Key takeaways:

• GLP-1 drugs were favored in those at moderate kidney failure risk while SGLT2 inhibitors were favored at high risk.
• Both drug classes had kidney, CV and mortality benefits vs. insulin glargine.

Kidney failure risk may impact treatment effectiveness of SGLT2 inhibitors vs. GLP-1 drugs for veterans with type 2 diabetes, according to study data published in the Journal of the American Society of Nephrology.

Currently, no randomized controlled trials have compared the effectiveness of SGLT2 inhibitors vs. non-exendin GLP-1 receptor agonists, according to Srinivasan Beddhu, MD, scientific director at the Cardiovascular, Renal and Metabolism Center, Sydney E. Hartsell, MD, MPH, physician scientist in the division of nephrology and hypertension, both at University of Utah Health, and colleagues. The researchers aimed to compare the therapies in a comparative effectiveness analysis using an active comparator and a new user study design.

Kidney and CV benefits of SGLT2 inhibitors and GLP-1 drugs for patients with type 2 diabetes may vary based on their risk for kidney failure. Image: Adobe Stock

“The goal isn’t so much setting up a fight between SGLT2 inhibitors and GLP-1s,” Hartsell told Healio. “It’s often hard for our patients to be on both of them due to a variety of reasons, including finances. So, the question was more if you have to choose between the two, what does the data show?”

The researchers compared kidney and CV outcomes among 160,428 veterans with type 2 diabetes on metformin who started treatment with an SGLT2 inhibitor (53%), a GLP-1 drug (14%) or insulin glargine (34%) between 2018 and 2021.

The primary outcomes were kidney failure (sustained stage 5 chronic kidney disease or need for long-term kidney replacement therapy), major adverse CV events (MACE), a composite cardiovascular-kidney-metabolic (CKM) outcome (kidney failure or MACE), all-cause mortality and composites of each outcome with mortality.

Most veterans with available data were estimated to be at low risk for kidney failure (94%), followed by moderate (4%) and high risk (2%).

Results in the overall cohort showed SGLT2 inhibitor users, compared with GLP-1 users, had modestly greater risks for MACE (HR = 1.14; 95% CI, 1.09-1.2), modestly lower but not statistically significant risks for kidney failure and similar risks for all-cause mortality, according to the researchers.

“SGLT2 inhibitors vs. GLP-1s reached significance for MACE, but not for kidney failure because there are a lot more MACE events and fewer kidney failure events,” Beddhu told Healio. “The point estimates of the effect sizes are similar.”

The study also found significant effect modification by baseline kidney failure risk, according to the researchers. GLP-1 users at moderate risk for kidney failure had lower risks for kidney, CV and composite CKM outcomes compared with those starting SGLT2 inhibitors. The trend was reversed in those at high risk for kidney failure, favoring SGLT2 inhibitors for kidney and CV protection over GLP-1 receptor agonists, the researchers said.

“These agents have totally different mechanisms by which they act,” Beddhu said. “It’s totally speculative at this point, but it’s possible that SGLT2 inhibitors might be more beneficial in those with more advanced disease while GLP-1s might be more beneficial in earlier disease.”

“The study certainly brings out some interesting hypotheses as we’re learning more about the mechanisms of these agents,” Hartsell said.

Furthermore, insulin glargine users faced greater risks for all outcomes compared with SGLT2 inhibitor users or GLP-1 users, according to the researchers.

“I practice at the VA, and I see a lot of people still on insulin and not on a SGLT2 inhibitor or GLP-1,” Beddhu said. “We need to focus on not only optimizing the better agents, but also making sure that we are not using other agents [that] may not be as beneficial.”

Overall, the benefits of SGLT2 inhibitors and GLP-1 drugs for patients may vary based on a patient’s risk for kidney failure, according to the researchers. Head-to-head trials are needed to compare the effectiveness of SGLT2 inhibitors and GLP-1s further, the researchers wrote.

“In the low-risk population, the signal favoring GLP-1s for cardiovascular events was interesting and different from the existing literature,” Hartsell said. “That finding [shows] the need for a randomized controlled trial of non-exendin GLP-1s vs. SGLT2 inhibitors because they might have a different kind of cardiovascular effect than exendin-based GLP-1s.”

For more information:

Srinivasan Beddhu, MD, professor and scientific director at the Cardiovascular, Renal and Metabolism Center in the department of internal medicine at University of Utah Health, can be reached at srinivasan.beddhu@hsc.utah.edu.

Sydney E. Hartsell, MD, MPH, assistant professor of internal medicine and a physician scientist in the division of nephrology and hypertension at University of Utah Health, can be reached at nephrology@healio.com.