Obesity is an increasingly prevalent global health concern, associated with numerous adverse health outcomes. Recent advancements in weight management have focused on pharmaceutical interventions, particularly glucagon-like peptide-1 (GLP-1) receptor agonists, which have demonstrated significant potential for body weight reduction and improved glycemic control in patients with type 2 diabetes (T2D). Tirzepatide, a dual GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, represents a promising new therapeutic avenue.
Tirzepatide: Mechanism of Action
Tirzepatide is a single molecule with a linear 39 amino acid peptide backbone, modified with an acyl fat-chain conjugation to enhance albumin binding and prolong its half-life. This dual-agonist activates both the GLP-1 and GIP receptors and is administered subcutaneously (s.c.) once weekly. 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%, with maximum plasma concentration reached 48 hours (range: 12-96 hours) after administration. Tirzepatide has a half-life of 117 hours and is eliminated through proteolytic cleavage, amide hydrolysis, and β-oxidation, without involving cytochrome P450 enzymes.
Clinical Trial Programs: SURPASS and SURMOUNT
The efficacy and safety of tirzepatide have been evaluated in two comprehensive clinical trial programs: SURPASS, which primarily assessed glucose-lowering effects in participants with T2D, and SURMOUNT, which focused on body weight reduction as the primary outcome.
SURPASS Program: Glycemic Control and Weight Loss in T2D
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. In the SURPASS-2 trial tirzepatide was compared to the GLP-1 agonist semaglutide 1 mg s.c. once weekly, and in the SURPASS J-Mono tirzepatide was compared to the GLP-1 agonist dulaglutide 0.75 mg s.c. once weekly. The SURPASS trials investigated the effect of tirzepatide in participants with T2D and reported weight reductions of 5-14%. 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. Trials in Japanese populations reported even greater reductions in HbA1C (reduction of 33.0 mmol/mol in the 15 mg tirzepatide s.c. once weekly dose). 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.
SURMOUNT Program: Weight Loss in Obese and Overweight Individuals
The SURMOUNT program has demonstrated the significant potential of tirzepatide for weight loss in individuals with obesity or overweight, with and without T2D.
Read also: Comprehensive guide: Tirzepatide and Semaglutide for weight management
SURMOUNT-1
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-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%.
SURMOUNT-2
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-2 trial, participants with T2D achieved a mean weight loss of up to 14.7% from baseline (11.6% estimated treatment difference relative to placebo) after 72 weeks.
SURMOUNT-3 and SURMOUNT-4
While full data from other SURMOUNT trials have not yet been published, a recent announcement from the manufacturer of tirzepatide (Eli Lilly and Company, Indianapolis, USA) revealed some results from the SURMOUNT-3 and −4 trials. Here, a mean weight reduction of 24.5% (placebo adjusted net weight loss) after 72 weeks of treatment with tirzepatide in obese adults with weight-related comorbidities, but without T2D, was reported for the SURMOUNT-3 trial. Furthermore, in the SURMOUNT-4 trial it was reported that overweight or obese participants without T2D, who remained on tirzepatide for a total of 88-weeks had a 26% reduction in bodyweight (not placebo adjusted).
Metabolic Benefits Beyond Weight Loss
Treatment with tirzepatide has been associated with improvements in several metabolic markers. In addition to reductions in HbA1C, the SURPASS trials reported reductions in systolic and diastolic blood pressure.
Body Composition
The SURPASS-1 trial reported a reduction in total body fat mass of 26% [95% confidence interval (CI): 20-31%] for all tirzepatide doses pooled (5 mg, 10 mg and 15 mg tirzepatide s.c. once weekly groups) compared to placebo. Magnetic resonance imaging (MRI) was performed for a subgroup in the SURPASS-3 trial to investigate changes in liver fat. Participants in the MRI sub-study had a fatty liver index ≥60. An absolute reduction of 8.1% from a baseline liver fat content of 15.7% was demonstrated for pooled 10 mg and 15 mg s.c. once weekly tirzepatide groups, compared to an absolute reduction in liver fat content of 3.4% in participants treated with insulin degludec. Tirzepatide has shown reductions in both body fat mass and lean body mass. 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.
Read also: Weight Loss Patterns with Tirzepatide 2.5 mg
Cardiovascular Safety
Risk of major adverse cardiovascular events (MACE) was analyzed in a meta-analysis for all SURPASS trials and showed no statistically significant differences between pooled tirzepatide groups and control groups (hazard-ratio (HR) 0.80 [95% CI: 0.57-1.11]).
Safety and Tolerability
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. In early clinical testing (phase I and Phase II trials) a gradual dose escalation was implemented, which increased tolerability and reduced the frequency of adverse events (AEs). Thus, in the trial programs tirzepatide was started with a dose of 2.5 mg tirzepatide s.c. 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.
Differences in Weight Loss Efficacy Between T2D and Non-T2D Participants
In clinical trials tirzepatide has been demonstrated to elicit substantial weight reduction, with less weight loss in trial participants with T2D compared to participants without T2D. On the other hand, in the SURMOUNT-1 trial with a similar dose-escalation and involving slightly younger and more overweight participants without T2D, a mean weight loss of up to 20.9% from baseline (17.8% difference from placebo in change in body weight) was reported after 72 weeks. As such, the difference in efficacy of tirzepatide between individuals with T2D compared with individuals without T2D may prove to be even greater than previously reported. While higher BMI is a predictor for higher absolute weight reduction, it cannot by itself explain these large differences in percentage body weight change from baseline. To our knowledge, no clear explanation has been provided for the difference in weight-reducing effects of GLP-1(/GIP) receptor agonists in patients with or without T2D. The GLP-1 receptor mono-agonists constitute relevant efficacy comparisors in terms of weight reduction. While some SURPASS trials compared tirzepatide directly with other GLP-1 receptor mono-agonists (dulaglutide and semaglutide), these comparators were not administered in adequate doses for optimal weight-lowering effects.
Semaglutide in doses approved for weight management (2.4 mg semaglutide once weekly) resulted in a weight loss of 6.2% relative to placebo (treatment policy estimand) in individuals with T2D after 68 weeks in the STEP-2 trial. As such, an indirect comparison of the highest approved doses of semaglutide (2.4 mg once weekly for 68 weeks) with highest dose of tirzepatide (15 mg once weekly for 72 weeks) suggests superior weight reducing effects of tirzepatide in individuals with T2D (ie, 6.2% versus 11.6%).
Is the suggested superiority of tirzepatide in terms of weight reduction a result of a better GLP-1 receptor agonism, or is it primarily the addition of the GIP receptor agonism that impacts body weight regulation - or is it perhaps a combination of the two? Tirzepatide activates both the GLP-1 and the GIP receptor, whereas the affinity and po…
Read also: Comprehensive Analysis: Tirzepatide and Semaglutide
Impact on Quality of Life
The SURMOUNT-1 trial investigated effects of tirzepatide, a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, on body weight in participants with obesity or overweight. PRO instruments included the Impact of Weight on Quality of Life-Lite Clinical Trials version (IWQOL-Lite-CT), Short Form Survey-36 version 2 (SF-36v2) and EQ-5D-5L. Scores were analysed by treatment group and by categorical degree of weight reduction group: >0 to <5%, ≥5 to <10%, ≥10 to <20% and ≥20%. All tirzepatide groups demonstrated significant improvements in PRO scores versus placebo. There was a consistent trend of incremental PRO improvement with greater degrees of weight reduction, starting from ≥5% weight reduction. Participants achieving ≥20% weight reduction demonstrated the greatest changes from baseline to week 72 (SF-36v2 Physical Component Summary, 4.60; SF-36v2 Mental Component Summary, 0.80; IWQOL-Lite CT Total score, 24.7). Tirzepatide treatment was associated with improved HRQoL compared to placebo in people with overweight or obesity. Higher percentages of weight reduction were associated with greater improvements.
tags: #tirzepatide #weight #loss #clinical #trials