Brendon Neuen, MBBS, PhD: Expanding Evidence of Combination Therapy with GLP-1 RAs and SGLT2 Inhibitors

Data from a systematic review and meta-analysis of placebo-controlled outcome trials of GLP-1 receptor agonists in type 2 diabetes is shedding further light on the effects of combination therapy with the class and SGLT2 inhibitors.

Leveraging data from around 17,000 patients, including more than 1700 using both GLP-1 receptor agonists and SGLT1 inhibitors, results of the study, which were presented at the European Society of Cardiology (ESC) Congress 2024, indicate both classes provide distinct cardiovascular and kidney benefits while also offering evidence of the consistency of GLP-1 receptor agonists’ benefit across different patient populations in type 2 diabetes.

Building off previous research exploring the effects of combination therapy in contemporary settings, investigators designed the current study as a systematic review and meta-analysis of data recorded within the MEDLINE and Embase databases from inception through July 12, 2024. For inclusion, studies needed to be randomized, double-blind, placebo-controlled outcome trials of GLP-1 receptor agonists in type 2 diabetes that reported treatment effects by baseline use of SGLT2 inhibitors.^1,2

A total of 3 trials met their inclusion criteria: FLOW, Harmony Outcomes, and AMPLITUDE-O. From these 3 trials, investigators obtained data from 17,072 people, including 1743 using both GLP-1 receptor agonists and SGLT2 inhibitors. The primary outcomes of interest for the study was the effect on cardiovascular and kidney outcomes.¹

Upon analysis, results indicated use of GLP-1 receptor agonists reduced the risk of major adverse cardiovascular events by 21% (Hazard Ratio [HR], 0.79, 95% CI, 0.71 to 0.87), with these effects consistent effects in those receiving and not receiving SGLT2 inhibitors at baseline (HR, 0.77; 95% CI 0.54 to 1.09 and HR, 0.79; 95% CI 0.71 to 0.87, respectively; P-heterogeneity = .78). When assessing kidney outcomes, GLP-1 receptor agonist use was associated with a reduction in a composite kidney outcome consisting of a 50% or greater reduction in estimated glomerular filtration rate (eGFR), kidney failure or death due to kidney failure (Risk Ratio, 0.79; 95% CI, 0.66 to 0.95) as well as eGFR slope (0.78 mL/min/1.73m2/year, 95%, CI 0.57 to 0.98). Similarly to the cardiovascular outcomes analysis, these results did not vary according to SGLT2 inhibitor use (P-heterogeneity = .53 and .94, respectively).¹

For more on this study and the implications, check out our on-site interview with lead investigator Brendon Neuen, MBBS, PhD, director of the Kidney Trials Unit at Royal North Shore Hospital and senior research fellow at The George Institute for Global Health.

Relevant disclosures for Neuen include AstraZeneca, Alexion, Bayer, Boehringer and Ingelheim, Janssen, NovoNordisk, Travere Therapeutics, and others.

References:

1. Neuen BL, Fletcher RA, Heath L, et al. Cardiovascular, kidney and safety outcomes with GLP-1 receptor agonists alone and in combination with SGLT2 inhibitors in type 2 diabetes: A systematic review and meta-analysis. Circulation. Published online August 30, 2024. doi:10.1161/circulationaha.124.071689
2. Brooks A. SGLT2 inhibitor, GLP-1 RA combination improves cardiovascular, Kidney Outcomes in diabetes. HCP Live. July 9, 2024. Accessed September 1, 2024. https://www.hcplive.com/view/sglt2-inhibitor-glp-1-ra-combination-improves-cardiovascular-kidney-outcomes-diabetes.