What treatments, aside from metformin, can improve insulin resistance in an adult with pre‑diabetes or early type 2 diabetes?

Treatments Beyond Metformin for Insulin Resistance

For adults with prediabetes or early type 2 diabetes, lifestyle modifications—specifically weight loss through caloric restriction and regular exercise—are the most effective non-pharmacologic interventions to improve insulin resistance, and when additional pharmacotherapy is needed beyond metformin, GLP-1 receptor agonists (particularly semaglutide or dulaglutide) should be added first due to their superior A1C reduction, cardiovascular benefits, and weight loss effects. 1, 2

Lifestyle Modifications: First-Line Non-Pharmacologic Approach

Weight loss and exercise are foundational interventions that directly improve insulin sensitivity:

• Caloric restriction and weight reduction improve insulin responsiveness independent of medication, with evidence showing sustained benefits in diabetes prevention 3, 4
• Regular physical activity including both aerobic exercise and resistance training enhances peripheral glucose uptake and reduces insulin resistance 3, 4
• The Diabetes Prevention Program demonstrated that intensive lifestyle modification (targeting 7% weight loss and 150 minutes/week of physical activity) reduced diabetes incidence by 58% in high-risk individuals 3

GLP-1 Receptor Agonists: Preferred Add-On Therapy

When metformin alone is insufficient, GLP-1 receptor agonists are the preferred second agent:

• Semaglutide or dulaglutide should be prioritized based on cardiovascular outcome trial data, providing 1.5-2.0% additional A1C reduction beyond metformin 1
• These agents reduce cardiovascular mortality, myocardial infarction, and stroke in patients with established cardiovascular disease or high cardiovascular risk 1
• GLP-1 receptor agonists promote significant weight loss, which independently improves insulin resistance 3, 5
• Reassess A1C at 3 months: if A1C remains >9%, add basal insulin; if A1C is 8-9%, consider SGLT2 inhibitor or increased GLP-1 RA dose 1

SGLT2 Inhibitors: Cardiovascular and Renal Benefits

SGLT2 inhibitors provide insulin-independent glucose lowering with additional metabolic benefits:

• These agents block glucose reabsorption in the proximal renal tubule, providing modest weight loss and blood pressure reduction 3
• Preferred for patients with heart failure, chronic kidney disease, or established atherosclerotic cardiovascular disease 2
• Empagliflozin is now FDA-approved for youth with type 2 diabetes, demonstrating 0.84% A1C reduction 3
• Caution: Verify eGFR ≥30 mL/min/1.73 m² before initiating, and avoid use with eGFR <45 mL/min/1.73 m² 1, 2

Thiazolidinediones: Direct Insulin Sensitizers

Thiazolidinediones (pioglitazone, rosiglitazone) directly target insulin resistance through different mechanisms than metformin:

• These agents increase peripheral glucose uptake while metformin primarily suppresses hepatic glucose output, making them complementary 6
• Thiazolidinediones reduce free fatty acids, improve lipid profiles, increase adiponectin, and reduce inflammatory markers like C-reactive protein 6
• Major limitation: Associated with weight gain, fluid retention, increased fracture risk, and heart failure exacerbation 3
• Rosiglitazone use is severely restricted by FDA due to cardiovascular concerns 3

Insulin Therapy: When Oral Agents Are Insufficient

Insulin becomes necessary as beta-cell function progressively declines:

• Initiate insulin immediately when presenting with ketoacidosis, random glucose ≥250 mg/dL, or A1C ≥8.5% 3
• Continue metformin when starting insulin to reduce insulin requirements, prevent weight gain, and improve lipid profiles 7
• Expect to reduce insulin doses by 10-15% when adding metformin to prevent hypoglycemia 7
• Long-acting insulin analogs (glargine, detemir, degludec) have lower hypoglycemia risk than NPH insulin 3

Treatment Algorithm for Insulin Resistance

Follow this stepwise approach:

1. At diagnosis: Initiate lifestyle modifications (targeting 7% weight loss, 150 min/week exercise) plus metformin 2000-2550 mg daily 3
2. At 3 months: If A1C not at goal, add GLP-1 receptor agonist (semaglutide or dulaglutide preferred) 1, 2
3. At 6 months: If A1C remains elevated, add SGLT2 inhibitor (especially if cardiovascular/renal disease present) or basal insulin 1, 2
4. Ongoing: Check vitamin B12 levels annually on metformin; monitor renal function every 3-6 months 3, 7

Common Pitfalls to Avoid

Critical safety considerations:

• Do not discontinue metformin when starting insulin—combination therapy is superior to insulin alone 7
• Avoid SGLT2 inhibitors in patients with eGFR <45 mL/min/1.73 m² 2
• Screen for contraindications before using GLP-1 receptor agonists in patients with family history of medullary thyroid cancer 3
• Monitor for vitamin B12 deficiency in long-term metformin users (occurs in 10-30%), which can cause peripheral neuropathy 3, 7
• Avoid thiazolidinediones in patients with heart failure due to fluid retention risk 3