Renal effects and safety of tirzepatide in subjects with and without diabetes: A systematic review and meta-analysis

BACKGROUND Type 2 diabetes (T2D), as well as obesity, are risk factors for chronic kidney disease (CKD) and end-stage renal disease. The renal impacts of glucose-lowering and weight-lowering drugs and their potential benefits in preventing CKD often guide clinicians in choosing them appropriately. Only limited data based on randomized controlled trials (RCTs) is currently available on the renal effects and safety profile of tirzepatide. AIM To explore the renal benefits and safety of tirzepatide vs controls. METHODS RCTs involving patients receiving tirzepatide for any indication in the intervention arm and placebo or active comparator in the control arm were searched through multiple electronic databases. The co-primary outcomes were percent change from baseline (CFB) in urine albumin-to-creatinine ratio (UACR) and absolute CFB in estimated glomerular filtration rate (eGFR; in mL/min/1.73 m2); the secondary outcome was tirzepatide’s renal safety profile. RevMan web was used to conduct meta-analysis using random-effects models. Outcomes were presented as mean differences (MD) or risk ratios with 95% confidence intervals. RESULTS Fifteen RCTs (n = 14471) with mostly low risk of bias (RoB) were included. Over 26-72 weeks, tirzepatide 10 mg [MD -26.95% (-40.13, -13.76), P < 0.0001] and 15 mg [MD -18.03% (-28.58, -7.47), P = 0.0008] were superior to placebo in percent reductions of UACR. Tirzepatide, at all doses, outperformed insulin in percent reductions of UACR. Compared to the placebo, the percent UACR reduction was greater in subjects with T2D than those with obesity but without T2D (MD -33.25% vs -7.93%; P = 0.001). The CFB in eGFR with all doses of tirzepatide was comparable [5 mg: MD- 0.36 (-1.41, 2.14); 10 mg: MD- 1.17 (-0.22, 2.56); 15 mg: MD- 1.42 (-0.04, 2.88)]; P < 0.05 for all] vs insulin. Tirzepatide (pooled and separate doses) did not increase the risks of adverse renal events, urinary tract infection, nephrolithiasis, acute kidney injury, and renal cancer compared to the placebo, insulin, and glucagon-like peptide-1 receptor agonists. CONCLUSION Short-term data from RCTs with low RoB suggests that tirzepatide positively impacts UACR without detrimental effects on eGFR in subjects with T2D and obesity without T2D, with a reassuring renal safety profile. Larger RCTs are warranted to prove the longer-term renal benefits of tirzepatide, which might also prevent eGFR decline and worsening of CKD.