What efficacy data are available on the use of tirzepatide for obesity?

Introduction
The goals of obesity treatment include improving weight status and reducing or eliminating the presence of comorbid conditions, which are achieved through lifestyle interventions, use of weight-loss medications, and in severe cases, metabolic or bariatric surgery. 1,2 Lifestyle interventions should focus on the adoption of healthier habits, increased physical activity, and reduction of sedentary behavior. Adult obesity guidelines generally recommend pharmacotherapy as an adjunct to lifestyle changes in adults with a body mass index (BMI) of ≥ 27 kg/m2 in the presence of a comorbidity, or with a BMI of ≥ 30 kg/m2. 3-5 Various medications are available for use to treat obesity including metformin, orlistat, phentermine-topiramate, phentermine monotherapy, naltrexone-bupropion, and diethylpropion, in addition to glucagon-like peptide (GLP)-1 receptor agonists. 3,6 These agents vary in their comparative efficacy to achieve weight reduction and their adverse event profile. Of the available GLP-1 receptor agonists, currently, only subcutaneous (SC) semaglutide and liraglutide carry Food and Drug Administration (FDA)-labeled indications for weight loss. 7,8 Tirzepatide is another GLP-1 agent currently being studied for the treatment of obesity and is the only agent with a dual mechanism of action, acting as an agonist on both glucose-dependent insulinotropic polypeptide (GIP) and GLP-1. 9,10 Its activity on GIP is thought to work in concert with GLP-1 to facilitate weight-loss effects. 9 This FAQ aims to review the available evidence thus far on tirzepatide use for obesity.

Guidelines
Current 2022 practice guidelines from the American Gastroenterological Association (AGA) recommend semaglutide 2.4 mg SC for the long-term treatment of obesity due to its superior safety and efficacy profile, and state that obesity treatment with liraglutide 3 mg daily can also be considered. 3 The 2015 Endocrine Society and Obesity Society guideline provides only general recommendations for the use of GLP-1 receptor agonists and suggest that in patients with type 2 diabetes mellitus (T2DM) who are overweight or obese, medications that promote weight loss such as GLP-1 receptor agonists or sodium-glucose transporter 2 (SGLT2) inhibitors that are also effective for diabetes, be added in addition to metformin. 4

Indirect Comparative Data
The results of 2 indirect comparative meta-analyses and a pooled data analysis that include tirzepatide indicate that there is more pronounced weight loss with tirzepatide versus other GLP-1s, although rates of discontinuation may be increased with higher doses. 11-13 These studies, along with placebo-controlled studies of tirzepatide, are summarized in the Table. In 1 meta-analysis of 7 RCTs of at least 52 weeks duration in patients without T2DM, more pronounced weight loss was observed with tirzepatide 10 mg and 15 mg doses versus other GLP-1 receptor agonists, including semaglutide 2.4 mg and liraglutide 3 mg, with no statistical differences shown between the 2 tirzepatide doses. 11 In another meta-analysis of 7 RCTs in patients with and without T2DM, tirzepatide doses of 5 mg, 10 mg, and 15 mg were determined superior to semaglutide for achieving a ≥ 5% weight reduction, although 10 mg (odds ratio [OR], 2.21; 95% confidence interval [CI], 1.26 to 3.87) and 15 mg (OR, 2.23; 95% CI, 1.15 to 4.30) doses were also associated with a significant higher rate of discontinuation when compared to semaglutide. 12 In a pooled analysis of data from the SURMOUNT-1 and STEP-1 studies, both tirzepatide 10 mg and 15 mg doses were shown to result in significantly greater weight loss versus semaglutide 2.4 mg SC (tirzepatide 10 mg: mean difference [MD], -4.67%; 95% CI, -5.91 to -3.43; tirzepatide 15 mg: MD, -5.92%; 95% CI, -7.16 to -4.68). 13

Clinical Trials of Tirzepatide
Major clinical trials of tirzepatide include SURMOUNT-1, SURMOUNT-2, and SURMOUNT-3, each placebo-controlled, randomized clinical trials conducted over a 72-week period in overweight and obese adults. 14-16 In SURMOUNT-1, a 15%, 19.5%, and 20.9% weight reduction from baseline was observed in patients on tirzepatide 5 mg, 10 mg, and 15 mg versus 3.1% with placebo after 72 weeks (p<0.001 all comparisons). 16 A ≥ 5%, 10%, 15%, and 20% weight reduction was also achieved in significantly more patients after 72 weeks versus placebo. In the study, rates of hypoglycemia were increased with tirzepatide versus placebo. In SURMOUNT-2, patients with T2DM were included, although patients who were receiving insulin therapy were excluded from enrollment. Both 15 and 10 mg tirzepatide doses achieved superiority versus placebo for the least-squares mean percentage change in body weight (BW) from baseline after 72 weeks (-12.8% for 10 mg, and -14.7% for 15 mg (p<0.0001 for each placebo comparison). 15 A ≥ 5%, 10%, 15%, and 20% weight reduction was also achieved in significantly more patients than placebo. By week 72, HbA1C also decreased by 2.07% on tirzepatide 10 mg, and 2.08% on tirzepatide 15 mg versus 0.51% on placebo (p<0.0001 each placebo comparison). No cases of severe hypoglycemia were reported in the study, although level 2 hypoglycemia (<54 mg/dL) was reported in 4%, 5%, and 1% of 10 mg, 15 mg, and placebo patients, respectively. In SURMOUNT-3, patients without T2DM who achieved a ≥ 5% weight reduction during a 12-week run-in phase of intensive lifestyle interventions were randomized to tirzepatide titrated to the maximally tolerated dose (MTD; 10 or 15 mg) or placebo for an additional 72 weeks. 14 The coprimary endpoint of additional mean percent weight change from randomization to week 72 was -18.4% in patients treated with tirzepatide versus 2.5% with placebo (estimated treatment difference [ETD], -20.8%; 95% CI, -23.2% to -18.5%). The coprimary endpoint of the proportion of individuals with an additional ≥ 5% weight reduction was achieved in 87.5% of patients on tirzepatide versus 16.5% on placebo. During the study, 87.1% of patients on tirzepatide had at least 1 treatment emergent adverse event (TEAE) compared to 76.7% on placebo. Some malignancies were reported in each group, although they were not considered related to study treatment.

Table. Summary of Evidence for Tirzepatide for Obesity in Adults. 11-16
Study design and duration

Subjects
 
Interventions
Results
Conclusions
Meta-analyses
Tan 202312

MA of 7 RCTs
N=5,800 adults with BMI considered overweight or obese based on country (with or without T2DM)
 
Tirzepatide (7 studies)

Semaglutide (2 studies)

Insulin (2 studies)

Placebo (3 studies)
 
Dose dependent effect shown with tirzepatide for weight loss.
5 mg: -7.2 kg; 95% CI, -12.35 to -2.06 kg;
10 mg: -10.18 kg; 95% CI, -16.3 kg to -4.06 kg;
15 mg: -11.77 kg; 95% CI, -17.12 kg to -6.43 kg
 
Tirzepatide 5 mg, 10 mg, and 15 mg doses superior to semaglutide for achieving a ≥ 5% weight loss. Odds were 1.50 (95% CI, 1.15 to 1.96), 3.05 (95% CI, 2.27 to 4.08), and 4.25 (95% CI, 3.10 to 5.82) times higher with 5 mg, 10 mg, and 15 mg doses of tirzepatide, respectively, versus semaglutide
 
Comparable AEs and mortality compared to semaglutide and placebo; most prevalent were GI-related events
 
Significantly higher rates of discontinuation with tirzepatide 10 mg (OR, 2.21; 95% CI, 1.26 to 3.87) and 15 mg (OR, 2.23; 95% CI, 1.15 to 4.30) doses versus semaglutide. Rates similar between tirzepatide 5 mg dose and semaglutide (NS)
Tirzepatide superior to semaglutide for weight loss but carries significantly higher rates of discontinuation versus semaglutide at 10 mg and 15 mg doses
Alkhezi 202311

MA of 7 RCTs (52 weeks duration)
N=12,300 adults with BMI of ≥ 30 kg/m2, or ≥ 27 kg/m2 with comorbidities

Patients did not have T2DM
Liraglutide (3 studies)

Semaglutide (daily or weekly; 4 studies)

Tirzepatide (1 study)

Placebo (6 studies)
 
 
Tirzepatide 15 mg was superior to:
Weekly semaglutide 2.4 mg DMD, -9.23 kg; 95% CI, -13.76 to -5.05
Daily semaglutide 0.4 mg DMD, -9.73; 95% CI, -14.57 to -4.97
Liraglutide 3 mg
DMD, -16.81 kg; 95% CI, -21.13 to -12.62
 
Tirzepatide associated with a greater reduction in weight loss versus:
Weekly semaglutide 2.4 mg
MD, -5.13%; 95% CI, -9.82 to -0.68
Daily semaglutide 0.4 mg
MD, -6.67%; 95% CI, -12.1 to -1.24
Liraglutide 3 mg
MD, -13.02%; 95% CI, -17.44 to -8.57
 
When ranked, tirzepatide 15 mg was ranked highest for percentage weight loss reduction, followed by tirzepatide 10 mg, then weekly semaglutide 2.4 mg, semaglutide 0.4 mg daily, then liraglutide 3 mg daily
Tirzepatide superior to semaglutide
Le Roux 202313

Pooled data from SURMOUNT-1 and STEP 1
N=3,870 adults with BMI of ≥ 30 kg/m2 or ≥ 27 kg/m2 with 1 comorbidity, excluding T2DM
Tirzepatide 10 mg and 15 mg SC (SURMOUNT 1 study)

Semaglutide 2.4 mg SC (STEP 1 study)

All patients received lifestyle interventions (500 kcal/day deficit and 150 minutes physical activity/week)
Both tirzepatide 10 mg and 15 mg doses resulted in significantly greater reductions versus semaglutide 2.4 mg (p<0.001 each comparison):
Tirzepatide 10 mg:
MD, -4.67%; 95% CI, -5.91 to -3.43
Tirzepatide 15 mg:
MD, -5.92%; -7.16 to -4.68,
 
Significantly more patients receiving tirzepatide 10 mg or 15 mg achieved ≥ 5% weight loss versus semaglutide (p<0.001 each comparison): Tirzepatide 10 mg:
OR, 2.61; 95% CI, 1.48 to 4.57
Tirzepatide 15 mg:
OR, 2.75; 95% CI, 1.57 to 4.81
Both 10 mg and 15 mg doses of tirzepatide superior to semaglutide 2.4 mg
Clinical Trials
Wadden 202314

SURMOUNT-3 (72 weeks)
N=579 adults with a BMI of ≥ 30 kg/m2, or 27 kg/m2 and 1 or more comorbidity (excluding T2DM) who achieved a ≥ 5% weight reduction after 12 weeks of lifestyle interventions
 
Tirzepatide MTD (10 or 15 mg) SC (n=287)

Placebo (n=292)

Of patients treated with tirzepatide, 86.4% had MTD of 15 mg
Primary:
Mean percent weight change from randomization to week was -18.4% in patients treated with tirzepatide versus 2.5% with placebo (ETD, -20.8%; 95% CI -23.2% to -18.5%).
 

Majority of tirzepatide-treated patients (87.5%) achieved a ≥ 5% weight loss from randomization versus 16.5% with placebo (OR, 34.6; 95% CI, 19.2 to 62.6)

Other:
≥ 10% BW reduction by week 72: 76.7% on tirzepatide versus 8.9% on placebo;
≥ 15% BW reduction: 65.4% on tirzepatide versus 4.2% on placebo
 ≥ 20% BW reduction: 44.7% on tirzepatide versus 2.2% on placebo
(p<0.001 all placebo comparisons)

Tirzepatide MTD superior to placebo over 72 weeks (ETD, -20.8%; 95% CI, -23.2 to -18.5

At 72 weeks, 94% of patients receiving tirzepatide maintained ≥ 80% of BW lost during 12-week run-in versus 43.8% on placebo (p<0.001)

Safety:
87.1% of tirzepatide-treated patients had at least 1 TEAE compared with 76.7% on placebo, and were most often GI-related
 
Serious AEs occurred in 5.9% and 4.8% of tirzepatide and placebo-treated patients, respectively
Tirzepatide versus placebo results in additional weight loss over 72-week period after lifestyle interventions
Garvey 202315

SURMOUNT-2 (72 weeks duration)
N=938 adults with a BMI of ≥ 27 kg/m2 and T2DM with a HbA1C of 7 to 10%

If on antihyperglycemic, had to be on stable dose for ≥ 3 months prior to screening; could not be on a DPP4 or other obesity meds
Tirzepatide SC 10 mg (n=312)

Tirzepatide SC 15 mg (n=311)

Placebo SC (n=315)

All patients received lifestyle interventions
Primary:
Both tirzepatide doses superior to placebo for the least-squares mean % change in BW from baseline to week 72:
10 mg: -12.8% (-12.9 kg)
15 mg: -14.7% (14.8 kg)
 
Treatment difference versus placebo ((p<0.0001 each placebo comparison):
10 mg: -9.6%; 95% CI, -11.1 to -8.1%
15 mg: -11.6%; 95% CI, -13 to -10.1

79% and 83% of tirzepatide patients had weight reduction of at least 5% from baseline to week 72 in 10 mg and 15 groups, respectively, compared to 32% with placebo (p<0.0001 for both)
 
Other:
≥ 10% BW reduction by week 72: 61% on 10 mg, 65% on 15 mg, 9% on placebo
 ≥ 15% BW reduction: 40% on 10 mg, 48% on 15 mg, 3% on placebo
 ≥ 20% BW reduction: 22% on 10 mg, 31% on 15 mg, 1% on placebo (p<0.0001 each placebo comparison)
 
Change in HbA1C from baseline to week 72: -2.07% on 10 mg, -2.08% on 15 mg, -0.51% on placebo (p<0.0001 each placebo comparison)
 
HbA1C <7% by week 72: 87% on 10 mg, 84% on 15 mg, and 36% on placebo;
HbA1C ≤6.5%: 80% on 10 mg, 79% on 15, and 20% on placebo
HbA1C ≤5.7%: 46% on 10 mg, 49% on 15 mg, 4% on placebo (p<0.0001 each placebo
 
Safety:
Most frequently reported AE was GI (diarrhea, nausea/vomiting)
 
No cases of severe hypoglycemia; level 2 hypoglycemia (<54 mg/dl) reported in 4% of 10 mg patients, 5% of 15 mg, and 1% of placebo
Both 10 mg and 15 mg doses of tirzepatide superior to placebo for weight loss
Jastreboff 202216

SURMOUNT-1 (72 weeks)
N=2539 adults with a BMI of ≥ 30 kg/m2, or 27 kg/m2 and 1 or more comorbidity

Patients with T2DM excluded
 
Tirzepatide SC 5 mg (n=630)

Tirzepatide SC  10 mg (n=636)

Tirzepatide SC 15mg (n=630)

Placebo (n=643)

All patients received lifestyle interventions
Primary:
All doses superior to placebo for mean percentage change in weight by week 72 (p<0.001 all placebo comparisons):
5 mg: -15% (95% CI, -15.9 to -14.2)
10 mg: -19.5% (95% CI, -20.4 to -18.5)
15 mg:  -20.9% (95% CI, -21.8 to -19.9)
Placebo: -3.1% (95% CI, -4.9 to -1.9%)
 
≥ 5% weight reduction by week 72: 85%, 89%, and 91%, in 5 mg, 10 mg, and 15 mg groups, respectively, versus 35% with placebo (p<0.001 all placebo comparisons)
Other:
≥ 10% weight reduction by week 72: 68.5%, 78.1% and 83.5% in 5 mg, 10 mg, and 15 mg groups, respectively, versus 18.8% with placebo (p<0.001 all placebo comparisons)
 
≥ 15% weight reduction by week 72: 48%, 66.6%, and 70.6% in 5 mg, 10 mg, and 15 mg groups, respectively, versus 8.8% with placebo (p<0.001 all placebo comparisons)
 
≥ 20% weight reduction by week 72: 30%, 50.1%, 56.7% in 5 mg, 10 mg, and 15 mg groups, respectively, versus 3.1% with placebo (p<0.001 all placebo comparisons)
 
Safety:
81.5% of patients on tirzepatide reported AE versus 72% of placebo patients; most frequent were GI events
 
Cholecystitis and acute cholecystitis reported in ≤ 0.6% of tirzepatide-treated patients
 
4 confirmed cases of pancreatitis evenly distributed across treatment groups, including placebo
 
Hypoglycemia occurred in 1.4 to 1.6% of tirzepatide groups versus 0.2% of placebo patients
All doses of tirzepatide superior to placebo for weight loss
Abbreviations: AE, adverse event; BMI, body mass index; BW, body weight; CI, confidence interval; DMD, difference-in-mean-difference; ETD, estimated treatment difference; GI, gastrointestinal; HbA1C, hemoglobin A1C; MA, meta-analysis; MD, mean difference; MTD, maximally tolerated dose; NS, nonsignificant; OR, odds ratio; RCT, randomized controlled trials; SC, subcutaneous; T2DM, type 2 diabetes mellitus.

Conclusion
Newly published literature adds to the pool of evidence currently available on tirzepatide use in obesity, which is not yet FDA-approved for the indication. Recent indirect comparative data indicate significant additional weight loss with the use of tirzepatide compared to semaglutide in adult patients, although this efficacy may be hampered by higher rates of discontinuation due to GI-related side effects with higher doses. Clinicians should closely monitor for updated guidance as the landscape of obesity medications continues to evolve and more evidence becomes available.

References

  1. Hampl SE, Hassink SG, Skinner AC, et al. Clinical practice guideline for the evaluation and treatment of children and adolescents with obesity. Pediatrics. 2023;151(2):e2022060640. doi:10.1542/peds.2022-060640.
  2. Vajravelu ME, Tas E, Arslanian S. Pediatric obesity: Complications and current day management. Life (Basel). 2023;13(7):1591. doi:10.3390/life13071591.
  3. Grunvald E, Shah R, Hernaez R, et al. AGA clinical practice guideline on pharmacological interventions for adults with obesity. Gastroenterology. 2022;163(5):1198-1225. doi:10.1053/j.gastro.2022.08.045
  4. Apovian CM, Aronne LJ, Bessesen DH, et al. Pharmacological management of obesity: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2015;100(2):342-362. doi:10.1210/jc.2014-3415
  5. ElSayed NA, Aleppo G, Aroda VR, et al. 8. Obesity and weight management for the prevention and treatment of type 2 diabetes: Standards of Care in Diabetes-2023. Diabetes Care. 2023;46(Suppl 1):S128-S139. doi:10.2337/dc23-S008.
  6. Kheniser K, Saxon DR, Kashyap SR. Long-term weight loss strategies for obesity. J Clin Endocrinol Metab. 2021;106(7):1854-1866. doi:10.1210/clinem/dgab091
  7. Wegovy [package insert]. Plainsboro, NJ: Novo Nordisk; 2023.
  8. Saxenda [package insert]. Plainsboro, NJ: Novo Nordisk; 2023.
  9. Jastreboff AM, Kushner RF. New frontiers in obesity treatment: GLP-1 and nascent nutrient-stimulated hormone-based therapeutics. Annu Rev Med. 2023;74:125-139. doi:10.1146/annurev-med-043021-014919.
  10. Mounjaro [package insert]. Indianapolis, IN: Eli Lilly; 2023.
  11. Alkhezi OS, Alahmed AA, Alfayez OM. Comparative effectiveness of glucagon-like peptide-1 receptor agonists for the management of obesity in adults without diabetes: A network meta-analysis of randomized clinical trials. Obes Rev. 2023;24(3):e13543. doi:10.1111/obr.13543
  12. Tan B, Pan XH, Chew HSJ, et al. Efficacy and safety of tirzepatide for treatment of overweight or obesity. A systematic review and meta-analysis. Int J Obes (Lond). 2023;47(8):677-685. doi:10.1038/s41366-023-01321-5.
  13. le Roux CW, Hankosky ER, Wang D, et al. Tirzepatide 10 and 15 mg compared with semaglutide 2.4 mg for the treatment of obesity: An indirect treatment comparison. Diabetes Obes Metab. 2023;25(9):2626-2633. doi:10.1111/dom.15148
  14. Wadden TA, Chao AM, Machineni S, et al. Tirzepatide after intensive lifestyle intervention in adults with overweight or obesity: the SURMOUNT-3 phase 3 trial. Nat Med. 2023;10.1038/s41591-023-02597-w. doi:10.1038/s41591-023-02597-w.
  15. Garvey WT, Frias JP, Jastreboff AM, et al. Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2023;402(10402):613-626. doi:10.1016/S0140-6736(23)01200-X.
  16. 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

Prepared by:
Christie Denton, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

November 2023

The information presented is current as October 23, 2023. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.