Management of Type 2 Diabetes Mellitus in Adults
Start metformin immediately at diagnosis alongside lifestyle modifications, then add an SGLT2 inhibitor or GLP-1 receptor agonist based on cardiovascular disease, heart failure, or chronic kidney disease status—regardless of current HbA1c—to reduce mortality and morbidity. 1
Lifestyle Modifications (Foundation for All Patients)
Prescribe at least 150 minutes per week of moderate-intensity aerobic activity (e.g., brisk walking) combined with resistance training on at least 2 non-consecutive days per week to improve glycemic control and cardiovascular health. 2, 1
Target 5–10% weight loss from baseline through a plant-forward, low-saturated-fat dietary pattern to reduce insulin resistance and cardiovascular risk. 1, 3
Limit sodium intake to less than 2 g/day (approximately 5 g of sodium chloride) to support blood pressure management. 2, 1
Counsel patients to interrupt prolonged sedentary periods (≥30 minutes) with brief standing or walking bouts to enhance metabolic benefits. 2, 1
Metformin: First-Line Pharmacotherapy
Initiation and Titration
Begin metformin 500 mg once or twice daily with meals at the time of diagnosis, even before laboratory confirmation if clinical suspicion is high. 4, 1
Increase the dose by 500 mg each week to minimize gastrointestinal side effects, targeting a total daily dose of 2000 mg (1000 mg twice daily) for maximal glucose-lowering efficacy. 4, 1
Doses above 2000 mg provide minimal additional benefit and increase the likelihood of intolerance; the effective ceiling is 2000–2550 mg/day. 4
Extended-release formulations may be used once daily to improve tolerability and adherence. 1
Why Metformin Must Be Continued
Never discontinue metformin when adding other agents (including insulin) unless contraindicated; it reduces cardiovascular events and mortality, lowers insulin requirements by 20–30%, mitigates weight gain, and carries minimal hypoglycemia risk. 4, 1, 5
Metformin provides proven cardiovascular mortality benefit independent of its glucose-lowering effect. 4, 1, 6
Renal Function Monitoring and Dose Adjustment
Continue metformin at full dose when eGFR ≥60 mL/min/1.73 m²; reduce to 50% of the dose when eGFR is 45–59; limit to 1 g/day when eGFR is 30–44; discontinue when eGFR falls below 30 mL/min/1.73 m². 2, 1, 6, 7
Check eGFR at baseline and at least annually; increase monitoring frequency to every 3–6 months when eGFR declines toward 45 mL/min/1.73 m². 1
Temporarily discontinue metformin during acute illness, dehydration, or procedures requiring iodinated contrast to prevent lactic acidosis. 6, 8
Vitamin B12 Monitoring
- Screen for vitamin B12 deficiency periodically (every 6–12 months), especially in patients on long-term metformin who develop anemia or peripheral neuropathy, and supplement if deficient. 4, 1
Individualized HbA1c Targets
Target HbA1c <7% for most adults to reduce microvascular and macrovascular complications. 4, 1, 9
Consider a more stringent target of <6.5% for younger patients with short disease duration, long life expectancy, no significant cardiovascular disease, and when achievable without hypoglycemia or treatment burden. 1, 9
Adopt a less stringent target of 7.5–8.0% (or up to 8.5%) for older adults (≥65–70 years), those with limited life expectancy (<10 years), history of severe hypoglycemia, advanced complications, or extensive comorbidities. 4, 1, 9
Second-Line Agent Selection Based on Comorbidities
Atherosclerotic Cardiovascular Disease (ASCVD) or High ASCVD Risk
Add a GLP-1 receptor agonist (preferably semaglutide, liraglutide, or dulaglutide) to metformin for patients with established ASCVD or high cardiovascular risk, regardless of current HbA1c, to reduce major adverse cardiovascular events, stroke, and all-cause mortality. 2, 1, 5
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
GLP-1 receptor agonists provide an additional 0.6–0.8% HbA1c reduction (up to 1.5% with semaglutide) and promote 2–5 kg weight loss, counteracting insulin-associated weight gain. 2, 1
GLP-1 receptor agonists carry minimal hypoglycemia risk when not combined with sulfonylureas or insulin. 2, 1
Heart Failure (HF) or Chronic Kidney Disease (CKD)
Add an SGLT2 inhibitor (empagliflozin, dapagliflozin, or canagliflozin) to metformin for patients with heart failure or CKD (eGFR ≥30 mL/min/1.73 m²), regardless of current HbA1c, to reduce CKD progression by 24–39%, lower heart failure hospitalizations, and decrease cardiovascular and all-cause mortality. 2, 1, 5
Empagliflozin reduced cardiovascular death by 38% (HR 0.62,95% CI 0.49–0.77) in the EMPA-REG OUTCOME trial. 1
SGLT2 inhibitors lower HbA1c by approximately 0.5–0.8%, promote weight loss, and do not increase hypoglycemia risk when combined with metformin alone. 1
Initiate SGLT2 inhibitors when eGFR ≥30 mL/min/1.73 m²; evidence supports continuation down to eGFR ≥20 mL/min/1.73 m² for cardiovascular and renal protection even if eGFR falls below the initiation threshold. 2, 1
Patients with Both ASCVD and HF/CKD
Employ triple therapy (metformin + SGLT2 inhibitor + GLP-1 receptor agonist) when both atherosclerotic and heart failure/renal protection are required. 1
Prioritize SGLT2 inhibitors when heart failure or CKD dominates; prioritize GLP-1 receptor agonists when ASCVD or weight loss is the primary goal. 1
Third-Line and Additional Agents
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 + SGLT2 inhibitor, owing to superior glycemic efficacy, weight loss, and cardiovascular benefit. 2, 1
Consider DPP-4 inhibitors (e.g., sitagliptin, linagliptin) when GLP-1 receptor agonists are unsuitable, recognizing modest glucose lowering (0.5–0.8% HbA1c reduction) 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 (e.g., gliclazide over glibenclamide) 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
Never combine GLP-1 receptor agonists with DPP-4 inhibitors, as no additional glucose-lowering benefit has been demonstrated. 4, 1
Insulin Initiation Criteria
When to Start Insulin Immediately
Initiate insulin (with or without additional agents) when HbA1c ≥10% or plasma glucose ≥300 mg/dL with symptomatic hyperglycemia (polyuria, polydipsia, weight loss) or catabolic features (ketosis, marked hypertriglyceridemia) to prevent metabolic decompensation and preserve β-cell function. 2, 4, 1
In patients with ketosis or ketoacidosis, administer immediate subcutaneous or intravenous insulin to correct hyperglycemia and metabolic derangement; once acidosis resolves, initiate metformin while continuing insulin. 2
Basal Insulin Initiation and Titration
Start basal insulin (NPH or long-acting analog such as glargine or degludec) at 10 units once daily at bedtime or calculate 0.1–0.2 units/kg body weight; for HbA1c ≥10%, use the higher end (0.2 units/kg). 4, 1
Titrate insulin by 2–4 units every 3 days until fasting glucose consistently reaches 80–130 mg/dL without hypoglycemia. 4, 1
If hypoglycemia occurs, identify the cause and reduce the insulin dose by 10–20%. 4
Continue metformin and the selected SGLT2 inhibitor or GLP-1 receptor agonist when adding insulin to preserve cardiovascular and renal protection. 4, 1
Adding Prandial Insulin
- If HbA1c remains >7% after 3–6 months despite optimized basal insulin, add rapid-acting prandial insulin (approximately 4 units before the largest meal or 10% of the basal dose) and titrate by 1–2 units every 3 days based on 2-hour postprandial glucose readings. 4
Monitoring and Treatment Intensification
Measure HbA1c every 3 months until the target is reached, then continue quarterly monitoring; this is the longest acceptable interval before reassessing therapy effectiveness. 4, 1
Do not postpone therapeutic intensification beyond 3 months of inadequate control, as treatment inertia raises microvascular complication risk. 4, 1
Reassess the medication regimen every 3–6 months, adjusting for comorbidities, hypoglycemia risk, weight effects, adverse events, cost, and patient preferences. 1
Watch for over-basalization with insulin (basal dose >0.5 units/kg/day, large bedtime-to-morning glucose gap, frequent hypoglycemia, or high glycemic variability) and modify therapy accordingly. 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
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 in this population. 1
Recommend low-dose aspirin (75–162 mg daily) for secondary prevention in patients with established ASCVD, unless contraindicated. 1
Critical Pitfalls to Avoid
Do not delay metformin initiation; start it immediately at diagnosis alongside lifestyle modifications. 4, 1
Do not discontinue metformin when adding insulin or other agents unless contraindicated (eGFR <30 mL/min/1.73 m²); it remains foundational therapy throughout intensification. 4, 1
Do not delay insulin initiation while trialing oral agents alone in patients with HbA1c ≥10% or symptomatic hyperglycemia; combination therapy is required for timely control. 4, 1
Do not add sulfonylureas to a metformin + insulin regimen; they markedly raise hypoglycemia risk (7-fold increase) and lack the cardiovascular benefits of GLP-1 receptor agonists or SGLT2 inhibitors. 4, 1
When SGLT2 inhibitors or GLP-1 receptor agonists achieve adequate glycemic control, immediately reduce or discontinue sulfonylureas or long-acting insulins to prevent severe hypoglycemia. 1
Do not combine GLP-1 receptor agonists with DPP-4 inhibitors; no incremental benefit has been demonstrated. 4, 1
Avoid therapeutic inertia: intensify therapy within 3 months if HbA1c remains above target, as delays prolong hyperglycemia exposure and increase complication risk. 4, 1