SGLT2 Inhibitors Add to GLP-1s’ Cardio, Kidney Benefits

STOCKHOLM — In the treatment of type 2 diabetes, sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) show independent benefits that complement each other when combined in treating cardiovascular and kidney disease, a major analysis from the SGLT2 Inhibitor Meta-Analysis Cardio-Renal Trialists’ Consortium (SMART-C) showed.

“These data represent the largest and most comprehensive assessment of the effects of SGLT2 inhibitors with and without GLP-1 receptor agonists in clinical outcomes,” said first author Brendon Neuen, a senior research fellow at The George Institute for Global Health and director of Kidney Trials at Royal North Shore Hospital, Sydney, Australia, who presented the research at the 61st European Renal Association (ERA) Congress 2024.

“The data have very important clinical implications given the rapidly expanding use of GLP-1 receptor agonists,” said Neuen, who is co-chair of SMART-C.

Evidence has shown that drugs in both classes offer benefits in kidney and cardiovascular outcomes in people with type 2 diabetes.

However, data regarding the effects of the drugs in combination, though supported in guidelines such as those from the American Diabetes Association and KDIGO, are largely based on small clinical trials of short duration.

To provide a more comprehensive assessment of the data, Neuen and colleagues conducted the collaborative meta-analysis of SMART-C, which includes all randomized double-blind placebo-controlled trials evaluating the effects of an SGLT2 inhibitor on primary clinical outcomes in trials with more than 500 patients in each treatment arm and a follow-up duration of greater than 6 months.

The 12 trials identified included nearly 73,000 participants with diabetes and about 3000 participants who were also being treated with a GLP-1 RA at baseline.

The studies were stratified based on those in which patients were or were not receiving GLP-1 RA therapy at baseline and then were treated with SGLT2 inhibitor therapy.

For the outcome of hospitalization for heart failure or cardiovascular death, among those not receiving GLP-1 RAs at baseline, treatment with SGLT2 inhibitors was associated with significant benefits vs placebo in high atherosclerotic cardiovascular risk trials (hazard ratio [HR], 0.80); stable heart failure trials (HR, 0.77); and chronic kidney disease (CKD) trials (HR, 0.74). Across the trials, the improvement with SGLT2 inhibitors was represented by an HR of 0.77.

When patients did have a baseline use of GLP-1 RAs, the addition of SGLT2 inhibitors provided further benefit on top of that provided by GLP-1 RA, with HRs similar to those observed in the respective trial categories of SGLT2 inhibitor vs placebo, hence underscoring that the independent benefits of SGLT2 inhibitors add to those provided by the baseline use of GLP-1 RA (heterogeneity based on use/no use of GLP-1 RAs: P = .90).

The benefits of SGLT2 inhibitors compared with those of placebo and baseline GLP-1 RA use were further observed in measures of CKD progression (heterogeneity by baseline use of GLP-1 RA: P = .81); chronic estimated glomerular filtration rate (eGFR) slope (absolute difference: P = .55); total eGFR slope (P = .92); all-cause mortality (P = .63); and safety outcomes (all P > .10).

The improvements in CKD progression were particularly notable, with significant slowing of progression with SGLT2 inhibitors compared with placebo without and with baseline GLP-1 RA use (HR, 0.67 and 0.65, respectively).

The relative difference with SGLT2 inhibitor use in terms of chronic eGFR slope was also substantial without and with GLP-1 RA use (relative difference, 57% and 60%, respectively).

“The CKD progression endpoint and the slope data are clearly important in the context of the FLOW trial results, providing the strongest evidence yet for combination of SGLT2 inhibitor and GLP-1 RA to reduce kidney failure due to diabetes,” Neuen said.

In addition to the relatively small number of patients on GLP-1 RAs, reflecting the timing of the studies, other limitations included potential differences between different GLP-1 RAs, which were considered a class. And the study did not address the question of combined initiation of SGLT2 inhibitors and GLP-1 RAs, which will require a dedicated clinical trial.

However, Neuen pointed to additional recent research that further details the benefits of GLP-1 RA on cardiovascular outcomes, independent of SGLT2 inhibitors.

Furthermore, landmark findings from the FLOW trial, reported at the meeting, show significant effects of GLP-1 RA semaglutide on reduction of kidney risk, additionally underscoring the independent contributions of GLP-1 RAs, Neuen said.

Considering the totality of the evidence, “it is difficult to argue that combined SGLT2 inhibitor and GLP-1 RA should not be routinely offered to most people with diabetes, given their clear benefit on clinical outcomes and anticipated benefits when used in combination,” Neuen said.

“These findings support clinical practice guidelines recommending the use of both agents in combination to optimize cardiovascular and kidney outcomes,” he said.

Commenting on the research, María José Soler, MD, head of the Clinical Nephrology and Dialysis Unit and research lab group leader at Vall d’Hebron Research Institute, in Barcelona, Spain, noted that considering the bulk of evidence and the latest findings from the FLOW study in GLP-1 RA kidney benefits, “I am not sure if it would be ethical to design a study in patients with diabetes without combining the two drugs together in one of the arms.”

She noted that “all my colleagues are currently prescribing the combination when permitted.” While a caveat is the condition that body mass index (BMI) is recommended to be higher than 30 for GLP-1 RA use, Soler said she anticipates that with the results of the FLOW trial, that recommendation will be modified to expand treatment to patients with a lower BMI.

Regarding issues of cost with the combined treatments, Soler underscored that “the added benefits [of the combination] justify the cost without any doubt, as delaying the progression of CKD saves a lot of money in patients.”

In Spain, for instance, hemodialysis costs around €50,000 (about $54,000 US) per year, whereas “if you delay only 1 year [with the combined therapy], you will save much more money than the expenses of the drugs.”

“In my opinion, the take-home message is clear: Use both protective drugs for patients with type 2 diabetes and CKD to stop the progression to ESKD, cardiovascular events, and to improve the patient’s quality of life and prognosis.”

Neuen reported consultancy or other relationships with AstraZeneca, Alexion, Bayer, Boehringer & Ingelheim, Novo Nordisk, Travere Therapeutics, Cambridge Healthcare Research, Cornerstone Medical Education, Dedham Group, The Limbic, Medscape Medical News, American Diabetes Association, and the Renal Society of Australasia Trial/Consortium steering committees: SMART-C, AstraZeneca, Bayer, and CSL Behring. Soler disclosed consulting and/or having other relationships with AstraZeneca, Ingelheim Lilly, Otsuka, Novo Nordisk, GSK, Sanofi, Esteve, Boehringer, Jansen, Mundipharma, Vifor, Fresenius, Travere Therapeutics, ICU Medical, and Bayer.