Reasons for discontinuing tirzepatide in randomized controlled trials: A systematic review and meta-analysis

Despite therapeutic benefits, discontinuation of tirzepatide is common in randomized controlled trials (RCTs) due to adverse events (AEs) and other causes. No previous systematic reviews have explored the reasons for discontinuing tirzepatide in the RCTs.

To explore the reasons for permanent discontinuation of tirzepatide vs controls [placebo, insulin, and glucagon-like peptide-1 receptor agonists (GLP-1Ras)] in RCTs.

Relevant RCTs were systematically searched using related terms through multiple databases such as MEDLINE (via PubMed), Scopus, Cochrane Central Register, and ClinicalTrials.gov from their inception until June 20, 2024. RevMan web was used to conduct meta-analysis using random-effects models. Outcomes were presented as risk ratios (RR) with 95% confidence intervals (CI).

Seventeen RCTs (n = 14645), mostly having low risks of bias, were analyzed. Compared to placebo, the risk of permanent discontinuation of the study drug was substantially lower with tirzepatide 10 mg (RR: 0.69, 95%CI: 0.51-0.93, P = 0.02) and similar with tirzepatide 5 mg (RR: 0.74, 95%CI: 0.47-1.17, P = 0.20) and 15 mg (RR: 0.94, 95%CI: 0.68-1.31, P = 0.71). Tirzepatide had identical discontinuation risks when compared to insulin at 5 mg (RR: 0.96, 95%CI: 0.75-1.24, P = 0.77) and 10 mg (RR: 1.19, 95%CI: 0.77-1.82, P = 0.44) doses, whereas such risk was higher with tirzepatide 15 mg than insulin (RR: 1.31, 95%CI: 1.03-1.67, P = 0.03). Compared to GLP-1RA, the permanent discontinuation risk was similar with tirzepatide 5 mg (RR: 0.98, 95%CI: 0.70-1.37, P = 0.90) but was higher with tirzepatide 10 mg (RR: 1.40, 95%CI: 1.03-1.90, P = 0.03) and 15 mg (RR: 1.70, 95%CI: 1.27-2.27, P = 0.0004). Tirzepatide, at all doses, had higher risks of AE-related discontinuation than insulin; such risks were only greater with higher doses of tirzepatide than with placebo or GLP-1RA. Discontinuation risk due to withdrawal by the study subjects was lower with tirzepatide than with placebo or insulin. Compared to the placebo, tirzepatide (all doses) conferred a lower risk of study drug discontinuation due to other causes not specifically mentioned.

The discontinuation risk is not higher in tirzepatide group than in the placebo arm. Many factors other than AEs led to drug discontinuation in the included RCTs.