Obesity is an increasingly prevalent global health concern, with projections estimating that it will affect 24% of the world's population by 2035. This escalating prevalence underscores the urgent need for effective weight management strategies. Recent advancements in obesity treatment have focused on pharmaceutical interventions, particularly harnessing the potential of incretin hormones, such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Tirzepatide, a dual GLP-1 and GIP receptor agonist, has emerged as a promising therapeutic option, demonstrating significant weight reduction in clinical trials. This article delves into the nuances of tirzepatide treatment, exploring weight loss patterns, response heterogeneity, and the implications for clinical decision-making.
Tirzepatide: A Novel Dual-Agonist for Weight Management
Tirzepatide is a dual-agonist molecule that activates both the GLP-1 and the GIP receptor, administered subcutaneously (s.c.) once weekly. It consists of a single molecule with a linear 39 amino acid peptide backbone with an acyl fat-chain conjugation to enhance albumin binding and prolong half-life. Tirzepatide binds to the GLP-1 receptor with a 20% affinity compared with native GLP-1 and activates the receptor (measured by cAMP generation) with a 20-fold lower potency. In comparison, the GLP-1 agonist semaglutide binds to the GLP-1 receptor with a 60% affinity of that of native GLP-1. The affinity and potency of tirzepatide on the GIP receptor is similar to that of native human GIP. The bioavailability of tirzepatide is 81% and the maximum plasma concentration is reached 48 hours (range: 12-96 hours) after administration. The half-life of tirzepatide is 117 hours and it is eliminated by proteolytic cleavage, amide hydrolysis and β-oxidation, while the cytochrome P450 enzymes are not involved in elimination.
Tirzepatide has shown strong effects on glycated hemoglobin (HbA1C) as a primary outcome in a range of clinical trials (SURPASS program). In addition, several clinical trials have investigated the effects of tirzepatide specifically for the treatment of obesity (SURMOUNT program). Tirzepatide, marketed as a treatment of Type 2 diabetes under the brand name Mounjaro, mimics the actions of two hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). These hormones work together to stimulate insulin secretion and slow stomach emptying extending the sensation of fullness following a meal.
Clinical Trial Programs: SURPASS and SURMOUNT
Two clinical trial programs investigating the efficacy and safety of tirzepatide have been performed; one primarily evaluating efficacy on bodyweight (SURMOUNT) and another primarily evaluating the glucose-lowering efficacy (SURPASS). The SURPASS clinical trial program included only participants with T2D and had mean change in HbA1C as the primary endpoint, whereas weight loss was reported as a secondary outcome. The SURMOUNT-1 trial investigated the weight-reducing effect of tirzepatide in obese participants without T2D (of note 1032 out of 2539 participants had prediabetes defined as having a HbA1C of 5.7-6.4% (39-47 mmol/mol)). The SURMOUNT-2 trial (N = 938) investigated weight loss in participants with T2D and overweight (BMI > 27), and both trials investigated the effect of 10 mg and 15 mg s.c. once weekly doses of tirzepatide, while the SURMOUNT-1 trial also investigated the effect of 5 mg s.c.
In the SURMOUNT-1 trial, investigating doses of 5 mg, 10 mg, and 15 mg s.c. once weekly in individuals with obesity (BMI > 30.0 or BMI > 27 and weight-related complications) but no T2D, reported a reduction in bodyweight of up to 20.9% (treatment policy estimand) after 72 weeks of treatment with maximum dose of tirzepatide (15 mg s.c. once weekly), while placebo elicited a weight loss of 3.1%. The SURMOUNT-2 trial investigated doses of 10 mg and 15 mg s.c. The SURPASS trials investigated the effect of tirzepatide in participants with T2D and reported weight reductions of 5-14%.
Read also: Comprehensive guide: Tirzepatide and Semaglutide for weight management
Weight Reduction and Metabolic Improvements with Tirzepatide
Tirzepatide has demonstrated substantial weight reduction in clinical trials, with the SURMOUNT-1 trial reporting a reduction in bodyweight of up to 20.9% after 72 weeks of treatment with the maximum dose of tirzepatide (15 mg s.c. once weekly) in individuals with obesity but no T2D, while placebo elicited a weight loss of 3.1%. The SURMOUNT-2 trial, which involved participants with T2D, showed that tirzepatide treatment resulted in a mean weight loss of up to 14.7% from baseline after 72 weeks.
Improvements in several metabolic markers have been reported following treatment with tirzepatide. The SURPASS trials reported reductions in HbA1C ranging from 20.4 mmol/mol (5 mg tirzepatide s.c. once weekly dose) to 28.2 mmol/mol (15 mg tirzepatide s.c. once weekly dose) after treatment durations lasting 40-52 weeks. Furthermore, reductions in systolic blood pressure of 4.7-12.6 mmHg and reductions in diastolic blood pressure of 0.8-5.6 mmHg were reported in the SURPASS trials. The SURPASS-1 trial reported a reduction in total body fat mass of 26% for all tirzepatide doses pooled compared to placebo.
MRI analysis of body composition in a subset of participants from the SURPASS-3 study revealed a larger decrease in muscle fat infiltration than anticipated. However, it also indicated an overall reduction in fat-free muscle mass (−0.76 liters for the 15 mg s.c.
Safety and Tolerability of Tirzepatide
Tirzepatide has in clinical testing shown to be safe and relatively well tolerated with mild to moderate adverse effects that most frequently were of gastrointestinal nature. Discontinuations due to AEs were primarily due to gastrointestinal events, and AEs were often reported in the dose-escalation phase and then decreased in frequency over time. The duration of diarrhea, nausea and vomiting was reported in the SURPASS-AP-Combo trial, a trial investigating the effect of tirzepatide in an Asian-Pacific population with T2D, in which the mean duration of these AEs were 3 days, 3-4 days, and 1-2 days, respectively. There was a similar frequency of gastrointestinal side-effects compared to semaglutide in the SURPASS-2 trial (1 mg s.c.
In total, 51% of participants developed antidrug antibodies (no difference between 5 mg, 10 mg, or 15 mg once weekly groups) with no observed differences in terms of pharmacokinetics or efficacy in reducing HbA1C for this group compared to participants with no antidrug antibodies. Participants with antidrug antibodies had a higher frequency of injection site reactions, but these were non-serious and transient.
Read also: Weight Loss Guide Andalusia, AL
SURMOUNT-3 Efficacy Results
After losing at least 5% of body weight after 12 weeks of diet and exercise, patients who took the dual glucagon-like peptide 1 and gastric inhibitory polypeptide receptor agonist tirzepatide lost an additional 18.4% of weight, according to results from the phase 3 SURMOUNT-3 trial. In total, 87.5% of tirzepatide-treated participants lost an additional 5% or more of their randomization weight compared with 16.5% of placebo-treated participants.
Post Hoc Analysis of SURMOUNT-1: Exploring Weight Loss Response Patterns
To gain a deeper understanding of weight loss patterns with tirzepatide, a post hoc analysis of the SURMOUNT-1 trial was conducted. This analysis aimed to assess baseline characteristics and weight reduction achieved at Weeks 24 and 72 based on treatment response status at Week 12. Treatment response was defined as late responders if <5% weight reduction was achieved at Week 12 or early responders if ≥5% weight reduction was achieved at Week 12. By assessing weight‐loss patterns over time, this study provides insights into the utility of the 12‐week response threshold in guiding clinical decision making for sustained obesity treatment with tirzepatide.
The present post hoc analyses included participants treated with tirzepatide who were adherent to treatment, defined as receiving 75% or more of the assigned treatment doses, and had weight measurement data available at Weeks 0, 12, 24 and 72. A total of 1545 participants (82% of all participants treated with tirzepatide in SURMOUNT‐1) met criteria and were included in the present analyses, with 278 (18.0%) categorized as late responders and 1267 (82.0%) categorized as early responders.
Baseline Characteristics of Early and Late Responders
At baseline, late responders compared to early responders (mean age 47 vs. 45 years) were more likely to be male (45% vs. 30%) and had higher body weight (110.2 vs. 103.6 kg), BMI (39.1 vs. 37.7 kg/m2) and waist circumference (117.5 vs. 113.4 cm) and reported a higher incidence of hypertension (45% vs. 30%). Early responders were more likely to be Hispanic or Latino (51% vs. 3..
Weight Reduction Outcomes at Weeks 24 and 72
Four weeks after the end of the dose escalation period (Week 24), 194 (70%) late responders had a body weight reduction of 5% or more, while 84 (30%) had less than a 5% body weight reduction. At Week 72, 250 (90%) late responders and 1267 (100%) early responders (by definition) had a body weight reduction of 5% or more. Furthermore, 59%, 30%, 17% and 7% of the late responders and 97%, 84%, 65% and 41% of the early responders had a body weight reduction of ≥10%, ≥15%, ≥20% and ≥25% at Week 72, respectively. Among late responders, there were 28 participants (10%) who were ultimately classified as non‐responders, defined as less than 5% weight reduction at Week 72.
Read also: Beef jerky: A high-protein option for shedding pounds?
At Week 72, participants achieved clinically significant weight reduction regardless of their 12-week response category at aggregate level. The mean percent body weight reductions at Week 72 were 11.0% (−12.0 kg) for late responders and 22.5% (−23.2 kg) for early responders. Greater weight reductions at Week 12 corresponded to greater weight reduction at Week 72. Higher doses of tirzepatide were associated with greater mean treatment responses, regardless of treatment response status. For example, the mean percent body weight reduction at Week 72 for late responders was 8.3%, 11.4% and 13.6% for 5, 10 and 15 mg, respectively. Early responders had a similar pattern of response at Week 72 with higher overall weight reduction compared to late responders (18.4%, 24.1% and 24.9%).
Implications of the Findings
In this post hoc analysis, 90% of the late responders to tirzepatide treatment, that is, participants who lost less than 5% body weight at Week 12, went on to achieve clinically meaningful weight reduction (≥5%) by Week 72, with 60% reaching between 5% and 15% weight reduction and 30% reaching 15% or greater weight reduction. Late responders had lower mean percent weight reduction for each tirzepatide dose compared to early responders at Week 72. Consistent with the lower weight reduction, for each categorical weight reduction target, there was a smaller proportion of late responders who achieved the target compared to early responders. Of the 1545 participants in this analysis, there was a small minority (n = 28, 1.8%) of non‐responders who lost less than 5% body weight at Week 72.
The early divergence in treatment response curves suggests that the early differences between late and early responders may be informative for understanding the heterogeneity of treatment response. Factors contributing to early differences in treatment response could include individual susceptibility to side effects, underlying causes and severity of obesity and social determinants of health that influence health behaviours and treatment engagement.
Following current clinical treatment guidelines to discontinue treatment at 12 weeks for the late responders would have prevented most of these participants from achieving clinically meaningful weight reduction with tirzepatide. The current guidance is based on data from OMMs that have shorter titration windows and achieve lower mean treatment responses.
Heterogeneity in Weight Loss Response
Various patient populations have been observed to respond differently to incretin therapy, and several potential mechanisms have been proposed to explain the variation in weight-loss response to incretin therapy among individuals. In the present study, a heterogeneity in weight-loss response to tirzepatide was observed. a greater proportion of late responders were male. Late responders also tended towards a higher baseline body weight. A greater proportion of late responders had hypertension. This finding in the late responders could be related to higher body weight, BMI and waist circumference, which are risk factors for hypertension. Interestingly, a higher proportion of late responders were also non-Hispanic or Latino. Patients treated with higher tirzepatide doses (10 and 15 mg) tended to have higher percent body weight reduction, even among late responders.