What is the best way to treat insulin resistance in someone?

Treatment of Insulin Resistance

First-line therapy for insulin resistance is metformin combined with comprehensive lifestyle modification including at least 150 minutes per week of moderate-intensity aerobic exercise and 5-7% weight loss. 1, 2

Initial Pharmacologic Approach

Metformin is the cornerstone medication for treating insulin resistance and should be started at diagnosis unless contraindicated. 1 The American Diabetes Association designates metformin as first-line therapy with Grade A evidence, meaning it has the strongest level of support from multiple high-quality studies. 1

Key Pharmacologic Considerations:

• Start metformin immediately at diagnosis of insulin resistance or type 2 diabetes, combined with lifestyle changes 1
• Metformin improves insulin sensitivity by enhancing cellular responsiveness to insulin and improving hepatic sensitivity to insulin 3
• Monitor vitamin B12 levels in patients taking metformin, as deficiency can occur with long-term use 2
• Continue metformin even when adding other medications, including insulin, for ongoing metabolic benefits 1

Intensive Lifestyle Modification

Lifestyle changes must be intensive to meaningfully improve insulin sensitivity—modest interventions are insufficient. 4 A landmark randomized controlled trial demonstrated that only intensive (not modest) lifestyle programs significantly improved insulin sensitivity by 23%, while current standard recommendations showed no significant benefit. 4

Exercise Requirements:

• Perform at least 150 minutes per week of moderate-intensity aerobic activity, spread over at least 3 days with no more than 2 consecutive days without activity 2
• Include 2-3 sessions of resistance exercise per week on non-consecutive days, involving major muscle groups 2
• Break up prolonged sedentary periods (≥30 minutes) by briefly standing, walking, or performing light physical activities 2
• Improved aerobic fitness appears to be the major determinant of insulin sensitivity improvement 4

Weight Management:

• Target 5-7% weight loss of initial body weight for those who are overweight or obese 2
• Create a caloric deficit of 500-1,000 calories per day from estimated maintenance needs 2
• Weight loss primarily explains the success of lifestyle modification in improving insulin sensitivity 5

Dietary Approach:

• Follow a diet rich in fruits, vegetables, whole grains, lean proteins, and low-fat dairy products 2
• Reduce intake of refined carbohydrates, added sugars, and sugar-containing beverages 2
• Maintain adequate fiber intake, which has been associated with improved insulin sensitivity 2
• Maintain consistency in timing and amount of food intake to help regulate blood glucose levels 2

Advanced Pharmacologic Options

When metformin and lifestyle modification are insufficient, consider adding medications with proven cardiovascular and renal benefits rather than simply intensifying glucose control. 1

Second-Line Agents (in order of preference):

For patients with or at high risk for cardiovascular disease, heart failure, or chronic kidney disease:

• GLP-1 receptor agonists are preferred over insulin when possible, as they improve insulin sensitivity while providing cardiovascular protection 1
• SGLT2 inhibitors offer both glucose-lowering and cardio-renal protection 1
• These agents can be initiated with or without metformin based on glycemic needs 1

Thiazolidinediones (TZDs):

• Pioglitazone directly improves insulin sensitivity by enhancing cellular responsiveness to insulin and improving hepatic sensitivity 3
• Pioglitazone reduces cardiovascular events in insulin-resistant patients with recent stroke or TIA 1
• Major limitations: weight gain, edema, fracture risk, and heart failure exacerbation 1, 3
• Should be reduced in dose or stopped when combined with insulin to avoid excessive edema and weight gain 1

Treatment Intensification Algorithm

Do not delay treatment intensification when goals are not met—therapeutic inertia worsens outcomes. 1

Stepwise Approach:

1. If A1C remains above goal after 3-6 months on metformin + lifestyle:

   • Add GLP-1 receptor agonist (preferred for CV benefit) OR
   • Add SGLT2 inhibitor (preferred for CV/renal benefit) 1

2. If A1C still above goal or basal insulin dose >0.5 units/kg/day:

   • Add basal insulin to metformin + GLP-1 RA combination 1
   • Fixed-ratio combination products (insulin degludec/liraglutide or insulin glargine/lixisenatide) are available 1

3. If fasting glucose controlled but A1C remains elevated:

   • Add prandial insulin starting with 4 units or 10% of basal dose before the largest meal 1

Critical Pitfall to Avoid:

Overbasalization with insulin occurs when basal insulin doses exceed 0.5 units/kg/day without adequate glycemic control. 1 Clinical signals include:

• Basal dose >0.5 units/kg/day
• Large bedtime-morning glucose differential (≥50 mg/dL)
• Hypoglycemia episodes
• High glycemic variability

When overbasalization is identified, add GLP-1 receptor agonist rather than increasing insulin further. 1

Special Populations

High-Risk Individuals Requiring Aggressive Treatment:

Individuals with BMI ≥35 kg/m², fasting glucose 110-125 mg/dL, 2-hour glucose 173-199 mg/dL, A1C ≥6.0%, or history of gestational diabetes require more intensive preventive approaches. 1 These patients have crude diabetes incidence of 14-22 cases per 100 person-years and warrant early combination therapy. 1

Patients on Insulin or Insulin Secretagogues:

• Monitor for hypoglycemia during exercise 2
• Added carbohydrate should be ingested if pre-exercise glucose levels are <100 mg/dL 1
• Hypoglycemia is rare in patients not treated with insulin or insulin secretagogues 1

Monitoring and Reassessment

Reevaluate medication regimen and medication-taking behavior every 3-6 months and adjust as needed. 1 Each new class of oral agent added to metformin generally lowers A1C by approximately 0.7-1.0%, while GLP-1 receptor agonists typically lower A1C by 1-2%. 1