Newer Oral Antidiabetic Drugs for Type 2 Diabetes
For patients with type 2 diabetes, SGLT-2 inhibitors and GLP-1 receptor agonists should be prioritized as the newer oral antidiabetic drugs after metformin, based on their proven cardiovascular and renal benefits, weight reduction properties, and low hypoglycemia risk. 1
First-Line Therapy
Metformin remains the cornerstone first-line pharmacologic treatment for most adults with type 2 diabetes due to:
- 1.0-2.0% reduction in HbA1c
- Weight neutral effects
- Low risk of hypoglycemia
- Reduction in cardiovascular mortality compared to sulfonylureas 2, 1
- Cost-effectiveness 2
Newer Oral Antidiabetic Drugs as Second-Line Agents
When metformin alone fails to achieve glycemic targets, the following newer agents should be considered:
1. SGLT-2 Inhibitors (e.g., canagliflozin, empagliflozin)
- Priority population: Patients with heart failure or chronic kidney disease 1
- Key benefits:
- Cardiorenal protection
- Weight reduction
- Low hypoglycemia risk
- Blood pressure reduction
- Clinical evidence: Empagliflozin has demonstrated significant cardiovascular benefits 1, 3
- Considerations: Monitor for genital mycotic infections, volume depletion
2. GLP-1 Receptor Agonists
- Priority population: Patients with established cardiovascular disease, increased stroke risk, or when weight loss is a priority 1
- Key benefits:
- Cardiovascular protection
- Significant weight reduction (greater than SGLT-2 inhibitors)
- Low hypoglycemia risk
- Reduction in postprandial glucose excursions
- Considerations: GI side effects may limit use in some patients
3. DPP-4 Inhibitors
- Priority population: When SGLT-2 inhibitors or GLP-1 receptor agonists are not appropriate 1
- Key benefits:
- Weight neutrality
- Low hypoglycemia risk
- Well tolerated in elderly patients
- Considerations: Less potent HbA1c reduction compared to SGLT-2 inhibitors or GLP-1 RAs
Older Oral Antidiabetic Agents
While newer agents are preferred, these established medications may still have roles in specific situations:
1. Sulfonylureas (e.g., glipizide)
- Effective for glycemic control but associated with:
2. Thiazolidinediones
- Effective insulin sensitizers but limited by:
Clinical Decision Algorithm
Start with metformin unless contraindicated (renal impairment, risk of lactic acidosis) 2
If HbA1c remains above target after 3 months of maximum tolerated metformin:
- For patients with heart failure or CKD: Add SGLT-2 inhibitor
- For patients with established CVD or high stroke risk: Add GLP-1 receptor agonist
- For patients with obesity: Add GLP-1 receptor agonist (preferred) or SGLT-2 inhibitor
- For elderly patients or those with GI intolerance to other agents: Add DPP-4 inhibitor
If dual therapy fails to achieve target HbA1c after 3 months:
- Add a third agent from a different class
- Consider insulin therapy if HbA1c >9% or patient is symptomatic
Important Clinical Considerations
- Extended-release metformin should be considered for patients with GI intolerance to immediate-release formulations 4
- Combination therapy more effectively reduces HbA1c levels but is associated with more adverse events 2
- Individualize HbA1c targets based on risk of complications, comorbidities, life expectancy, and patient preferences, with a general target of <7% for most patients 2
- Monitor renal function regularly, especially with SGLT-2 inhibitors and metformin
- Cardiovascular risk reduction should be a primary consideration when selecting agents, favoring SGLT-2 inhibitors and GLP-1 receptor agonists over older agents 1
The landscape of oral antidiabetic medications has evolved significantly, with newer agents offering benefits beyond glycemic control. While metformin remains the foundation of therapy, SGLT-2 inhibitors and GLP-1 receptor agonists represent significant advances in diabetes management due to their proven cardiovascular and renal benefits.