Should SGLT2 (Sodium-Glucose Linked Transporter 2) inhibitors and GLP1 (Glucagon-Like Peptide-1) receptor agonists be started at the same time?

Concomitant Initiation of SGLT2 Inhibitors and GLP-1 Receptor Agonists

It is reasonable to use both an SGLT2 inhibitor and a GLP-1 receptor agonist with demonstrated cardiovascular benefit concomitantly if clinically indicated, even though such combination therapy has not been extensively studied for cardiovascular disease risk reduction. 1

Evidence for Combined Use

• No trials to date have specifically studied the cardiovascular outcome effects of concomitant use of both an SGLT2 inhibitor and a GLP-1 receptor agonist in patients with atherosclerotic cardiovascular disease (ASCVD) 1
• Mechanistically, these drug classes have opposite effects on glucagon, suggesting the possibility of an interaction 1
• DURATION-8 trial (a 28-week, multicenter, double-blind, phase 3 randomized controlled trial) demonstrated greater reductions in blood pressure and body weight in patients randomly allocated to the combination of exenatide and dapagliflozin compared to either agent alone 1
• Limited data suggest that the non-glycemic effects of these medication classes may be additive 1
• Combination therapy with both an SGLT2 inhibitor and a GLP-1 receptor agonist for glycemic management aligns with current type 2 diabetes management guidelines 1

Practical Considerations When Initiating Both Agents

Monitoring and Dose Adjustments

• When starting both agents, dose adjustment of background medications may be required to avoid hypoglycemia, particularly in patients on insulin, sulfonylurea, or glinide therapy 1
• For patients on insulin or insulin secretagogues:
  • Consider reducing sulfonylurea or glinide dose by 50% (to at most 50% of maximum recommended dose) 1
  • Consider discontinuing these agents if already on a minimal dose 1
  • Consider reducing total daily insulin dose by 20% to reduce hypoglycemia risk 1, 2
• Patients on complex insulin regimens or with "brittle" diabetes should have these medications initiated in collaboration with their diabetes care provider 1

Specific Monitoring for SGLT2 Inhibitors

• Inform patients about the risk of genital mycotic infections and the importance of personal hygiene 1, 3
• Educate about the rare risk of euglycemic diabetic ketoacidosis and symptoms requiring immediate medical attention (nausea, vomiting, abdominal pain, weakness) 1
• Monitor renal function:
  • Baseline assessment of eGFR and urine albumin-to-creatinine ratio (ACR) 3
  • Follow-up monitoring of eGFR every 3-6 months if <60 mL/min/1.73 m², and annually if ≥60 mL/min/1.73 m² 3
• Consider reducing diuretic doses if the patient is also on diuretic therapy 3
• Temporarily withhold SGLT2 inhibitor during periods of prolonged fasting, surgery, critical illness, or reduced oral intake 3

Cost Considerations

• The out-of-pocket cost of using drugs from both classes together would likely be very high 1
• To be cost-effective at under $150,000 per QALY, costs for SGLT2 inhibitors would need to be under $5 per day and under $6 per day for oral GLP-1 receptor agonists 4

Clinical Benefits of Combined Therapy

• Both SGLT2 inhibitors and GLP-1 receptor agonists are associated with reduced risk of major adverse cardiovascular events compared to DPP-4 inhibitors or sulfonylureas 5
• Both medication classes have complementary mechanisms of action that may provide additive cardiorenal protection 6
• Combined therapy promotes weight loss and lowers blood pressure in an additive manner 6
• Both agents reduce severe hypoglycemia compared with either usual care or other medication classes such as sulfonylureas and insulin 1

Approach to Initiation

• For patients with type 2 diabetes and cardiovascular disease, consider starting either a GLP-1 receptor agonist, SGLT2 inhibitor, or both in high-risk cases 2
• When initiating both agents simultaneously, closely monitor for:
  • Hypoglycemia, especially if on insulin or insulin secretagogues 1
  • Volume depletion symptoms (lightheadedness, orthostasis, weakness) 3
  • Genital mycotic infections 1
• The cardiovascular benefits of SGLT2 inhibitors or GLP-1 receptor agonists are not contingent upon A1C lowering; therefore, initiation can be considered independent of the current A1C or A1C goal 1

Common Pitfalls and Caveats

• Avoid substantial initial reductions in insulin dose (>20%) when initiating SGLT2 inhibitors 1
• Be aware that approximately 5-10% of adult-onset diabetes is late-onset type 1; these patients have an increased risk of diabetic ketoacidosis with SGLT2 inhibitors 1
• Monitor renal function regularly, as declining renal function may require dose adjustments 3
• Despite the theoretical benefits, there is limited evidence from randomized controlled trials on the cardiovascular outcomes of combination therapy 1