With respect to cardiovascular and renal outcomes, combined therapy with SGLT2 inhibitors and GLP-1 receptor agonists has scant benefit compared with using either drug alone in patients with type 2 diabetes, according to a new study.

In a meta-analysis of 12 randomized controlled trials that included close to 1 million patients with type 2 diabetes, combined therapy did not significantly reduce the risk for major adverse cardiovascular or kidney events compared with SGLT2 or GLP-1 therapy alone.

It was, however, associated with a slight reduction in the risk for hospitalization for heart failure. Min-Hsiang Chuang, MD, of the Division of Nephrology at Chi-Mei Medical Center in Tainan, Taiwan, and coauthors called for randomized trials to clarify the comparative effectiveness of combined therapy in patients with type 2 diabetes.

The study was published on July 13 in CMAJ.

Few Differences Overall

In their meta-analysis, Chuang and colleagues sought to explore whether using a combination of SGLT2 and GLP-1 therapies is more effective in avoiding adverse cardiovascular and renal events than either therapy alone in this patient population. Many clinicians who treat patients with type 2 diabetes have been asking this question. Their analysis of 12 randomized controlled trials included 99,683 participants.

The risk for major adverse cardiovascular events did not differ significantly with combined SGLT2 and GLP-1 therapy compared with SGLT2 alone (risk ratio [RR], 0.86; very low certainty) or GLP-1 alone (RR, 0.95; very low certainty). Results were similar with regard to risk for major adverse kidney events with combination therapy vs therapy with SGLT2 alone (RR, 1.05; very low certainty) or GLP-1 alone (RR, 0.86; very low certainty).

Combined therapy was, however, associated with a lower risk for heart-failure-related hospital admissions than SGLT2 alone (RR, 0.72; very low certainty) or with GLP-1 alone (RR, 0.62; very low certainty). The risks for serious adverse events or hypoglycemia did not differ significantly between combined therapy and monotherapy, the authors reported.

The analysis has several limitations, such as postrandomization changes in the studies analyzed, differences between studies in outcome reporting, and a reliance on subgroup data. “Consequently, caution is warranted when interpreting our findings,” the authors wrote. “Randomized controlled trials directly comparing combined therapy with monotherapy are needed to clarify the comparative effectiveness of combined therapy in patients with type 2 diabetes mellitus,” they concluded.

Not a Practice-Changer

“As the authors have outlined well in the manuscript, there are many limitations to the analysis,” Alice Y. Y. Cheng, MD, associate professor of medicine at the University of Toronto and endocrinologist at Trillium Health Partners and St Michael’s Hospital in Toronto, told Medscape News Canada.

“There are lots of data supporting the cardiorenal benefits of SGLT2 inhibitors, as well as GLP-1 receptor agonists in certain populations. International guidelines, including our own Diabetes Canada guidelines, recommend the use of these therapies for their organ-protecting properties. I would definitely continue my practice of giving both,” Cheng said.

Observational data from large databases have suggested that SGLT2 and GLP-1 combination therapy is associated with better organ outcomes than combinations that include other therapies, such as sulfonylurea or DPP-4 inhibitors, she noted. “These analyses may be in a better position to address this question of combination therapy than the randomized controlled trials included in this study because of the numbers involved. As the authors pointed out, the proposed mechanisms of organ protection are quite different, and there is no reason for us to think that the mechanisms will cancel each other out,” Cheng said.

A randomized controlled trial could answer the question definitively but might not be cost-effective. “I wonder if that is the best use of limited resources as the benefits of each drug are so well proven,” she said. “Our limited resources may be better spent researching how to implement guideline-directed therapy.”

Study Raises Doubts

“I’m glad they did this study,” Kaberi Dasgupta, MD, professor of medicine and senior scientist at the Centre for Outcomes Research and Evaluation at McGill University in Montreal, told Medscape News Canada.

“The authors did the best with the information they had, but I don’t know if the results convince me that we need a randomized trial. I will take each patient according to their individual needs. Some might have more need for an SGLT2 inhibitor, others might benefit more from a GLP-1 receptor agonist,” Dasgupta said.

Though the evidence for a benefit of combination therapy related to heart failure is significant, the evidence supporting the combination is not particularly strong, she noted. “Even when we look at this outcome, the combined therapy vs SGLT2 may have similar results, given that the upper end of the confidence interval, 0.99, is close to 1. This study adds doubt as to whether combining therapies is worthwhile in this population for the purpose of preventing cardiovascular and renal outcomes in this group of patients,” Dasgupta said.

“If they had shown that the combination seemed better, then I would have agreed we need a proper trial to prove this, but the fact that they didn’t show that the combination was better is evidence against doing a trial,” she said.

The study was supported by the Chi-Mei Medical Center. Chuang and Dasgupta reported having no relevant financial relationships. Cheng reported having financial relationships with Abbott, Amgen, Aspen, Astellas, AstraZeneca, Bausch, Bayer, Boehringer Ingelheim, Biomea Fusion, Biosyent, Callway Biopharmaceuticals, Elsai, Eli Lilly, GSK, HLS Therapeutics, Insulet, Medtronic, Novo Nordisk, Sanofi, and Sandoz.