Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes

Cathy Eichler, Parkview Health Resident

October 5, 2022
OVERVIEW
Citation  Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus semaglutide once weekly in patients with type 2
diabetes. N Engl J Med. 2021;385:503-15. DOI: 10.1056/NEJMoa2107519
Location  128 sites in the US, Argentina, Australia, Brazil, Canada, Israel, Mexico, and the United Kingdom
Funding  Funded by Eli Lilly
INTRODUCTION
Background  The GLP-1 receptor agonist drug class has become a mainstay in the management of type 2 diabetes
(T2DM). The American Diabetes Association recommends GLP-1 receptor agonists as a first-line treatment
option for T2DM.1 Tirzepatide is a single molecule that has activity as a GLP-1 receptor agonist and as
glucose-dependent insulinotropic polypeptide (GIP) agonist. The GIP modality stimulates the release of
insulin and lowers glucagon levels in a hyperglycemic state while increasing glucagon levels in a
euglycemic or hypoglycemic state. It may also decrease the amount of triglycerides deposited in non-
adipose cells by increasing the capacity of white adipose tissue to remove lipids from the bloodstream,
and it may act centrally to further the reduced food intake induced by GLP-1. Tirzepatide was FDA
approved as Mounjaro in May 2022.2
Previous Trials  Phase 2 trial3: efficacy and safety of LY3298176 (tirzepatide) at 1mg, 5mg, 10mg, and 15mg in patients
with T2DM compared to dulaglutide 1.5mg and placebo
 Estimated treatment difference of reduction in A1C
 LY3298176 compared to placebo: 1mg -1.00%, 5mg -1.67%, 10mg -1.83%, and 15mg -1.89%
 LY3298176 compared to dulaglutide: 1mg 0.15%, 5mg -0.52%, 10mg -0.67%, and 15mg -0.73%
 SURPASS-14: phase-3 trial comparing tirzepatide 5mg, 10mg, and 15mg to placebo in patients naïve to
injectable T2DM therapy
 Change in A1C from baseline after 40 weeks: 5mg -1.87%, 10mg -1.89%, 15mg -2.07%; placebo +0.04%
 Estimated treatment differences: 5mg -1.91% (p<0.0001), 10mg -1.93% (p<0.0001), 15 mg -2.11%
(p<0.0001)
Potential Impact  Could establish tirzepatide in clinical practice as non-inferior to semaglutide which is already established
in clinical practice as a first-line treatment option for T2DM.
Objectives  To compare the efficacy and safety of multiple tirzepatide doses to the maximum (at the time) dose of
semaglutide in patients with T2DM who are inadequately controlled on metformin monotherapy.
METHODS
Study Design  40-week, multi-centered, international, open-label, parallel-group, active-controlled, phase III trial
 Randomized to a 1:1:1:1 ratio of once-weekly subcutaneous injection of tirzepatide 5mg, 10mg, 15mg
and semaglutide 1mg
 Stratified according to country and baseline glycated hemoglobin (A1C) level
Inclusion Criteria  18 years or older  A1C of 7.0-10.5%
 T2DM inadequately controlled with metformin of at  Body mass index (BMI) of at least 25
least 1500mg daily  Stable weight in three months prior to screening
Exclusion Criteria  Type 1 diabetes  History of non-proliferative diabetic retinopathy
 Estimated glomerular filtration rate (eGFR) less than needing urgent treatment, proliferative diabetic
45 ml/min/1.73m2 retinopathy, or diabetic maculopathy
 History of pancreatitis
Interventions  Randomized to receive 5mg tirzepatide weekly, 10mg tirzepatide weekly, 15mg tirzepatide weekly, or 1mg
semaglutide weekly
 Tirzepatide therapy was started at 2.5mg weekly on Week 0 and was titrated by 2.5mg every 4 weeks until
the randomized dose was reached
 Semaglutide therapy was started at 0.25mg weekly on Week 0 and dose was doubled every 4 weeks until
1mg was reached
 Not double-blinded due to differences in administration devices and dose escalation processes
 Dose de-escalation was not allowed
 New antihyperglycemics could be initiated if allowed by specified criteria
Primary Endpoint  Change in A1C level from baseline to week 40
Secondary  Change in body weight from baseline to week 40
Endpoints  Attainment of A1C targets of less and 7.0% and less than 5.7%
 Attainment of A1C of 6.5% or less
  Weight loss of at least 5%, 10%, or 15%
 Mean change from baseline in the fasting serum glucose level and in the daily, patient-measured, mean
seven-point blood glucose profiles
 Composite endpoint of A1C of 6.5% or less with at least 10% weight loss and without clinically significant
hypoglycemia or severe hypoglycemia events
Safety Endpoints  Adverse events
 Discontinuation of tirzepatide or semaglutide because of adverse events
 Pancreatic adverse events
 Serum calcitonin level
 Incidence of hypersensitivity reaction
 Mean changes from baseline in the heart rate and blood pressure
 Occurrence of hypoglycemia events
 Incidence of rescue antihyperglycemic therapy initiation
Statistical Analyses  Sample size of 1872 to meet 90% power, calculated to show noninferiority of tirzepatide at a dose of
10mg or 15mg as compared with semaglutide at a dose of 1mg with respect to change of A1C from
baseline after 40 weeks
 Margin of 0.3%, standard deviation of 1.1%, two-sided alpha of 0.025
 Two “estimands”
 Treatment regimen estimand: included all patients who underwent randomization
 Efficacy estimand: included patients who continued on therapy without rescue medication
RESULTS
Enrollment  2526 assessed for eligibility, 1879 randomized, 1878 received at least one dose of randomized medication
Baseline  Average age 56.6 years old, 53% female
Characteristics  Baseline A1C 8.28%, baseline fasting blood glucose 172.9 mg/dL, duration of diabetes 8.6 years
 Baseline BMI 34.2, baseline weight 93.7 kg
 100% use of metformin
Primary Endpoint  Tirzepatide 5mg -2.01%, 10mg -2.24%, 15mg -2.30%; semaglutide 1mg 1.86%
(Change in A1C  Estimated treatment differences:
from baseline to  5mg -0.15% (95% CI -0.28 to -0.03, p=0.02)
 10mg -0.39% (95% CI -0.51 to -0.26, p<0.001)
week 40)
 15 mg -0.45% (95% CI -0.57 to -0.32, p<0.001)
Secondary  Reduction in body weight from baseline:
Endpoints  Tirzepatide 5mg -7.6kg, 10mg -9.3kg, 15mg -11.2kg; semaglutide 1mg -5.7kg
 Estimated treatment differences:
 5mg -1.9 kg (95% CI -2.8 to -1.0)
 10mg -3.6 kg (95% CI -4.5 to -2.7)
 15 mg -5.5 kg (95% CI -6.4 to -4.6)
 Weight loss attainment:
 ≥5%: tirzepatide 5mg 65%, 10mg 76%, 15mg 80%; semaglutide 1mg 54%
 ≥10%: tirzepatide 5mg 34%, 10mg 47%, 15mg 57%; semaglutide 1mg 24%
 ≥15%: tirzepatide 5mg 15%, 10mg 24%, 15mg 36%; semaglutide 1mg 8%
 A1C attainment: 82-86% tirzepatide, 79% semaglutide attained <7.0%; 69-80% tirepatide, 64%
semaglutide, attained <6.5%; 27-46% tirzepatide, 19% semaglutide, attained < 5.7%
 Tirzepatide showed a greater reduction in fasting blood glucose compared to semaglutide
 Efficacy estimand: composite end point met by 32-60% tirzepatide and 22% semaglutide
Safety Endpoints  Change in triglycerides from baseline: tirzepatide 5mg -19%, 10mg -24.1%, 15mg -24.8%; semaglutide 1mg
-11.6%
 Most frequent adverse effects were GI-related events
 Nausea: 17-20% in tirzepatide and 18% in semaglutide
 Diarrhea: 13-16% in tirzepatide and 12% in semaglutide
 Vomiting: 6-10% in tirzepatide and 8% in semaglutide
 Decreased appetite: 7-9% in tirzepatide and 5% in semaglutide
AUTHORS’ CONCLUSIONS
  Tirzepatide at 5mg, 10mg, and 15mg were noninferior and superior to semaglutide 1mg with regards to reduction in A1C
from baseline to 40 weeks
 The three doses of tirzepatide were also superior to semaglutide 1mg with regards to reduction in body weight from
baseline to 40 weeks
 No plateau in body weight reduction in any of the 4 treatment groups over the 40 weeks of the trial
 Treatments could not be blinded due to differences in administration devices and dose-titration
 Relatively short duration of 40 weeks which only allowed for 16 weeks at steady state for the highest dose of tirzepatide
GENERALIZABILITY/CRITIQUE/DISCUSSION
Journal/Authors  New England Journal of Medicine is a highly respected peer-reviewed journal with an impact factor of
176.079.5
 Some authors and investigators were employed by Eli Lilly, the details were disclosed in the methods
section
 Eli Lilly funded the study
Patient Population  Inclusion of metformin therapy (one of possible first-line treatments)
 Exclusion of those with history of pancreatitis due to risk of pancreatitis shown in previous GLP-1 agonists
Design/Intervention  Semaglutide dose used in intervention was the maximum dose at the time – is now approved up to 2mg,
tirzepatide 5mg showed a greater A1C reduction than semaglutide 1mg, so it is likely higher doses of
tirzepatide would still show greater A1C reduction, but specifics cannot be proven at this time
 Only certain doses of tirzepatide were included in study, but those included cover the lowest therapeutic
dose, the maximum dose, and a dose in the middle
 Including dose escalation in the treatment duration increases external validity, but does not allow direct
comparison of doses in terms of duration
 Initiation of new antihyperglycemic medications allowed only under certain circumstances decreases the
risk of confounding variables while continuing ethical, realistic treatment
Statistics  Met power requirement of 1872 subjects with 1879 patient undergoing randomization and 1878 patients
receiving at least one dose of randomized medication
 Noninferior margin of 0.3% matches the FDA guidance for a non-inferiority margin in HbA1C reduction 6
 Including treatment-regimen (intention-to-treat) and efficacy (per-protocol) estimands allows for external
validity in superiority comparison with intention-to-treat, but decreases the risk of falsely showing non-
inferiority by including per-protocol population as well
Endpoints/Results  Average baseline A1C of 8.28% - in clinical practice, oftentimes the patients referred to pharmacists have
A1Cs higher than this
 Average age of 56.6 years old – T2DM is most often diagnosed after 45 years of age, so this baseline is
reasonable
 Average baseline BMI of 34.2 is reasonable due to BMI>25 is a risk factor for T2DM, however clinically,
patients with uncontrolled diabetes oftentimes have a BMI higher than 34.2
 More patients on tirzepatide 5mg achieved the recommended 5% weight loss 5 than did on semaglutide
1mg
OVERALL STUDY EVALUATION
Strengths  Includes an active comparator that is a highly utilized GLP-1 agonist allowing for potential to establish
tirzepatide in therapy algorithm
 Inclusion factor of patient uncontrolled on metformin therapy increases generalizability
 Lowest therapeutic dose of tirzepatide showed superiority over the second highest dose of semaglutide in
multiple endpoints including reduction in A1C and body weight from baselines.
 The majority of patients on tirzepatide, even the 5mg, achieved at least 5% weight loss which is the ADA
recommended weight loss in T2DM.1
Limitations  Employees of the sponsor were involved in trial design and statistical analysis
 Maximum dose of semaglutide increased since this study, so dose used in this study is not the current
maximum dose
 Limited duration of treatment at randomized dose due to dose escalation process
 Lack of double-blinded intervention decreases internal validity
 Due to exclusion factors, tirzepatide should be avoided in patients with diabetic retinopathy and/or
pancreatitis
Clinical Impact  This clinical trial was included in the new drug application for tirzepatide (Mounjaro) 7. The range of
tirzepatide doses showing inferiority and potential superiority in multiple efficacy endpoints and similar
results in safety endpoints when compared to semaglutide 1mg indicates that tirzepatide could be
considered an alternative therapy to established GLP-1 agonists.
LEADER’S CONCLUSION
This study indicates that in patients with T2DM that are uncontrolled on metformin therapy, tirzepatide is noninferior and superior
to semaglutide in efficacy of lowering A1C and reducing weight and has a similar side effect profile to semaglutide. Based on the
data, there is potential that tirzepatide, as a dual GIP-GLP1 receptor agonist, could be clinically superior and could become a
preferred treatment over the existing GLP-1 agonists. However, more research needs to be done to prove this. Since this study was
published, data from other trials have been published. In terms of A1C lowering, SURPASS-3 trial showed superiority of tirzepatide
in patients taking metformin with/without SGLT-2 inhibitor compared to insulin degludec. 8 SURPASS-4 compared tirzepatide to
insulin glargine in patients at increased cardiovascular risk taking metformin with/without sulfonylurea or SGLT2 inhibitor, in which
tirzepatide showed superiority at lowering A1C, but not in decreasing major adverse cardiovascular events. 8 Two studies currently
underway are first the SURPASS-6 study, comparing tirzepatide to insulin lispro in patients taking insulin glargine with/without
metformin, and SURPASS-CVOT which is comparing tirzepatide to dulaglutide in patients with confirmed atherosclerotic
cardiovascular disease and overweight. 8 These trials will provide more information on the efficacy of tirzepatide in different patient
populations in addition to any possible cardiovascular benefits.
REFERENCES
Eichler, C. (2022). Tirzepatide versus Semaglutide 1. American Diabetes Association. Standards of Medical Care in Diabetes – 2022. Diabetes
Once Weekly in Patients with Type 2 Diabetes Care. December 2021;45(1), S1-S264. doi:https://doi.org/10.2337/dc22-in01
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novel-dual-targeted-treatment-type-2-diabetes.
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surmount-trials/18478154.