Both SGLT2 and GLP-1 Drugs Help Heart and Kidneys in Type 2 Diabetes

When it comes to kidney and cardiovascular outcomes, there is no significant difference between treatment with an SGLT2 inhibitor or GLP-1 receptor agonist in patients with type 2 diabetes, according to a new observational study.

Use of an SGLT2 inhibitor did, however, result in a lower risk of patients experiencing a 40% decline in the estimated glomerular filtration rate (eGFR), as well as a “superior eGFR slope,” which is a surrogate for kidney disease progression, when compared with a GLP-1 receptor agonist. 

“There is a lot of overlap between these two medication classes, both from a kidney and a cardiovascular perspective,” first author investigator Daniel Edmonston, MD (Duke Clinical Research Institute, Durham, NC), told TCTMD. “If you were to really do a deep dive, then there's appears to be a separation of the kidney outcomes in favor of the SGLT2 inhibitors. Even though they both have kidney benefits as shown in clinical trials versus placebo, there does appear to be some incremental benefit of an SGLT2 inhibitor versus a GLP-1 receptor agonist.”

The treatment landscape for chronic kidney disease (CKD) and cardiovascular events associated with type 2 diabetes has altered dramatically in recent years, with multiple large outcomes trials showing several new drug classes—SGLT2 inhibitors, GLP-1 receptor agonists, and the mineralocorticoid receptor antagonist (MRA) finerenone (Kerendia; Bayer AG)—reduce the risk of CKD progression and CVD events. 

With the SGLT2 inhibitors, several dedicated studies in CKD patients, including CREDENCE with canagliflozin (Invokana; Janssen), the EMPA-KIDNEY trial with empagliflozin (Jardiance; Boehringer Ingelheim/Eli Lilly), and DAPA-CKD with dapagliflozin (Farxiga; AstraZeneca), have confirmed the benefit of SGLT2 inhibition in this population. In the FLOW trial, investigators showed that the GLP-1 receptor agonist semaglutide (Ozempic; Novo Nordisk) dramatically reduced the risk of major kidney events, MACE, and all-cause mortality in patients with type 2 diabetes and CKD. 

“It brings up this excellent conundrum where we have two therapies with kidney benefits and cardiovascular benefits,” said Edmonston. “We think they might have a lot of overlap, but they also might have opportunities for complementary benefits.”

Propensity-Weighted Analysis

With no head-to-head comparisons between the two drug classes to determine if there are any differences that could guide individualized treatment, investigators collected electronic health records from 20 US health systems to capture patients with type 2 diabetes newly prescribed an SGLT2 inhibitor or GLP-1 receptor agonist between 2015 and 2020. The study, which was published last week in the Journal of the American College of Cardiology, included 82,272 people, of whom 35,004 were prescribed an SGLT2 inhibitor and 47,268 prescribed a GLP-1 receptor agonist.

In a propensity score-weighted model, there was no difference in the primary composite kidney endpoint (40% decline in eGFR, end-stage kidney disease, or mortality) between the two treatments after a median follow-up of 1.2 years (HR 0.91; 95% CI 0.81-1.02). There was a reduction in the risk of a 40% decline in eGFR favoring the SGLT2 inhibitors (HR 0.77; 95% CI 0.65-0.91) but no difference in the other individual endpoints. In subgroup analyses stratifying patients with and without CKD at baseline, the results were similar.

There was no significant difference in the risk of MI, stroke, or all-cause mortality between treatments (HR 1.03; 95% CI 0.93-1.14). Results were similar when revascularization was added to the composite cardiovascular endpoint. Additionally, there was no difference in the risk of heart failure. Again, results were similar in patients with and without CKD at baseline.

While genital mycotic infections were more frequent with SGLT2 inhibitors, the safety profile was similar with the SGLT2 inhibitors and GLP-1 receptor agonists.

Edmonston said the analysis has limitations, notably the potential for confounding inherent to observational studies, although the researchers tried to account for this with inverse probability weighting with propensity scores. He also noted that the analysis was based on prescriptions and thus lacked information on medication refills and adherence to therapy.  

US and European Guidelines

To TCTMD, Darren McGuire (UT Southwestern Medical Center, Dallas, TX), who wasn’t involved in the study, said that treatment for patients with type 2 diabetes involves both SGLT2 inhibitors and GLP-1 receptor agonists independent of glucose control.

In the European Society of Cardiology guidelines for the management of cardiovascular disease in patients with diabetes, for example, both drug classes are class 1 recommendations for patients with type 2 diabetes and atherosclerotic cardiovascular disease (ASCVD). For patients with type 2 diabetes and confirmed CKD, again both SGLT2 inhibitors and GLP-1 receptor agonists are class 1 recommendations.

“SGLT2 inhibitors would have a slight preference in the setting of CKD, but those patients also should be on both SGLT2 inhibitors and GLP-1 receptor agonists independent of glucose control,” McGuire told TCTMD.

In contrast, US consensus statements recommend a GLP-1 receptor agonist with proven cardiovascular benefit in patients with type 2 diabetes and CKD who do not meet their glycemic target with metformin and/or an SGLT2 inhibitor (or those unable to use the drugs). Edmonston noted that those guidelines were drafted prior to the FLOW trial with semaglutide.

“The most recent KDIGO guidelines, which were updated this year, and the ADA standards of care: both similarly have [guideline-directed medical therapy] for CKD and type 2 diabetes as an SGLT2 inhibitor alone if you have no albuminuria or a combination of ACE inhibitor or ARB with an SGLT2 inhibitor plus or minus finerenone, depending on if you still have persistent albuminuria,” he said. “They really don't lay out that the GLP-1 receptor agonists are part of the same algorithm, but they do feature the GLP-1 receptor agonists as a definite priority as part glycemic management, especially for people that have kidney disease.”

Edmonston said that when the guidelines are updated in the future, he presumes that GLP-1 receptor agonists will formally become the “fourth pillar” of guideline-directed medical therapy for people with type 2 diabetes and CKD. He did note that stacking multiple medications, including SGLT2 inhibitors and GLP-1 receptor agonists, can be challenging given their expense, noting that “some patients can barely afford one.”

Clinically, Edmonston said that for doctors faced with choosing between treatments, their data suggest an SGLT2 inhibitor is likely better than a GLP-1 receptor agonist if a patient’s primary concern is decreasing the risk of kidney dialysis. If weight loss is a factor, an argument could be made for the GLP-1 receptor agonist, particularly if they are at a high risk for ASCVD, he said.

In an editorial, Brendon Neuen, MBBS, PhD (George Institute for Global Health/University of New South Wales, Sydney, Australia), and Scott Solomon, MD (Brigham and Women’s Hospital, Boston, MA), write that one of the most pressing questions is not which drug class is most effective, but rather who would benefit most from both SGLT2 inhibitors and GLP-1 receptor agonists. Both drugs are underused and increasing their uptake has the potential to improve health outcomes around the world, they add.  

“The anticipated benefits of a multimedicine approach, especially for preventing CKD progression, are substantial, with implications for health systems worldwide,” write Neuen and Solomon.