The Ohio State University College of Pharmacy Journal Club

Megan Kirkpatrick, PharmD Candidate 2022

Background and Overview
Title Frias JP, et al. Tirzepatide versus Semaglutide Once Weekly in patients with Type
2 Diabetes. N Engl J Med. 2021 Aug 5;385(6):503-515. Doi:
10.1056/NEJMoa2107519. Epub 2021 Jun 25.
Funding Source Funding/sponsoring provided by Eli Lilly and Company
 Active comparator drug manufacturer: Novo Nordisk
 Diabetes affects more than 34.2 million (1 in 10) Americans
o 90-95% type 2 diabetes mellitus (T2DM)
Introduction/Background  New cases decreased from 2008-2018 (except in those under 20 yo)
o 15% smokers, 89% overweight, 38% physically inactive
o 50% A1C > 7.0%
 7th leading cause of death for 2017
 $327 billion in total direct and indirect costs in the US in 2017
o Symptoms: frequent urination, thirst, loss of weight, hungry, blurry
vision, fatigue, dry skin, slow healing sores, increased infections
 T2DM causes:
o Insulin is a hormone produced by the pancreas  allows cells to
uptake blood sugar for energy
o Insulin resistance occurs in T2DM  cells do not respond
normally to insulin
o T1DM in comparison does not make enough insulin
 Consequences:
o High blood sugar  damages the body
 Heart disease, vision loss, and kidney disease
 Diagnosis: HbA1C testing

 Initial Pharmacological Treatment inT2DM:

o Metformin is the preferred initial pharmacological agent
o GLP-1 receptor agonist is preferred to insulin when possible
 Objective(s) Determine the efficacy and safety of once-weekly tirzepatide, a dual glucose-
dependent insulinotropic polypeptide and glucagon-like peptide (GLP-1) receptor
agonist, as compared with semaglutide, a selective GLP-1 receptor agonist.
Methods
 Phase III, randomized, open-label trial
o July 30, 2019-February 15, 2021
o Randomized 1:1:1:1 to treatment arms
o 40 week treatment period; 4-week safety follow-up period
 Interventions: (all dosed sc once a week)
o Tirzepatide 5 mg
Study Design
o Tirzepatide 10 mg
o Tirzepatide 15 mg
o Semaglutide 1 mg
 Tirzepatide initiated at 2.5 mg and increased by 2.5 mg
every 4 weeks
 Semaglutide initiated at 0.25 mg and dose was doubled
every 4 weeks
 2526 patients assessed for trial eligibility
o 1879 patients underwent randomization
Study Population  Inclusion Criteria:
o > 18 years of age
o Diagnosed with T2DM
o HbA1c between > 7.0% and < 10.5%
o On stable treatment with unchanged dose of metformin >1500
mg/day for at least 3 months prior to screening
o Stable weight (+/- 5%) for at least 3 months before screening
o BMI > 25 kg/m2 at screening
 Exclusion Criteria:
o T1DM diagnosis
o Hx of chronic or acute pancreatitis, acute or chronic hepatitis, or
any other liver disease
o Proliferative diabetic retinopathy or maculopathy
o eGFR < 45 mL/min/1.73m2
o Heart attack, stroke, or hospitalization for CHF in the past 2
months
o Taking any other diabetes medicines other than metformin
during the last 3 months
 Baseline Characteristics were balanced between all cohorts via PSM
o Mean age: ~56
o Large representation of White and Hispanic participants
 o Mean duration of diabetes: 8.6 years
o Mean glycated hemoglobin level: 8.28%
o Mean body weight: 93.7 kg
 Designed to provide 90% power to show noninferiority of tirzepatide at a dose
of 10 mg or 15 mg for the primary endpoint.
Statistical Analysis  Two estimands:
o Treatment-regimen estimand  regardless of discontinuation
and use of rescue medications
o Efficacy estimand  all patients continuing threatment without
rescue medication
 Both included those that received at least 1 dose
Results
(additional graphics in figures at the bottom of the document)
Primary endpoint:
Results of Study  Mean reductions in glycated hemoglobin level at week 40 (percentage pts):
o Tirzepatide 5 mg: -2.01
o Tirzepatide 10 mg: -2.24
o Tirzepatide 15 mg: -2.30
o Semaglutide 1 mg: -1.86
 All tirzepatide doses superior to semaglutide (P<0.001)
Secondary Endpoints:
 Mean reduction in body weight at week 40:
o Tirzepatide 5 mg: -7.6 kg
o Tirzepatide 10 mg: -9.3 kg
o Tirzepatide 15 mg: -11.2 kg
o Semaglutide 1 mg: -5.7 kg
 All tirzepatide doses superior to semaglutide (P<0.001)
 % participants achieving a HbA1C < 7.0%:
o 82-86% tirzepatide
o 79% semaglutide
 % participants achieving a HbA1C < 6.5%:
o 69-80% tirzepatide
o 64% semaglutide
 % participants achieving a HbA1C < 5.7%:
o 27-46% tirzepatide
o 19% semaglutide
Subgroup analysis:
 Mean reductions in glycated hemoglobin level at week 40 (percentage pts) in
patients with an HbA1C > 8.5%:
o -3.22 tirzepatide 15 mg vs. -2.68 semaglutide
At week 40, TG and LDL levels were lower and HDL levels higher in those
receiving tirzepatide than semaglutide.
Safety:
 Higher number of serious AE in tirzepatide group
o Most frequent: COVID-19
 Most frequent AEs: gastrointestinal
o Nausea: 17-22% tirzepatide vs 18% semaglutide
o Diarrhea: 13-16% tirzepatide vs 12% semaglutide
o Vomiting: 6-10% tirzepatide vs 18% semaglutide
 Hypoglycemia: tirzepatide 5mg, 10mg, 15 mg (0.6%, 0.2%, 1.7%) vs 0.4%
semaglutide
 Injection site reaction: 1.9-4.5% tirzepatide vs 0.2% semaglutide
Authors’ Conclusion Tirzepatide at a dose of 5mg, 10mg, or 15mg was noninferior and superior to
semaglutide at a dose of 1 mg, with respect to a reduction in HbA1C in patients
with T2DM receiving metformin. Tirzepatide was also superior to semaglutide with
respect to reductions in body weight.
Student’s Discussion and Conclusion
 Strengths:
o Large sample size and adherence to protocol
 o Head-to-head active comparator trial
o Reductions in HbA1C and body weight were consistent with
Strengths/Limitations SUSTAIN and STEP-2 trials
o External validity: representative baseline characteristics
 Limitations:
o Treatments were not blinded
o Only 16 weeks at highest dose of tirzepatide
o Non-Hispanic Black adults underrepresented in trial population
o Semaglutide weight loss dose not available at time of trial
 Tirzepatide achieved clinically significant HbA1C and weight reduction in
Conclusion/ patients in comparison with semaglutide
Recommendations for o Advantages:
practice site  Weight reduction did not plateau in any treatment arm at 40
weeks
 Better health outcomes and reductions of cost related
complications surrounding T2DM and obesity/overweight

o Barriers:
 Long-term effects and safety of tirzepatide
 6 months to titrate to 15 mg dose vs. 3 months for semaglutide
 Applicability to patients at practice site:
o Tirzepatide does not have an impact on inpatient admissions
 Place in therapy: outpatient diabetes clinics and bariatrics
References Introduction: Standards of Medical Care in Diabetes—2021
Diabetes Care Jan 2021, 44 (Supplement 1) S1-S2; DOI: 10.2337/dc21-Sint
Type 2 Diabetes Data and Statistics. cdc.gov. Updated August 10, 2021.
Accessed October 6, 2021.
Centers for Disease Control and prevention. National Diabetes Statistics Report,
2020. Atlanta, GA: Centers for Disease Control and Prevention, US Dept of Health
and human Services; 2020.