Analysis of 1,601,389 patients with type 2 diabetes indicates that initiation of GLP-1 receptor agonists is associated with varying kidney outcomes compared to other glucose-lowering agents.
GLP-1 receptor agonist initiators may have higher risks for and kidney-related hospitalizations compared to those starting sodium-glucose cotransporter-2 inhibitors.
Risks for a ≥ 40% reduction in kidney function are greater for GLP-1 RA initiators compared to sodium-glucose cotransporter-2 inhibitors.
Compared to dipeptidyl-peptidase 4 inhibitors, GLP-1 RA initiation is associated with lower risks for experiencing a ≥ 50% reduction in kidney function and kidney-related hospitalizations.
Initiation of GLP-1 RA is linked to a lower risk of compared to dipeptidyl-peptidase 4 inhibitors and sulfonylureas.
GLP-1 RA initiation may reduce the risk of albuminuria progression compared to basal insulin, although the evidence regarding end-stage kidney disease risk is inconsistent.
Simplified
AIMS: Randomized placebo-controlled clinical trials showed that glucagon-like peptide-1 receptor agonists (GLP-1 RA) reduce kidney risk in patients with type 2 diabetes (T2D), prominently in those with chronic kidney disease. It is unclear whether these findings may apply to broader populations of patients with T2D treated in real-world settings and compared to active controls. We summarised real-world data of adverse kidney outcomes among patients with T2D initiating GLP-1 RA versus other glucose-lowering agents.
MATERIALS AND METHODS: We searched PubMed and Embase for observational cohort studies (April 2005-January 2025; PROSPERO CRD42023405356). Initiators of GLP-1 RA were compared to sodium-glucose cotransporter-2 inhibitors (SGLT2i), dipeptidyl-peptidase 4 inhibitors (DPP4i), sulfonylureas, or basal insulin. Outcomes included risks of albuminuria progression, ≥ 40 or ≥ 50% eGFR reduction from baseline, (AKI), kidney-related hospitalizations, and (ESKD), per data availability. We synthesised the data using inverse variance-weighted averages of logarithmic hazard ratios (HR)s in random-effect models.
RESULTS: Thirty-one studies were eligible, encompassing 1,601,389 patients (mean age 49-78 years, 5%-64% women), with 21, 6, 5, and 1 of them using SGLT2i, DPP4i, basal insulin, and sulfonylureas as a comparator, respectively. Compared with SGLT2i, GLP-1 RA initiators had higher risks for AKI (HR [95% CI] 1.12 [1.05-1.20]), kidney-related hospitalizations (1.66 [1.01-2.73]), and ≥ 40% reduction in eGFR (1.40 [1.27-1.53]), without evidence for differences in risks of ≥ 50% eGFR reduction or ESKD. Compared to DPP4i, GLP-1 RA initiators had lower risks for experiencing ≥ 50% eGFR reduction (0.84 [0.76-0.92]), kidney-related hospitalizations (0.73 [0.65-0.83]), and ESKD (0.70 [0.63-0.78]). Similar benefits were observed when comparing GLP-1 RA to sulfonylureas. Compared to basal insulin, GLP-1 RA initiation was associated with a lower risk of albuminuria progression (0.89 [0.80-0.99]), with inconsistent data regarding possible benefits in reducing ESKD risk.
CONCLUSIONS: In patients with T2D, initiation of GLP-1 RA in real-world settings may be associated with improved kidney outcomes compared to DPP4i, sulfonylureas, and basal insulin, and worse kidney outcomes compared to SGLT2i.
Key numbers
1.12
Increase in Risk
Hazard Ratio (HR) for among GLP-1 RA vs. SGLT2i initiators
0.70
Decrease in Risk
Hazard Ratio (HR) for among GLP-1 RA vs. DPP4i initiators
1.66
Increase in Kidney-Related Hospitalizations
Hazard Ratio (HR) for kidney-related hospitalizations among GLP-1 RA vs. SGLT2i initiators
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A.F. and D.R.S. have no conflict of interest to declare. I.Y. and A.R. received hourly payments from AstraZeneca through Hadassah Medical Centre and from Novo Nordisk. M.S. reports travel support from Novo Nordisk and AstraZeneca through Hadassah Medical Centre and lecturing fees from AstraZeneca (2022). O.M. reports Advisory Board membership for Novo Nordisk, Eli Lilly, Sanofi, MerckSharp and Dohme, Boehringer Ingelheim, AstraZeneca and BOL Pharma, research grant support through Hadassah Hebrew University Hospital from Novo Nordisk and AstraZeneca, and Speaker's Bureau participation for AstraZeneca, Novo Nordisk, Eli Lilly, Sanofi, Merck Sharp and Dohme, and Boehringer Ingelheim. From May 1st, 2023, Ofri Mosenzon has been an employee of Regeneron Pharmaceuticals Inc. G.A.H. reported previous Advisory Board: Sanofi and Eli Lilly. She is a current PI in several RCTs conducted by Novo Nordisk, Eli Lilly, Sanofi, AstraZeneca and Bayer, including the Confidence study, through Hadassah Medical Centre. G.A.H. reports travel support from Novo Nordisk and Medetronic through Hadassah Medical Centre and AstraZeneca through Sheba medical centre. Speakers Bureau: AstraZeneca, Novo Nordisk, Eli Lilly and Sanofi. G.L. reports participation in previous Advisory Boards: Novo Nordisk, Eli Lilly, Sanofi, Merck Sharp and Dohme, Boehringer Ingelheim, AstraZeneca and Medtronic. He reports travel support from Novo Nordisk, Boehringer Ingelheim and AstraZeneca through Hadassah Medical Centre. Speakers Bureau: AstraZeneca, Novo Nordisk, Eli Lilly, Boehringer Ingelheim.
