Adding a GLP-1 Receptor Agonist to Empagliflozin
For a patient already on empagliflozin who needs further HbA1c reduction, add a GLP-1 receptor agonist (semaglutide or liraglutide) as the next step, which will provide an additional 1.0-1.5% HbA1c reduction along with weight loss and cardiovascular benefits. 1
Rationale for GLP-1 Receptor Agonist Addition
The American Diabetes Association recommends adding a GLP-1 receptor agonist to metformin and an SGLT2 inhibitor for patients requiring intensification beyond dual therapy, as this combination provides robust HbA1c reduction, promotes weight loss, and reduces cardiovascular events in patients with established cardiovascular disease. 1
The European Association for the Study of Diabetes positions GLP-1 receptor agonists as the preferred third agent when SGLT2 inhibitors fail to achieve glycemic targets, due to their superior glucose-lowering potency compared to other options. 1
Empagliflozin alone provides moderate HbA1c reduction of 0.5-0.8%, with efficacy decreasing substantially as renal function declines. 2 This moderate effect often necessitates combination therapy to reach target.
Specific Agent Selection and Dosing
For patients with established cardiovascular disease, prioritize semaglutide or liraglutide due to their demonstrated cardiovascular outcome benefits in SUSTAIN-6 and LEADER trials. 1
Semaglutide Dosing Protocol:
- Start with once-weekly semaglutide 0.25 mg subcutaneously for 4 weeks 1
- Increase to 0.5 mg weekly after the initial month 1
- Escalate to 1.0 mg weekly if needed for glycemic control after another 4 weeks 1
Liraglutide Dosing Protocol:
- Start with liraglutide 0.6 mg daily subcutaneously 1
- Increase to 1.2 mg after one week 1
- Escalate to 1.8 mg if needed for glycemic control 1
Expected Outcomes
- HbA1c reduction of 1.0-1.5% from baseline with GLP-1 receptor agonist addition 1
- Weight loss of 2-4 kg over 6 months, contrasting with weight gain seen with insulin or sulfonylureas 1
- Cardiovascular and renal benefits independent of glucose-lowering effects when empagliflozin is continued 1
Pre-Treatment Screening Requirements
Before initiating GLP-1 receptor agonist therapy:
- Assess renal function to ensure empagliflozin continuation is appropriate (eGFR should be ≥20 mL/min/1.73 m² for empagliflozin use) 1
- Screen for contraindications: personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2 1
- Do not use GLP-1 receptor agonists in individuals with a family history of medullary thyroid cancer 3
Monitoring and Follow-Up Strategy
- Reassess HbA1c in 3 months after GLP-1 receptor agonist initiation 1
- If target HbA1c <7% is not achieved, consider further dose escalation of the GLP-1 receptor agonist before adding a fourth agent 1
- Continue current empagliflozin dose as it provides complementary mechanisms and cardiorenal protection independent of glucose-lowering effects 1
- Monitor for gastrointestinal side effects (nausea, vomiting, diarrhea), which are common but typically diminish over time 3
Why Not Other Options
Avoid sulfonylureas and insulin as third-line agents due to their association with hypoglycemia risk and weight gain, lacking the cardiorenal protective effects of GLP-1 receptor agonists. 1
DPP-4 inhibitors are inferior choices because saxagliptin increases heart failure hospitalization risk (3.5% vs. 2.8% with placebo), and even neutral DPP-4 inhibitors provide less HbA1c reduction than GLP-1 receptor agonists. 3
Common Pitfalls to Avoid
- Do not reduce empagliflozin dose when adding a GLP-1 receptor agonist, as both provide independent cardiorenal benefits 1
- Do not skip the dose titration period for GLP-1 receptor agonists, as this increases gastrointestinal side effects and reduces tolerability 1
- Do not use empagliflozin for glycemic control when eGFR <45 mL/min/1.73 m², though it should be continued for cardiovascular and renal protection down to eGFR ≥25 mL/min/1.73 m² in patients with established cardiovascular disease 2