What is the best treatment for diabetes?

Best Treatment for Diabetes

For Type 2 diabetes, start metformin immediately at diagnosis alongside lifestyle modifications (diet and exercise), and if cardiovascular disease, heart failure, or chronic kidney disease is present or the patient is at high cardiovascular risk, add a GLP-1 receptor agonist or SGLT2 inhibitor regardless of baseline glucose control. 1

Type 2 Diabetes Treatment Algorithm

Initial Treatment at Diagnosis

Start pharmacotherapy immediately—do not delay 1:

• Metformin is the preferred first-line agent for most patients with Type 2 diabetes 1, 2
  • Effective at lowering A1C, inexpensive, reduces cardiovascular mortality, and causes no hypoglycemia or weight gain 1
  • Start at diagnosis alongside lifestyle modifications—not as a substitute for them 1
  • Can be continued with declining kidney function down to eGFR 30-45 mL/min/1.73 m² with dose reduction 1
  • Main side effects are gastrointestinal (bloating, diarrhea)—mitigate by gradual titration or using extended-release formulation 1
  • Monitor vitamin B12 levels periodically as metformin causes deficiency and may worsen neuropathy 1

However, if the patient has established atherosclerotic cardiovascular disease, heart failure, chronic kidney disease, or high cardiovascular risk, prioritize adding a GLP-1 receptor agonist or SGLT2 inhibitor immediately 1:

• These agents reduce major adverse cardiovascular events by 12-26%, heart failure hospitalizations by 18-25%, and kidney disease progression by 24-39% over 2-5 years 2
• GLP-1 receptor agonists are preferred over insulin when possible in patients with established cardiovascular disease 1
• This recommendation supersedes traditional glucose-centric approaches 1

When to Start Insulin Immediately

Bypass oral agents and start insulin if 1:

• A1C >10% (>86 mmol/mol) OR blood glucose ≥300 mg/dL (≥16.7 mmol/L) 1
• Symptoms of hyperglycemia are present 1
• Evidence of catabolism (weight loss, ketosis, hypertriglyceridemia) 1
• Diabetic ketoacidosis or marked ketosis 1

Combination Therapy

Add a second agent when A1C remains ≥1.5% above individualized goal after 3 months on metformin 1:

• Options include: sulfonylureas, thiazolidinediones, DPP-4 inhibitors, SGLT2 inhibitors, GLP-1 receptor agonists, or basal insulin 1
• For A1C ≥9% at diagnosis, consider starting dual combination therapy immediately 1
• Early combination therapy extends time to treatment failure 1

Choice of second agent depends on 1:

• Cardiovascular/kidney comorbidities: Use GLP-1 RA or SGLT2i 1
• Weight management goals: GLP-1 RAs (especially semaglutide) and dual GIP/GLP-1 RAs (tirzepatide) cause >5% weight loss in most patients, often >10% 1, 2
• Hypoglycemia risk: Avoid sulfonylureas in elderly, those with erratic meals, or high hypoglycemia risk 1
• Cost and access: Metformin and sulfonylureas are least expensive 1

Important Caveats

When adding new glucose-lowering medications, reassess and reduce doses of sulfonylureas, meglitinides, and insulin to minimize hypoglycemia risk 1:

• Do not combine DPP-4 inhibitors with GLP-1 RAs—no additional benefit 1
• Thiazolidinediones (pioglitazone, rosiglitazone) are contraindicated in serious heart failure 1
• If insulin is used, combination with a GLP-1 receptor agonist is recommended 1

Do not delay treatment intensification—clinical inertia worsens outcomes 1:

• Reevaluate medication regimen every 3-6 months 1
• Individualize A1C targets based on life expectancy, comorbidities, hypoglycemia risk, and patient preferences, but <7% is reasonable for many patients 1

Type 1 Diabetes Treatment

All patients with Type 1 diabetes require insulin—multiple daily injections (≥3 injections/day) or continuous subcutaneous insulin infusion 1:

• Use insulin analogues to reduce hypoglycemia risk 1
• Intensive insulin therapy reduces microvascular complications and cardiovascular disease 1
• Match prandial insulin to carbohydrate intake, preprandial glucose, and anticipated activity 1
• Consider continuous glucose monitoring to reduce severe hypoglycemia 1

Lifestyle Modifications (Essential for All Patients)

All patients must receive diabetes self-management education and medical nutrition therapy 1:

• Physical activity: ≥150 minutes/week of moderate-intensity aerobic activity plus resistance training ≥2 times/week 1
• Weight loss: Counsel overweight/obese patients to lose ≥5% body weight 1
• Diet: No specific diet proven superior, but individualized nutrition plan by registered dietitian recommended 1, 2

Children and Adolescents with Type 2 Diabetes

Start metformin as first-line therapy after ruling out Type 1 diabetes 1:

• Use insulin initially if random glucose ≥250 mg/dL or A1C ≥8.5% (≥69 mmol/mol), then add metformin after resolution of ketosis 1
• GLP-1 receptor agonists are safe and effective for A1C reduction and weight loss in youth 1
• Empagliflozin (SGLT2i) is now approved for pediatric Type 2 diabetes 1
• Target A1C <7% in youth (lower than Type 1 diabetes due to lower hypoglycemia risk and higher complication risk) 1