Tirzepatide: A winning weight-loss therapy for nondiabetic, obese adults

Non-diabetic overweight or obese adults experienced a greater reduction in weight and cardiometabolic measures with the addition of tirzepatide to their lifestyle interventions, findings of the SURMOUNT-1 trial showed.

“All tirzepatide doses demonstrated superior, clinically meaningful, and sustained body weight reduction vs placebo in participants with obesity,” mentioned study author Associate Professor Ania Jastreboff from the Yale University School of Medicine, New Haven, Connecticut, US, at ADA 2022.

“Treatment with tirzepatide … [also] translated to clinically meaningful improvements in cardiometabolic risk factors [such as waist circumference, blood pressure, and fasting insulin, lipid, and aspartate aminotransferase levels],” said Jastreboff and co-authors.

The phase III, multinational, double-blind trial involved 2,539 non-diabetic overweight/obese adults (BMI ≥30 kg/m² or ≥27 kg/m² plus ≥1 weight-related complication except diabetes; mean age 44.9 years, 67.5 percent female, 70.6 percent White). They were randomized 1:1:1:1 to receive subcutaneous tirzepatide at 5, 10, or 15 mg, or placebo QW for 72 weeks* in addition to lifestyle intervention.

Mean BMI and body weight as baseline were 38 kg/m² and 104.8 kg, respectively, with 94.5 percent of patients having a BMI ≥30 kg/m². Average duration of obesity was 14.4 years and 40.6 percent were prediabetic.

At week 72, percentage change in weight from baseline was significantly greater with all doses of tirzepatide compared with placebo (-15.0 percent [5 mg], -19.5 percent [10 mg], and -20.9 percent [15 mg] vs -3.1 percent; p<0.001 for all vs placebo). [ADA 2022, abstract 3-CT-SY24; N Engl J Med 2022;doi:10.1056/NEJMoa2206038]

More patients in the tirzepatide than placebo group achieved a ≥5 percent reduction in weight from baseline at week 72 (85 percent, 89 percent, and 91 percent for tirzepatide 5, 10, and 15 mg, recipients, respectively, vs 35 percent for placebo recipients). Additionally, 50 and 57 percent of tirzepatide 10 and 15 mg recipients, respectively, experienced a ≥20 percent reduction in body weight at week 72 vs 3 percent of placebo recipients (p<0.001 for all vs placebo). Thirty-two and 36 percent of tirzepatide 10 and 15 mg recipients, respectively, experienced a ≥25 percent reduction in body weight vs 1.5 percent of placebo recipients.

Patients on tirzepatide also experienced greater reductions in waist circumference than those on placebo (-14.0, -17.7, and -18.5 cm for tirzepatide 5, 10, and 15 mg, respectively, vs -4.0 cm for placebo), as well as greater reductions in total body fat mass (mean -33.9 percent [tirzepatide] vs -8.2 percent [placebo]).

In the tirzepatide group, about 95 percent of patients with prediabetes had reverted to normoglycaemia by week 72 compared with 61.9 percent of the placebo group.

Treatment-emergent adverse events (TEAEs) occurred at a comparable rate between the tirzepatide 5, 10, and 15 mg, and placebo groups (81.0, 81.8, 78.9, and 72.0 percent, respectively). The most frequent AEs were gastrointestinal (nausea, diarrhoea, and constipation) and affected more tirzepatide than placebo recipients. These AEs were generally mild-to-moderate in severity, transient, and mostly occurred during dose escalation. Serious AEs also occurred at a comparable rate between groups (6.3, 6.9, 5.1, and 6.8 percent, respectively), 21 percent of which were COVID-19–related. There was one case of pancreatitis in each group (none severe). Cholelithiasis incidence was comparable across groups. Cholecystitis incidence was low but more common in tirzepatide than placebo recipients. There were no cases of medullary thyroid cancer.

AEs led to treatment discontinuations in 4.3, 7.1, 6.2, and 2.6 percent of tirzepatide 5, 10, and 15 mg, and placebo recipients, respectively. Eleven deaths occurred, four, two, one, and four in the tirzepatide 5, 10, and 15 mg, and placebo groups, respectively.

 

Ground-breaking results?

According to the authors, the weight reductions with tirzepatide in this study are substantially greater than that observed with other anti-obesity therapeutics in other phase III trials.

“Given that tirzepatide is both a GIP** receptor and GLP-1** receptor agonist, we speculate that there may be additive benefit in targeting multiple endogenous nutrient-stimulated hormone pathways that have been implicated in energy homeostasis,” they said. Nonetheless, they cautioned against comparing results between trials given the variation in trial design and population.

“Obesity should be treated like any other chronic disease—with effective and safe approaches that target underlying disease mechanisms, and these results underscore that tirzepatide may be doing just that,” said Jastreboff.

“These results are an important step forward in potentially expanding effective therapeutic options for people with obesity. Notably, about nine out of 10 individuals with obesity lost weight while taking tirzepatide,” she said.

The weight loss and cardiometabolic benefits “may translate to reduced risk of cardiovascular disease, chronic kidney disease, non-alcoholic fatty liver disease, and type 2 diabetes,” the authors said, highlighting the need for research to investigate this hypothesis.