Latest ADA Guideline on Oral Antidiabetic Drugs for Type 2 Diabetes
Metformin is the preferred first-line oral pharmacologic agent for type 2 diabetes and should be initiated at diagnosis unless contraindicated, combined with lifestyle modifications. 1
Initial Pharmacologic Therapy
Metformin must be started at the time of type 2 diabetes diagnosis for most patients, as it is effective, safe, inexpensive, and may reduce cardiovascular events and death. 1
Once initiated, metformin should be continued as long as tolerated and not contraindicated, with other agents added to metformin rather than replacing it. 1
Metformin demonstrates superior efficacy compared to other oral agents, with beneficial effects on A1C, weight, and cardiovascular mortality when compared to sulfonylureas as first-line therapy. 1
When to Deviate from Metformin Monotherapy
Early combination therapy or alternative agents should be considered in specific high-risk scenarios:
If baseline A1C is ≥9.0% or glucose ≥300 mg/dL, consider starting dual therapy immediately or insulin if symptoms of catabolism (weight loss) or ketonuria are present. 1
For patients with established atherosclerotic cardiovascular disease, indicators of high cardiovascular risk, established kidney disease, or heart failure, an SGLT2 inhibitor or GLP-1 receptor agonist with demonstrated cardiovascular benefit should be added to the regimen independent of A1C level. 1
When A1C is ≥10% (86 mmol/mol) or blood glucose ≥300 mg/dL (16.7 mmol/L) with hyperglycemic symptoms, early introduction of insulin should be strongly considered. 1
Combination Therapy Approach
When metformin monotherapy fails to achieve glycemic targets, add a second agent rather than delaying treatment intensification. 1
The VERIFY trial demonstrated that initial combination therapy (metformin plus DPP-4 inhibitor) is superior to sequential medication addition for extending time to treatment failure. 1
GLP-1 receptor agonists are preferred over insulin when greater glucose lowering is needed beyond oral agents. 1
Patient-Centered Selection Factors
The choice of additional agents beyond metformin should consider: 1
- Cardiovascular and renal comorbidities (prioritize SGLT2 inhibitors or GLP-1 agonists if present)
- Hypoglycemia risk (avoid sulfonylureas in high-risk patients)
- Impact on weight (GLP-1 agonists and SGLT2 inhibitors promote weight loss)
- Cost considerations
- Patient preferences
Critical Safety Considerations
Metformin contraindications and monitoring:
Can be safely used when eGFR ≥30 mL/min/1.73 m² per revised FDA labeling. 1
Contraindicated when eGFR <30 mL/min/1.73 m², in acute renal failure, severe liver disease, alcohol abuse, heart failure with hemodynamic instability, or conditions predisposing to lactic acidosis. 1, 2
Periodic vitamin B12 testing is recommended as metformin use is associated with B12 deficiency and potential worsening of neuropathy symptoms. 1
Start at low dose with gradual titration to minimize gastrointestinal side effects (bloating, diarrhea, abdominal discomfort). 1
Medication Regimen Review
Reevaluate the medication regimen and adherence every 3-6 months, adjusting based on patient-specific factors and treatment response. 1
Do not delay treatment intensification when patients fail to meet glycemic goals. 1
Common Pitfalls to Avoid
Never discontinue metformin when adding other agents unless contraindications develop—it should remain the foundation of therapy. 1
Avoid using sulfonylureas as first-line therapy due to higher hypoglycemia risk and inferior cardiovascular outcomes compared to metformin. 1
Do not overlook cardiovascular and renal risk assessment—patients with these comorbidities require SGLT2 inhibitors or GLP-1 agonists regardless of A1C level. 1
Extended-release metformin formulations can be used once daily and may improve gastrointestinal tolerability compared to immediate-release formulations. 1