What alternative medications can be used to treat type 2 diabetes in an adult patient with no significant renal impairment who cannot tolerate metformin or requires additional therapy?

Alternative Medications for Type 2 Diabetes Besides Metformin

Add an SGLT-2 inhibitor or GLP-1 receptor agonist to metformin (or as monotherapy if metformin is contraindicated), prioritizing SGLT-2 inhibitors for patients with heart failure or chronic kidney disease, and GLP-1 receptor agonists for those with high stroke risk or when weight loss is a priority. 1

First-Line Alternatives When Metformin Cannot Be Used

SGLT-2 inhibitors are the preferred first-line alternative when metformin is contraindicated or not tolerated, based on their proven cardiovascular and renal protection independent of metformin use. 2

SGLT-2 Inhibitors (Preferred First Alternative)

• Empagliflozin, canagliflozin, or dapagliflozin reduce all-cause mortality, major adverse cardiovascular events (MACE), chronic kidney disease progression, and heart failure hospitalization. 1

• These agents reduce cardiovascular death or heart failure hospitalization by 31% and MACE by 20%, with benefits consistent across the full spectrum of cardiovascular risk. 2

• Canagliflozin demonstrated a 30% reduction in development of end-stage renal disease in the CREDENCE trial and is FDA-approved for use in combination with metformin. 3, 4

• Dapagliflozin is approved for use down to eGFR 25 mL/min/1.73 m². 3

• Empagliflozin provides statistically significant HbA1c reductions of 0.7-0.9% as monotherapy, with additional benefits of 2.5-2.8% body weight reduction and systolic blood pressure reduction of 2.6-3.4 mmHg. 5

GLP-1 Receptor Agonists (Preferred Second Alternative)

• Semaglutide, liraglutide, or dulaglutide are the guideline-recommended alternative when SGLT-2 inhibitors cannot be used, particularly for patients with established atherosclerotic cardiovascular disease or high cardiovascular risk. 3, 2

• These agents reduce all-cause mortality, MACE, and stroke risk. 1

• GLP-1 receptor agonists achieve HbA1c reduction of 0.7-1.0% with significant weight loss and low hypoglycemia risk when used without insulin or sulfonylureas. 3, 6

• Liraglutide has demonstrated cardiovascular mortality reduction, with particularly strong benefits in patients with eGFR <60 mL/min/1.73 m². 3

• Dulaglutide showed slower GFR decline compared to insulin glargine in patients with moderate-to-severe chronic kidney disease. 3

Algorithm for Selecting Second-Line Therapy After Metformin

Step 1: Assess for High-Risk Comorbidities

If atherosclerotic cardiovascular disease (ASCVD), heart failure, or chronic kidney disease is present:

• Add an SGLT-2 inhibitor as the preferred agent for patients with heart failure or CKD (eGFR ≥30 mL/min/1.73 m²). 1, 6

• Add a GLP-1 receptor agonist as the preferred agent for patients with high stroke risk or when total body weight loss is an important treatment goal. 1

• Both SGLT-2 inhibitors and GLP-1 receptor agonists have proven cardiovascular benefit and should be prioritized over other agents in these populations. 1, 6

Step 2: If No High-Risk Comorbidities Present

Choose from the following based on patient-specific factors:

• DPP-4 inhibitors (sitagliptin, linagliptin) provide intermediate glucose-lowering effect (0.7-1.0% HbA1c reduction) with low hypoglycemia risk and no weight gain, but the American College of Physicians recommends against adding DPP-4 inhibitors to reduce morbidity and all-cause mortality. 1, 3

• Sulfonylureas (glimepiride, glipizide) provide high glucose-lowering effect (0.9-1.1% HbA1c reduction) but have moderate to high hypoglycemia risk and cause weight gain. 3, 6

• Thiazolidinediones (pioglitazone) can be considered but are associated with weight gain, fluid retention, and increased fracture risk in postmenopausal women. 1

• Basal insulin (NPH, glargine, detemir) should be considered when HbA1c is very high (≥9.0%) or when severe hyperglycemia is present. 1

Step 3: Immediate Insulin Initiation Required

Start insulin therapy immediately (with or without additional agents) if:

• A1C ≥10% (86 mmol/mol) and/or blood glucose ≥300 mg/dL with symptoms. 3, 6

• Ketosis or ketoacidosis is present, reflecting profound insulin deficiency. 1, 6

• Severe hyperglycemia with catabolic features (weight loss, hypertriglyceridemia) is present. 1

Critical Implementation Points

• Continue metformin when adding a second agent unless contraindicated (eGFR <30 mL/min/1.73 m²) or not tolerated, as combination therapy is more effective than switching. 3, 2, 6

• Reassess HbA1c after 3 months of the new therapy and proceed to triple therapy or insulin if the A1C target is not achieved. 1, 3, 6

• When adding an SGLT-2 inhibitor or GLP-1 agonist results in adequate glycemic control, reduce or discontinue existing treatment with sulfonylureas or long-acting insulins due to increased risk for severe hypoglycemia. 1

• Do not combine GLP-1 receptor agonists with DPP-4 inhibitors, as they work through similar mechanisms without additive benefit. 6

• Self-monitoring of blood glucose might be unnecessary in patients receiving metformin combined with either an SGLT-2 inhibitor or a GLP-1 agonist. 1

Common Pitfalls to Avoid

• Avoid delaying treatment intensification when glycemic targets are not met; recommendations for treatment intensification should not be delayed. 1

• Sulfonylureas and long-acting insulins are inferior to SGLT-2 inhibitors and GLP-1 agonists in reducing all-cause mortality and morbidity but may still have some limited value for glycemic control. 1

• Be aware of overbasalization with insulin therapy, indicated by basal dose >0.5 IU/kg/day, high bedtime-morning glucose differential, hypoglycemia, or high glycemic variability. 1

• Consider vitamin B12 deficiency with long-term metformin use, as it is associated with worsening symptoms of neuropathy and may require periodic testing. 1