Tirzepatide (Tisiparatide) is a dual glucose-dependent insulin-stimulating polypeptide and glucagon-like peptide-1 (GLP-1) receptor agonist that is being developed for the treatment of type 2 diabetes. The GLP-1 receptor agonist sommarlutide has previously been approved for the treatment of type 2 diabetes. However, the efficacy and safety of once-weekly tirzepatide compared to sommarutide is unknown.
A Phase 3 trial study published in NEJM in 2021 showed that tirzepatide was no worse than and superior to sommarutide in terms of mean change in HBA1c levels from baseline to 40 weeks in patients with type 2 diabetes. It was also found that tirzepatide had greater weight loss than semaglutide (least squares mean estimated treatment differences of -1.9 kg, -3.6 kg, and -5.5 kg, respectively; P< 0.001 is used for all comparisons).
SURMOUNT-1 evaluated the efficacy and safety of tisiparatide in adults who are obese or overweight but do not have diabetes.
The SURMOUNT-1 trial is a phase 3 randomized, double-blind, placebo-controlled clinical trial design at 119 centers in nine countries. People who were 18 years of age or older, had a body mass index (BMI) of 30 or more, or a BMI of 27 or more with at least one weight-related complication (such as hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease) and reported one or more weight loss failures through controlled diets were eligible to participate. The main exclusion criteria were diabetes, weight change of more than 5 kg in the 90 days prior to screening, previous or planned bariatric surgery, and treatment with drugs that promote weight loss in the 90 days prior to screening.
After a 2-week screening period, participants were randomly assigned to receive 5 mg, 10 mg, or 15 mg doses of Tirzepatide or placebo subcutaneously once a week for 72 weeks as an adadjuvant to the lifestyle intervention in a 1:1:1 ratio. Lifestyle interventions include regular lifestyle counseling sessions provided by a dietitian or qualified health care professional to help subjects adhere to a healthy, balanced diet of less than 500 calories per day and at least 150 minutes of physical activity per week.
The co-primary endpoint was the percentage change in body weight from baseline to week 72 and a weight loss of 5% or more at week 72. Key secondary endpoints included weight loss of 10% or more, 15% or more, and 20% or more at week 72; Weight change from baseline to week 20; And changes in waist circumference, systolic blood pressure, fasting insulin and lipid levels, and SF-36 physical function scores from baseline to week 72. Percentage change in total fat mass from baseline to week 72 was assessed in a subgroup of 255 participants who underwent dual-energy X-ray absorptiometry.
By calculation, a sample size requiring 2,400 subjects would provide greater than 90% efficacy to demonstrate that tisiparatide (10 mg, 15 mg, or both) is superior to placebo relative to the co-primary endpoint, with each endpoint at two significance levels of 0.025. The sample size calculation assumed that tisiparatide (10 mg, 15 mg, or both) would differ at least 11 percentage points from baseline in average weight loss at 72 weeks compared to placebo, with a common standard deviation of 10% and a dropout rate of 25%.
The results show that the trial was conducted from December 2019 to April 2022 and included 2,539 participants. Overall, 86.0% of participants completed the primary trial treatment phase (88.4% to 89.8% in the tirzepatide group and 77.0% in the placebo group). 81.9% of participants adhered to the treatment or placebo assignment (83.5% to 85.7% in the tirzepatide group and 73.6% in the placebo group). Discontinuation of treatment due to adverse events in the 5 mg, 10 mg, and 15 mg tisiparatide groups was 4.3%, 7.1%, and 6.2%, respectively, compared with 2.6% in the placebo group.
Demographic and clinical baseline characteristics were generally similar across treatment groups (Table 1). The average age of the participants was 44.9 years; The majority were female (67.5%) and white (70.6%); The average body weight was 104.8 kg, the average body mass index was 38.0, and the average waist circumference was 114.1 cm. 94.5 percent of the participants had a BMI of 30 or higher. The average duration of participants reporting obesity was 14.4 years; 40.6 percent had prediabetes at baseline, and nearly two-thirds had one or more weight-related complications.
For the evaluation of treatment options, the mean change in weight at week 72 was measured by:
Tisiparatide 5 mg per week was -15.0% (95% CI, -15.9 to -14.2)
Tisiparatide 10 mg weekly was -19.5% (95% CI, -20.4 to -18.5)
Tisiparatide 15 mg per week was -20.9% (95% CI, -21.8 to -19.9).
Placebo was -3.1% (95% CI, -4.3 to -1.9)
All three tirzepatide doses were superior to placebo, with an estimated treatment difference of -11.9 percentage points (95% CI, -13.4 to -10.4) for the 5 mg dose and -16.4 percentage points (95% CI, -13.4 to -10.4) for the 10 mg dose. -17.9 to -14.8), 15 mg dose differences were -17.8 percentage points (95% CI, -19.3 to -16.3) (all comparisons P< 0.001).
In terms of treatment effect, the average change in weight at week 72 was:
The mean change in body weight was -16.0% (95% CI, -16.8 to -15.2) with a weight loss of 16.1 kg at tisiparatide 5 mg.
At tisiparatide 10 mg dose, the mean change in body weight was -21.4%(95% CI, -22.2 to 20.6), with a weight loss of 22.2 kg;
At tisiparatide 15 mg, the mean change in body weight was -22.5% (95% CI, -23.3 to -21.7) and the weight loss was 23.6 kg.
The mean change in placebo was -2.4% (95% CI, -3.2 to −1.6) with a decrease of 2.4 kg (Figure 1B).
The corresponding estimated treatment difference for tirzepatide relative to placebo was -13.5 percentage points (95% CI, -14.6 to -12.5), -18.9 percentage points (95% CI, -14.6 to -12.5). -20.0 to -17.8) and -20.1 percentage points (95%CI for percentages of 5-mg, 10-mg, and 15-mg doses, -21.2 to -19.0, respectively).
At 72 weeks, participants in the 5 mg, 10 mg, and 15 mg tisiparatide groups lost 5% or more of their body weight to 85% (95% CI, 82 to 89), 89% (95% CI, 86 to 92), and 91% (95% CI, 95 percent). 88 to 94), compared to only 35% (95% CI, 30 to 39) in the placebo group (P < 0.001 for all comparisons with placebo).
Overall fat mass decreased by an average of 33.9% in the tirzepatide group and 8.2% in the placebo group compared with placebo, with an estimated treatment difference of -25.7 percentage points (95% CI, -31.4 to -20.0) compared with placebo. Participants receiving dual-energy X-ray absorptiometry (efficacy estimates included 160 of the 255 participants in the subgroup who had evaluable data at baseline and at week 72) (Figure S8). The ratio of total fat mass to total lean mass decreased more in the tirzepatide group (from 0.93 at baseline to 0.70 at week 72) than in the placebo group (from 0.95 to 0.88).
And the security is pretty good.
The results of this study showed that obese adults who took 10 mg and 15 mg doses of tisiparatide lost an average of 19.5 percent and 20.9 percent of their body weight, respectively, compared with a 3.1 percent weight loss in the placebo group (treatment protocol estimates). This is an unusually significant degree of weight loss after treatment with an anti-obesity drug, compared to results reported in other phase 3 clinical trials. Given that tirzepatide is both a GIP receptor and a GLP-1 receptor agonist, we speculate that targeting multiple endogenous nutrition-stimulating hormone pathways involved in energy homeostasis may have additional benefits.
