When should treatment with SGLT2 (sodium-glucose cotransporter 2) inhibitors and/or GLP1 (glucagon-like peptide-1) agonists be started in a patient with diabetes mellitus?

When to Start SGLT2 Inhibitors and GLP-1 Receptor Agonists in Diabetes Mellitus

SGLT2 inhibitors and GLP-1 receptor agonists should be initiated early in the treatment of type 2 diabetes, independent of baseline HbA1c levels, particularly in patients with established cardiovascular disease, heart failure, chronic kidney disease, or high cardiovascular risk factors.

Patient-Specific Recommendations for SGLT2 Inhibitors

First-Line Use for:

• Patients with established atherosclerotic cardiovascular disease (ASCVD) to reduce major adverse cardiovascular events (MACE), hospitalization for heart failure, and cardiovascular death 1
• Patients with heart failure, particularly those with reduced ejection fraction (HFrEF <45%), regardless of baseline HbA1c 1
• Patients with chronic kidney disease (eGFR 30-60 mL/min/1.73m² or urinary albumin-to-creatinine ratio >30 mg/g, especially >300 mg/g) 1
• Initiate when eGFR is ≥20 mL/min/1.73m² and continue as tolerated until dialysis or transplantation 1

Monitoring and Precautions:

• If HbA1c is well-controlled at baseline, reduce dose of sulfonylurea by 50% or basal insulin by 20% when starting therapy 1
• Monitor for genital mycotic infections and provide education on genital hygiene 1
• Assess for volume depletion and consider reducing diuretic doses if necessary 1
• Use with caution in patients with foot ulcers or at high risk for amputation, particularly with canagliflozin 1

Patient-Specific Recommendations for GLP-1 Receptor Agonists

First-Line Use for:

• Patients with established atherosclerotic cardiovascular disease to reduce MACE 1, 2
• Patients without established CVD but with high-risk indicators (age ≥55 years with coronary, carotid, or lower extremity artery stenosis >50%, left ventricular hypertrophy, eGFR <60 mL/min/1.73m², or albuminuria) 1, 2
• Patients with obesity where weight loss is a priority 1, 2
• Patients when SGLT2 inhibitors are contraindicated or not tolerated 1, 2

Monitoring and Precautions:

• Start at lowest dose and titrate slowly to mitigate nausea 1
• Discontinue DPP-4 inhibitors before starting GLP-1 receptor agonists 1
• If HbA1c is well-controlled, reduce insulin dose by approximately 20% when initiating therapy 1
• Use with caution in patients with history of pancreatitis, gastroparesis, or medullary thyroid cancer 1

Combined Use Considerations

• Consider combination therapy with both SGLT2 inhibitors and GLP-1 receptor agonists in high-risk patients with multiple comorbidities 1, 3
• The combination provides complementary mechanisms for cardiorenal protection and may have additive benefits for weight loss and blood pressure reduction 3
• Prioritize based on specific patient characteristics:
  • For atherosclerotic disease: Consider GLP-1 receptor agonist first 1
  • For heart failure or CKD: Consider SGLT2 inhibitor first 1

Decision Algorithm

1. Assess cardiovascular and renal risk factors:

   • If established ASCVD: Start SGLT2 inhibitor or GLP-1 receptor agonist regardless of HbA1c 1
   • If heart failure (especially HFrEF): Prioritize SGLT2 inhibitor 1
   • If CKD: Prioritize SGLT2 inhibitor 1
   • If high CV risk without established disease: Consider GLP-1 receptor agonist (strongest evidence for dulaglutide) 1
   • If obesity is a major concern: Consider GLP-1 receptor agonist 1, 2

2. Consider contraindications:

   • For SGLT2 inhibitors: Avoid in severe renal impairment (eGFR <20 mL/min/1.73m²), active foot ulcers, or history of diabetic ketoacidosis 1, 4
   • For GLP-1 receptor agonists: Avoid in history of medullary thyroid cancer, multiple endocrine neoplasia type 2, or severe gastroparesis 1

3. Adjust concomitant medications:

   • Reduce insulin or sulfonylurea doses when initiating either class to prevent hypoglycemia 1
   • Consider reducing diuretic doses when starting SGLT2 inhibitors 1

Common Pitfalls and Caveats

• Delaying initiation until glycemic control worsens: These medications should be considered independent of baseline HbA1c for their cardiorenal benefits 1
• Discontinuing therapy when eGFR declines: SGLT2 inhibitors provide cardiorenal benefits even as eGFR declines and should be continued until dialysis or transplantation 1
• Failing to educate patients about potential side effects: Proper education about genital hygiene (SGLT2 inhibitors) and gradual dose titration (GLP-1 receptor agonists) can improve adherence 1
• Underutilizing these medications in eligible patients: Despite strong evidence, these medications remain underprescribed in appropriate high-risk patients 5