (7.5%–8.5%) for older adults, those with limited life expectancy, advanced complications, or prior severe hypoglycemia 2

Add Second-Line Therapy Based on Comorbidities (Not HbA1c Alone)

If Patient Has Chronic Kidney Disease (eGFR 20–59 mL/min/1.73 m² or albuminuria ≥30 mg/g)

Add an SGLT-2 inhibitor to metformin immediately, regardless of current HbA1c 1, 2

• Empagliflozin 10 mg once daily (may increase to 25 mg) 2
• Dapagliflozin 10 mg once daily 2
• Canagliflozin 100 mg once daily (may increase to 300 mg if eGFR ≥60 mL/min/1.73 m²) 2
• SGLT-2 inhibitors reduce CKD progression by 24–39%, lower heart-failure hospitalizations, and decrease cardiovascular death by 38% (HR 0.62,95% CI 0.49–0.77) 1, 2
• Initiate when eGFR ≥20 mL/min/1.73 m² and continue even if eGFR later falls below this threshold 1, 2

If Patient Has Atherosclerotic Cardiovascular Disease or High ASCVD Risk

Add a GLP-1 receptor agonist (semaglutide or liraglutide) to metformin immediately, regardless of current HbA1c 2

• Semaglutide: start 0.25 mg subcutaneously weekly for 4 weeks, then 0.5 mg weekly; may increase to 1 mg weekly after ≥4 weeks 2
• GLP-1 receptor agonists reduce major adverse cardiovascular events, stroke, and all-cause mortality with minimal hypoglycemia risk 2
• These agents provide 0.6–1.5% HbA1c reduction and 2–5 kg weight loss 2

If Patient Has Heart Failure (Especially Reduced Ejection Fraction)

Add an SGLT-2 inhibitor to metformin immediately, independent of HbA1c, using the same agents and doses listed for CKD 2

If Patient Has No Cardiovascular or Renal Comorbidities

Add a second agent only after 3 months if HbA1c remains above target on metformin plus lifestyle modifications 1, 2

• Preferred second-line options: SGLT-2 inhibitor or GLP-1 receptor agonist 1, 2
• Alternative agents: DPP-4 inhibitor (sitagliptin, linagliptin) for modest HbA1c reduction of 0.5–0.8% with weight neutrality 2
• Avoid sulfonylureas in adults ≥65 years or those at high hypoglycemia risk 2

Initiate Insulin Immediately in Severe Hyperglycemia

Start basal insulin (glargine, degludec, or detemir) when HbA1c ≥10% or plasma glucose ≥300 mg/dL with symptomatic hyperglycemia or catabolic features (weight loss, ketosis) 1, 2, 4, 3

• Begin with 10 units subcutaneously once daily or 0.1–0.2 units/kg body weight 4, 3
• Continue metformin when adding insulin to reduce insulin requirements and prevent weight gain 4, 3
• For ketosis or ketoacidosis, administer immediate insulin; once acidosis resolves, add metformin while continuing insulin 2, 3

Monitor and Intensify Treatment

Measure HbA1c every 3 months until target is achieved, then continue quarterly monitoring 1, 2

Do not delay therapeutic intensification beyond 3 months of inadequate control, as treatment inertia increases microvascular complication risk 2

• Reassess the medication regimen every 3–6 months for comorbidities, hypoglycemia risk, weight effects, adverse events, cost, and patient preferences 2

Third-Line Therapy When Dual Therapy Fails

• If HbA1c remains above target after 3 months of metformin + SGLT-2 inhibitor, add a GLP-1 receptor agonist 2
• If HbA1c remains above target after 3 months of metformin + GLP-1 receptor agonist, add an SGLT-2 inhibitor 2
• Do not combine DPP-4 inhibitors with GLP-1 receptor agonists due to overlapping mechanisms 2

Critical Safety Measures

When adding SGLT-2 inhibitors or GLP-1 receptor agonists, immediately reduce or discontinue sulfonylureas or long-acting insulin to prevent severe hypoglycemia 2

• Screen for vitamin B12 deficiency periodically in patients on long-term metformin, especially those with anemia or neuropathy 2
• Watch for over-basalization with insulin (basal dose >0.5 U/kg/day, large bedtime-to-morning glucose gap, frequent hypoglycemia) and modify therapy accordingly 2

Adjunctive Cardiovascular Risk Management

• Prescribe moderate-to-high intensity statin therapy for all adults aged 40–75 years with diabetes, independent of baseline LDL 2
• Target blood pressure <130/80 mmHg using ACE inhibitors or ARBs as first-line agents 2