What is the sequence of use of oral hypoglycemic agents (OHAs) in type 2 diabetes?

Sequence of Oral Hypoglycemic Agents in Type 2 Diabetes

Metformin monotherapy should be initiated at or soon after diagnosis of type 2 diabetes as first-line therapy, followed by sequential addition of a second agent (sulfonylurea, DPP-4 inhibitor, SGLT2 inhibitor, GLP-1 receptor agonist, or thiazolidinedione) if A1C remains above target after 3 months, with progression to combination injectable therapy or basal insulin if dual therapy fails to achieve glycemic goals. 1

Initial Therapy: Metformin as Foundation

• Start metformin 500 mg once or twice daily with meals at the time of diagnosis unless contraindicated or not tolerated, titrating gradually to a maximum effective dose of 2000 mg/day over 2-4 weeks to minimize gastrointestinal side effects 1, 2

• Metformin is preferred because it is effective (reduces A1C by 1.1-1.5%), safe, inexpensive, weight-neutral or promotes modest weight loss, and may reduce cardiovascular events and death 1, 3

• Metformin can be safely used in patients with estimated glomerular filtration rate as low as 30 mL/min/1.73 m², though dose reduction is required 1

• Monitor for vitamin B12 deficiency with periodic testing, especially in patients with anemia or peripheral neuropathy, as long-term metformin use is associated with biochemical B12 deficiency 1, 4

Exception: When to Skip Metformin and Start Insulin

Consider initiating insulin therapy (with or without additional agents) in patients with newly diagnosed type 2 diabetes who present with:

• A1C ≥10-12% and/or blood glucose ≥300-350 mg/dL (16.7-19.4 mmol/L), especially if symptomatic or showing catabolic features 1
• Markedly symptomatic hyperglycemia at presentation 1
• In these cases, basal insulin plus one mealtime insulin is the preferred initial regimen 1

Second-Line Therapy: Adding a Second Agent

If metformin monotherapy at maximum tolerated dose does not achieve or maintain A1C target after 3 months, add a second oral agent, GLP-1 receptor agonist, or basal insulin 1

Selection of Second Agent Based on Patient Factors:

• For patients with established cardiovascular disease or high cardiovascular risk: Add an SGLT2 inhibitor or GLP-1 receptor agonist with demonstrated cardiovascular benefit, independent of A1C level 1, 2

• For patients with chronic kidney disease (eGFR 20-60 mL/min/1.73 m²): Prioritize SGLT2 inhibitors for renal protection 2

• For patients with heart failure: Add SGLT2 inhibitors 1, 2

• For patients prioritizing weight loss: Add GLP-1 receptor agonist (provides 5 kg weight loss over one year) or SGLT2 inhibitor (provides 2-3% body weight reduction) 2

• For cost-conscious patients without specific comorbidities: Add sulfonylurea (glimepiride, glipizide, or glyburide) as the most economical option 1

• For patients at high risk of hypoglycemia: Add DPP-4 inhibitor, SGLT2 inhibitor, or thiazolidinedione rather than sulfonylurea 1, 5

Initial Dual Combination Therapy

• Consider starting dual therapy at diagnosis when A1C is ≥9% to more rapidly achieve glycemic control 1
• The VERIFY trial demonstrated that initial combination therapy (metformin plus DPP-4 inhibitor) is superior to sequential addition for extending durability of glycemic control 1

Third-Line Therapy: Triple Combination or Insulin

If dual therapy fails to maintain A1C at target after 3 months, advance to triple oral therapy or add basal insulin 1

Basal Insulin Addition:

• Start basal insulin (NPH, glargine, detemir, or degludec) at 10 units or 0.1-0.2 units/kg depending on degree of hyperglycemia 1
• Continue metformin and possibly one additional noninsulin agent when adding basal insulin 1
• GLP-1 receptor agonist is preferred to insulin when possible to avoid weight gain and hypoglycemia risk 1

Progression to Intensive Insulin Therapy:

• If basal insulin has been titrated to acceptable fasting blood glucose but A1C remains above target, add either:
  • GLP-1 receptor agonist (preferred to avoid further insulin intensification) 1
  • Mealtime insulin: 1-3 injections of rapid-acting insulin analog (lispro, aspart, or glulisine) before meals 1

Critical Timing Principle

Do not delay treatment intensification—reassess every 3 months and add agents promptly if A1C is not at target 1, 4, 2

• The progressive nature of type 2 diabetes means monotherapy typically maintains glycemic targets for only a few years before combination therapy becomes necessary 1
• Stepwise addition allows clearer assessment of positive and negative effects of new drugs while reducing patient risk and expense 1

Common Pitfalls to Avoid

• Avoid sulfonylureas and thiazolidinediones in weight-concerned patients as they consistently promote weight gain 2, 6, 5
• Avoid glibenclamide (glyburide) in elderly patients or those with renal impairment due to high hypoglycemia risk; glimepiride or glipizide are safer alternatives 5
• Do not continue metformin monotherapy beyond 3 months if A1C remains above target—early intensification prevents prolonged hyperglycemia exposure 1, 4
• Monitor for SGLT2 inhibitor-associated genital mycotic infections and rare diabetic ketoacidosis risk 2
• Titrate GLP-1 receptor agonists slowly to minimize gastrointestinal side effects, which typically diminish with continued use 2