What are alternative treatments for a patient with diabetes who refuses a Glucagon-like peptide-1 (GLP-1) agonist injection?

Alternative Treatments for Patients Who Refuse GLP-1 Agonist Injections

For patients with diabetes who refuse GLP-1 receptor agonist injections, sodium-glucose cotransporter-2 (SGLT2) inhibitors are the preferred alternative treatment option, especially for patients with eGFR ≥30 ml/min per 1.73 m².

First-Line and Alternative Treatment Options

First-Line Therapy

• Metformin remains the cornerstone first-line therapy for most patients with type 2 diabetes 1
• Dose adjustments required when eGFR <45 ml/min per 1.73 m², and discontinuation when eGFR <30 ml/min per 1.73 m² 1

Alternative Injectable Options

• If injectable therapy is necessary despite GLP-1 RA refusal, insulin therapy is the alternative 1
• Consider initiating insulin when blood glucose is ≥300 mg/dL (16.7 mmol/L) or HbA1c is ≥10% (86 mmol/mol), especially if catabolic features are present 1

Preferred Oral Alternatives to GLP-1 RAs

1. SGLT2 Inhibitors:

   • Recommended for patients with T2D and eGFR ≥30 ml/min per 1.73 m² 1
   • Provide cardiovascular and renal benefits 1
   • Associated with weight loss 1
   • Low risk of hypoglycemia 1

2. DPP-4 Inhibitors:

   • Weight-neutral option 1
   • Well-tolerated with good adherence 1
   • Particularly suitable for patients with BMI <30 kg/m² 1
   • Lower efficacy for HbA1c reduction compared to SGLT2i or GLP-1 RAs 1

3. Thiazolidinediones (TZDs):

   • Consider for insulin-resistant patients 2
   • Caution with heart failure risk 1
   • Associated with weight gain 1

4. Sulfonylureas:

   • More effective for severely hyperglycemic non-obese patients 2
   • Higher risk of hypoglycemia and weight gain 2
   • Consider in cost-constrained settings 1

Treatment Algorithm Based on Patient Characteristics

Based on BMI:

• BMI <30 kg/m²: SGLT2 inhibitors or DPP-4 inhibitors 1
• BMI 30-35 kg/m²: SGLT2 inhibitors preferred 1
• BMI >35 kg/m²: Consider oral semaglutide if available (GLP-1 RA in pill form) 3

Based on Comorbidities:

• Established cardiovascular disease: SGLT2 inhibitors 1
• Heart failure: SGLT2 inhibitors 1
• Chronic kidney disease: SGLT2 inhibitors if eGFR ≥30 ml/min per 1.73 m² 1
• Advanced CKD (eGFR <30 ml/min per 1.73 m²): Insulin or DPP-4 inhibitors 1, 4

Combination Therapy Considerations

When monotherapy is insufficient:

• Two-drug combination: Metformin + SGLT2 inhibitor 1
• Three-drug combination: Metformin + SGLT2 inhibitor + DPP-4 inhibitor or other agent 1
• Four-drug combination: Consider referral to specialty care for complex regimens 1

Important Caveats and Pitfalls

1. Don't delay insulin in cases of severe hyperglycemia, catabolism, or suspected type 1 diabetes 4

2. Monitor renal function regularly, especially with SGLT2 inhibitors and metformin 1

3. Reassess therapy every 3-6 months and adjust if glycemic targets are not met 1

4. Consider medication costs as high costs can affect adherence and treatment effectiveness 1

5. Watch for hypoglycemia risk when combining certain agents (e.g., sulfonylureas with insulin) 1

6. Oral GLP-1 RA option: For patients who refuse injections but not the GLP-1 class itself, oral semaglutide is now available 3, 5

By following this algorithm and considering patient-specific factors, effective glycemic control can be achieved even when GLP-1 receptor agonist injections are refused.