What are suitable adjunctive therapies to metformin (biguanide) for patients with inadequate glycemic control?

Adjunctive Therapy to Metformin for Type 2 Diabetes

Add an SGLT-2 inhibitor or GLP-1 agonist to metformin when glycemic control is inadequate after 3 months of maximized metformin therapy. These agents reduce all-cause mortality and major cardiovascular events, unlike older alternatives 1.

When to Add a Second Agent

• Add a second agent when HbA1c remains above target after 3 months on maximum tolerated metformin dose 1.
• If HbA1c is ≥9% at diagnosis, start dual therapy immediately rather than waiting for metformin monotherapy to fail 1.
• If HbA1c is ≥10% or blood glucose ≥300 mg/dL with symptoms (polyuria, polydipsia, weight loss), initiate basal insulin with or without metformin 1.

First-Line Add-On Therapy: SGLT-2 Inhibitors or GLP-1 Agonists

The 2024 American College of Physicians guidelines represent the most recent high-quality evidence and prioritize these two classes based on mortality and morbidity outcomes 1.

SGLT-2 Inhibitors (Preferred for specific comorbidities)

• Use SGLT-2 inhibitors to reduce all-cause mortality, major adverse cardiovascular events (MACE), progression of chronic kidney disease, and hospitalization for heart failure 1.
• Prioritize SGLT-2 inhibitors in patients with heart failure or chronic kidney disease 1.
• Empagliflozin demonstrated superior glycemic control compared to sulfonylureas (glimepiride) with significantly lower hypoglycemia risk (2% vs 24% at 104 weeks) 2.
• SGLT-2 inhibitors cause modest weight loss (approximately 2-3 kg) 3, 2.

GLP-1 Agonists (Preferred for stroke risk and weight loss)

• Use GLP-1 agonists to reduce all-cause mortality, MACE, and stroke 1.
• Prioritize GLP-1 agonists in patients with increased stroke risk or when weight loss is an important treatment goal 1.
• GLP-1 agonists are the preferred injectable option over basal insulin due to lower hypoglycemia risk and beneficial weight effects, though gastrointestinal side effects are more common 1.
• Fixed-ratio combinations of basal insulin plus GLP-1 agonist (lixisenatide/glargine or liraglutide/degludec) are available for patients requiring both 1.

Alternative Second-Line Options

While SGLT-2 inhibitors and GLP-1 agonists are preferred based on mortality/morbidity outcomes, other agents remain options when cost, tolerability, or patient factors preclude first-line choices 1.

Sulfonylureas

• Provide similar HbA1c reduction (0.64-0.97%) to other classes but cause weight gain (1.77-2.08 kg) and 4-7 times higher hypoglycemia risk 4.
• Reduce or discontinue sulfonylureas if adding SGLT-2 inhibitors or GLP-1 agonists to avoid severe hypoglycemia 1.
• Remain an option when cost is prohibitive, as they are inexpensive 1, 5.

DPP-4 Inhibitors

• The American College of Physicians recommends against adding DPP-4 inhibitors to metformin for reducing morbidity and mortality (strong recommendation, high-certainty evidence) 1.
• Despite this, older ADA guidelines list them as acceptable options for glycemic control alone 1.

Thiazolidinediones (Pioglitazone)

• Cause weight gain (similar to sulfonylureas) but lower hypoglycemia risk 4.
• Can be used adjunctively with insulin in patients requiring large doses to reduce insulin requirements 1.
• Empagliflozin added to pioglitazone/metformin reduced HbA1c by 0.5-0.6% versus placebo 3.

Basal Insulin

• Initiate basal insulin when HbA1c ≥10%, blood glucose ≥300 mg/dL, or catabolic features present 1.
• Start at 10 units or 0.1-0.2 units/kg daily, typically with continued metformin 1.
• Reduce or discontinue long-acting insulin if adding SGLT-2 inhibitors or GLP-1 agonists due to increased hypoglycemia risk 1.

Key Clinical Considerations

• Continue metformin when adding any second agent unless contraindicated 1.
• All noninsulin agents reduce HbA1c by approximately 0.7-1.0% when added to metformin 1, 4.
• Self-monitoring of blood glucose may be unnecessary with metformin plus SGLT-2 inhibitor or GLP-1 agonist (no hypoglycemia risk) 1.
• Metformin can be continued with declining renal function down to eGFR 30-45 mL/min with dose reduction 1.

Common Pitfalls to Avoid

• Do not use DPP-4 inhibitors as first-line add-on therapy given lack of mortality/morbidity benefit 1.
• Do not continue sulfonylureas or long-acting insulin at full doses when adding SGLT-2 inhibitors or GLP-1 agonists due to severe hypoglycemia risk 1.
• Avoid assuming all second-line agents are equivalent—mortality and cardiovascular outcomes differ substantially between classes 1.