Surpass 1 JC Lecture

JOURNAL ARTICLE #2
SURPASS-1
Divya Desai, PharmD
Regulatory Pharmaceutical Fellow in Drug Information
Purdue University | Eli Lilly and Company | FDA
October 15, 2021
Review Review background information on diabetes and
weight loss, including current treatment guidelines
Review Review SURPASS-1 trial
OUTLINE
Critique Critique SURPASS-1 trial
Apply Apply the findings of SURPASS-1 to a clinical case

DIABETES OVERVIEW
Type 1: absolute insulin deficiency
• 5-10% of all diabetes mellitus
Type 2: B-cell dysfunction and insulin resistance
• 90-95% of all diabetes mellitus

• Prevalence in US adults: 12.1%
EPIDEMIOLOGY
Trujillo J, Haines S. Diabetes Mellitus. In: Pharmacotherapy: A Physiologic Approach. 11e. DiPiro JT, Yee GC, Posey LM, et al., eds. New York: McGraw Hill; 2020.
Diabetes and Prediabetes. Centers for Disease Control and Prevention. https://www.cdc.gov/chronicdisease/resources/publications/factsheets/diabetes-prediabetes.htm. Published November 3, 2020. Accessed October 11, 2021.
TYPE 2 DIABETES RISK FACTORS
Family history
Obesity ≥45 years old
of diabetes
History of
Sedentary Race/Ethnicity
gestational
lifestyle
diabetes
Diabetes and Prediabetes. Centers for Disease Control and Prevention. https://www.cdc.gov/chronicdisease/resources/publications/factsheets/diabetes-prediabetes.htm. Published November 3, 2020. Accessed October 11, 2021.
PRESENTATION AND DIAGNOSIS
Clinical Presentation of Type 2 DM
• Age > 30 years, overweight/obese, family history of T2DM, insulin

resistance, gradual onset
Diagnosis of Type 2 DM
• A1C > 6.5%

• Fasting plasma glucose > 126 mg/dL
• Two-hour plasma glucose > 200 mg/dL
• Patients with symptoms of hyperglycemia/hyperglycemic crisis:
random plasma glucose concentration > 200mg/dL
Trujillo J, Haines S. Diabetes Mellitus. In: Pharmacotherapy: A Physiologic Approach. 11e. DiPiro JT, Yee GC, Posey LM, et al., eds. New York: McGraw Hill; 2020.
TREATMENT
Pharmacologic Approaches to Glycemic Management: Standards of Medical Care in Diabetes - 2021. Diabetes Care 2021;44(Suppl. 1):S111-S124
DIABETES
TREATMENT
Based on SURPASS-1
where does tirzepatide fit?
Anti-Hyperglycemic Medications. RxNotes. Grepmed. https://www.grepmed.com/images/7850/pharmacotherapy-

endocrinology-treatment-comparison-table. Published April 30 2020. Accessed Oct 11 2020.
Hollander P. Anti-diabetes and anti-obesity medications: Effects on weight in people with diabetes. Diabetes Spectrum. 2007;20(3):159-165. doi:10.2337/diaspect.20.3.159
DIABETES AND OBESITY
OVERVIEW
EPIDEMIOLOGY
Making Healthy Living Easier. CDC Division of Nutrition, Physical Activity, and Obesity. https://www.cdc.gov/nccdphp/dnpao/docs/Obesity-
Fact-Sheet-508.pdf Published February 2021. Accessed Oct 11 2021.
OBESITY
AND
DIABETES
https://pro.aace.com/disease-state-resources/nutrition-and-obesity/slide-library/21-epidemiology
Sleep apnea and
Hypertension Many types of cancer
breathing problems
Dyslipidemia Osteoarthritis Low quality of life

OBESITY-
RELATED
Type 2 diabetes Gallbladder disease
Mental illness such
as clinical
depression, anxiety,
HEALTH
and other mental
disorders
COMPLICATIONS
Body pain and
Coronary heart
Stroke difficulty with
disease
physical functioning
The health effects of overweight and obesity. Centers for Disease Control and Prevention. https://www.cdc.gov/healthyweight/effects/index.html. Published September 17, 2020. Accessed October 12, 2021.
OBESITY CLASSIFICATION
Classification BMI
Underweight < 18.5 kg/m2
Normal weight 18.5 – 24.9 kg/m2
Overweight 25 – 29.9 kg/m2
Obesity (class 1) 30 – 34.9 kg/m2
Obesity (class 2) 35 – 39.9 kg/m2
Extreme obesity > 40 kg/m2
Defining Adult Overweight and Obesity. Centers for Disease Control and Prevention.https://www.cdc.gov/obesity/adult/defining.html. Published June 7 2021. Accessed October 11 2021.
OBESITY TREATMENT
American Diabetes Association. 8. Obesity Management for the Treatment of Type 2 Diabetes: Standards of Medical Care in Diabetes-2021. Diabetes Care. 2021;44(Suppl 1):S100-S110. doi:10.2337/dc21-S008
OBESITY TREATMENT
https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treatment-chronic-weight-management-first-2014
OBESITY
TREATMENT
Based on SURPASS-1
where does tirzepatide fit?
Anti-Hyperglycemic Medications. RxNotes. Grepmed. https://www.grepmed.com/images/7850/pharmacotherapy-

endocrinology-treatment-comparison-table. Published April 30 2020. Accessed Oct 11 2020.
TIRZEPATIDE
https://medcitynews.com/2021/05/eli-lilly-looks-ahead-to-fda-after-diabetes-drug-wraps-up-last-clinical-test/
TIRZEPATIDE
• Multi-functional peptide based on the native
GIP peptide sequence, modified to bind to
both GIP and GLP-1 receptors
• GIP may enhance GLP-1’s effect on

food intake and increase energy
expenditure, resulting in body weight
reduction
• Mean half-life of ~5 days enabling once-

weekly dosing
Bailey CJ. Tirzepatide: a new low for bodyweight and blood glucose. Lancet Diabetes Endocrinol. 2021;9(10):646-648. doi:10.1016/S2213-8587(21)00217-5
EFFICACY AND SAFETY OF A NOVEL
DUAL GIP AND GLP-1 RECEPTOR
AGONIST TIRZEPATIDE IN PATIENTS
WITH TYPE 2 DIABETES
(SURPASS-1): A DOUBLE-BLIND,
RANDOMISED, PHASE 3 TRIAL
Rosenstock J, Wysham C, Frías JP, et al. Efficacy and safety of a

novel dual GIP and GLP-1 receptor agonist tirzepatide in patients
with type 2 diabetes (SURPASS-1): a double-blind, randomised,
phase 3 trial [published correction appears in Lancet. 2021 Jul
17;398:212]. Lancet. 2021;398:143-155.
STUDY OBJECTIVE
STUDY OBJECTIVE
Study Objective
• In adults diagnosed with type 2 diabetes

who have failed lifestyle modification, does
subcutaneous once-weekly tirzepatide 5
mg, 10 mg, or 15 mg induce a significant
reduction in HbA1C from baseline?
Rosenstock J, Wysham C, Frías JP, et al. Lancet. 2021;398:143-155.

METHODS
ULTIMATE QUESTION AND STUDY DESIGN
Study Design
• 40-week, double-blind, randomized,

placebo-controlled, multicenter trial at 52
medical research centers and hospitals in
India, Japan, Mexico, and the USA

INCLUSION AND EXCLUSION CRITERIA
Inclusion Exclusion
• Age > 18 • Type 1 diabetes mellitus
• Type 2 diabetes mellitus • History of chronic or acute pancreatitis
• No diabetic medication use 3 months prior to • History of hyperglycemic crisis
randomization • Diabetic microvascular/macrovascular
• HbA1c 7.0% - 9.5% despite diet and complications
exercise • Diabetic retinopathy
• Stable weight 3 months prior to • History of ASCVD event
randomization • Estimated glomerular filtration rate
• Body Mass Index ≥23 kg/m^2 (eGFR) <30 mL/min per 1.73 m2 of body-
surface area
• History of injectable diabetic medication use
• History of weight loss pharmacotherapy use
• History of chronic glucocorticoid therapy

INTERVENTIONS

INTERVENTIONS
Treatment Arms:
• 1:1:1:1 Randomization
• Tirzepatide 5 mg, 10 mg, 15 mg, and placebo administered sc
once weekly
Rescue Medication Use:
• Metformin was the first choice of therapy unless
contraindicated for participants with persistent severe
hyperglycemia.
• Insulin was the first choice of therapy in severe, persistent
hyperglycemia with an average fasting serum glucose ≥300
mg/dL
General counselling:
• Participants received counselling regarding hypoglycemia,
hyperglycemia, and diet/exercise

EFFICACY ENDPOINTS
Primary
• Mean change from baseline in HbA1c at 40 weeks
Endpoint
HbA1c
• Proportion of patients achieving HbA1c <7.0% at 40 weeks
• Proportion of patients achieving HbA1c <5∙7% at 40 weeks
Secondary Weight Loss
Endpoints • Body weight change from baseline at 40 weeks
Biomarkers
• Fasting serum glucose (FSG) change from baseline at 40
weeks

SAFETY ENDPOINTS
Treatment-emergent adverse events
Study drug discontinuation due to adverse events
Specific adverse events:

• Adjudicated pancreatic adverse events
• Serum calcitonin
• Allergic and hypersensitivity reactions
• Treatment-emergent antidrug antibodies for tirzepatide
Vital sign monitoring

• Mean changes from baseline
• Pulse rate
• Systolic blood pressure
• Diastolic blood pressure
Diabetes-specific monitoring
• Hypoglycemia events of blood glucose less than 70 mg/dL
• Clinically significant concentrations less than 54 mg/dL
• Severe hypoglycemia

STATISTICAL ANALYSIS
• Primary outcome: Mean change from

baseline in HbA1c at 40 weeks
• Minimum clinical difference in
HbA1c calculated to be -0.65%
Is this difference reasonable?
Anti-Hyperglycemic Medications. RxNotes. Grepmed.

https://www.grepmed.com/images/7850/pharmacotherapy-endocrinology-treatment-comparison-
table. Published April 30 2020. Accessed Oct 11 2020.

STATISTICAL ANALYSIS
Treatment analyzed using two methods:
• Efficacy Estimand (“per-protocol”)
• What if all the patients in the study did not discontinue tirzepatide or need rescue
medications?
• Treatment-regimen Estimand (“intention-to-treat”)
• What was the observed efficacy of tirzepatide including those who needed rescue
medications or discontinued the drug?
Traditional “Per Protocol” Efficacy Estimand “Per Protocol”
Adherent Needed Discontinued Per-protocol Adherent Needed Discontinued Data set changed so that all
patient rescue meds drug population patient rescue meds drug patients are adherent
RESULTS
BASELINE
CHARACTERISTICS
• 478 eligible patients (mean baseline
HbA1c 7.94%, age 54.1 years,
48% women, ~50% Hispanic/Latino,
diabetes duration 4.7 years, and BMI
31.9 kg/m²).
• Restricted randomization
• Previous diabetic medication use
• HbA1c (≤8.5% vs. >8.5%)
• Country of study
• Pts included if exposed to at least 1 dose

of study drug.

• No significant differences were seen in study drug
INTERVENTIONS discontinuation due to adverse events across treatment

groups.
• Reasons for study drug discontinuation were adverse
event, death, did not meet randomization criteria, loss to
follow-up, physician decision, protocol deviation, withdrawal
by participant, or other.
• A greater number of study drug discontinuations were
observed with tirzepatide 15 mg, and most discontinuations
in the tirzepatide 15 mg group were for reasons other than
adverse events.
• Study drug discontinuations due to gastrointestinal adverse
events were 2–7% with tirzepatide versus 1% with placebo.

EFFICACY OUTCOMES
What % of patients
achieved diabetic
control?
What % of patients
achieved diabetic
resolution?

SAFETY OUTCOMES • Serious AEs: 4% in tirzepatide 5 mg group, 2% in
tirzepatide 10 mg group, 1% in the tirzepatide 20
mg group, compared with 3% in placebo group
• Most frequent AEs with tirzepatide:

• nausea (12–18% vs 6%)
• diarrhea (12–14% vs 8%),
• vomiting (2–6% vs 2%).
• No adjudicated pancreatitis observed
• Injection site reactions occurred in 11 (2-3%) of

participants, no reports in the placebo group
• Rescue diabetic therapy was required for two

participants who received tirzepatide 5 mg, four
who received tirzepatide 10 mg, and two who
received tirzepatide 10 mg and 15 mg, vs 29 with
placebo.

AUTHOR CONCLUSION
"In conclusion, tirzepatide once a week, a novel dual
GIP and GLP-1 receptor agonist, at doses of 5, 10,
and 15 mg as monotherapy for type 2 diabetes,
showed robust reductions compared with placebo in
glycaemic control with 31–52% of participants
reaching normoglycaemia (HbA1c <5∙7%
[<39 mmol/mol]), and meaningful reductions
in bodyweight, without increased risk of clinically
significant (<54 mg/dL [<3 mmol/L])
or severe hypoglycaemia, and a safety profile
consistent with GLP-1 receptor agonists, indicating a
potential use of tirzepatide as an option for type 2
diabetes treatment."

CRITIQUE
JOURNAL
Began in 1823
• International weekly general medical journal founded in 1823 by Thomas

Wakley
Impact Factor: 79.321
• Ranks second among 169 general and internal medicine journals globally
Review Process
• Rigorous peer review and publication process

About the Lancet. The Lancet website. https://www.thelancet.com/lancet/about. Accessed October 11, 2021.
AUTHORS
Pimary Author: Julio Rosenstock
• Director of theDallas Diabetes Research Center
• Clinical Professor of Medicine at the University of
Texas Southwestern Medical Center, Dallas.
Numerous publications in the diabetes space

• Many publications regarding semaglutide in the
treatment of diabetes and obesity
• Investigator in PIONEER trials (investigated oral
semaglutide for type 2 diabetes)
The primary author is not employed by Eli Lilly and Company, and
is a well-known researcher in type 2 diabetes pharmacotherapy
Our Staff. Dallas Diabetes Research Center.https://dallasdiabetes.com/our-staff. Accessed October 11, 2021.
AUTHORS
Funding/Conflict of Interest
• Trial was sponsored by Eli Lilly and Company
Many authors had financial disclosures with

pharmaceutical companies
• Several received honoraria, grant support, lecture
fees, or advisory board fees from Eli Lilly
• 6/10 authors are direct employees and
shareholders of Eli Lilly
Trial was sponsored by Eli Lilly and Company, who along with the
executive committee designed and oversaw the entire conduct and
analysis of trial which could potentially introduce bias.

METHODS
Study Design
Multicenter, Multinational ↑ generalizability/external validity

Double-blinded Blinding of sponsor, investigators,
and patients reduces bias; ↑ internal
validity
Placebo-controlled Gold standard for RCTs; ↑ internal
validity
Restricted randomization Reduces confounding; ↑ internal
validity

METHODS
Inclusion/Exclusion Criteria
All patients were required to wash out all Reduces effect of potentially confounding
diabetic medication use for at least medications; ↑ internal validity
3 months prior to initiating study
All patients were required to be naïve to Reduces effect of potentially confounding

injectable diabetic medications medications; ↑ internal validity
Inclusion of HbA1c between 7.5% - 9.0% ↓ generalizability/external validity
Excluded diabetic complications such ↓ generalizability/external validity

as diabetic retinopathy and nephropathy
Excluded patients with a history of Appropriate based on known adverse events
pancreatitis associated with GLP-1 agonists

METHODS
Patient Screening/Drop-outs
High rate of exclusion after screening Most likely due to extensive exclusion
(705 assessed --> 478 randomized = ~30% criteria; ↓ generalizability/external validity
of potential patients excluded)
No significant differences in Treatment groups remain balanced; ↑

drug discontinuation due to adverse events internal validity
among treatment groups
Tirzepatide 15 mg had the highest rate of Reasons given for non-adverse event related
discontinuation overall; authors state most discontinuation are limited and
of these discontinuations were not adverse vague; ↓ internal validity
event related

BASELINE CHARACTERISTICS
• 43% patients recorded as

Hispanic/Latino in each group, 25%
patients American Indian or Alaska
Native increases external validity
to this population
• Predominantly North American

population (~32% USA, ~34%
Mexico); included Japanese
(~19%) and Indian populations
(~15%) increases external validity
to this population
• Small representation of Black or

African American (5%) reduces
generalizability/external validity to
this population

• Most (79%) patients had an HbA1c of <8.5% suggesting a group of diabetic patients that required minimal
intervention to achieve control; these patients could be appropriately treated using already available diabetic
standard of care
• All treatment groups had similar percentages of patients with an Hba1c <8.5% and >8.5%
• Average age of 54.1 years is generalizable to T2DM as those > 45 years are at higher risk. Average length of diabetes 4.7
years described in the study would put most at around the expected age
• Mean HbA1c 7.94% at baseline + a mean disease period of 4.7 years suggests a newly diagnosed population.
• Only 46% of all patients had previously tried oral antihyperglycemic therapy. Per ADA guidelines, an HbA1C of >7.5%
requires combination pharmacotherapeutic intervention in newly diagnosed individuals. This may represent a more
underserved population that may not have access to optimized diabetic therapy but is not representative of United States
patient access to medications.
OUTCOMES
• Surrogate endpoint
• Primary endpoint does not
compare to placebo
• Mean change from baseline in HbA1c at 40 • mITT analysis
Primary Endpoint weeks • Efficacy estimand utilized
for paper
• Treatment-Regimen Estimand
HbA1c Surrogate endpoints

• Proportion of patients achieving HbA1c <7.0% at 40
weeks
• Proportion of patients achieving HbA1c <5∙7% at 40
Secondary weeks
Endpoints Weight Loss
• Body weight change from baseline at 40 weeks
Biomarkers
• Fasting serum glucose (FSG) change from baseline
at 40 weeks

STATISTICAL ANALYSIS: ESTIMANDS
• Definitions:
• Estimand: A new way of defining the objective of a
study that is slightly different than the traditional PICO
question by including intercurrent events and controlling
for them
• Intercurrent event: a confounding event that happens
at any time between randomization to the completion of
the study
Traditional “Per Protocol” Efficacy Estimand “Per Protocol”
Adherent Needed Discontinued Per-protocol Adherent Needed Discontinued Data set changed so that all
patient rescue meds drug population patient rescue meds drug patients are adherent
EFFICACY OUTCOMES

SAFETY OUTCOMES
• Most frequent adverse events (nausea,
vomiting, and diarrhea) are what we
would expect based on tirzepatide's
mechanism of action
• No increased incidence of pancreatitis

provides valuable information about
potential safety concerns of a dual-acting
incretin analog
• Very low incidence of hypoglycemic

events is beneficial to the management
of diabetic populations

•Randomized, double-blind trial design↓ confounding variables and bias.
Strengths
•Randomization was stratified to reduce confounding and increase internal validity

•Primary endpoint appropriate as it is well-established surrogate marker to
evaluate efficacy T2DM management.
•Multinational, multicenter design increased external validity
•Used a modified intent-to-treat analysis for treatment regimen estimand, which
provides a conservative estimate of efficacy and ↑ external validity.
•Patients were naïve to injectable hyperglycemic medications, and unless indicated
with a rescue protocol did not receive additional diabetic therapy beyond tirzepatide or
placebo improving internal validity-- Reducing any confounding effects of other
treatments.
•Exclusion criteria for history of pancreatitis were appropriate based on known
adverse events of GLP1 agonists.
•Tirzepatide dosing followed a slow escalation to reduce known ADRs with GLP1
agonists
•Results replicated in part by other trials (additional SURPASS trials being
performed with tirzepatide) improving strength of the conclusion

• Only patients with HbA1c of ≤9% were included in the study, therefore the effect
of tirzepatide in more severe diabetes cannot be assessed
• Data presented in the paper utilizes the efficacy analysis set of data (efficacy estimand),
meaning that the data utilized to draw conclusions in the study does not include patients
who withdrew from the study or utilize rescue medications (per-protocol analysis)
reducing external validity
• Doses of rescue medications were not provided, therefore it is difficult to know if these
patients were optimized on additional therapy
• Patients with a BMI >40 kg/m2 were not identified
• No comparison to GLP-1 agent standard of care
• Half of the patients included in the study never received diabetic pharmacotherapy
before, and were not optimally being treated utilizing current standard of care
Limitations
defined in the ADA guidelines reducing generalizability of the study results
• Small representation of Black or African American (5%) patients reduces
generalizability to this population
• Subjects did not receive additional diabetic therapy beyond tirzepatide or
placebo reducing external validity of study results

STUDY IMPLICATIONS
PRACTICE IMPLICATION
When studied, tirzepatide showed a significant reduction in HbA1c and similar safety profile to GLP-1 agonsts. Tirzepatide also showed
a significant weight reduction compared to placebo; however, tirzepatide has not been compared to subcutaneous high-
dose semaglutide. Tirzepatide may be useful as a monotherapeutic first-line agent in early type-2 diabetes; however, further studies
should examine efficacy compared to the active agents and multi-drug regimens seen in practice. Cost-benefit analysis compared to
GLP-1 agonists could be a significant issue when implementing treatment in clinical practice.
Safety Efficacy Convenience Cost Clinical Practice

•Tirzepatide is marketed as an incretin dual- Efficacy estimand (in Once weekly injections Average monthly cost
acting analog agent that showed a significant
HbA1c reduction with a reduced incidence of
paper): Mean HbA1c may promote better of GLP-1 agonists Guidelines
GI events. When studied, tirzepatide showed decreased from baseline adherence in patients anywhere from $400 - The ADA recommends an
a similar safety profile to GLP-1 agonsts. by 1.87% with tirzepatide 5 who are injection averse $700/month HbA1c target of <7.0%,
•No increased incidence of mg,
Wegovy which can be accomplished
pancreatitis provides valuable information 1.89% with tirzepatide 10
about potential safety concerns of a dual- ~$1,627/month via a number of different
mg, and 2.07%
acting incretin analog diabetic medications, the
with tirzepatide 15 mg (all
Tirzepatide may be first-line agent being
•Very low incidence of hypoglycemic events is p<0∙0001).
beneficial to the management of diabetic just as costly (or more) metformin
populations
FUTURE DIRECTIONS
https://investor.lilly.com/static-files/250f223d-a0f9-431a-8c01-e78676daecf2
QUESTIONS?
CLINICAL CASES
• BD is a 42-year-old black male with T2DM x 12 years
with a history of diabetic retinopathy
• Relevant vitals/labs: A1c: 10% FBG: 130 mg/dL
• Current medications: Metformin 1000mg BID, lisinopril
20 mg QD, metoprolol succinate 25mg QD
You are a pharmacist who works at the clinic and a

physician asks if you would recommend tirzepatide 15 mg
in this patient in order to control his HbA1c. Based on the
SURPASS-1 trial, would you recommend the use of
tirzepatide in BD? If not, what would you recommend?
• JL is a 67-year-old white male with a history of Class 3
obesity (BMI 41 kg/m^2) without diabetes.
JL presents to clinic today for follow-up after trialing diet and
exercise. He has never tried weight loss medications. After
completing your medication reconciliation with the patient
and his wife, the patient’s wife asks if you think JL would be
a good candidate for “the new diabetes medicine that can
help with weight loss”.
What additional studies would need to be conducted to utilize

tirzepatide in JL? Ideally, what would the results of those
studies show?

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JOURNAL ARTICLE #2

Review Review SURPASS-1 trial

Apply Apply the findings of SURPASS-1 to a clinical case

• 5-10% of all diabetes mellitus

Type 2: B-cell dysfunction and insulin resistance

• 90-95% of all diabetes mellitus

• Age > 30 years, overweight/obese, family history of T2DM, insulin

• A1C > 6.5%

Anti-Hyperglycemic Medications. RxNotes. Grepmed. https://www.grepmed.com/images/7850/pharmacotherapy-

Dyslipidemia Osteoarthritis Low quality of life

Anti-Hyperglycemic Medications. RxNotes. Grepmed. https://www.grepmed.com/images/7850/pharmacotherapy-

• GIP may enhance GLP-1’s effect on

• Mean half-life of ~5 days enabling once-

Rosenstock J, Wysham C, Frías JP, et al. Efficacy and safety of a

• In adults diagnosed with type 2 diabetes

Rosenstock J, Wysham C, Frías JP, et al. Lancet. 2021;398:143-155.

• 40-week, double-blind, randomized,

Rosenstock J, Wysham C, Frías JP, et al. Lancet. 2021;398:143-155.

Rosenstock J, Wysham C, Frías JP, et al. Lancet. 2021;398:143-155.

Rosenstock J, Wysham C, Frías JP, et al. Lancet. 2021;398:143-155.

Rosenstock J, Wysham C, Frías JP, et al. Lancet. 2021;398:143-155.

Rosenstock J, Wysham C, Frías JP, et al. Lancet. 2021;398:143-155.

Study drug discontinuation due to adverse events

Specific adverse events:

Vital sign monitoring

Rosenstock J, Wysham C, Frías JP, et al. Lancet. 2021;398:143-155.

• Primary outcome: Mean change from

Is this difference reasonable?

Anti-Hyperglycemic Medications. RxNotes. Grepmed.

Rosenstock J, Wysham C, Frías JP, et al. Lancet. 2021;398:143-155.

Traditional “Per Protocol” Efficacy Estimand “Per Protocol”

• Pts included if exposed to at least 1 dose

Rosenstock J, Wysham C, Frías JP, et al. Lancet. 2021;398:143-155.

INTERVENTIONS discontinuation due to adverse events across treatment

Rosenstock J, Wysham C, Frías JP, et al. Lancet. 2021;398:143-155.

Rosenstock J, Wysham C, Frías JP, et al. Lancet. 2021;398:143-155.

• Most frequent AEs with tirzepatide:

• No adjudicated pancreatitis observed

• Injection site reactions occurred in 11 (2-3%) of

• Rescue diabetic therapy was required for two

Rosenstock J, Wysham C, Frías JP, et al. Lancet. 2021;398:143-155.

Rosenstock J, Wysham C, Frías JP, et al. Lancet. 2021;398:143-155.

• International weekly general medical journal founded in 1823 by Thomas

Impact Factor: 79.321

• Rigorous peer review and publication process

Numerous publications in the diabetes space

Many authors had financial disclosures with

Rosenstock J, Wysham C, Frías JP, et al. Lancet. 2021;398:143-155.

Multicenter, Multinational ↑ generalizability/external validity

Rosenstock J, Wysham C, Frías JP, et al. Lancet. 2021;398:143-155.

All patients were required to be naïve to Reduces effect of potentially confounding

Inclusion of HbA1c between 7.5% - 9.0% ↓ generalizability/external validity

Excluded diabetic complications such ↓ generalizability/external validity

Rosenstock J, Wysham C, Frías JP, et al. Lancet. 2021;398:143-155.

No significant differences in Treatment groups remain balanced; ↑

Rosenstock J, Wysham C, Frías JP, et al. Lancet. 2021;398:143-155.

• 43% patients recorded as

• Predominantly North American

• Small representation of Black or

Rosenstock J, Wysham C, Frías JP, et al. Lancet. 2021;398:143-155.

HbA1c Surrogate endpoints

Rosenstock J, Wysham C, Frías JP, et al. Lancet. 2021;398:143-155.