What is the recommended management strategy for an adult with type 2 diabetes mellitus, including lifestyle modifications, first‑line medication, and subsequent therapy choices based on cardiovascular, renal, or heart‑failure comorbidities and glycemic targets?

Management of Type 2 Diabetes Mellitus

Start metformin immediately at diagnosis alongside lifestyle modifications, then add an SGLT-2 inhibitor or GLP-1 receptor agonist based on comorbidities—prioritizing SGLT-2 inhibitors for heart failure or chronic kidney disease, and GLP-1 receptor agonists for atherosclerotic cardiovascular disease or weight loss needs. 1, 2

Lifestyle Modifications

• Implement a heart-healthy dietary pattern with adequate protein intake to prevent sarcopenia in older adults and achieve 5-7% weight loss if overweight or obese. 1, 2
• Prescribe at least 150 minutes weekly of moderate-intensity aerobic activity combined with resistance training and weight-bearing exercise as tolerated. 1, 2
• Inadequate protein intake increases sarcopenia and frailty risk, particularly in older adults with diabetes, so special attention to nutritional adequacy is essential. 1

First-Line Pharmacotherapy

• Initiate metformin at diagnosis (unless contraindicated) as it reduces cardiovascular events and death, is inexpensive, and should be continued indefinitely as long as tolerated. 1, 2
• Start with gradual dose titration to mitigate gastrointestinal side effects (bloating, diarrhea), aiming for at least 2000 mg daily (1000 mg twice daily) or extended-release formulation once daily. 1, 3
• Metformin is safe with eGFR ≥30 mL/min/1.73 m² and should not be discontinued when adding other agents. 4, 3

Glycemic Targets

• Target HbA1c of 7-8% for most adults, with individualized goals based on life expectancy, comorbidities, and hypoglycemia risk. 2
• In older adults, avoid overtreatment and select medications with low hypoglycemia risk (avoid sulfonylureas, meglitinides, and excessive insulin). 1

Second-Line Therapy Selection Algorithm

When to Add Second Agent

• Add a second agent after 3 months if HbA1c remains above goal on maximum tolerated metformin dose—do not delay intensification. 4, 2
• Check HbA1c every 3 months until glycemic targets are achieved. 4

Choice Based on Comorbidities

For established atherosclerotic cardiovascular disease (ASCVD) or high ASCVD risk:

• Add a GLP-1 receptor agonist (semaglutide or tirzepatide preferred) as they primarily reduce atherosclerotic events, stroke risk, and provide very high efficacy for weight loss. 1, 4, 2, 5
• GLP-1 receptor agonists are preferred over insulin when possible. 1

For heart failure (HF) or chronic kidney disease (CKD):

• Add an SGLT-2 inhibitor as they reduce CKD progression by 24-39%, decrease heart failure hospitalizations, and lower cardiovascular and all-cause mortality. 1, 4, 2, 5, 6, 7
• SGLT-2 inhibitors provide cardiorenal protection through multiple mechanisms including natriuresis, reduced glomerular hyperfiltration, RAAS modulation, and anti-inflammatory effects. 6, 7, 8

For patients requiring maximum weight loss:

• Prioritize semaglutide or tirzepatide (GLP-1 receptor agonists) which demonstrate very high efficacy for weight loss. 1, 4, 2

Critical principle: In patients with established ASCVD, HF, or CKD, add SGLT-2 inhibitors or GLP-1 receptor agonists regardless of current HbA1c level to reduce mortality and morbidity, independent of glycemic control. 1, 4, 2

Special Intensification Scenarios

Severe Hyperglycemia at Diagnosis

• For HbA1c ≥9%: Initiate dual therapy immediately (metformin plus SGLT-2 inhibitor or GLP-1 receptor agonist) rather than sequential monotherapy. 4
• For HbA1c ≥10% or glucose ≥300 mg/dL: Consider initiating insulin therapy (with or without additional agents) from the outset, especially if symptomatic with weight loss or evidence of catabolism, to prevent metabolic decompensation and preserve beta-cell function. 1, 4, 3

Insulin Initiation Protocol

• Start basal insulin at 10 units once daily or 0.1-0.2 units/kg/day, targeting fasting glucose 80-130 mg/dL. 3
• Titrate by 2-4 units every 3 days based on fasting glucose readings with daily monitoring during titration. 3
• Add prandial insulin (4 units rapid-acting before largest meal or 10% of basal dose) when basal insulin exceeds 0.5 units/kg/day and postprandial glucose remains elevated—do not continue escalating basal insulin alone. 3
• Continue metformin unless contraindicated, as it reduces total insulin requirements. 3

Critical Safety Measures and Pitfalls to Avoid

Hypoglycemia Prevention

• When SGLT-2 inhibitors or GLP-1 receptor agonists achieve adequate glycemic control, immediately reduce or discontinue sulfonylureas or long-acting insulins due to severe hypoglycemia risk. 4, 2
• SGLT-2 inhibitors and GLP-1 receptor agonists do not cause hypoglycemia when used without insulin or sulfonylureas. 4
• In older adults, deintensify hypoglycemia-causing medications (insulin, sulfonylureas, meglitinides) for those at high risk, using individualized glycemic goals. 1

Treatment Inertia

• Do not delay intensification beyond 3 months of inadequate control, as this increases microvascular complication risk. 4
• Recommendation for treatment intensification should not be delayed for patients not meeting goals. 1

Medication Continuation

• Never stop metformin when adding other agents unless contraindicated or not tolerated—it should be continued at maximum tolerated dose. 4, 3

Older Adults Specific Considerations

• Simplify complex treatment plans (especially insulin regimens) to reduce hypoglycemia risk, polypharmacy, and treatment burden within individualized glycemic goals. 1
• In older adults with T2D and established or high risk of ASCVD, HF, or CKD, the treatment plan should include agents that reduce cardiovascular and kidney disease risk, irrespective of glycemia. 1
• Consider costs of care and coverage when developing treatment plans to reduce cost-related barriers to medication adherence. 1

Comprehensive Cardiovascular Risk Management

• Initiate moderate-intensity statin therapy in adults 40-75 years with diabetes regardless of 10-year cardiovascular disease risk. 2
• Treat hypertension to individualized target levels with strong evidence supporting treatment in older adults. 1
• Calculate BMI annually or more frequently to identify adults with overweight and obesity for weight loss interventions. 2