CardioNerds Journal Club is a monthly forum for CardioNerds to discuss and breakdown recent publications on twitter and are produced with a corresponding infographic and detailed blog post. For more information, check out the CardioNerds Journal Club Page. This Journal Club focuses on the SURMOUNT-1 Trial.

Table of contents for the SURMOUNT-1 Trial summary:

• Visual abstract
• Summary
• References
• Credits
• Twitter Archive

July 21, 2022

Tirzepatide Once Weekly for the Treatment of Obesity

Ania M. Jastreboff, M.D., Ph.D., Louis J. Aronne, M.D., Nadia N. Ahmad, M.D., M.P.H.,

Sean Wharton, M.D., Pharm.D., Lisa Connery, M.D., Breno Alves, M.D., Arihiro Kiyosue, M.D., Ph.D.,

Shuyu Zhang, M.S., Bing Liu, Ph.D., Mathijs C. Bunck, M.D., Ph.D., and Adam Stefanski, M.D., Ph.D., for the

SURMOUNT-1 Investigators*

Link to Manuscript

Relevant Literature – SURMOUNT-1 Trial

Relevant Guidelines -SURMOUNT-1 Trial

Pharmacological Management of Obesity: An Endocrine Society Clinical Practice Guidelines (2015)

• Drugs may amplify adherence to behavior change and improve physical functioning such that increased physical activity is easier for those who cannot exercise initially. Patients with a history of being unable to lose and maintain weight successfully with label indications are candidates for weight loss medications.
• To promote long-term weight maintenance, the use of approved weight loss medication (over no pharmacological therapy) is suggested to ameliorate comorbidities and amplify adherence to behavior changes, which may improve physical functioning and allow for greater physical activity in individuals with a BMI of 30 kg/m² or higher or in individuals with a BMI of 27 kg/m² and at least one associated comorbid medical condition.

Study Rationale – SURMOUNT-1 Trial

• Historically, the treatment of obesity focused almost exclusively on lifestyle-based approaches. However, several clinical guidelines now recommend treatment with anti-obesity medications for people with obesity or for those with overweight and weight-related complications. Recent studies with long-acting glucagon-like peptide-1 (GLP-1) receptor agonists demonstrated 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.
• Tirzepatide is a once-weekly subcutaneous injectable peptide (approved by the Food and Drug Administration [FDA] for type 2 diabetes) engineered from the native GIP sequence, with agonist activity at both the GIP and GLP-1 receptors.
• The efficacy and safety of tirzepatide, a novel glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist, in people with obesity are not known.

Objective – SURMOUNT-1 Trial

To evaluate the efficacy and safety of tirzepatide versus placebo in overweight adults/adults with obesity who did not have diabetes.

Trial – SURMOUNT-1 Trial

Phase 3 multicenter, double-blind, randomized, placebo-controlled trial was conducted at 119 sites in nine countries

Intervention

1. Participants were randomly assigned in a 1:1:1:1 ratio to receive tirzepatide at a dose of 5 mg, 10 mg, or 15 mg or placebo, administered subcutaneously once weekly for 72 weeks as an adjunct to lifestyle intervention.
2. Lifestyle intervention included regular counseling sessions, delivered by a dietitian or a qualified health care professional, to help the participants adhere to healthful, balanced meals, with a deficit of 500 calories per day and at least 150 minutes of physical activity per week.
3. All randomly assigned participants were to undergo a planned 72-week treatment period that included a dose-escalation period of up to 20 weeks.
4. Tirzepatide was initiated at a dose of 2.5 mg once weekly (or matching placebo) and was increased by 2.5 mg every 4 weeks during the dose-escalation period to reach a maintenance dose of up to 15 mg once weekly by week 20.

Enrollment Criteria

Outcomes

1. Coprimary Outcomes
   • Percentage change in body weight from baseline to week 72
   • A weight reduction of 5% or more at week 72
2. Secondary Outcomes
   • Weight reduction of:
     • 10% or more
     • 15% or more
     • 20% or more at week 72
   • Change in weight from baseline to week 20
   • Change from baseline to week 72 in:
     • Waist circumference
     • Systolic blood pressure
     • Fasting insulin and lipid levels
   • Physical function score on the 36-Item Short Form Health Survey (SF-36)
   • Percentage change in total body-fat mass from baseline to week 72 was assessed in a subgroup of 255 participants who underwent dual-energy x-ray absorptiometry

Statistical Analysis

1. Calculated that a sample size of 2400 participants would provide an effective power of greater than 90% to demonstrate the superiority of tirzepatide (10 mg, 15 mg, or both) to placebo, relative to the coprimary end points, each at a two-sided significance level of 0.025
2. Both efficacy and safety endpoints were analyzed with data from all randomly assigned participants (intention-to-treat population)
3. Two estimands were used to assess treatment efficacy from different perspectives and accounted for intercurrent events differently:
   • “treatment regimen” estimand: representing the average treatment effect of tirzepatide relative to placebo for all participants who had undergone randomization, regardless of treatment discontinuation
   • “efficacy” estimand: representing the average treatment effect of tirzepatide relative to placebo for all participants who had undergone randomization, if the treatment was administered as intended

Participant Characteristics:

1. Mean age of the participants was 44.9 years
2. Most were female (67.5%) and White (70.6%)
3. Mean body weight was 104.8 kg
4. The mean BMI was 38.0 kg/m²
5. The mean waist circumference was 114.1 cm
6. 94.5% of the participants had a BMI of 30 kg/m² or higher
7. The average duration of obesity of 14.4 years
8. 40.6% had prediabetes at baseline
9. Nearly two-thirds had one or more weight-related complications

Outcomes

Coprimary Outcomes

1. Percentage weight change at week 72:
   • Treatment-regimen estimand, the mean change in weight at week 72 was:
     •  −15.0% (95% CI, −15.9 to −14.2) with a 5-mg weekly dose of tirzepatide
     •  −19.5% (95% CI, −20.4 to −18.5) with a 10-mg dose
     •  −20.9% (95% CI, −21.8 to −19.9) with a 15-mg dose
     •  −3.1% (95% CI, −4.3 to −1.9) with placebo
   • Estimated treatment differences relative to placebo of:
     • −11.9 percentage points (95% CI, −13.4 to −10.4) for the 5-mg dose
     • −16.4 percentage points (95% CI, −17.9 to −14.8) for the 10-mg dose
     • −17.8 percentage points (95% CI, −19.3 to −16.3) for the 15-mg dose
     • P<0.001 for all comparisons
   • Efficacy estimand, the mean change in weight at week 72 with tirzepatide was:
     • −16.0% (95% CI, −16.8 to −15.2), a weight reduction of 16.1 kg (35.5 lb), with the 5-mg dose
     • −21.4% (95% CI, −22.2 to −20.6), a reduction of 22.2 kg (48.9 lb), with the 10-mg dose
     • −22.5% (95% CI, −23.3 to −21.7), a reduction of 23.6 kg (52.0 lb) with the 15-mg dose
     • Mean change with placebo was −2.4% (95% CI, −3.2 to−1.6), a reduction of 2.4 kg (5.3 lb)
   • Corresponding estimated treatment differences with tirzepatide relative to placebo were:
     •  −13.5 percentage points (95% CI, −14.6 to −12.5) for 5-mg dose
     •  −18.9 percentage points (95% CI, −20.0 to −17.8) for 10-mg dose
     • −20.1 percentage points (95% CI, −21.2 to −19.0) for 15-mg dose
2. Weight reduction of 5% or more at week 72:
   • With the treatment-regimen estimand:
     1. 85% (95% CI, 82 to 89) of 5-mg
     1. 89% (95% CI, 86 to 92) of 10-mg
     1. 91% (95% CI, 88 to 94) of 15-mg
     1.  35% (95% CI, 30 to 39) of participants in the placebo group
     1. P<0.001 for all comparisons with placebo
   • With use of the efficacy estimand:
     1. 89% (95% CI, 87 to 92) of 5-mg
     1. 96% (95% CI, 95 to 98) of 10-mg
     1. 96% (95% CI, 95 to 98) of 15-mg
     1. 28% (95% CI, 24 to 31) of participants in placebo group

Secondary Outcomes:

1. Benefits with tirzepatide were noted with respect to changes in waist circumference, systolic and diastolic blood pressure, fasting insulin level, and lipid levels.
2. At week 72, most (95.3%) of the participants with prediabetes at baseline in the tirzepatide groups had reverted to normoglycemia, as compared with 61.9% of participants in the placebo group.
3. SF-36 physical function scores increased more with tirzepatide than with placebo, an indication that participants’ perspective on their physical functioning was more likely to improve with tirzepatide.
4. Treatment with tirzepatide was associated with greater improvements from baseline than that with placebo in all key secondary end-points.

• Likelihood of being diagnosed with new AF at a primary care visit in a study practice was greater in the screening versus the control group (0.24% [92 events/38382 encounters] versus 0.15% [62 events/40003 encounters]; RD, 0.08% [95% CI, 0.02 to 0.15]) 
• Proportion of individuals with newly diagnosed AF who were initiated on oral anticoagulants was not different in the screening (n=194, 73.5%) and control (n=172, 70.8%) arms (RD, 2.7% [95% CI, –5.5 to 10.4] 

1. 78.9 to 81.8% of participants treated with tirzepatide reported at least one adverse event that emerged during the treatment period as compared with 72.0% of participants in the placebo group
2. Most frequently reported adverse events were gastrointestinal (nausea, diarrhea, and constipation)
3. Serious adverse events were reported by 160 participants (6.3%) overall
4. Approximately 21% of serious adverse events were considered to be related to coronavirus disease 2019 (Covid-19), which affected participants in all treatment groups
5. Eleven deaths were reported: 4 (0.6%) in the 5-mg tirzepatide group, 2 (0.3%) in the 10-mg group, 1 (0.2%) in the 15-mg group, and 4 (0.6%) in the placebo group
6. Four reported cases of adjudication-confirmed pancreatitis, evenly distributed across treatment groups, including the placebo group (none severe)
7. No cases of medullary thyroid cancer were reported
8. Reported incidence of cholelithiasis was similar among the tirzepatide and placebo groups
9. Cholecystitis and acute cholecystitis were reported more frequently in the tirzepatide groups than in the placebo group

Conclusions

• In this 72-week trial in participants with obesity, 5 mg, 10 mg, or 15 mg of tirzepatide once weekly provided substantial and sustained reductions in body weight.

Limitations & Considerations

1. The enrolled participants with obesity and overweight may represent a subpopulation with a greater commitment to weight-management efforts than the general population with obesity
2. The measured baseline cardiometabolic risk factors in the trial population, such as blood pressure and lipids, were relatively normal, possibly attenuating the potential to show improvement, though meaningful changes in these variables were observed.
3. Overall, only 5.5% of trial participants with overweight (BMI of 27 to <30) were included

World Obesity Federation. World obesity atlas 2022 (https://www.worldobesity.org/resources/resource-library/world-obesity-atlas-2022).

Apovian CM, Aronne LJ, Bessesen DH, et al. Pharmacological management of obesity: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2015; 100: 342-62.

Wharton S, Lau DCW, Vallis M, et al. Obesity in adults: a clinical practice guideline. CMAJ 2020; 192(31): E875-E891.

Pi-Sunyer X, Astrup A, Fujioka K, et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Engl J Med 2015; 373: 11-22.

Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med 2021; 384: 989-1002.

The published archive features curated twitter highlights from the journal club event.