Optimal dose of tirzepatide for type 2 diabetes mellitus: A meta-analysis and trial sequential analysis

Abstract

ObjectiveThe purpose of this study is to evaluate the optimal dose of tirzepatide (TZP) for the treatment of type 2 diabetes mellitus (T2DM) by meta-analysis and trial sequential analysis (TSA).MethodsClinical trials of TZP for T2DM were obtained by searching 8 databases with a time limit from database creation to May 2022. Mean differences (MD) and 95% confidence intervals (95%CI) were used for continuous variables, and relative risk (RR) and 95%CI were used for dichotomous variables.ResultsCompared with TZP 5 mg, meta-analysis showed that TZP 10 mg significantly reduced glycosylated hemoglobin type A1c (HbA1c) (MD −0.24, 95%CI −0.31~-0.17, P < 0.00001), fasting serum glucose (FSG) (MD −5.82, 95%CI −8.35~-3.28, P < 0.00001) and weight (MD −2.47, 95%CI −2.95~-1.98, P < 0.00001), and TZP 15 mg significantly reduced HbA1c (MD −0.37, 95%CI −0.44~-0.29, P < 0.00001), FSG (MD −8.52, 95%CI −11.07~-5.98, P < 0.00001) and weight (MD −4.63, 95%CI −5.45~-3.81, P < 0.00001). Compared with TZP 10 mg, TZP 15 mg dramatically reduced HbA1c (MD −0.12, 95%CI −0.19~-0.05, P = 0.001), FSG (MD −2.73, 95%CI −5.29~-0.17, P = 0.04) and weight (MD −2.18, 95%CI −2.67~-1.70, P < 0.00001). The TSA indicated that the benefits observed in the current information set were conclusive, except for the FSG of “TZP 15 mg vs. TZP 10 mg”. In terms of safety endpoints, meta-analysis revealed that there was no significant difference in the serious adverse events (AEs), major adverse cardiovascular events-4 (MACE-4), cardiovascular death, hypertension, cancer and hypoglycemic of the three dose groups of TZP. Compared with TZP 5 mg, TZP 10 mg increased total adverse events (RR 1.06, 95%CI 1.01~1.11, P = 0.03) and gastrointestinal (GI) AEs (RR 1.17, 95%CI 1.03~1.33, P = 0.02), and TZP 15 mg increased total AEs (RR 1.10, 95%CI 1.05~1.15, P = 0.0001). There were no significant differences in total AEs and GI AEs for TZP 15 mg compared to TZP 10 mg. The TSA demonstrated that the total AEs of “TZP 15 mg vs. TZP 5 mg” were conclusive.ConclusionsTZP 15 mg >TZP 10 mg > TZP 5 mg in terms of lowering glycemia and reducing weight. TZP 5 mg > TZP 10 mg = TZP 15 mg in terms of safety. On this basis, we recommend TZP 5 mg as the first-choice dose for patients with T2DM to minimize AEs while reducing glycemia and weight. If patients cannot effectively control their glycemia after taking TZP 5 mg, it is recommended to take TZP 15 mg directly to achieve the best effect of glycemic reduction. However, most of the included studies have the background of basic medication, the independent efficacy and safety of different doses of TZP still need to be tested.Systematic review registrationUnique Identifier: CRD42022341966.

A systematic review of the safety of tirzepatide-a new dual GLP1 and GIP agonist - is its safety profile acceptable?

“…Previous studies (25-27) showed that reducing refined sugar and fat intake may help to reduce GADE by GLP-1 RAs, but whether these methods are suitable for TZP needs to be confirmed by further research. The current view is that, consistent with GLP-1 RAs, the higher dose of TZP is associated with more GADE (22). But our result did not seem to support this point.…”

Adverse Events Related to Tirzepatide

“…In particular, the rate of drug discontinuation due to AEs was up to 10% (8%-13%) with the 15-mg dose of tirzepatide. The study by Yu and our colleagues [ 27 ] and our study have similar findings for no significant difference in AEs including MACE, hypertension, cancer, and hypoglycemic events with 3 different doses of tirzapatide. In a study by Karagiannis et al [ 28 ], the authors found 2-fold higher odds of study drug discontinuation at the highest dose of tirzepatide.…”

“…For the majority of GI AEs, we found a significant dose-dependent relationship with higher dose being associated with higher incidence rates of AEs. A recent study by Yu et al [ 27 ] reported increased total AEs and GI AEs (relative risk [RR] 1.17; P = .02) with 10 mg, and increased total AEs (RR 1.10; P = .0001) with 15-mg compared to the 5-mg dose of tirzepatide. No statistically significant differences were observed in total AEs and GI AEs for 15-mg compared to 10-mg tirzepatide.…”

Pharmacotherapy of obesity: an update on the available medications and drugs under investigation

“…A recent trial sequential analysis exploring the optimal dose of tirzepatide in patients with DM, showed a dose dependent effect on glycemic control and weight reduction, without a significant increase in the rate of adverse events with higher doses. 131 Interestingly, pooled data from SURMOUNT-1 and SURPASS clinical trials programs showed a significant relative risk reduction in major adverse CV events and CV death, by 48 and 49% respectively, with Tirzepatide, compared to control. 132 …”