Combination of SGLT2i, GLP-1 RA, and Non-Steroidal MRA Proposed for Patients With Type 2 Diabetes and Albuminuria

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) reduce the risk of cardiovascular events and progression of chronic kidney disease (CKD) in patients with type 2 diabetes. Finerenone, a nonsteroidal mineralocorticoid receptor antagonist (MRA), is now approved for the same purposes in patients with type 2 diabetes and albuminuria.

These drug classes have different mechanisms of action and prevent different types of events. SGLT2i and nonsteroidal MRA have more pronounced effects on heart failure and kidney outcomes, whereas GLP-1 RA seems to yield greater reductions in atherosclerotic events. Considerable interest has arisen in whether combination therapy might further reduce cardiorenal risk.

After analyzing data from pivotal trials of these agents, researchers at Brigham and Women’s Hospital believe treatment with a combination SGLT2i, GLP-1 RA, and nonsteroidal MRA has the potential to improve survival in patients with type 2 diabetes and at least moderately increased albuminuria.

Scott Solomon, MD, director of the Clinical Trials Outcomes Center at the Brigham and Edward D. Frohlich distinguished chair in Cardiovascular Pathophysiology in the Division of Cardiovascular Medicine, Muthiah Vaduganathan, MD, MPH, a cardiologist in the Division, Brendon Neuen, MSc, PhD, former postdoc at the Brigham, and colleagues report in Circulation.


The researchers conducted an age-based survival analysis using:

Those trials compared the medication of interest against placebo on a background of conventional care (renin–angiotensin system blockade and traditional risk factor control).

The primary outcome for this analysis was major adverse cardiovascular events (MACE), defined as nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Other key endpoints included hospitalization for heart failure, CKD progression, cardiovascular mortality, and all-cause mortality.

Relative Treatment Effects

Compared with conventional care alone, adding the hypothetical combination of SGLT2i, GLP-1 RA, and non-steroidal MRA was associated with significant estimated aggregate relative risk reductions in:

  • MACE—35%
  • Hospitalization for heart failure—55%
  • CKD progression—58%
  • Cardiovascular mortality—36%
  • All-cause mortality—33%

Absolute Risk Reductions

Estimated absolute risk reductions over three years were also clinically meaningful:

  • MACE—4.4%; number needed to treat (NNT) to prevent one event; 23
  • Hospitalization for heart failure—3.4%; NNT, 30
  • CKD progression—4.4%; NNT, 23
  • Cardiovascular mortality—2.4%; NNT, 42
  • All-cause mortality—3.1%; NNT, 33

Event-free Survival

For patients who were age 50 at baseline, it was predicted that gains in event-free survival would be substantial:

  • Free of MACE—3.2 years
  • Free of hospitalization for heart failure—3.2 years
  • Free of CKD progression— 5.5 years
  • Free of cardiovascular mortality—2.2 years
  • Free of all-cause mortality—2.4 years

Absolute gains in event-free and overall survival were evident across all ages studied, with the greatest absolute benefit in younger patients. Gains in event-free and overall survival were modestly attenuated but still observed in analyses that assumed only 50% additive effects or waning efficacy over time.

Improved Adherence to Guidelines Needed

Updated major guidelines already recommend certain combination therapeutic strategies, tailored to individuals’ residual cardiorenal risk. The Kidney Disease: Improving Global Outcomes guidelines recommend renin–angiotensin system blockade and SGLT2i as first-line therapy, then GLP-1 RA and nonsteroidal MRA if needed for additional cardiorenal protection.

Joint guidelines of the American Diabetes Association and the European Association for the Study of Diabetes advise adding a GLP-1RA as second-line therapy for a patient receiving an SGLT2i and vice versa. The UK National Institute for Health and Care Excellence recommends adding finerenone to an SGLT2i in patients with type 2 diabetes and CKD who have residual albuminuria.

It’s hoped the results of this analysis will increase the uptake of these guidelines, inform policy decisions about access to the medications, and improve shared decision-making by patients and clinicians. Randomized controlled trials now underway are specifically studying some of the combinations put forth by this study.

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