Tirzepatide-associated improvements in cardiometabolic risk factors linked to degree of weight loss

1. In this post-hoc analysis of the SURMOUNT-1 trial, there was a mostly linear relationship between percentage change in weight reduction and cardiometabolic risk factors such as waist circumference and blood pressure.

2. Decreases in hemoglobin A1c were seen even with modest weight reduction, whereas improvements in lipid profile were primarily demonstrated with more significant weight reductions.

Evidence Rating Level: 2 (Good)

Study Rundown: Obesity is the most prevalent chronic disease in the world and is associated with significant morbidity and mortality. Previous studies have established that obesity is associated with cardiovascular risk and that risk level increases with body mass index (BMI). The management of obesity has historically encompassed modifications in lifestyle, including diet and exercise, but the advent of novel pharmacologic agents like semaglutide have changed its landscape, with several clinical guidelines recommending the use of anti-obesity medications for the management of weight and weight-related complications. The SURMOUNT-1 (Efficacy and Safety with Tirzepatide Once Weekly in Participants Without Type 2 Diabetes Who Have Obesity or Are Overweight With Weight-Related Comorbidities) trial showed that tirzepatide, a once-weekly glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1) receptor agonist, significantly reduced BMI and improved cardiometabolic risk factors in individuals with obesity. However, there was limited analysis correlating the extent of improvement in cardiometabolic risk factors with the degree of weight loss, particularly with weight reductions greater than 20%. This post-hoc analysis showed that the relationship between percentage change in weight reduction and cardiometabolic risk factors was mostly linear for waist circumference and blood pressure, with a steeper slope for systolic blood pressure (SBP) than diastolic blood pressure (DBP). In addition, decreases in glycated hemoglobin were seen even with modest weight reduction, whereas improvements in lipid profile were primarily demonstrated with weight reductions of greater than ten percent. This study was limited by its post-hoc nature as well as a sample size and short duration which precluded the evaluation of cardiovascular outcomes.

Click to read the study in AIM

Relevant Reading: Tirzepatide once weekly for the treatment of obesity

In-Depth [randomized controlled trial]: This post-hoc analysis of SURMOUNT-1, a phase 3, randomized controlled trial, evaluated tirzepatide-associated changes in cardiometabolic risk factors by degree of weight reduction. Adults without diabetes who had a BMI of 30 kg/m² or higher, or 27 kg/m² or higher with at least 1 weight-related complication, were randomly assigned in a 1:1:1:1 ratio to 5, 10, or 15 mg of weekly tirzepatide or matching placebo for 72 weeks. Outcomes were the change from baseline to week 72 in various cardiometabolic risk factors including waist circumference, blood pressure, lipid profile (triglycerides, high-density lipoprotein [HDL] cholesterol, non-HDL cholesterol, and low-density lipoprotein [LDL] cholesterol), hemoglobin A1c, and homeostatic model assessment of insulin resistance (HOMA-IR). A total of 1,605 participants were included in the analysis. Participants had a mean age of 45.4 years and a mean BMI of 37.9 kg/m² ; two-thirds of the participants were female. Generally, tirzepatide-treated individuals with greater weight reduction had greater improvements in all cardiometabolic risk factors. Among individuals who lost at least 35% of their body weight, changes of -14.2 mm Hg (95% confidence interval [CI], -16.1 to -12.3 mm Hg) in SBP, -9.2 mm Hg (95% CI, -10.6 to -7.8 mm Hg) in DBP, -32.4 cm (95% CI, -33.5 to -31.3 cm) in waist circumference, -0.65 percentage point (95% CI, -0.70 to -0.61 percentage point) in hemoglobin A1c, and -59.7% (95% CI, -63.6% to -55.3%) in HOMA-IR were observed. Modest weight reduction was also associated with decreases in hemoglobin A1c and HOMA-IR, but small weight reductions were not associated with improvements in LDL or HDL levels. In summary, this post-hoc analysis demonstrated that improvements in cardiometabolic risk factors were associated with greater weight reductions in tirzepatide-treated patients with obesity.

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