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TIRZEPATIDE (ZEPBOUND®)





Acronyms


DRUGS IN CLASS


MECHANISM OF ACTION


FDA-APPROVED INDICATIONS


WEIGHT LOSS


RCT
SURMOUNT-1 trial - Tirzepatide vs Placebo for Weight Loss in Obese Patients Without Diabetes, NEJM (2022) [PubMed abstract]
  • The SURMOUNT-1 trial enrolled 2539 adults with a BMI ≥ 30 or a BMI ≥ 27 and at least one weight-related complication
Main inclusion criteria
  • Age ≥ 18 years
  • History of unsuccessful dieting
  • BMI ≥ 30 or ≥ 27 and 1 or more of the following:
    • Hypertension
    • Dyslipidemia
    • OSA
    • CVD
Main exclusion criteria
  • Diabetes
  • Previous bariatric surgery
  • Other weight loss drug within 90 days
Baseline characteristics
  • Average age 45 years
  • Female sex - 68%
  • Average body weight - 231 lbs (105 kg)
  • Average BMI - 38
Randomized treatment groups
  • Group 1 (630 patients): Tirzepatide 5 mg once weekly
  • Group 2 (636 patients): Tirzepatide 10 mg once weekly
  • Group 3 (630 patients): Tirzepatide 15 mg once weekly
  • Group 4 (643 patients): Placebo once weekly
  • 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
Primary outcome: The coprimary end points were the percentage change in body weight from baseline to week 72 and a weight reduction of 5% or more at week 72
Results

Duration: 72 weeks
Outcome Tir 5 mg Tir 10 mg Tir 15 mg Placebo Comparisons
% change in body weight −15% −19.5% −20.9% −3.1% Tir (all doses) vs Placebo p<0.001
≥ 5% weight loss 85% 89% 91% 35% Tir (all doses) vs Placebo p<0.001
Body weight lost 35.5 lbs (16.1 kg) 48.9 lbs (22.2 kg) 52.0 lbs (23.6 kg) 5.3 lb (2.4 kg) N/A
Nausea 24.6% 33.3% 31% 9.5% N/A
Diarrhea 18.7% 21.2% 23% 7.3% N/A
Constipation 16.8% 17.1% 11.7% 5.8% N/A
Pancreatitis 0.2% 0.2% 0.2% 0.2% N/A
Gallbladder disease 0.8% 1.7% 1.0% 0.8% N/A
  • Treatment discontinuations due to adverse events were 4.3%, 7.1%, and 6.2% with 5 mg, 10 mg, and 15 mg of tirzepatide, respectively, and 2.6% with placebo
  • Gastrointestinal side effects were transient, mild to moderate in severity, and occurred primarily during the dose-escalation period
  • In a substudy that included patients with prediabetes (N=1032), treatments were continued for a total of 176 weeks. The incidence of diabetes during the 176 weeks was 1.3% in the pooled tirzepatide groups and 13.3% in the placebo group. [PMID 39536238]

Findings: 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.




OBSTRUCTIVE SLEEP APNEA (OSA)


RCT
SURMOUNT-OSA trial - Tirzepatide vs Placebo for OSA and Obesity, NEJM (2024) [PubMed abstract]
  • SURMOUNT-OSA enrolled patients with OSA who were (N=235) and were not (N=234) using positive airway pressure (PAP) at baseline
Main inclusion criteria
  • OSA (AHI ≥ 15/hour)
  • BMI ≥ 30 (≥ 27 in Japan)
Main exclusion criteria
  • Type 1 or 2 diabetes
  • Central or mixed apnea
  • Major craniofacial abnormalities
Baseline characteristics
  • Average age 50 years
  • Average BMI - 39
  • Average weight - 253 lbs (115 kg)
  • Average AHI - 50 events/hr
Randomized treatment groups
  • Group 1 (234 patients): Tirzepatide titrated to 10 or 15 mg once weekly
  • Group 2 (235 patients): Placebo
  • Patients using PAP at baseline continued to use it but were instructed to suspend it for 7 days before polysomnographic and patient-reported outcome (PRO) assessments at baseline, week 20, and week 52
Primary outcome: Change in the apnea–hypopnea index (AHI, the number of apneas and hypopneas during an hour of sleep) from baseline. Results for patients using PAP and those who were not were reported separately.
Results

Duration: 52 weeks
Outcome Tirzepatide Placebo Comparisons
Primary outcome (no PAP) -25.3 -5.3 p<0.001
Primary outcome (PAP) -29.3 -5.5 p<0.001
% change in weight (no PAP) -17.7% -1.6% diff −16.1 95%CI (−18.0 to −14.2)
% change in weight (PAP) -19.6% -2.3% diff −17.3 95%CI (−19.3 to −15.3)
  • GI side effects (nausea, vomiting, constipation, diarrhea) were more common in the tirzepatide group, while adverse events leading to drug discontinuation were similar between tirzepatide and placebo (3.9% vs 4.3%)
  • The tirzepatide group had significant reductions in systolic blood pressure, hsCRP concentrations, and sleep disturbances

Findings: Among persons with moderate-to-severe obstructive sleep apnea and obesity, tirzepatide reduced the AHI, body weight, hypoxic burden, hsCRP concentration, and systolic blood pressure and improved sleep-related patient-reported outcomes.


NONALCOHOLIC STEOTOHEPATITIS (NASH)


RCT
SYNERGY-NASH trial - Tirzepatide vs Placebo for NASH with Fibrosis, NEJM (2024) [PubMed abstract]
  • The SYNERGY-NASH trial enrolled 190 people with biopsy-confirmed NASH and stage F2 or F3 fibrosis
Main inclusion criteria
Main exclusion criteria
  • Other liver disease
  • Cirrhosis
  • Heavy alcohol use
  • HgA1C > 9.5%
Baseline characteristics
  • Average age 54 years
  • Average BMI - 36
  • Average weight - 220 lbs (100 kg)
  • Type 2 diabetes - 58%
  • Average NAFLD activity score - 5.3
  • Liver fibrosis stage: F2 - 43% | F3 - 57%
Randomized treatment groups
  • Group 1 (47 patients): Tirzepatide 5 mg once weekly
  • Group 2 (47patients): Tirzepatide 10 mg once weekly
  • Group 3 (48 patients): Tirzepatide 15 mg once weekly
  • Group 4 (48 patients): Placebo
  • Therapy was initiated at 2.5 mg, and patients were titrated to their assigned dose in 2.5 mg increments every 4 weeks
Primary outcome: Resolution of NASH (defined as no steatotic liver disease [steatosis score of 0] or simple steatosis [a steatosis score of 1, 2, or 3] without steatohepatitis and an inflammation score of 0 or 1 and a ballooning score of 0), without worsening of fibrosis (defined as no increase in the fibrosis stage) at week 52
Results

Duration: 52 weeks
Outcome Tir 5 Tir 10 Tir 15 Placebo Comparisons
Primary outcome 44% 56% 62% 10% p<0.001 for all 3 vs placebo
Decrease of ≥ 1 fibrosis stage 55% 51% 51% 30% p<0.05 for all 3 vs placebo
% weight loss 10.7% 13.3% 15.6% 0.8% N/A
Drug discontinuation due to side effects 4% 0% 4% 2% N/A
  • Gastrointestinal side effects, including nausea, diarrhea, and constipation, were more common in the tirzepatide groups

Findings: In this phase 2 trial involving participants with NASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of NASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of NASH.


HEART FAILURE WITH PRESERVED EJECTION FRACTION (HFpEF)


RCT
SUMMIT - Tirzepatide vs Placebo for Heart Failure with Preserved Ejection Fraction and Obesity, NEJM (2024) [PubMed abstract]
  • The SUMMIT trial enrolled 731 patients with heart failure, an ejection fraction of at least 50%, and a BMI of 30 or more
Main inclusion criteria
  • Age ≥ 40 years
  • NYHA class II-IV
  • EF ≥50%
  • BMI ≥30
  • KCCQ-CSS of 80 or lower
Main exclusion criteria
  • Cardiomyopathy
  • Uncontrolled hypertension
  • History of bariatric surgery
  • HgA1C ≥ 9.5%
Baseline characteristics
  • Age - 65.3 years
  • Female sex - 53.8%
  • NYHA class: II - 72.5% | III or IV - 27.5%
  • Average body weight - 227 lbs (103 kg)
  • Average BMI - 38.3
  • Average EF - 60.8%
  • History of CAD - 30%
  • Median NT-proBNP level - 183 pg/ml
  • Average GFR - 64.4 ml/min
  • Average KCCQ-CSS score - 53.6
  • Heart failure exacerbation within 12 months - 46.9%
  • Atrial fibrillation - 25.5%
  • Type 2 diabetes - 48.2%
Randomized treatment groups
  • Group 1 (364 patients): Tirzepatide with a target dose of 15 mg once weekly
  • Group 2 (367 patients): Placebo
  • Tirzepatide was started at 2.5 mg once weekly and increased by 2.5 mg every 4 weeks as tolerated
Primary outcomes: (1) Composite of adjudicated death from cardiovascular causes or a worsening heart-failure event; and (2) the change from baseline to 52 weeks in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating better quality of life).
Results

Duration: median 104 weeks
Outcome Tirzepatide Placebo Comparisons
Primary outcome (1) 9.9% 15.3% HR 0.62, 95% CI 0.41-0.95, p=0.026
Primary outcome (2) 19.5 12.7 p<0.001
Death from cardiovascular causes 2.2% 1.4% HR 1.58, 95% CI 0.52 - 4.83
Worsening heart-failure event 8.0% 14.2% HR 0.54, 95% CI 0.34 - 0.85
Death from any cause 5.2% 4.1% HR 1.25, 95% CI 0.63 - 2.45
% change in body weight -13.9% -2.2% p<0.001
Drug discontinuation due to adverse event 6.3% 1.4% N/A
  • The incidence of serious adverse events was similar between groups; however, the tirzepatide group had a higher incidence of GI side effects

Findings: Treatment with tirzepatide led to a lower risk of a composite of death from cardiovascular causes or worsening heart failure than placebo and improved health status in patients with heart failure with preserved ejection fraction and obesity.


SIDE EFFECTS


  • Reference [1]
Gastrointestinal Side effects
Side effect Placebo
(N=958)		 Tir 5 mg
(N=630)		 Tir 10 mg
(N=948)		 Tir 15 mg
(N=941)
Nausea 8% 25% 29% 28%
Diarrhea 8% 19% 21% 23%
Vomiting 2% 8% 11% 13%
Constipation 5% 17% 14% 11%
Abdominal Pain 5% 9% 9% 10%
Dyspepsia 4% 9% 9% 10%
Injection site reactions 2% 6% 8% 8%
Fatigue 3% 5% 6% 7%
Hypersensitivity reactions 3% 5% 5% 5%
Burping 1% 4% 5% 5%
Hair loss✝ 1% 5% 4% 5%
GERD 2% 4% 4% 5%
Flatulence 2% 3% 3% 4%
Abdominal distension 2% 3% 3% 4%
Dizziness 2% 4% 5% 4%
Hypotension‡ 0% 1% 1% 2%
✝ Hair loss in tirzepatide-treated patients was more common in women than men (7.1% vs 0.5%)
‡ Hypotension in tirzepatide-treated patients was more common in those receiving antihypertensives (2.2% vs 1.2%)












CONTRAINDICATIONS


PRECAUTIONS





DRUG INTERACTIONS



DOSING




LONG-TERM SAFETY


BIBLIOGRAPHY