Treatment of Insulin Resistance

Initial Pharmacologic Approach

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, for patients with insulin resistance or type 2 diabetes 1
Metformin is the cornerstone medication for treating insulin resistance and should be started at diagnosis unless contraindicated, with a recommendation to start metformin immediately at diagnosis of insulin resistance or type 2 diabetes, combined with lifestyle changes 1, 2
Continue metformin even when adding other medications, including insulin, for ongoing metabolic benefits 1

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, as part of a comprehensive lifestyle modification program for patients with insulin resistance 3
Include 2-3 sessions of resistance exercise per week on non-consecutive days, involving major muscle groups, to improve insulin sensitivity 3
Target 5-7% weight loss of initial body weight for those who are overweight or obese, through a combination of diet and exercise, to improve insulin sensitivity 3
Follow a diet rich in fruits, vegetables, whole grains, lean proteins, and low-fat dairy products, and reduce intake of refined carbohydrates, added sugars, and sugar-containing beverages, to support weight loss and improve insulin sensitivity 3

For patients with or at high risk for cardiovascular disease, heart failure, or chronic kidney disease, consider adding medications with proven cardiovascular and renal benefits, such as GLP-1 receptor agonists or SGLT2 inhibitors, to metformin and lifestyle modification 1, 2
GLP-1 receptor agonists are preferred over insulin when possible, as they improve insulin sensitivity while providing cardiovascular protection, and can be initiated with or without metformin based on glycemic needs 1, 2
SGLT2 inhibitors offer both glucose-lowering and cardio-renal protection, and can be used in combination with metformin and GLP-1 receptor agonists 1, 2

Do not delay treatment intensification when goals are not met—therapeutic inertia worsens outcomes, and consider adding GLP-1 receptor agonist or SGLT2 inhibitor to metformin and lifestyle modification if A1C remains above goal after 3-6 months 1, 2
If A1C still above goal or basal insulin dose >0.5 units/kg/day, consider adding basal insulin to metformin and GLP-1 receptor agonist combination, or using fixed-ratio combination products (insulin degludec/liraglutide or insulin glargine/lixisenatide) 1, 2, 6
Monitor for overbasalization with insulin, which occurs when basal insulin doses exceed 0.5 units/kg/day without adequate glycemic control, and consider adding GLP-1 receptor agonist rather than increasing insulin further if overbasalization is identified 1, 2, 7

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, including early combination therapy with metformin and lifestyle modification 4
Patients on insulin or insulin secretagogues should monitor for hypoglycemia during exercise, and added carbohydrate should be ingested if pre-exercise glucose levels are <100 mg/dL 3, 8

Reevaluate medication regimen and medication-taking behavior every 3-6 months and adjust as needed, with a goal of achieving an 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 1, 2