What is the recommended management plan for an adult with type 2 diabetes, including lifestyle modification, first‑line pharmacotherapy, and subsequent treatment steps?

Management of Type 2 Diabetes in Adults

Start metformin immediately at diagnosis alongside lifestyle modifications, then add an SGLT-2 inhibitor or GLP-1 receptor agonist based on comorbidities—this dual or triple therapy approach reduces cardiovascular death, heart failure hospitalizations, and kidney disease progression independent of glucose lowering. 1, 2

Lifestyle Modifications (Foundation for All Patients)

Physical Activity

• Prescribe at least 150 minutes per week of moderate-intensity aerobic exercise spread over ≥3 days, with no more than 2 consecutive days without activity, to improve insulin sensitivity and glycemic control 1, 2, 3
• Add resistance training at least 2 days per week on non-consecutive days, targeting all major muscle groups with 8–10 exercises of 8–12 repetitions each 2, 3
• Interrupt prolonged sitting every 30 minutes with brief movement to support glucose regulation 2, 3
• The combination of aerobic and resistance training produces additive improvements in HbA1c beyond either modality alone 3

Nutrition and Weight Management

• Target 5–10% weight loss from baseline through a heart-healthy dietary pattern (Mediterranean, DASH, or plant-based) that emphasizes vegetables, whole fruits, legumes, whole grains, and low-fat dairy while limiting red meat, sugar-sweetened beverages, and ultraprocessed foods 1, 2, 4
• Restrict sodium intake to <2 g/day (approximately 5 g salt) to support blood pressure management 1
• Create an energy deficit of 500–750 kcal/day through reduced intake combined with increased physical activity 3, 5
• Refer to a registered dietitian at diagnosis for individualized medical nutrition therapy, which reduces HbA1c by 0.3–2.0% 3, 4

First-Line Pharmacotherapy

Metformin Initiation and Dosing

• Start metformin 500–850 mg once or twice daily at diagnosis, titrating gradually to ≥2 g/day (or extended-release formulation once daily) to minimize gastrointestinal side effects while maximizing cardiovascular and mortality benefits 1, 2, 4
• Continue metformin indefinitely while tolerated, as it reduces cardiovascular events and all-cause mortality at low cost with a long-standing safety record 2, 6
• Adjust dose according to eGFR: 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 1, 2
• Screen for vitamin B12 deficiency periodically, especially in patients with anemia or peripheral neuropathy, because long-term metformin use can cause biochemical deficiency 2, 3

Second-Line Agent Selection Based on Comorbidities

Patients with Atherosclerotic Cardiovascular Disease (ASCVD) or High ASCVD Risk

• Add a GLP-1 receptor agonist (preferably semaglutide or liraglutide) to metformin regardless of current HbA1c to reduce major adverse cardiovascular events, stroke risk, and achieve substantial weight loss 1, 2, 4
• Liraglutide demonstrated a 22% relative reduction in cardiovascular death (HR 0.78,95% CI 0.66–0.93) and 15% reduction in all-cause mortality (HR 0.85,95% CI 0.74–0.97) in the LEADER trial 2
• Prioritize GLP-1 receptor agonists over insulin when feasible for patients with established ASCVD 1, 2

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

• Add an SGLT-2 inhibitor (empagliflozin, dapagliflozin, or canagliflozin) to metformin regardless of glycemic level to reduce CKD progression by 24–39%, lower heart failure hospitalizations, and decrease cardiovascular and all-cause mortality 1, 2, 6
• Empagliflozin reduced cardiovascular death by 38% (HR 0.62,95% CI 0.49–0.77) in the EMPA-REG OUTCOME trial 2
• 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 1, 2

Patients with Both ASCVD and HF/CKD

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

Third-Line and Additional Agents

When Dual Therapy Fails to Achieve Glycemic Targets

• 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 1, 2
• Consider DPP-4 inhibitors (sitagliptin, linagliptin) when GLP-1 receptor agonists are unsuitable, recognizing modest glucose lowering and no proven cardiovascular advantage 1, 2
• 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 2
• Thiazolidinediones (pioglitazone) may be used selectively, but weigh risks of weight gain, fluid retention, and possible heart failure exacerbation 1, 2

Insulin Initiation Criteria

• 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 long-acting insulin while initiating and titrating metformin 1, 2
• In ketosis or diabetic ketoacidosis, administer immediate subcutaneous or intravenous insulin, then add metformin once acidosis resolves 1, 2
• Prefer long-acting insulin analogs (glargine, degludec, detemir) for their lower weight-gain and hypoglycemia profiles 2
• Continue metformin and the selected SGLT-2 inhibitor or GLP-1 receptor agonist when adding insulin to preserve cardiovascular and renal protection 2

Glycemic Targets

• Target HbA1c 7–8% for most adults to balance efficacy with hypoglycemia risk 2, 4
• Consider a stricter target (<6.5%) for younger, early-disease patients without significant comorbidities, provided hypoglycemia is unlikely 2, 4
• Adopt less stringent targets (7.5–8.5%) for older adults, those with limited life expectancy, advanced complications, extensive comorbidities, or prior severe hypoglycemia 2

Monitoring and Treatment Intensification

• Measure HbA1c every 3 months until the target is reached, then continue quarterly monitoring 2, 4
• Do not postpone therapeutic intensification beyond 3 months of inadequate control, as treatment inertia raises microvascular complication risk 2
• Reassess medication regimen every 3–6 months, adjusting for comorbidities, hypoglycemia risk, weight effects, adverse events, cost, and patient preferences 2
• Watch for over-basalization with insulin (basal dose >0.5 U/kg/day, large bedtime-to-morning glucose gap, frequent hypoglycemia, or high glycemic variability) 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 or calculated cardiovascular risk 2, 3, 4
• Target blood pressure <130/80 mmHg using ACE inhibitors or angiotensin receptor blockers as first-line agents in this population 1, 2, 4
• Initiate lifestyle intervention (weight loss, DASH-style eating pattern, sodium restriction, alcohol moderation, increased physical activity) for blood pressure >120/80 mmHg 1
• For blood pressure ≥140/90 mmHg, begin pharmacologic therapy promptly alongside lifestyle modifications; for blood pressure ≥160/100 mmHg, initiate two drugs or a single-pill combination 1
• Recommend low-dose aspirin (75–162 mg daily) for secondary prevention in patients with established ASCVD, unless contraindicated 2

Common Pitfalls to Avoid

• Do not delay metformin initiation; it should start at diagnosis, not after failed lifestyle modification alone 2, 3, 4
• Do not allow more than two consecutive days without exercise, as this reduces acute insulin-sensitizing effects 2, 3
• Failing to add SGLT-2 inhibitors or GLP-1 receptor agonists early in patients with cardiovascular or kidney disease misses critical opportunities to reduce mortality and morbidity independent of glucose lowering 1, 2, 6
• Do not combine ACE inhibitors with angiotensin receptor blockers or direct renin inhibitors, as this increases hyperkalemia, syncope, and acute kidney injury without added cardiovascular benefit 1
• When adding SGLT-2 inhibitors or GLP-1 receptor agonists, immediately reduce or discontinue sulfonylureas or long-acting insulins to prevent severe hypoglycemia 2