How to treat insulin resistance?

Treatment of Insulin Resistance

Begin with intensive lifestyle modification as the foundation of treatment, targeting 5-10% weight loss through structured programs combining dietary changes and at least 150 minutes weekly of moderate-intensity aerobic exercise, then add metformin as first-line pharmacological therapy starting at 500 mg daily and titrating to 2000 mg daily in divided doses. 1, 2

Lifestyle Interventions: The Cornerstone of Treatment

Lifestyle modification is not optional—it is the primary treatment for insulin resistance and must be implemented immediately. 1

Weight Loss Targets

• Achieve 5-10% reduction in body weight for overweight/obese individuals, which significantly improves insulin sensitivity independent of the mechanism used to achieve weight loss. 1, 2
• Structured programs emphasizing education, reduced energy intake with fat comprising ≤30% of total energy, and consistent participant contact produce long-term sustainable results. 1

Exercise Prescription (Specific Requirements)

• Perform at least 150 minutes per week of moderate-intensity aerobic exercise (50-70% maximum heart rate), spread over at least 3 days with no more than 2 consecutive days without activity. 1, 2
• Add resistance training at least twice weekly involving all major muscle groups, as this improves insulin sensitivity to the same or greater extent as aerobic exercise. 1
• Combined aerobic and resistance training provides additive benefits beyond either modality alone. 1
• For pediatric patients, increase the target to at least 60 minutes of physical activity daily. 1

Dietary Modifications (Specific Framework)

• Follow the DASH (Dietary Approaches to Stop Hypertension) diet framework emphasizing fruits, vegetables, low-fat dairy products, whole grains, poultry, fish, and nuts while reducing fats, red meat, sweets, and sugar-containing beverages. 1, 2
• Avoid low-carbohydrate diets restricting total carbohydrate to <130 g/day, as long-term effects are unknown and cardiovascular risk profile impact is uncertain. 1

Pharmacological Management: Metformin as First-Line

Start metformin immediately at diagnosis unless contraindicated, and continue it even when adding other medications including insulin. 2

Metformin Dosing Protocol

• Begin at 500 mg daily with gradual titration, increasing by 500 mg every 1-2 weeks to minimize gastrointestinal side effects. 1
• Target dose is 2000 mg daily in divided doses for optimal metabolic benefit. 1
• Metformin has Grade A evidence (strongest level of support from multiple high-quality studies) as first-line therapy. 2

Advanced Pharmacological Options: When to Escalate

Do not delay treatment intensification—therapeutic inertia worsens outcomes. 2

Adding Second-Line Agents

• If A1C remains above goal after 3-6 months of metformin plus lifestyle modification, add GLP-1 receptor agonist or SGLT2 inhibitor. 2
• For patients with or at high risk for cardiovascular disease, heart failure, or chronic kidney disease, prioritize medications with proven cardiovascular and renal benefits (GLP-1 receptor agonists or SGLT2 inhibitors). 2
• GLP-1 receptor agonists are preferred over insulin when possible, as they improve insulin sensitivity while providing cardiovascular protection. 2

Insulin Therapy for Severe Insulin Resistance

• For patients requiring large insulin doses due to severe insulin resistance, concentrated insulin preparations (U-500 regular insulin, U-300 glargine, U-200 degludec, U-200 lispro) may be more convenient and improve treatment adherence. 3
• U-500 regular insulin is available in both prefilled pens and vials; other concentrated insulins are available only in prefilled pens to minimize dosing errors. 3
• Monitor for overbasalization when basal insulin doses exceed 0.5 units/kg/day without adequate glycemic control—consider adding GLP-1 receptor agonist rather than increasing insulin further. 2

Fixed-Ratio Combination Products

• Consider insulin degludec/liraglutide (IDegLira) or insulin glargine/lixisenatide (iGlarLixi) for patients requiring both basal insulin and GLP-1 receptor agonist therapy. 3, 2
• These combinations demonstrate greater durability of glycemic treatment effect compared with basal insulin alone. 3

Alternative Insulin Sensitizers

Thiazolidinediones (Pioglitazone)

• Pioglitazone improves insulin sensitivity by decreasing insulin resistance in muscle and adipose tissue and inhibiting hepatic gluconeogenesis. 4
• This class enhances cellular responsiveness to insulin and improves dysfunctional glucose homeostasis. 4
• Consider in patients with severe insulin resistance who cannot tolerate or have inadequate response to metformin, though use has declined due to side effect profile. 5, 6

Special Population Considerations

Exercise Precautions

• In proliferative diabetic retinopathy or severe non-proliferative diabetic retinopathy, avoid vigorous aerobic or resistance exercise that may trigger vitreous hemorrhage or retinal detachment. 1
• In severe peripheral neuropathy, avoid treadmill, prolonged walking, jogging, and step exercises; instead recommend swimming, bicycling, rowing, and chair exercises. 1
• Patients on insulin or insulin secretagogues should monitor for hypoglycemia during exercise and ingest added carbohydrate if pre-exercise glucose <100 mg/dL. 2

High-Risk Individuals Requiring Intensive Approaches

• 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 early combination therapy with metformin and lifestyle modification. 2

Elderly Patients (≥65-70 years)

• Focus on drug safety, prioritizing strategies that minimize hypoglycemia risk, heart failure, renal dysfunction, bone fractures, and drug-drug interactions. 1
• Less stringent glycemic targets (HbA1c <7.5-8.0%) may be appropriate for those with long-standing or complicated disease. 1

Pregnancy

• Insulin is the preferred medication for treating hyperglycemia in pregnancy, with target fasting glucose <95 mg/dL and either one-hour postprandial <140 mg/dL or two-hour postprandial <120 mg/dL. 1

Monitoring and Reassessment

• Monitor HbA1c every 3 months until target is achieved, then at least twice yearly. 1
• Reevaluate medication regimen and medication-taking behavior every 3-6 months and adjust as needed. 2
• Expect A1C reduction of 0.7-1.0% with each new class of oral agent added to metformin, and 1-2% with GLP-1 receptor agonists. 2
• Assess for improvement in markers of insulin resistance including fasting glucose, lipid profile, and blood pressure. 1
• Comprehensive cardiovascular risk reduction must remain a major focus of therapy, as insulin resistance is strongly associated with cardiovascular disease, hypertension, and dyslipidemia. 1, 2

Common Pitfalls to Avoid

• Therapeutic inertia: Delaying treatment intensification when goals are not met worsens outcomes—act decisively at 3-6 month intervals. 2
• Overbasalization with insulin: Continuing to increase basal insulin beyond 0.5 units/kg/day without adding other agents leads to weight gain and hypoglycemia without adequate glycemic control. 2
• Discontinuing metformin when adding insulin: Metformin should be continued for ongoing metabolic benefits even when insulin is initiated. 2
• Ignoring lifestyle modification: Pharmacotherapy without concurrent intensive lifestyle intervention significantly reduces treatment effectiveness. 1, 2