What other medication options are available for a typical adult patient with type 2 diabetes mellitus (T2DM) who is not adequately controlled on metformin?

Medication Options for Type 2 Diabetes Beyond Metformin

Add either an SGLT-2 inhibitor or a GLP-1 agonist to metformin when glycemic control remains inadequate, as these are the only drug classes proven to reduce all-cause mortality and major cardiovascular events. 1

Primary Add-On Options: SGLT-2 Inhibitors vs GLP-1 Agonists

The American College of Physicians provides a strong recommendation with high-certainty evidence that only two drug classes should be added to metformin: SGLT-2 inhibitors or GLP-1 agonists. 1 Both classes reduce all-cause mortality compared to usual care, but they have distinct advantages that guide selection. 1, 2

Choose SGLT-2 Inhibitors When:

• The patient has congestive heart failure - SGLT-2 inhibitors uniquely reduce hospitalization for heart failure with high-certainty evidence. 1, 2
• The patient has chronic kidney disease - SGLT-2 inhibitors slow CKD progression with high-certainty evidence. 1, 3
• Cardiovascular mortality reduction is the primary goal - SGLT-2 inhibitors reduce major adverse cardiovascular events (MACE) with moderate to high certainty. 1, 4

Choose GLP-1 Agonists When:

• The patient has elevated stroke risk - GLP-1 agonists specifically reduce stroke beyond other cardiovascular benefits with high-certainty evidence. 1, 2
• Weight loss is an important treatment goal - GLP-1 agonists produce greater weight reduction than SGLT-2 inhibitors, with high-potency agents achieving >5% weight loss in most patients and potentially >10%. 1, 2, 5
• The patient wants to avoid genital mycotic infections - GLP-1 agonists do not cause this common SGLT-2 inhibitor side effect. 3

Both drug classes reduce all-cause mortality and MACE with high-certainty evidence, so either is appropriate when the patient lacks specific comorbidities favoring one over the other. 1, 4

What NOT to Add

The American College of Physicians strongly recommends against adding DPP-4 inhibitors to metformin because they do not reduce morbidity or all-cause mortality despite lowering HbA1c. 1, 2 This is a strong recommendation based on high-certainty evidence. 1

DPP-4 inhibitors fail to reduce death, cardiovascular events, or hospitalizations in clinical trials. 3, 4

Alternative Options with Limited Role

Sulfonylureas and Long-Acting Insulin

These older agents are inferior to SGLT-2 inhibitors and GLP-1 agonists for reducing all-cause mortality and morbidity but may still provide glycemic control value in cost-constrained situations. 1, 2

The UKPDS 33 trial showed only a 6% relative reduction in all-cause mortality with sulfonylureas or insulin that was not statistically significant (P = 0.44). 4

Sulfonylureas cause significantly more hypoglycemia than SGLT-2 inhibitors or GLP-1 agonists, with approximately 30% annual hypoglycemic events versus 1% with conventional therapy. 4

Thiazolidinediones (Pioglitazone)

Thiazolidinediones can be added to metformin for glycemic control but lack mortality benefit evidence. 1 They cause weight gain and are contraindicated in severe heart failure or liver disease. 1, 6

Basal Insulin

Consider initiating insulin therapy when HbA1c ≥10% at any point, or if blood glucose is markedly elevated with symptoms (polyuria, polydipsia, weight loss). 1, 3 Insulin does not reduce all-cause mortality compared to usual care. 4

Critical Safety Measures After Adding Second Agent

When SGLT-2 inhibitors or GLP-1 agonists achieve adequate glycemic control, immediately reduce or discontinue sulfonylureas or long-acting insulins to prevent severe hypoglycemia. 1, 2 This is essential because the newer agents carry minimal hypoglycemia risk when combined with metformin alone. 2, 3

Self-monitoring of blood glucose is typically unnecessary when using metformin plus SGLT-2 inhibitor or GLP-1 agonist, as these combinations do not cause hypoglycemia. 1, 2

Continue metformin at the current dose when adding the second agent unless contraindications develop. 1

Glycemic Targets and Treatment Timing

Target HbA1c between 7% and 8% for most adults with type 2 diabetes. 1, 2 Deintensify treatment when HbA1c falls below 6.5% to avoid hypoglycemia and overtreatment. 1, 2

Add a second agent after 3 months if HbA1c is not at goal on metformin monotherapy - do not delay drug intensification. 1, 3

Specific Agent Considerations

Dual GIP/GLP-1 Agonists (Tirzepatide/Mounjaro)

Tirzepatide functions as a GLP-1 receptor agonist with superior efficacy to traditional GLP-1 agonists and should be prioritized when substantial weight loss is needed (>10% body weight reduction goal). 2

Canagliflozin (Invokana)

This SGLT-2 inhibitor carries an increased risk of lower-limb amputation (HR 1.97,95% CI 1.41-2.75), so monitor patients for infection or ulcers of the lower limb and discontinue if these occur. 4, 7

Cost and Access Considerations

No generic SGLT-2 inhibitors or GLP-1 agonists currently exist, so discuss medication costs with patients when selecting specific agents within these classes. 1, 2 Prescribe generic medications when available rather than brand-name alternatives. 1, 2

Fixed-dose combination tablets containing SGLT-2 inhibitors plus metformin are FDA-approved and may improve adherence. 8

Common Pitfalls to Avoid

• Do not wait indefinitely on failing metformin monotherapy - add a second agent after 3 months if HbA1c is not at goal. 3
• Do not choose DPP-4 inhibitors based solely on HbA1c reduction - outcomes that matter (death, MI, stroke) are not improved. 3, 4
• Do not continue full-dose sulfonylureas or insulin when adding SGLT-2 inhibitor or GLP-1 agonist without dose reduction to prevent severe hypoglycemia. 3, 4
• Do not stop metformin when adding a second agent unless contraindications emerge. 1, 3