Drug Classifications for Type 2 Diabetes Mellitus and Mechanisms of Action
First-Line Therapy: Metformin
Metformin is the preferred initial pharmacological agent for type 2 diabetes and should be started at diagnosis alongside lifestyle modifications unless contraindicated or not tolerated 1, 2, 3.
Mechanism of Action
- Metformin reduces blood glucose through three primary mechanisms: enhancing peripheral insulin sensitivity for greater glucose uptake, decreasing hepatic glucose production, and reducing gastrointestinal glucose absorption 1, 4, 5.
- It does not stimulate insulin secretion, thereby avoiding hypoglycemia and weight gain—blood glucose and insulin levels are lowered with minimal hypoglycemia risk 4, 5.
Practical Dosing
- Start with 500 mg once or twice daily of immediate-release formulation and titrate gradually to minimize gastrointestinal side effects, with a typical target dose of 2000 mg daily in divided doses 2.
- Extended-release formulations improve gastrointestinal tolerability and allow once-daily dosing, making them preferable for patients with GI intolerance 6.
- Metformin is safe with eGFR ≥30 mL/min/1.73 m²; reduce dose when eGFR falls to 30-45 mL/min/1.73 m² 1, 2.
Important Monitoring
- Monitor vitamin B12 levels periodically due to risk of deficiency and potential worsening of neuropathy symptoms 1, 3.
Second-Line Agents: Cardiovascular and Renal Benefit Priority
SGLT2 Inhibitors (Sodium-Glucose Cotransporter 2 Inhibitors)
For patients with established atherosclerotic cardiovascular disease (ASCVD), heart failure, or chronic kidney disease, add an SGLT2 inhibitor to metformin independent of A1C level 1, 3.
Mechanism of Action
- Block glucose reabsorption in the proximal renal tubule by inhibiting SGLT2, providing insulin-independent glucose lowering 1, 7.
- Result in modest weight loss (2-4% body weight) and blood pressure reduction (5-7 mmHg systolic) 7.
Clinical Benefits Beyond Glycemic Control
- Reduce all-cause mortality by 12-26%, major adverse cardiovascular events, and hospitalization for heart failure by 18-25% 1, 8.
- Reduce progression of chronic kidney disease by 24-39% over 2-5 years 8.
- Prioritize SGLT2 inhibitors specifically for patients with heart failure or CKD 1.
Efficacy Data
- Lower A1C by 0.6-0.9% when added to metformin 7.
- Achieve A1C <7% in 46-58% of patients when combined with metformin 7.
GLP-1 Receptor Agonists (Glucagon-Like Peptide-1 Receptor Agonists)
For patients with established ASCVD, high cardiovascular risk, or when weight loss is a primary treatment goal, add a GLP-1 RA to metformin 1, 3.
Mechanism of Action
- Enhance glucose-dependent insulin secretion from pancreatic β cells 1.
- Suppress glucagon secretion, slow gastric emptying, and promote satiety 1.
Clinical Benefits
- Reduce all-cause mortality, major adverse cardiovascular events, and stroke risk 1.
- Produce weight loss >5% in most patients, with high-potency agents (semaglutide) achieving >10% weight loss 8.
- Lower A1C by approximately 0.7-1.0% 1.
Practical Considerations
- GLP-1 RAs are preferred over insulin when injectable therapy is needed, due to lower hypoglycemia risk and favorable weight effects 1.
- Prioritize GLP-1 RAs for patients with increased stroke risk or when weight loss is a critical treatment goal 1.
Dual GIP/GLP-1 Receptor Agonists
Tirzepatide (dual glucose-dependent insulinotropic polypeptide/GLP-1 RA) provides the greatest A1C reduction among non-insulin agents 1.
- Mechanism combines GIP and GLP-1 receptor activation for enhanced glucose-dependent insulin secretion and weight loss 1.
- Weight loss may exceed 10% in most individuals 8.
Additional Second-Line Options (Without Cardiovascular/Renal Comorbidities)
DPP-4 Inhibitors (Dipeptidyl Peptidase-4 Inhibitors)
The American College of Physicians recommends against adding DPP-4 inhibitors to metformin to reduce morbidity and all-cause mortality 1.
Mechanism of Action
- Inhibit DPP-4 enzyme, prolonging the action of endogenous GLP-1 and GIP 1.
- Lower A1C by approximately 0.7% with weight-neutral effects and low hypoglycemia risk 1.
Clinical Context
- Despite adequate glycemic control, DPP-4 inhibitors lack demonstrated cardiovascular or mortality benefits compared to SGLT2 inhibitors and GLP-1 RAs 1.
Sulfonylureas
Sulfonylureas are inferior to SGLT2 inhibitors and GLP-1 RAs for reducing mortality and morbidity but may have limited value for glycemic control when cost is prohibitive 1.
Mechanism of Action
- Stimulate insulin secretion from pancreatic β cells independent of glucose levels 1.
- Lower A1C by approximately 1.0% 1.
Critical Pitfalls
- Cause weight gain (approximately 1-2 kg) and carry significant hypoglycemia risk 7.
- When adding SGLT2 inhibitors or GLP-1 RAs achieves adequate control, reduce or discontinue sulfonylureas to avoid severe hypoglycemia 1.
Thiazolidinediones
Mechanism of Action
- Enhance insulin sensitivity by activating peroxisome proliferator-activated receptor gamma (PPAR-γ) in adipose tissue, muscle, and liver 1.
- Lower A1C by approximately 0.7-1.0% 1.
Adverse Effects
- Cause weight gain, fluid retention, and increased fracture risk 1.
- Use is limited by these side effects in clinical practice 1.
Insulin Therapy
Consider initiating insulin therapy (with or without additional agents) in patients with newly diagnosed type 2 diabetes who are markedly symptomatic and/or have A1C ≥10% (86 mmol/mol) or blood glucose ≥300 mg/dL (16.7 mmol/L) 1.
Mechanism of Action
- Exogenous insulin replaces or supplements endogenous insulin, directly lowering blood glucose by promoting cellular glucose uptake and suppressing hepatic glucose production 1.
Practical Approach
- Start with basal insulin in combination with metformin 3.
- Approximately one-third of patients with type 2 diabetes require insulin during their lifetime due to progressive β-cell failure 1, 8.
- Continue metformin when adding insulin to reduce insulin requirements and improve metabolic control 1.
Initial Combination Therapy Strategy
Consider starting metformin plus a second agent immediately if A1C ≥9% (75 mmol/mol) at diagnosis to achieve glycemic targets more rapidly 1, 2, 3.
- Initial combination therapy (metformin + DPP-4 inhibitor) is superior to sequential addition for extending time to treatment failure 1.
- The second agent should be an SGLT2 inhibitor or GLP-1 RA if cardiovascular disease, heart failure, or CKD is present at diagnosis 2, 3.
Critical Treatment Intensification Principles
Do not delay treatment intensification—reassess the medication regimen every 3 months and add agents promptly if A1C target is not achieved 1, 3.
- When SGLT2 inhibitors or GLP-1 RAs result in adequate glycemic control, reduce or discontinue sulfonylureas or long-acting insulins due to increased severe hypoglycemia risk 1.
- Self-monitoring of blood glucose may be unnecessary in patients receiving metformin combined with either an SGLT2 inhibitor or GLP-1 RA 1.