The weight loss effect is not affected by the "gastrointestinal reaction", Tirzepatide Mechanism of Weight Loss explored in 2022EASD

Translator: Tang Keke, Department of Endocrinology, Affiliated Hospital of Ningbo University School of Medicine

Introduction: On September 19-23, 2022, the international endocrine field conference "2022 European Association for Diabetes Research Annual Meeting" was held
in Stockholm, Sweden in the form of "online + offline".
Scholars at the conference shared a study entitled "Tirzepatide-induced weight loss in type 2 diabetes that is not associated with nausea, vomiting or diarrhea
".
According to the analysis of the SURPASS1-5 clinical trial, the weight loss effect of Tirzepatide does not appear to be related
to reported gastrointestinal reactions such as nausea, vomiting or diarrhea.

Exploration of the correlation between the effect of Tirzepatide weight loss and adverse reactions

In the SURPASS1-5 randomized clinical trial, novel biglucose-dependent insulin polypeptides (GIP)/glucagon-like peptide-1 (GLP-1) Tirzepatide (TZP) exhibited superior HbA1c reduction and weight loss in
patients with type 2 diabetes mellitus compared with the control group.
The most common adverse event (AEs) among TZP treatment participants were gastrointestinal reactions
.
This postmortem analysis assessed the effect of
adverse events such as nausea, vomiting or diarrhea in the SURPASS1-5 trial on TZP weight loss.

Phase 3 participants in the SURPASS 1-5 trial were all patients with type 2 diabetes who had or had no treatment
with hypoglycemic drugs.
Trial participants were randomized (1:1:1:1, except SURPASS-4, 1:1:1:3 randomization) to a once-weekly TZP treatment group (5 mg, 10 mg, or 15 mg) or a control group (placebo, sumarotide 1 mg once a week, or daily titration of basal insulin
).
Based on any symptoms of nausea, vomiting, or diarrhea filled in the self-monitoring report, participants in the trial were divided into different subgroups
.
Changes
in body weight from baseline examination to primary endpoint were assessed in each trial and subgroup.
A mediated analysis was performed compared to the control group to assess the direct and indirect effects
of TZP on weight changes (mediated by nausea, vomiting, or diarrhea).

The benefit of Tirzepatide weight loss is not affected by gastrointestinal adverse effects

In SURPASS1-5 trials (SURPASS1, n=475; SURPASS2, n=1876; SURPASS3, n=1435; SUPPASS4, n=2989; SURPAS5, n=47), nausea, vomiting, or diarrhea occurred in 19%-36% of TZP-treated participants, compared with 5%-26%
in the control group.

Participants who reported nausea, vomiting, or diarrhea had similar average weight loss at the primary endpoint of TZP treatment to participants who did not report gastrointestinal adverse events, (-6.
16 to -14.
86 kg) and (-6.
17 to -13.
29 kg),
respectively.

The mediated analysis (pictured) showed that the estimated therapeutic difference (ETD) (95% confidence interval [CI]) for body weight change compared to baseline supported TZP (total and direct effect) at all doses, and the proportion of TCP-induced weight loss caused by nausea, vomiting, or diarrhea (indirect effects) was minimal, not exceeding 5%
of the total efficacy of all trials.

In some cases, TZP compared to the control group, compared to participants who reported gastrointestinal reactions, lost more weight than participants who reported gastrointestinal reactions, resulting in a positive ETD value for indirect effects
.

Figure 1.
Analysis of treatment differences for weight changes in SURPASS1-5

conclusion

The study concluded that in the SURPASS1-5 clinical trial, the weight loss effect of taking TZP did not appear to be related
to reported gastrointestinal reactions such as nausea, vomiting, or diarrhea.

Introduction of translators

Tang Keke

· Deputy Chief Physician, Department of Endocrinology, Affiliated Hospital of School of Medicine, Ningbo University

· Graduated from Zhejiang University, master's degree, engaged in endocrine work for more than 10 years, once studied in Shanghai Ruijin Hospital for half a year

· At present, he is a youth member of the Endocrinology Branch of Ningbo Medical Association and the teaching secretary of the Internal Medicine Base of the Affiliated Hospital of Ningbo University School of Medicine

· He has presided over and participated in a number of provincial and municipal projects, published nearly 10 articles, and won awards in many provincial and municipal competitions
.