New Haven, CT—In the past, obese patients were often sent home with the advice—sometimes delivered sternly—to alter their lifestyle. That has changed recently because of increasing evidence that diet and exercise cause the body to respond in a way that limits weight reduction and makes weight maintenance exceedingly difficult.

A recent study in the New England Journal of Medicine noted that research "has led to the realization that obesity is a complex, multi-component metabolic disease of energy homeostasis involving central and peripheral mechanisms. Once obesity is present, those mechanisms render a return to lower weight difficult. Accordingly, several clinical guidelines now recommend treatment with antiobesity medications for people with obesity or for those with overweight and weight-related complications."

According to Yale University School of Medicine–led researchers, among the most promising candidates are long-acting glucagon-like peptide-1 (GLP-1) receptor agonists, which have "demonstrated that greater efficacy with acceptable safety could be achieved by targeting the pathways of endogenous nutrient-stimulated hormones. Glucose-dependent insulinotropic polypeptide (GIP), another nutrient-stimulated hormone, regulates energy balance through cell-surface receptor signaling in the brain and adipose tissue. A molecule that combines both GIP and GLP receptor agonism theoretically may lead to greater efficacy in weight reduction."

That is why researchers have found tirzepatide, a once-weekly SC injectable peptide (approved by the FDA for type 2 diabetes). It has agonist activity at both the GIP and GLP-1 receptors. "In phase 2 studies in people with type 2 diabetes, tirzepatide induced clinically relevant weight reduction, warranting further investigation for the treatment of obesity," according to the authors, who added that the current trial, SURMOUNT-1, sought to evaluate the efficacy and safety of tirzepatide in adults with obesity or overweight who did not have diabetes.

The phase III double-blind, randomized, controlled trial included 2,539 adults with a BMI of >30 or >27 and at least one weight-related complication, excluding diabetes. The group was divided to receive one of three SC dosages of once-weekly tirzepatide, 5 mg, 10 mg, 15 mg, or a placebo for 72 weeks, including a 20-week dose-escalation period.

The two primary endpoints were defined as the percentage change in weight from baseline and a weight reduction of 5% or more.

When the trial began, participants had a mean body weight of 104.8 kg, a mean BMI of 38.0, and 94.5% of participants had a BMI of 30 or higher. Results indicated that the mean percentage change in weight at Week 72 with weekly doses was:

• -15.0% (95% CI, -15.9 to -14.2) with 5 mg of tirzepatide
• -19.5% (95% CI, -20.4 to -18.5) with 10 mg of tirzepatide
• -20.9% (95% CI, -21.8 to -19.9) with 15 mg of tirzepatide
• -3.1% (95% CI, -4.3 to -1.9) with placebo (P <.001 for all comparisons with placebo).

The majority of participants met the weight-reduction endpoint: 85% (95% CI, 82-89); 89% (95% CI, 86-92); and 91% (95% CI, 88-94) with 5 mg, 10 mg, and 15 mg of tirzepatide, respectively; and 35% (95% CI, 30-39) with placebo.

In fact, more than half of participants in the larger dosage groups lost 20% or more of their body weight: 50% (95% CI, 46-54) and 57% (95% CI, 53-61) of participants in the 10-mg and 15-mg groups had a reduction in body weight of 20% or more compared with 3% (95% CI, 1-5) in the placebo group (P <.001 for all comparisons with placebo), the researchers reported.

"Improvements in all prespecified cardiometabolic measures were observed with tirzepatide," the authors wrote. Gastrointestinal issues were the most common adverse events with tirzepatide and tended to be mild to moderate in severity, occurring primarily during dose escalation, according to the study.

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