What are the treatment options for a patient with Type 2 diabetes mellitus (T2DM)?

Treatment Options for Type 2 Diabetes

Start metformin 500-850 mg once or twice daily with meals alongside comprehensive lifestyle modifications as first-line therapy for all newly diagnosed Type 2 diabetes patients without contraindications. 1

Initial Pharmacologic Therapy

Metformin is the cornerstone first-line medication for Type 2 diabetes management, supported by the American College of Physicians and American Diabetes Association guidelines. 1 The drug works by reducing hepatic glucose production and improving insulin sensitivity, with a well-established safety profile spanning decades of clinical use. 2

When to Start Insulin Immediately (Without Delay)

Bypass metformin and initiate insulin therapy immediately if any of the following are present: 3, 1

• Diabetic ketoacidosis or ketonuria
• Random blood glucose ≥250 mg/dL (≥13.9 mmol/L)
• HbA1c ≥8.5% (≥69 mmol/mol)

Initial insulin dosing: Start at 0.5 units/kg/day, adjusting every 2-3 days based on blood glucose monitoring. 3, 1 Once ketosis resolves and glucose normalizes, add metformin while continuing insulin. 3 Many patients can subsequently be weaned off insulin and managed with metformin alone. 3

For newly diagnosed patients with HbA1c >9.0% or fasting plasma glucose ≥11.1 mmol/L with symptomatic hyperglycemia, consider short-term intensive insulin therapy (2 weeks to 3 months) to restore beta-cell function. 4

Second-Line Therapy: Adding Cardioprotective Agents

Add an SGLT-2 inhibitor or GLP-1 receptor agonist to metformin when HbA1c remains above target after 3 months at maximum tolerated metformin dose. 1 This recommendation represents a paradigm shift from older guidelines that prioritized glycemic control alone—these newer agents provide substantial cardiovascular and renal protection beyond glucose lowering. 5

SGLT-2 Inhibitors

SGLT-2 inhibitors reduce hospitalization for congestive heart failure more effectively than GLP-1 agonists and reduce chronic kidney disease progression by 24-39%. 1, 5 Empagliflozin is now FDA-approved for Type 2 diabetes in children ≥10 years old. 4, 3

Common adverse effects: Genital mycotic infections, urinary tract infections; rare but serious risks include ketoacidosis, acute kidney injury, bone fracture, and toe amputation (specifically with canagliflozin). 4

GLP-1 Receptor Agonists

GLP-1 receptor agonists specifically reduce stroke risk beyond SGLT-2 inhibitors and provide substantial weight loss (>5% in most patients, often exceeding 10% with high-potency agents). 1, 5 These medications enhance glucose-dependent insulin secretion, inhibit glucagon secretion, delay gastric emptying, and suppress appetite centrally. 4

Available agents include: Exenatide, liraglutide, lixisenatide, and beinaglutide (all require subcutaneous injection). 4 Liraglutide is FDA-approved for youth ≥10 years old. 4

Contraindication: Do not use in patients with personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2. 4

Common adverse effects: Gastrointestinal symptoms (nausea, vomiting) occur mainly during initial treatment and gradually diminish with continued use. 4

Cardiovascular benefits: Liraglutide, lixisenatide, and exenatide provide protective effects in patients with established cardiovascular disease or cardiovascular risk factors, with 12-26% risk reduction for atherosclerotic cardiovascular disease over 2-5 years. 4, 5

Third-Line and Add-On Options

When Second-Line Agents Are Insufficient

If glycemic targets are not met with metformin plus SGLT-2 inhibitor or GLP-1 receptor agonist, consider: 1

• Dual GIP/GLP-1 receptor agonists (provide superior weight loss compared to single GLP-1 agonists)
• Basal insulin (start with intermediate-acting or long-acting insulin analogs)
• Combination therapy with multiple agents

Medications to Avoid

Strong recommendation against adding DPP-4 inhibitors to metformin for reducing morbidity and mortality—they demonstrate inferior outcomes compared to SGLT-2 inhibitors and GLP-1 agonists. 1

Sulfonylureas are no longer recommended due to higher mortality and adverse effects versus SGLT-2 inhibitors/GLP-1 agonists. 1 While they effectively lower glucose, they increase hypoglycemia risk and cause weight gain.

Thiazolidinediones (pioglitazone) can reduce HbA1c by 0.8-1.3% when added to metformin or sulfonylureas, but cause weight gain and fluid retention. 6 They are not preferred second-line agents given superior alternatives.

Insulin Intensification Strategies

Approximately one-third of patients with Type 2 diabetes require insulin during their lifetime. 5 When basal insulin alone is insufficient:

• Add prandial insulin to create a basal-bolus regimen (2-4 injections daily) 4
• Consider premixed insulin (2-3 times daily) as an alternative 4
• Continuous subcutaneous insulin infusion (CSII) is available for selected patients 4

Total daily insulin requirements may exceed 1 unit/kg/day in insulin-resistant patients. 4

Lifestyle Interventions: The Foundation

While no specific diet has proven most effective for improving health outcomes, physical activity reduces HbA1c by 0.4-1.0% and improves cardiovascular risk factors including hypertension and dyslipidemia. 5, 7 Exercise should include aerobic, muscle-strengthening, and bone-strengthening activities. 4

Intensive glucose-lowering strategies (HbA1c <7%) demonstrate absolute reductions in microvascular disease (3.5%), myocardial infarction (3.3-6.2%), and mortality (2.7-4.9%) two decades after trial completion. 5 This legacy effect underscores the importance of early aggressive management.

Monitoring and Targets

• Check HbA1c every 3 months until target is reached 3, 1
• Target HbA1c between 7-8% in most adults; individualize based on hypoglycemia risk, life expectancy, and comorbidities 1
• Deintensify therapy if HbA1c <6.5% to reduce hypoglycemia risk 1
• Blood glucose monitoring required for: patients on insulin, medications with hypoglycemia risk, treatment initiation/changes, not meeting goals, or during intercurrent illness 3, 1

Cardiovascular Risk Management

For all adults 40-75 years with diabetes: Moderate-intensity statin therapy is indicated regardless of 10-year ASCVD risk. 1 With multiple ASCVD risk factors, high-intensity statin therapy targeting ≥50% LDL-C reduction is reasonable. 1

For patients with established cardiovascular disease, kidney disease, or high cardiovascular risk: Add SGLT-2 inhibitor or GLP-1 receptor agonist regardless of HbA1c level. 1 These agents provide cardioprotection independent of glycemic effects.

Special Considerations for Metabolic Surgery

Metabolic surgery may be considered for patients with Type 2 diabetes and severe obesity (BMI >35 kg/m²) who have uncontrolled glycemia and/or serious comorbidities despite lifestyle and pharmacologic intervention. 4 Surgery should only be performed by experienced surgeons within a multidisciplinary team. 4