Chronic kidney disease made heart failure worse in obese patients, but tirzepatide still improved heart failure outcomes regardless of kidney function—and creatinine-based kidney tests may underestimate how well tirzepatide actually improves kidney function.
2×Higher baseline risk of cardiovascular death or heart failure events in CKD patients compared to non-CKD patients in the SUMMIT trial
What the researchers found
Tirzepatide improved heart failure outcomes equally in patients with and without CKD, but creatinine-based eGFR appeared to decline on tirzepatide while cystatin C-based eGFR improved—indicating the creatinine decline is an artifact of muscle loss from weight reduction, not true kidney deterioration.
Why it matters
Millions of patients with obesity have both CKD and HFpEF simultaneously. Understanding that tirzepatide benefits extend to CKD patients—and that conventional kidney tests may mislead clinicians about drug safety—has immediate clinical relevance for monitoring and prescribing decisions.
The numbers in context
- 731 SUMMIT trial patients, enriched for CKD
- CKD patients had 2x risk of worsening heart failure events
- Baseline eGFR-cystatin C was ~9 mL/min/1.73m2 lower than eGFR-creatinine
- Tirzepatide improved eGFR at 52 weeks by both measures
- eGFR-creatinine dipped at 12 weeks then recovered; eGFR-cystatin C improved throughout
How the study worked
Pre-specified sub-analysis of the SUMMIT RCT (n=731); CKD subgroup analyses stratified by creatinine- and cystatin C-based eGFR; eGFR measured at baseline, 12, 24, and 52 weeks; KCCQ-CSS and cardiovascular outcomes as endpoints.
Who was studied
N=731 patients from SUMMIT trial with HFpEF and BMI 30+, enriched for CKD. Kidney function assessed by both creatinine- and cystatin C-based eGFR at multiple timepoints.
What this study cannot tell us
Subgroup analysis from an RCT—not powered for CKD-specific endpoints. Cystatin C measurement was not part of the original trial design and required post-hoc analysis. Generalizability to non-obese or non-HFpEF CKD populations is unclear.
How to read the evidence
Rated strong as a pre-specified sub-analysis of a large international RCT (SUMMIT), though CKD-specific endpoints were not the primary trial objective.
When this study was published
Published in 2025 in the Journal of the American College of Cardiology; part of the SUMMIT trial dataset.
The bigger picture
The measurement discrepancy between creatinine and cystatin C when weight loss occurs is a broadly important issue for all GLP-1 and GLP-1/GIP trials. This finding suggests current prescribing guidelines may need to be updated to prefer cystatin C-based monitoring in patients on these drugs.
Questions still open
- Should cystatin C replace creatinine as the standard kidney marker in all GLP-1/GIP drug trials?
- Does tirzepatide provide direct kidney protection beyond what is explained by weight loss?
- Can this same measurement artifact affect other metabolic drugs that cause substantial weight loss?
Common questions
Why does creatinine go down on tirzepatide even if kidneys aren't getting worse?
Is tirzepatide safe for patients with kidney disease?
Read the original research
Interplay of Chronic Kidney Disease and the Effects of Tirzepatide in Patients With Heart Failure, Preserved Ejection Fraction, and Obesity: The SUMMIT Trial.
Journal of the American College of Cardiology, 85(18), 1721-1735
Citation
Packer, Milton; Zile, Michael R; Kramer, Christopher M; Murakami, Masahiro; Ou, Yang; Borlaug, Barry A. (2025). Interplay of Chronic Kidney Disease and the Effects of Tirzepatide in Patients With Heart Failure, Preserved Ejection Fraction, and Obesity: The SUMMIT Trial.. Journal of the American College of Cardiology, 85(18), 1721-1735. https://doi.org/10.1016/j.jacc.2025.03.009