Management of Type 2 Diabetes Mellitus in Adults
Immediate First-Line Therapy at Diagnosis
Start metformin 500–850 mg once or twice daily at the time of diagnosis alongside lifestyle modifications, then titrate to ≥2 g/day (or extended-release formulation once daily) within 1–2 months while tolerating gastrointestinal side effects. 1, 2, 3
- Continue metformin indefinitely as the foundation of therapy; it reduces cardiovascular events and mortality, costs little, and has decades of safety data. 1
- Adjust metformin dose according to kidney function: use full dose if eGFR ≥60 mL/min/1.73 m²; reduce to 50% if eGFR 45–59; limit to 1 g/day if eGFR 30–44; discontinue if eGFR <30. 4, 1
Exception: When to Start Insulin Instead of Metformin
Initiate basal insulin immediately (with or without metformin) if the patient presents with HbA1c ≥10%, plasma glucose ≥300 mg/dL with symptoms (polyuria, polydipsia, weight loss), ketosis, or diabetic ketoacidosis—these presentations indicate severe metabolic decompensation requiring urgent correction. 4, 1, 2, 3
- Use long-acting insulin analogs (glargine, degludec, or detemir) for lower hypoglycemia and weight-gain profiles. 1, 5
- Once acidosis resolves or glucose stabilizes, add metformin and continue insulin. 4, 1
Lifestyle Modifications (Mandatory for All Patients)
Prescribe ≥150 minutes per week of moderate-intensity aerobic activity (e.g., brisk walking) plus resistance training ≥2 days per week; this lowers HbA1c by 0.4–1.0% and improves cardiovascular risk factors. 4, 1, 2
- Counsel patients to avoid prolonged sitting and to break up sedentary periods throughout the day. 4, 1
Recommend a plant-forward diet emphasizing vegetables, fruits, whole grains, legumes, unsaturated fats, and nuts while limiting processed meats, refined carbohydrates, and sugar-added beverages; target 5–10% weight loss from baseline in overweight or obese individuals. 4, 1, 2
- Restrict sodium intake to <2 g/day (≈5 g sodium chloride) to support blood-pressure management. 4, 1
- Refer to a registered dietitian at diagnosis for culturally appropriate, individualized nutrition counseling. 2
Second-Line Agent Selection: Prioritize Comorbidities Over Glycemic Control Alone
If the Patient Has Established Atherosclerotic Cardiovascular Disease (ASCVD) or High ASCVD Risk
Add a GLP-1 receptor agonist (semaglutide, tirzepatide, or liraglutide) to metformin regardless of current HbA1c; these agents reduce major adverse cardiovascular events by 12–26%, lower stroke risk, and promote substantial weight loss (often >10%). 1, 2, 3
- 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 for patients with ASCVD. 1
If the Patient Has Heart Failure (HF) or Chronic Kidney Disease (CKD)
Add an SGLT-2 inhibitor (empagliflozin, dapagliflozin, or canagliflozin) to metformin regardless of current HbA1c; this class reduces CKD progression by 24–39%, lowers heart-failure hospitalizations by 18–25%, and decreases cardiovascular and all-cause mortality. 4, 1, 6
- Empagliflozin reduced cardiovascular death by 38% (HR 0.62,95% CI 0.49–0.77) in the EMPA-REG OUTCOME trial. 1
- Initiate SGLT-2 inhibitors when eGFR ≥30 mL/min/1.73 m² for glucose lowering; evidence supports continuation down to eGFR ≥20 mL/min/1.73 m² for renal and cardiovascular protection even if eGFR falls below the start threshold. 4, 1
If the Patient Has Both ASCVD and HF/CKD
Use triple therapy: metformin + SGLT-2 inhibitor + GLP-1 receptor agonist to capture both atherosclerotic protection and heart-failure/renal benefits. 1
- Prioritize the SGLT-2 inhibitor when HF or CKD dominates; prioritize the GLP-1 receptor agonist when ASCVD or weight loss is the primary goal. 1
Glycemic Targets
Target HbA1c 7–8% for most adults with type 2 diabetes; this range balances efficacy with hypoglycemia risk. 1, 2, 3
- Consider a stricter target <6.5% for younger patients with short disease duration, long life expectancy, and no significant cardiovascular disease—only if achievable without hypoglycemia or treatment burden. 4, 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
Third-Line Therapy When Dual Therapy Fails to Achieve Target
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. 4, 1
- If GLP-1 receptor agonists are unsuitable (e.g., intolerable nausea, patient refusal), consider a DPP-4 inhibitor (sitagliptin, linagliptin), recognizing modest glucose lowering and no proven cardiovascular advantage. 4, 1
- Avoid sulfonylureas in older adults or those at high hypoglycemia risk; if required, select agents with lower hypoglycemia potential (e.g., glimepiride) and use the minimal effective dose. 1
- Thiazolidinediones (pioglitazone) may be used selectively, but weigh risks of weight gain, fluid retention, and possible HF exacerbation. 4, 1
When to Initiate or Intensify Insulin Therapy
Start basal insulin promptly when HbA1c ≥10% (or plasma glucose ≥300 mg/dL) with symptomatic or catabolic presentation to prevent metabolic decompensation and preserve β-cell function. 1, 2
- For marked hyperglycemia (blood glucose ≥250 mg/dL or HbA1c ≥8.5%) with symptoms (polyuria, polydipsia, nocturia, weight loss), begin basal insulin while initiating metformin and titrating. 4, 1
- Continue metformin and the selected SGLT-2 inhibitor or GLP-1 receptor agonist when adding insulin to preserve cardiovascular and renal protection. 1
- Prefer long-acting insulin analogs (glargine, degludec, detemir) for lower weight-gain and hypoglycemia profiles. 1, 5
If basal insulin up to 0.5 U/kg/day fails to achieve target (watch for over-basalization: large bedtime-to-morning glucose gap, frequent hypoglycemia, high glycemic variability), switch to multiple daily injections with basal and premeal bolus insulins. 4, 1
Monitoring and Treatment Intensification
Measure HbA1c every 3 months until the target is reached, then continue quarterly monitoring. 4, 1, 2, 3
Do not postpone therapeutic intensification beyond 3 months of inadequate control; treatment inertia raises microvascular complication risk. 1, 3
- Reassess the medication regimen every 3–6 months, adjusting for comorbidities, hypoglycemia risk, weight effects, adverse events, cost, and patient preferences. 1
Critical Safety Measure to Prevent Hypoglycemia
When adding an SGLT-2 inhibitor or GLP-1 receptor agonist that achieves adequate glycemic control, immediately reduce or discontinue sulfonylureas or long-acting insulins to avoid severe hypoglycemia. 2, 3
- Self-monitoring of blood glucose may be unnecessary in patients receiving metformin combined with either an SGLT-2 inhibitor or a GLP-1 receptor agonist. 3
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, 2
Target blood pressure <130/80 mmHg using ACE inhibitors or angiotensin receptor blockers as first-line agents, especially in patients with albuminuria. 4, 1, 2
- Titrate ACE inhibitors or ARBs to the highest approved dose tolerated in patients with diabetes, hypertension, and albuminuria. 4
Recommend low-dose aspirin (75–162 mg daily) for secondary prevention in patients with established ASCVD, unless contraindicated. 1
Common Pitfalls and How to Avoid Them
- Delaying metformin initiation: Start metformin immediately at diagnosis alongside lifestyle modifications, not after a "trial" of lifestyle alone. 2, 3
- Failing to add SGLT-2 inhibitors or GLP-1 receptor agonists based on comorbidities: These agents provide mortality and morbidity benefits independent of glycemic control; initiate them regardless of current HbA1c in patients with ASCVD, HF, or CKD. 1, 3
- Not reducing hypoglycemia-causing medications: When adding SGLT-2 inhibitors or GLP-1 agonists, immediately reduce or stop sulfonylureas or long-acting insulins to prevent severe hypoglycemia. 2, 3
- Clinical inertia: Do not wait beyond 3 months to intensify therapy when glycemic targets are unmet; delays increase microvascular complication risk. 1, 3
- Over-basalization with insulin: If basal insulin exceeds 0.5 U/kg/day without achieving target, switch to a basal-bolus regimen rather than continuing to escalate basal doses. 1
- Ignoring renal function: Adjust metformin dose according to eGFR; initiate SGLT-2 inhibitors only when eGFR ≥30 mL/min/1.73 m² for glucose lowering. 4, 1
- Forgetting vitamin B12 screening: Screen periodically for vitamin B12 deficiency in patients on long-term metformin, especially those with anemia or peripheral neuropathy. 1
Special Considerations for Older Adults
Avoid overtreatment; select agents with low hypoglycemia risk (avoid sulfonylureas, meglitinides, and high-dose insulin). 1
De-intensify hypoglycemia-causing medications (insulin, sulfonylureas, meglitinides) in older adults at high risk, while maintaining individualized glycemic targets. 1
Simplify complex regimens (especially insulin) to reduce hypoglycemia, polypharmacy, and treatment burden, and ensure inclusion of agents that lower cardiovascular and renal risk irrespective of glycemia. 1
Multidisciplinary Team Approach
Implement a structured self-management educational program involving a physician, certified diabetes care and education specialist, registered dietitian nutritionist, and behavioral health specialist or social worker. 4, 2
- Address social determinants of health and integrate collaborative efforts for dietary improvement, weight management, physical activity, and stress management. 3