The quality of evidence is downgraded by suspected publication bias (commercially funded studies) and upgraded by a clear dose-response gradient.
A systematic review and meta-analysis «Tsukamoto S, Tanaka S, Yamada T, et al. Effect of tirzepatide on glycaemic control and weight loss compared with other glucagon-like peptide-1 receptor agonists in Japanese patients with type 2 diabet»1 comparing the therapeutic effects of dual GIP+ GLP-1 agonists with GLP-1 agonists in Japanese patients with type 2 diabetes included 18 trials. Tirzepatide 15 mg showed the most significant reduction in HbA1c levels and body weight compared with subcutaneous semaglutide 1.0 mg and oral semaglutide 14 mg (HbA1c: mean difference -0.52 [95% CI -0.96 to -0.08] and - 1.23 [-1.64 to -0.81]; body weight: -5.07 [-8.28 to -1.86] and -6.84 [-8.97 to -4.71], respectively). Subcutaneous semaglutide showed a superior reduction in HbA1c compared with oral semaglutide. Both subcutaneous and oral semaglutide were more effective than conventional GLP-1 agonists, such as dulaglutide, liraglutide and lixisenatide.
A multicentre, randomised, double-blind, placebo-controlled phase 3 trial «Kadowaki T, Kiyosue A, Shingaki T, et al. Efficacy and safety of once-weekly tirzepatide in Japanese patients with obesity disease (SURMOUNT-J): a multicentre, randomised, double-blind, placebo-contro»2 included 267 patients (73 in the tirzepatide 10 mg group, 77 in the tirzepatide 15 mg group, and 75 in the placebo group). Estimated treatment differences relative to placebo in change in body weight at week 72 were -16.1% (95% CI -18.7 to -13.5) and -21.1% (95% CI -23.6 to -18.5) following tirzepatide 10 mg and 15 mg, respectively. A higher proportion of participants achieved at least 5% body weight reduction with tirzepatide 10 mg (94%) and 15 mg (96%) compared with placebo (20%). Participants treated with tirzepatide experienced adverse events more frequently, most commonly gastrointestinal symptoms. Study discontinuations due to adverse events were infrequent (placebo: 4%; tirzepatide 10 mg: 1%; tirzepatide 0%).
The SUMMIT trial «Packer M, Zile MR, Kramer CM, et al. Interplay of Chronic Kidney Disease and the Effects of Tirzepatide in Patients With Heart Failure, Preserved Ejection Fraction, and Obesity: The SUMMIT Trial. J Am»3 randomly assigned 731 patients with heart failure with a preserved ejection fraction (HFpEF) and a body mass index ≥ 30 kg/m², who were enriched for participants with chronic kidney diasease (CKD). Patients with CKD had greater severity of heart failure, as reflected by: 1) worse functional class, KCCQ-CSS scores, and 6-minute walk distance; 2) higher levels of NT-proBNP and cardiac troponin T; and 3) a 2-fold increase in the risk of worsening heart failure events. CKD did not influence the effect of tirzepatide to reduce the relative risk of major adverse heart failure events and to improve KCCQ-CSS, quality of life, and functional capacity, but the absolute risk reduction in the primary events was numerically greater in patients with CKD. Tirzepatide increased eGFR at 52 weeks, assessed by both creatinine-based and cystatin C-based formulae, but with considerable discordance in individual patients.