APhA 2025: GLP-1 Receptor Agonists vs SGLT2 Inhibitors Show Varied Benefit for Cardiovascular Outcomes in Patients With Diabetes

Both glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors offer significant cardiovascular (CV) benefits for patients with diabetes, but the optimal choice depends on individual patient factors. While GLP-1 receptor agonists provide superior stroke prevention, weight loss, and glycemic control, SGLT2 inhibitors excel in heart failure management, CV death reduction, and renal protection. In a debate at the 2025 American Pharmacists Association (APhA) Annual Meeting & Exposition in Nashville, Tennessee, Heather Roth, BSPharm, and Heather Johnson, PharmD, BCACP, discussed these differences, providing a comprehensive comparison of these 2 drug classes.

The Case for GLP-1 Receptor Agonists

Ozempic, Mounjaro and Wegovy injectable pens. Image Credit: © K KStock - stock.adobe.com

Roth, a clinical pharmacy specialist at Corewell Health in Grand Rapids, Michigan, opened the debate by advocating for GLP-1 receptor agonists, emphasizing their well-documented benefits in reducing major adverse CV events (MACE). She highlighted key mechanisms of GLP-1 therapy, which include increased glucose-dependent insulin secretion, decreased inappropriate glucagon secretion, slowed gastric emptying, and reduced food intake—ultimately leading to weight loss. These effects, in turn, contribute to reductions in blood pressure, cholesterol, and blood glucose levels, making GLP-1s a powerful tool for patients with type 2 diabetes (T2D).

The American Diabetes Association (ADA) guidelines now prioritize CV and renal health over simply managing A1c levels, and GLP-1s have demonstrated significant impact in this regard, according to Roth. Additionally, several pivotal trials showed reductions in MACE, specifically non-fatal myocardial infarction (MI), non-fatal stroke, and CV death. These trials included the LEADER trial (NCT01179048) which looked at liraglutide (Victoza; Novo Nordisk); ); SUSTAIN-6 (NCT01720446), which looked at semaglutide (Ozempic; Novo Nordisk); and the REWIND trial (NCT01394952), which looked at dulaglutide (Trulicity; Eli Lilly). Further, a meta-analysis of 8 CV outcome trials further cemented these findings, revealing an overall 14% reduction in MACE with GLP-1 therapy, with specific reductions in CV death (13%), non-fatal stroke (16%), and non-fatal MI (9%).

“The highest percent is that non-fatal stroke,” Roth said during the APhA session. “That is an advantage that GLP-1s have.”

A particularly compelling argument for GLP-1s is their superiority in stroke prevention, a critical advantage over SGLT2 inhibitors, according to Roth. The American Stroke Association now includes GLP-1 receptor agonists in its guidelines for stroke prevention. Additionally, weight reduction—a key factor in CV health—is more pronounced with GLP-1s than with SGLT2 inhibitors. Roth emphasized that achieving and maintaining weight and glycemic goals is crucial for long-term CV benefits, further positioning GLP-1s as an optimal choice.

“With GLP-1s, there are very high categories of weight reduction,” Roth said. “GLP-1s are also a little bit more effective here in reducing glycemic goals overall.”

The Case for SGLT2 Inhibitors

Health care professionals inspect a heart. Image Credit: © Marina Zlochin - stock.adobe.com

Johnson, an assistant professor of clinical pharmacy and family medicine in West Virginia University School of Pharmacy in Morgantown, discussed the case for SGLT2 inhibitors, particularly emphasizing their role in heart failure (HF) and chronic kidney disease (CKD). She pointed out that over 6 million Americans suffer from heart failure, which is a leading cause of death and a major risk factor for CV events. Unlike GLP-1s, which primarily act through metabolic pathways, SGLT2 inhibitors provide direct benefits to patients with heart failure by reducing hospitalizations and mortality, even in those without diabetes.

Johnson noted there are also clinical trials that support SGLT2 use, including studies on empagliflozin (Jardiance; Boehringer Ingelheim and Eli Lilly) and canagliflozin (Invokana; Janssen), which demonstrated superiority in reducing CV death, non-fatal MI, and non-fatal stroke. These studies include EMPA-REG (NCT01131676; HR 0.65 [0.50-0.85]) with empagliflozin and CANVAS (NCT01032629; HR 0.67 [0.52-0.87]) with canagliflozin. Notably, the benefits observed in these studies were largely driven by reductions in CV death, making SGLT2 inhibitors a critical component in improving overall survival rates in high-risk patients.

“These studies, it's really hard to give a general overview, but they're anywhere from 6000 to 10,000 patients [in a study period of] 2 to 5 years,” Johnson said. “So really robust studies showing a superiority, especially with those 2 specific agents.”

Additionally, Johnson highlighted the emerging role of dapagliflozin (Farxiga; AstraZeneca) in preserving ejection fraction and reducing morbidity and mortality in heart failure patients, as seen in the DECLARE-TIMI trial (NCT01730534; 0.73 [0.61-0.88]).

“We can't leave dapagliflozin out. Although it didn't show superiority, we do have that preserved ejection fraction benefit seen,” Johnson said. “We saw that about 3% lower risk of composite death and worsening heart failure, so morbidity and mortality [is impacted] with this agent in patients with heart failure. “

A crucial advantage of SGLT2 inhibitors lies in their impact on renal protection, according to Johnson. The intricate relationship between CV and renal health underscores the importance of preserving kidney function to reduce CV death. Johnson pointed out that as estimated glomerular filtration rate (eGFR) declines, the risk of CV death increases. Notably, SGLT2 inhibitors have been shown to slow the progression of CKD and reduce acute kidney injury (AKI), whereas GLP-1s have been associated with a risk of AKI.

“Anything to preserve that eGFR is going to have a significant impact on cardiovascular health,” Johnson said. “SGLT2s are also known to be protective against AKI, while GLP-1 can cause AKIs.”

Rebuttal and Counterpoints

Roth acknowledged the strong role of SGLT2 inhibitors in heart failure and CKD but countered that GLP-1 receptor agonists also provide renal benefits, particularly semaglutide. She referenced the FLOW trial (NCT03819153), which demonstrated that semaglutide offers both CV and renal protection. Additionally, she argued that GLP-1s contribute to insulin dose sparing, have more convenient weekly dosing options, and hold promise in treating non-alcoholic steatohepatitis (NASH), an emerging area of interest in diabetes management.

“Well, there are some really great advantages GLP-1s have that could be a potential you reason why you want to choose that class,” Roth said. “Insulin dose sparing can be a really big advantage for our patients. GLP-1s also have convenient dosing. Depending on the patient, a weekly dose of a GLP-1 might be a lot easier to manage than daily medications [with SGLT2s]. Of course, that's patient specific. Then there is also the potential benefit in NASH and evidence is coming out for that.”

Johnson, in her final arguments, reinforced the superiority of SGLT2 inhibitors in CV death prevention. She emphasized that while GLP-1s are effective for weight loss and stroke reduction, SGLT2 inhibitors provide a more comprehensive benefit for heart failure, renal protection, and acute coronary syndrome management.

“In emerging data for SGLT2 inhibitors, going back to that cardiovascular death, we're even seeing benefit in acute coronary syndromes when we really need it the most,” Johnson said. “We also are seeing them used to prevent instet restentinosis and then also pulmonary arterial hypertension, which, as we know, is an area that is desperately in need of other medications.”

Furthermore, she highlighted the cost-effectiveness of SGLT2 inhibitors, making them a more accessible option for a broader patient population.

“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 said. “I do have one more argument. It's always going to come back to money for me. SGLT2s are cheaper.”

Conclusion

There is a growing body of evidence supporting both GLP-1 receptor agonists and SGLT2 inhibitors in CV health for patients with diabetes. While GLP-1s excel in weight loss, glycemic control, and stroke prevention, SGLT2 inhibitors offer unmatched benefits in heart failure, CV death reduction, and renal protection. Ultimately, patient-specific factors, including existing comorbidities, treatment goals, and cost considerations, will guide clinicians in selecting the most appropriate therapy.

REFERENCE

Roth H, Johnson H. Moonshine vs Tennessee Wine: Debate on Controversies in Diabetes. Presented at: APhA Annual Meeting & Exposition; Nashville, Tennessee; March 21-24, 2025.