Treatment Guidelines for Type 2 Diabetes Mellitus
Initial Treatment: Lifestyle Modifications PLUS Metformin
Start metformin at or soon after diagnosis (500 mg daily, increasing by 500 mg every 1-2 weeks up to 2000 mg daily in divided doses) concurrently with lifestyle modifications—do not wait to see if lifestyle changes alone work. 1, 2, 3
Lifestyle Modifications (Implement Immediately)
- Physical activity: Prescribe at least 150 minutes per week of moderate-intensity exercise or 75 minutes of vigorous activity, combining aerobic and resistance training 1, 4
- Weight loss: Target at least 5-10% reduction in body weight for overweight/obese patients through high-intensity interventions (≥16 sessions over 6 months) with a 500-750 kcal/day deficit 1, 2, 4
- Dietary modifications: Focus on nutrient-dense foods, limit calorie-dense/nutrient-poor foods, restrict fat intake to 30-35% of total daily energy (reserving 10% for monounsaturated fatty acids), and avoid trans-fats 1, 2
Why Metformin First-Line
- Metformin reduces all-cause mortality and cardiovascular mortality compared to sulfonylureas 1
- Lowers HbA1c by 1.0-1.5%, reduces body weight, improves lipid profiles, and causes fewer hypoglycemic episodes 1
- Cost-effective with favorable safety profile 1, 2
- Common gastrointestinal side effects are typically transient 1, 2
Exception: When to Start Insulin Instead of Metformin
Initiate insulin as first-line therapy (not metformin) if the patient presents with: 2, 3
- Ketosis or diabetic ketoacidosis
- Random blood glucose ≥250 mg/dL
- HbA1c >8.5-9%
- Symptomatic hyperglycemia with polyuria, polydipsia, and weight loss
Treatment Intensification: Add SGLT-2 Inhibitor or GLP-1 Receptor Agonist
If glycemic targets are not met within 3 months with metformin plus lifestyle modifications, add a second agent—prioritize SGLT-2 inhibitors or GLP-1 receptor agonists based on comorbidities. 2, 4, 3
Selection Algorithm for Second Agent
Add SGLT-2 inhibitor if patient has: 2, 4, 5
- Heart failure (reduces hospitalization by 18-25%)
- Chronic kidney disease (reduces progression by 24-39%)
- Need for cardiovascular protection (reduces major adverse cardiovascular events by 12-26%)
Add GLP-1 receptor agonist if patient has: 2, 4, 5
- High cardiovascular risk (reduces major adverse cardiovascular events by 12-26% and stroke risk)
- Need for significant weight loss (>5-10% body weight reduction)
- Obesity as primary concern
Consider triple therapy (metformin + SGLT-2 inhibitor + GLP-1 receptor agonist) if dual therapy insufficient—real-world evidence shows this combination provides superior reduction in mortality, cardiovascular events, and heart failure compared to other combinations. 6
What NOT to Add
Do not add DPP-4 inhibitors to metformin—the American College of Physicians explicitly recommends against this. 2, 4
Glycemic Targets and Monitoring
- Target HbA1c <7% for most adults 1, 2, 3
- More stringent target of <6.5% may be appropriate for selected individuals if achievable without significant hypoglycemia 2
- De-intensify therapy if HbA1c <6.5% to reduce hypoglycemia risk 4
- Monitor HbA1c every 3 months until target reached, then at least twice yearly 2, 3
- Self-monitoring of blood glucose may be unnecessary in patients on metformin alone or combined with SGLT-2 inhibitor/GLP-1 receptor agonist 2, 4
When to Add Insulin
Consider insulin therapy when triple oral therapy fails to achieve glycemic targets: 3
- Start with basal insulin at 0.5 units/kg/day
- Titrate every 2-3 days based on blood glucose monitoring
- Add prandial insulin if escalating basal insulin doses don't achieve targets
Important adjustment: When adding SGLT-2 inhibitor or GLP-1 receptor agonist achieves adequate control, reduce or discontinue existing sulfonylureas or long-acting insulin due to severe hypoglycemia risk 4
Critical Pitfalls to Avoid
- Clinical inertia: Do not delay treatment intensification when glycemic targets are not met after 3 months—this leads to worse long-term outcomes 2, 3
- Sulfonylurea use: Avoid sulfonylureas as they are associated with higher mortality compared to modern SGLT-2 inhibitors and GLP-1 receptor agonists 6
- Thiazolidinediones in heart failure: Both rosiglitazone and pioglitazone are contraindicated in patients with serious heart failure 1
- Medication adjustment during illness: Always adjust medications during acute illness or procedures 2, 3
Special Considerations for Children and Adolescents
- Metformin remains first-line for youth with mild hyperglycemia without ketonuria 1
- Short-term insulin may be beneficial in newly diagnosed youth with poor glycemic control but without ketosis 1
- Important caveat: The TODAY trial showed metformin alone is inadequate for sustained glycemic control in the majority of youth with diabetes, suggesting more aggressive therapy may be needed earlier 1