Tirzepatide for the Treatment of Obesity. Is it a Weight Loss Game-changer?
Britain Lehrer, PharmD
Park Nicollet Health Services
Background: Obesity is the most prevalent disease worldwide, which can lead to a myriad of health issues for patients and is a significant cause of morbidity and mortality. Tirzepatide, an injectable medication with a novel dual mechanism of action, may help promote weight loss in patients with obesity. Secondary outcomes in the SURPASS trials demonstrated that tirzepatide exhibited a greater reduction in weight loss in participants when compared to various standards of care treatment options for type 2 diabetes. The safety and efficacy of this glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 receptor agonist (GLP-1 RA) in obese patients without type 2 diabetes is unknown.
Purpose: This trial sought to evaluate the efficacy and safety of tirzepatide in adults with obesity (BMI >30) or who are overweight (BMI >27) with one or more weight related comorbidities, not including diabetes.
Study Design: This study was a phase 3 multicenter, double-blind, randomized, placebo-controlled trial conducted at 119 sites across nine countries. The study included adults 18 years or older with BMI >30 kg/m2 or BMI >27 kg/m2 with at least one weight-related complication including hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease. Participants needed to report at least one unsuccessful dietary effort to lose weight to be included. Important exclusion criteria included diabetes, change in body weight more than 5 kg within 90 days prior to screening, previous or planned surgical intervention for obesity, and treatment with medication that promotes weight loss within 90 days prior to screening. Upon conclusion of a 2-week screening period, trial participants were randomly assigned in a 1:1:1:1 ratio to receive tirzepatide 5 mg, 10 mg, 15 mg, or placebo. Treatment regimens were administered subcutaneously once a week for 72 weeks. The treatment regimens were used in adjunction to lifestyle changes including a daily deficit of 500 calories and 150 minutes of weekly physical activity. The two primary outcomes of the study were the percentage of change in weight from baseline and a weight reduction of 5% or more. Key secondary endpoints included weight reduction of 10% or more, 15% or more, and 20% or more at week 72. Also included was the change in weight from baseline to week 20 and change from baseline to week 72 in waist circumference, systolic blood pressure, fasting insulin and lipid levels, and physical function score on a 36-item short form survey. Safety outcomes including serious adverse events were also evaluated during the reporting period.
Results: The trial ran from December 2019 through April 2022. It included 2539 participants. Adherence during the trial was higher in the treatment groups (83.5% to 85.7%) compared to placebo (73.6%). The rate of discontinuation of treatment due to adverse effects was 4.3%, 7.1%, and 6.2% with the 5 mg, 10 mg, and 15 mg doses respectively, compared to 2.6% with placebo. Demographic characteristics were similar across all treatment groups: mean age of participants was 44.9 years, 67.5% were female, 70.5% were White, mean starting weight was 104.8 kg, mean BMI was 38.0 kg/m2, and 94% had a BMI >30 kg/m2. Across participants, the average duration of obesity was 14.4 years, 40.6% had prediabetes at baseline, and approximately 66% of patients had one or more weight-related comorbidities. For the treatment estimand, the mean change in weight at week 72 was -15.0% (95% CI, -15.9 to -14.2) in the 5 mg group, -19.5% (95% CI, -20.4 to -18.5) in the 10 mg group, -20.9% (95% CI, -21.8 to -19.9) in the 15 mg group and -3.1% (95% CI, -4.3 to -1.9) in the placebo group. For the efficacy estimand, the mean change in weight at week 72 was -16.0% (95% CI, -16.8 to -15.2 ) in the 5 mg group, -21.4% (95% CI, -22.2 to -20.6) in the 10 mg group, -22.5% (95% CI, -23.3 to -21.7) in the 15 mg group and -2.4% (95% CI, -3.2 to -1.6) in the placebo group. Weight reduction was 16.1 kg, 22.2 kg, 23.6 kg, and 2.4 kg respectively. Roughly 78.9% to 81.8% of participants treated with tirzepatide reported at least one adverse event that occurred during the treatment period, compared with 72.0% of participants in the placebo group. Frequently reported adverse events included nausea, diarrhea, and constipation. Adverse events were more common in the tirzepatide group, though they were generally self-limiting and non-severe. Severe adverse events included pancreatitis and cholecystitis. There were four cases of pancreatitis evenly distributed across treatment groups including placebo. Cholecystitis and acute cholecystitis were reported more frequently in the tirzepatide group than the placebo group although incidences were low.
Conclusions: Weight reduction of 5% or more has been considered the threshold for clinical significance on the improvement of metabolic health. In this trial, 88% of patients in the tirzepatide 10 mg group and 91% of patients in the tirzepatide 15 mg group achieved the benchmark. In clinical practice, there has been an uptake in the demand for higher doses of semaglutide, a once weekly, GLP-1 RA to promote A1C lowering and weight loss. A recent trial of semaglutide (2.4 mg) demonstrated a mean weight reduction of 12.4% with approximately one-third of participants achieving a weight reduction of 20% or greater. In comparison, the tirzepatide 5 mg group had a mean placebo-adjusted weight reduction of 11.9% from baseline, with 30% of participants reaching the weight loss target of 20% or more. It is clear tirzepatide’s dual mechanism of action targeting both the GIP and GLP-1 receptors may have additive effects for weight loss. Tirzepatide was also accompanied by greater improvements with respect to metabolic and cardiovascular risk factors including waist circumference, blood pressure, fasting insulin, and liver enzymes compared to placebo. Going forward, tirzepatide could serve as a key tool for the management of obesity.
Key Point: In this trial, all three doses of once weekly tirzepatide demonstrated both substantial and sustained weight reduction in adults with obesity. It has not been FDA approved for weight loss yet. This novel medication could provide great benefit to a significant subset of the population in the United States and can be a valuable tool for practitioners moving forward.
- Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022;387(3):205-216. doi: 10.1056/NEJMoa2206038