The most predominant chronic disease worldwide, obesity affects some 650 million adults, leading to complications that include cardiovascular disease and type 2 diabetes. Additionally, obesity poses a significant economic burden and contributes largely to global morbidity and mortality. In the recent past, treatment of obesity focused primarily on lifestyle-based approaches, however, evidence has emerged that obesity is a complex, multifaceted metabolic disease of energy homeostasis involving central and peripheral mechanisms. For the obese person, those mechanisms make returning to a reduced weight more difficult.
Dr. Louis Aronne
“The evidence is now overwhelming that there are physical changes in weight regulating pathways that make it difficult for people to lose weight and maintain their weight loss,” says Louis J. Aronne, MD, an obesity medicine specialist and Director of the Comprehensive Weight Control Center at NewYork-Presbyterian/
Several clinical guidelines now recommend treatment with anti-obesity medications, including long-acting glucagonlike peptide-1 (GLP-1) receptor agonists that have demonstrated greater efficacy and safety by targeting the pathways of endogenous nutrient-stimulated hormones. Glucose-dependent insulinotropic polypeptide (GIP), another nutrient-stimulated hormone, controls energy balance through cell-surface receptor signaling in the brain and adipose tissue. Theoretically, a molecule that combines both GIP and GLP receptor agonism may lead to greater success in weight reduction. Tirzepatide is a novel investigational once-weekly GIP and GLP-1 receptor agonist in the new class of medicines being studied for the treatment of obesity, which was recently approved by the FDA for the treatment of type 2 diabetes.
A leading authority on obesity and its treatment, Dr. Aronne served as co-investigator of the SURMOUNT-1 trial to evaluate the efficacy and safety of tirzepatide in adults with obesity or overweight who did not have diabetes. The phase 3 multicenter, double-blind, randomized, placebo-controlled trial, initiated in December 2019, was conducted at 119 sites in nine countries. Dr. Aronne and his colleagues published the study’s pivotal results in the June 4, 2022, online issue of The New England Journal of Medicine.
The SURMOUNT-1 trial enrolled 2,539 adults with a body-mass index of 30 or more, or a BMI of 27 or more and at least one weight-related complication, excluding diabetes. Participants received once weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 72 weeks, including a 20-week dose-escalation period, and a program of diet and physical activity.
Those in the 15 mg group who completed the full trial achieved weight loss of 22.5 percent, just below sleeve gastrectomy bariatric surgery and significantly more than the lap band procedure. This is among the most important findings in the field of obesity treatment...ever.
— Dr. Louis Aronne
Overall, participants in the trial had substantial and sustained reductions in body weight. Some trial participants, notes Dr. Aronne, lost enough weight to fall into the normal range. “Those in the 15 mg group who completed the full trial achieved weight loss of 22.5 percent, just below sleeve gastrectomy bariatric surgery and significantly more than the lap band procedure,” he says. “This is among the most important findings in the field of obesity treatment...ever.”
Additional key findings included:
Average body weight reductions:
- 15.0 percent at 5 mg
- 19.5 percent at 10 mg
- 20.9 percent at 15 mg
- 3.1 percent on the placebo
Percentage of participants achieving body weight reductions of ≥5 percent:
- 85 percent at 5 mg
- 89 percent at 10 mg
- 91 percent at 15 mg
- 35 percent on placebo
Percentage of participants achieving body weight reductions of ≥20 percent:
- 30 percent at 5 mg (not controlled for type 1 error)
- 50 percent at 10 mg
- 57 percent at 15 mg
- 3.1 percent on placebo
Clinically meaningful improvements in all prespecified cardiometabolic measures were observed, including:
- 17 percent on average reduction in waist circumference for the two highest dosages
- 34 percent average drop in total fat mass
- 0.5 percentage on average point reduction in baseline A1c at the two highest dosages
- 28 percent average drop in triglyceride levels
- an average systolic blood pressure reduction of about 8 mm Hg within 24 weeks
Overall, 78.9 to 81.8 percent of participants reported at least one adverse event, as compared with 72.0 percent of participants in the placebo group. Most frequently reported adverse events were gastrointestinal – transient and mild to moderate nausea, diarrhea, and constipation.
Dr. Aronne and his research colleagues noted, “Our trial had several strengths. Its global nature, large sample size, and overall high completion rate make the findings relatively generalizable. Despite the COVID-19 pandemic, 86 percent – approximately 90 percent across the tirzepatide groups – of the participants completed the trial. Finally, the duration of the 72-week trial enabled participants to reach a weight plateau in the 5 mg group and near-plateaus in the 10 mg and 15 mg groups. The additional two-year treatment period for participants with prediabetes should provide further insight into the maximum and long-term weight-lowering effect of tirzepatide in people with prediabetes.”
“Obesity is a chronic disease that often does not receive the same standard of care as other conditions, despite its impact on physical, psychological and metabolic health," says Dr. Aronne. “Now that we can treat obesity safely and effectively, it makes sense to treat obesity first, which in the past has often been secondary to treatments for dyslipidemia, hypertension, and diabetes. Tirzepatide delivered unprecedented body weight reductions in SURMOUNT-1, squarely in the range of weight loss achieved with bariatric surgery, which represents an important step forward for helping the patient and physician partnership treat this complex disease. This is the beginning of the development of new super-effective obesity treatments, and at Weill Cornell Medicine we are now gearing up to study even more effective combination compounds.”