In diabetics with ischemic heart disease, is a GLP-1 agonist or SGLT2 inhibitor more beneficial?

SGLT2 Inhibitors Should Be Prioritized in Diabetics with Ischemic Heart Disease

In diabetics with established ischemic heart disease, SGLT2 inhibitors should be the first-line choice because they provide comparable atherosclerotic cardiovascular event reduction to GLP-1 agonists while additionally offering superior benefits for heart failure prevention and kidney disease progression—complications that commonly coexist with ischemic heart disease. 1

Primary Recommendation Based on Most Recent Guidelines

The 2025 ADA Standards of Care provide the clearest guidance for this clinical scenario 1:

• SGLT2 inhibitors with demonstrated cardiovascular benefit are recommended (Class I, Level A) in people with type 2 diabetes and established atherosclerotic cardiovascular disease (ASCVD) to reduce major adverse cardiovascular events AND heart failure hospitalization 1

• GLP-1 receptor agonists with demonstrated cardiovascular benefit are recommended (Class I, Level A) in people with type 2 diabetes and established ASCVD to reduce major adverse cardiovascular events 1

The critical distinction: SGLT2 inhibitors address both atherosclerotic events AND heart failure, while GLP-1 agonists primarily target atherosclerotic events alone 1.

Why SGLT2 Inhibitors Have the Edge

Dual Cardiovascular Protection

SGLT2 inhibitors provide protection against both atherosclerotic events and heart failure—a crucial advantage since up to 50% of diabetics with ischemic heart disease will develop heart failure 1:

• Empagliflozin, canagliflozin, and dapagliflozin all demonstrate statistically significant reductions in major adverse cardiovascular events comparable to GLP-1 agonists 1
• SGLT2 inhibitors uniquely reduce heart failure hospitalization by 33-35% 1, 2
• They slow progression of kidney disease, which frequently coexists with ischemic heart disease 1

Specific Evidence for Atherosclerotic Disease

The 2024 ESC Guidelines for Chronic Coronary Syndromes explicitly recommend SGLT2 inhibitors (Class I, Level A) for all patients with type 2 diabetes and chronic coronary syndromes to reduce cardiovascular events 1. This represents the most recent high-quality guideline specifically addressing ischemic heart disease.

Empagliflozin reduces cardiovascular death by 38% (HR 0.62; 95% CI 0.49-0.77) in patients with established cardiovascular disease—the most robust mortality benefit among glucose-lowering agents 2.

When to Choose GLP-1 Agonists Instead

GLP-1 agonists should be selected in specific scenarios 1:

• Patients who cannot tolerate SGLT2 inhibitors (e.g., recurrent genital infections, risk of diabetic ketoacidosis)
• Patients with obesity requiring significant weight loss (GLP-1 agonists produce greater weight reduction) 1
• Patients without heart failure risk or kidney disease where atherosclerotic event reduction is the sole concern 1

The 2024 ESC guidelines note that semaglutide reduces cardiovascular mortality, MI, or stroke in overweight/obese patients with chronic coronary syndromes (Class IIa, Level B) 1.

Combination Therapy for Highest-Risk Patients

For patients with established ischemic heart disease at very high cardiovascular risk, combined therapy with both an SGLT2 inhibitor and GLP-1 agonist may be considered for additive cardiovascular and kidney protection 1:

• The 2025 ADA guidelines now explicitly state that combination therapy may provide additive reduction of adverse cardiovascular and kidney events 1
• This approach is particularly relevant for patients with multiple high-risk features: prior MI, heart failure, chronic kidney disease, or recurrent events 1

Critical Implementation Points

SGLT2 Inhibitor Selection

Choose agents with proven cardiovascular benefit 1:

• Empagliflozin: Strongest cardiovascular mortality reduction (38%) 2
• Canagliflozin: Significant MACE and heart failure reduction 1
• Dapagliflozin: Proven benefits across cardiovascular and renal outcomes 1
• Ertugliflozin: Lesser cardiovascular benefits; not preferred 1

GLP-1 Agonist Selection (if chosen)

Select agents with cardiovascular outcomes data 1:

• Semaglutide: 26% MACE reduction, FDA-approved for cardiovascular risk reduction 3, 4
• Liraglutide: Proven cardiovascular benefit 1
• Dulaglutide: Demonstrated cardiovascular event reduction 1
• Avoid extended-release exenatide: No significant cardiovascular benefit demonstrated 1

Common Pitfalls to Avoid

Do not assume all agents within each class are equivalent 1:

• Only specific SGLT2 inhibitors and GLP-1 agonists have proven cardiovascular benefits
• Ertugliflozin and extended-release exenatide lack robust cardiovascular outcome data 1

Monitor for SGLT2 inhibitor-specific risks 2:

• Euglycemic diabetic ketoacidosis during metabolic stress (illness, surgery, fasting)
• Genital mycotic infections
• Volume depletion in elderly or those on diuretics
• Reduced efficacy with eGFR <60 mL/min/1.73m² for glucose lowering (though cardiovascular benefits persist) 5

Recognize that meta-analyses show comparable atherosclerotic event reduction between classes, but SGLT2 inhibitors provide additional heart failure and renal benefits that tip the balance in their favor for ischemic heart disease patients 1.