Recent clinical debates and research findings have highlighted the distinct cardiovascular benefits of two leading diabetes medication classes—glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors—with each offering unique advantages for patients with type 2 diabetes.
At the 2025 American Pharmacists Association (APhA) Annual Meeting & Exposition in Nashville, Tennessee, clinical pharmacy specialists Heather Roth and Heather Johnson presented comprehensive evidence comparing these medication classes, emphasizing their differential impacts on cardiovascular outcomes.
Distinct Cardiovascular Benefits of GLP-1 Receptor Agonists
GLP-1 receptor agonists work through multiple mechanisms, including increased glucose-dependent insulin secretion, decreased inappropriate glucagon secretion, slowed gastric emptying, and reduced food intake. These effects contribute to significant weight loss and reductions in blood pressure, cholesterol, and blood glucose levels.
Clinical evidence strongly supports GLP-1 receptor agonists' cardiovascular benefits. Multiple pivotal trials have demonstrated their efficacy in reducing major adverse cardiovascular events (MACE), particularly non-fatal stroke. The LEADER trial (liraglutide), SUSTAIN-6 (semaglutide), and REWIND trial (dulaglutide) all showed significant cardiovascular protection.
"A meta-analysis of 8 cardiovascular outcome trials revealed an overall 14% reduction in MACE with GLP-1 therapy, with specific reductions in cardiovascular death (13%), non-fatal stroke (16%), and non-fatal myocardial infarction (9%)," noted Roth during the session.
The American Stroke Association now includes GLP-1 receptor agonists in its guidelines for stroke prevention, recognizing their superior efficacy in this area compared to SGLT2 inhibitors. Additionally, GLP-1s produce more pronounced weight reduction—a critical factor in cardiovascular health—than SGLT2 inhibitors.
SGLT2 Inhibitors: Excellence in Heart Failure and Renal Protection
SGLT2 inhibitors demonstrate particular strength in heart failure management and renal protection. With over 6 million Americans suffering from heart failure—a leading cause of death and major risk factor for cardiovascular events—these medications provide direct benefits by reducing hospitalizations and mortality, even in patients without diabetes.
Clinical trials including EMPA-REG (empagliflozin) and CANVAS (canagliflozin) have demonstrated superiority in reducing cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. Johnson emphasized that these benefits were "largely driven by reductions in cardiovascular death, making SGLT2 inhibitors a critical component in improving overall survival rates in high-risk patients."
The DECLARE-TIMI trial highlighted dapagliflozin's role in preserving ejection fraction and reducing morbidity and mortality in heart failure patients. "We saw about 3% lower risk of composite death and worsening heart failure with this agent in patients with heart failure," Johnson noted.
A crucial advantage of SGLT2 inhibitors lies in their renal protection capabilities. As estimated glomerular filtration rate (eGFR) declines, the risk of cardiovascular death increases. SGLT2 inhibitors slow the progression of chronic kidney disease and reduce acute kidney injury risk.
"Anything to preserve that eGFR is going to have a significant impact on cardiovascular health," Johnson explained. "SGLT2s are also known to be protective against acute kidney injury, while GLP-1s can cause AKIs."
Real-World Evidence from Danish Cohort Study
A recent Danish cohort study published in eClinicalMedicine provides compelling real-world evidence supporting both medication classes. The study analyzed data from 35,679 elderly patients (≥70 years) with type 2 diabetes between 2012 and 2020, comparing cardiovascular outcomes among new users of GLP-1 RAs, SGLT2 inhibitors, or dipeptidyl-peptidase-4 (DPP-4) inhibitors.
Both GLP-1 RAs and SGLT2 inhibitors were associated with significantly lower rates of MACE and hospitalization for heart failure compared to DPP-4 inhibitors. The incidence rate ratios for 3-point MACE were 0.68 for GLP-1 RAs and 0.65 for SGLT2 inhibitors relative to DPP-4 inhibitors.
For hospitalization for heart failure, GLP-1 RAs showed an incidence rate ratio of 0.81 and SGLT2 inhibitors showed 0.60 compared to DPP-4 inhibitors. Notably, while no significant difference was observed between SGLT2 inhibitors and GLP-1 RAs for MACE, SGLT2 inhibitors were linked to a significantly lower risk of heart failure hospitalization than GLP-1 RAs, with an incidence rate ratio of 0.75.
The researchers concluded: "We found that both GLP1-RAs and SGLT-2is were associated with reduced risk of 3P-MACE and HHF, compared to DPP-4is and independent of age, and that SGLT-2is were associated with reduced risk of HHF, largely independent of age, compared to GLP1-RAs."
Practical Considerations for Clinical Decision-Making
Beyond efficacy, practical considerations influence medication selection. GLP-1 receptor agonists offer convenient weekly dosing options for some formulations and contribute to insulin dose sparing. They also show promise in treating non-alcoholic steatohepatitis (NASH), an emerging area of interest in diabetes management.
SGLT2 inhibitors, meanwhile, demonstrate cost advantages. "SGLT2s may not be the most effective for diabetes overall, but my argument is that, just looking at cardiovascular outcomes, they're your best bet," Johnson argued. "SGLT2s are cheaper."
Tailoring Treatment to Individual Patient Needs
The growing body of evidence supports both GLP-1 receptor agonists and SGLT2 inhibitors for cardiovascular health in patients with diabetes, with each class offering distinct advantages. GLP-1s excel in weight loss, glycemic control, and stroke prevention, while SGLT2 inhibitors provide unmatched benefits in heart failure, cardiovascular death reduction, and renal protection.
Patient-specific factors—including existing comorbidities, treatment goals, and cost considerations—should guide clinicians in selecting the most appropriate therapy. The American Diabetes Association guidelines now prioritize cardiovascular and renal health over simply managing A1c levels, recognizing the importance of these newer medication classes in comprehensive diabetes management.
As research continues to evolve, these medications are increasingly becoming standard of care for patients with type 2 diabetes, particularly those at elevated cardiovascular risk.
