GLP-1 RAs, SGLT2 Inhibitors Associated With Reduced MACE, HHF in Patients With Diabetes

Newer glucose-lowering medications glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 (SGLT2) inhibitors significantly reduced the risk of major cardiovascular events and heart failure in older adults with type 2 diabetes (T2D), according to one study.¹ The findings suggest these treatments outperform dipeptidyl-peptidase-4 (DPP-4) inhibitors, regardless of age, and support their use in clinical guidelines for elderly populations.

The Danish cohort study is published in eClinicalMedicine.

Cardiovascular effectiveness was observed, largely independent of age, in a cohort of older patients with type 2 diabetes. | Image credit: Sherry Young - stock.adobe.com

“To our knowledge, this is the first 3-arm, real-world comparative study to comprehensively analyze the cardiovascular effectiveness of SGLT-2is, GLP1-RAs, and DPP-4is in elderly (≥70 years) individuals with T2D, as well as the first to provide age-specific IRR [incidence rate ratios] for these outcomes,” wrote the researchers of the study.

It is estimated that nearly 589 million individuals are living with diabetes globally, with more than 250 million being unaware that they have it, according to insights from the 11th edition of the International Diabetes Atlas.² Moreover, diabetes has significant health complications, such as cardiovascular disease, kidney failure, nerve damage, and loss of vision. For those with T2D, 84% are at a higher risk of heart failure than those who do not have the condition.

The researchers utilized health registry data from 2012 to 2020 to emulate a 3-arm randomized clinical trial.¹ The study included individuals 70 years or older with T2D who were new users of either GLP-1 RAs, SGLT2 inhibitors, or DPP-4 inhibitors. To assess cardiovascular outcomes, they compared the incidence of 3-point major adverse cardiovascular events (3P-MACE)—including heart attack, stroke, and cardiovascular death—and hospitalization for heart failure (HHF). Additionally, the researchers estimated overall and age-specific incidence rate ratios (IRRs), while adjusting for baseline characteristics and treatment adherence across groups.

Among 35,679 participants, the study found that both GLP-1 RAs and SGLT 2 inhibitors were associated with significantly lower rates of MACE and HHF compared with DPP-4 inhibitors. IRRs for 3P-MACE were 0.68 for GLP1-RAs and 0.65 for SGLT2 inhibitors, relative to DPP-4is. For HHF, GLP1-RAs showed an IRR of 0.81 and SGLT2 inhibitors showed an IRR of 0.60 compared with DPP-4 inhibitors. Notably, while no significant difference was observed between SGLT2 inhibitors and GLP-1 RAs for 3P-MACE, the former were linked to a significantly lower risk of HHF than GLP-1 RAs, with an IRR of 0.75. These cardiovascular benefits were largely consistent across age groups within this patient population.

However, the researchers acknowledged some limitations, including residual confounding from unmeasured factors like body mass index, smoking, and disease severity. Medication use was based on prescription redemptions, which may not reflect actual intake. Additionally, cause-specific death was excluded due to concerns about diagnostic accuracy. Furthermore, the researchers excluded 3.7% of participants for missing data, which have may introduced slight bias, while the largely homogeneous Danish population limited generalizability.

Despite these limitations, the researchers believe the study supports the effectiveness of GLP-1 RAs and SGLT2 inhibitors in reducing the risk of cardiovascular events.

“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,” the researchers wrote. “These results could help strengthen the implementation of current guidelines into clinical practice.”

References

1. Kosjerina V, Parsa M, Scheuer SH, et al. Comparative cardiovascular effectiveness of newer glucose-lowering drugs in elderly with type 2 diabetes: a target trial emulation cohort study. eClinicalMedicine. 2025;82:103162. doi:10.1016/j.eclinm.2025.103162

2. Steinzor P. More than 250 million individuals unaware they have diabetes. AJMC^®. April 7, 2025. Accessed April 9, 2025. https://www.ajmc.com/view/more-than-250-million-individuals-unaware-they-have-diabetes