TIRZE ASUNCION 18AGO22.pptx

TIRZEPATIDE EN DM2
SIMPOSIO CARDIO-RENO-METÁBOLICO
@CristobMorales

@CristobMorales
CONFLICTO DE INTERESES
Ensayos clínicos Novonordisk, Sanofi,
Astra Zeneca, Pzifer, Lilly, Merck, Lexicon,
FPS,Hanmi, Janssen Boehringer, Takeda, Roche,
Theracos, LeeGanz
Advisory board Novonordisk, Lilly, MSD,
Boehringuer, Astra, Sanofi, Abbot
Ponente Sanofi, Novonordisk, Astra Zeneca,
Roche, Lilly, Boehringher, MSD, Ferrer, Janssen,
Abbot

DIABETES OBESIDAD HTA
DISLIPEMIA
TABACO
DIABETES WARS

DIABETES OBESIDAD HTA
DISLIPEMIA
TABACO

Metabolic health: a priority for the post-pandemic era
•The Lancet Diabetes & EndocrinologyPublished:March
04, 2021DOI:https://doi.org/10.1016/S2213-
8587(21)00058-9
Avoiding the Coming Tsunami of Common, Chronic Disease:
What the Lessons of the COVID-19 Pandemic Can Teach Us
Robert M. Califf Originally published6 Apr
2021https://doi.org/10.1161/CIRCULATIONAHA.121.053461Circulati
on.
LO IMPOSIBLE

TIRZEPATIDE (coAgonista GLP1/GIP):
Desarrollo clínico SURPASS en DM2
Cristóbal Morales
INTRO: COAGONISTA GIP/GLP1
RESULTADOS F2
F3: SURPASS
CONCLUSIONES CLINICAS

Stomach
• ↓ Gastric Emptying
Skeletal Muscle
• ↑ Insulin Sensitivity
• ↑ Metabolic Flexibility
• ↓ Ectopic Lipid Accumulation
Subcutaneous White Adipose Tissue
• ↑ Lipid Buffering & Storage Capacity
• ↑ Blood Flow
• ↓ Proinflammatory Immune Cell Infiltration
Liver
• ↓ Hepatic Glucose Production
• ↓ Ectopic Lipid Accumulation
Pancreas
• ↑ Insulin
• ↓ Glucagon
Systemic
• ↓ Hyperglycemia
Systemic
• ↓ Hyperglycemia, Dietary Triglyceride
Pancreas
• ↑ Insulin
• ↑ Glucagon
Central Nervous System
Skeletal
Muscle
Liver
Subcutaneous
White Adipose
Tissue
Pancreas
Stomach
• ↑ Satiety
• ↓ Food Intake
• ↑ Nausea
• ↓ Body Weight
• ↓ Food intake
• ↓ Nausea
• ↓ Body weight
GLP-1 Receptor Agonism GIP Receptor Agonism
GIP Receptor Agonism
GLP-1 Receptor Agonism
Indirect Action
Can next generation incretin therapies combine
GLP-1R and GIPR-mediated actions?
Adapted from: Samms RJ, et al. Trends Endocrinol Metab. 2020;31(6):410-421

GIP = glucose-dependent insulinotropic polypeptide; GLP-1 = glucagon-like peptide-1.
Coskun T, et al. Mol Metab. 2018;18:3-14.
Tirzepatide: Dual GIP/GLP-1 Receptor Agonist
Company Confidential © 2021 Eli Lilly and Company
 Tirzepatide is a multi-functional peptide based
on the native GIP peptide sequence, modified
to bind to both GIP and GLP-1 receptors
 Tirzepatide is a 39 amino acid linear peptide
and includes a C20 fatty diacid moiety
 In vitro, it has higher potency to native GIP
and is less potent to native GLP-1
 Tirzepatide has a mean half-life of ~5 days
(116.7 h), enabling once-weekly dosing

 In vitro, tirzepatide has a potency/affinity for the GIP receptor similar to native GIP
 Potency/affinity for the GLP-1 receptor is slightly weaker compared with native GLP-1
Tirzepatide potency and affinity for
GIP and GLP-1 receptors
Coskun T, et al. Mol Metab 2018;18:3-14
cAMP
activation
(%)
0
20
40
60
80
100
120
-14 -13 -12 -11 -10 -9 -8 -7
log [Treatment] M
GIP
TZP
GIP-R
cAMP
activation
(%)
0
20
40
60
80
100
120
-14 -13 -12 -11 -10 -9 -8 -7
log [Treatment] M
GLP1-R
GLP-1
TZP

2022 Q2 https://investor.lilly.com/webcasts-and-presentations

https://investor.lilly.com/webcasts-and-presentations

SURPASS4
15RAND 7SF
SURPASS5
12RAND 5SF
SURPASS6
11 RANDO 3SF
SURPASS
CVOT
42 RAND +12SF
UPDATE: 1 AGO 22
@CristobMorales
SURMOUNT obesity
APERTURA OCT 22

10 JUNIO 2019
PRIMERA DOSIS
TIRZEPATIDE EN
HUVM
@CristobMorales

SURPASS General Study Design1-5
HbA1c = glycated hemoglobin; QW = once weekly; TZP = tirzepatide.
1. Rosenstock J, et al. Lancet. 2021;398(10295):143-155. 2. Frias JP, et al. N Eng J Med. 2021;385(6):503-515. 3. Ludvik B, et al. Lancet. 2021;398(10300):583-598. 4. Del Prato S, et al. Lancet. 2021;(Accepted). 5. Dahl D, et al. Poster
presented at: ADA 2021. Poster LB-20.
Primary Objective: Superiority and/or noninferiority of TZP 5 mg and/or 10 mg and/or 15 mg vs. placebo or
active comparator in mean change in HbA1c from baseline at 40 or 52 weeks.
TZP 5 mg QW
TZP 10 mg QW
TZP 15 mg QW
Injectable placebo or active comparator QW
Randomization
Safety
follow-up
Screening
Lead-in 5 mg
2.5 mg
2.5 mg 5 mg 7.5 mg 10 mg
2.5 mg 5 mg 7.5 mg 10 mg 12.5 mg 15 mg
Primary endpoint
End of treatment
4 weeks
0 4 8 12 16 20 40, 52, or 104

© 2021 Eli Lilly and Company.
SURPASS Program: Clinical Trials Across the T2D Spectrum
OAM = oral antihyperglycemic medication; SGLT2i = sodium-glucose co-transporter-2 inhibitor; SU = sulfonylurea; TID = three times daily; T2D = type 2 diabetes.
presented at: ADA 2021. Poster LB-20. 6. https://clinicaltrials.gov/ct2/show/NCT04537923 (Accessed August 17, 2021). 7. https://clinicaltrials.gov/ct2/show/NCT04255433 (Accessed August 17, 2021).
SURPASS-1
vs. placebo1
Drug-naïve or
washout from
any OAM
SURPASS-2
vs.semaglutide2
Add-on to metformin
SURPASS-3
vs. insulin degludec3
Add-on to metformin with or
without SGLT-2i
SURPASS-5
vs. placebo5
Both with insulin glargine
with or without metformin
SURPASS-6
vs. insulin lispro6 (TID)
Both with insulin glargine
with or without metformin
(ongoing)
SURPASS-4
vs. insulin glargine4
Add-on to ≥1 and ≤3 OAMs
(metformin, SGLT-2i, or SU)
SURPASS-CVOT7
H2H comparing TZP vs. dulaglutide
>12,000 participants (ongoing)
Monotherapy
2-Drug
Combination
2-3 Drug
Combinations
2-4 Drug
Combinations
Combination
With Insulin

Julio Rosenstock1, Carol Wysham2, Juan P. Frias3,
Shizuka Kaneko4, Clare J. Lee5, Laura Fernández Landó5,
Huzhang Mao5, Xuewei Cui5, Vivian T. Thieu5
Efficacy and Safety of Once Weekly
Tirzepatide, a dual GIP/GLP-1 Receptor
Agonist Versus Placebo as Monotherapy
in People with Type 2 Diabetes
(SURPASS-1)
1Dallas Diabetes Research Center at Medical City, Dallas, TX, USA; 2Rockwood Clinic,
Spokane, WA, USA; 3National Research Institute, Los Angeles, CA, USA; 4Takatsuki Red
Cross Hospital, Osaka, Japan; 5Eli Lilly and Company, Indianapolis, IN, USA
SURPASS-1
TIRZEPATIDE

SURPASS 1
Key Inclusion Criteria
• T2D
• HbA1c ≥7.0% to ≤9.5%
• BMI ≥23 kg/m2 Stable Weight
• Naïve to T2D injectable
therapya
• Have not used any oral
antihyperglycaemic
medication in the 3 months
prior to screening
Study Period I Study Period II Study Period III
Tirzepatide 5 mg QW
Tirzepatide 10 mg QW
Tirzepatide 15 mg QW
Injectable Placebo QW
2.5 mg
2.5 mg 5 mg 7.5 mg 10 mg
2.5 mg 5 mg 7.5 mg 10 mg 12.5 mg 15 mg
5 mg
Safety
Follow-up
40 weeks 4 weeks
1
weeks
2
weeks
Screening
Lead-in
-3 -2 -0 4 8 12 16 20 24 40 44
Randomisation
1:1:1:1
(N=478)
Primary
Endpoint
aExcept for the use of insulin for treatment of gestational diabetes, or short-term use (≤14 days) for acute conditions such as acute illness, hospitalisation, or elective surgery
Randomised, Double-Blind, Placebo-Controlled, Parallel Group Trial

HbA1c
Change from Baseline at 40 Weeks
Data are LSM (SE). Efficacy Estimand: Estimated treatment differences are LSM (95% CI). MMRM analysis, mITT population (efficacy analysis set). Treatment-regimen estimand:
ANCOVA analysis, mITT population (full analysis set).
SURPASS-1

Body Weight
Change from Baseline at 40 Weeks
Data are LSM (SE). Efficacy Estimand: Estimated treatment differences are LSM (95% CI). MMRM analysis, mITT population (efficacy analysis set). Treatment-
regimen estimand: ANCOVA analysis, mITT population (full analysis set).
SURPASS-1

EQ-5D-5L INDEX
EQ-5D-5L Index (UK) Score (Scale <0 to 1)
– Measures overall health status
– Includes 5 dimensions: mobility; self-care; usual activities; pain/discomfort;
anxiety/depression
– Algorithm based on van Hout B et al. (2012)3
Change at 40 weeks
EQ visual analogue scale (EQ VAS) (Scale 0 – 100)
– Measures records the patient’s health-
related quality of life on a vertical visual analogue
scale
EQ VAS
– overall health status EQ visual analogue scale

IW-SP
IW-SP Questionnaire (Score 0 - 100)
– Measures patients’ self-perception relating to their body weight
– Includes 3 items: feel unhappy with appearance due to weight; feel
self-conscious in public due to weight; feel unhappy due to comparing
weight with others
Change at 40 weeks
APPADL Questionnaire (Score 0 - 100)
– Measures self-reported ability to perform tasks of daily living
– Includes difficulty in 7 items: getting up from floor/ground; getting
down to floor/ground; standing; climbing stairs; household
chores/yard work; moderate physical activity; strenuous physical
activity
APPADL
– self-perception relating to their body weight – self-reported ability to perform tasks of daily living

Efficacy and Safety of
Tirzepatide Versus
Semaglutide Once
Weekly as Add-on
Therapy to Metformin in
People with Type 2
Diabetes (SURPASS-2)
Melanie Davies, MD1, Juan P. Frias, MD2, Julio Rosenstock, MD3, Federico Pérez
Manghi, MD4, Laura Fernández Landó, MD5, Brandon K Bergman, PharmD5, Bing Liu,
PhD, MS5, Xuewei Cui, PhD5, Katelyn Brown, PharmD5
1Diabetes Research Centre, Leicester Diabetes Centre – Bloom, University of Leicester,
Leicester, UK; 2National Research Institute, Los Angeles, CA, USA; 3Dallas Diabetes Research
Center at Medical City, Dallas, TX, USA; 4CINME S.A., Buenos Aires, Argentina; 5Eli Lilly and
Company, Indianapolis, IN, USA
SURPASS-2
TIRZEPATIDE

Study Design
Randomised, open-label, active-controlled, parallel group, multicentre, multinational trial
 Type 2 diabetes
 HbA1c ≥7.0% to ≤10.5% at
screening
 BMI ≥25 kg/m2 with stable
weight
 On stable dose of metformin
≥1500 mg/day
Key Exclusion Criteria
 Type 1 diabetes
 History of acute pancreatitis
 eGFR <45 mL/min/1.73 m2
 Use of any antihyperglycemic
treatment other than metformin in the
3 months prior to screening
Participating Countries: US, Argentina, Australia, Brazil, Canada, Israel, Mexico and UK. aStable doses of metformin ≥1500 mg/day for at least 3 months prior to Visit 1 and during
the screening/lead-in period. bAll tirzepatide doses were double-blinded.
SURPASS-2

Incidence of Nausea and Diarrhoea
Nausea Diarrhoea
SURPASS-2

Tirzepatide, a Dual GIP/GLP-1
Receptor Agonist, Compared to
Insulin Degludec in Patients with
Type 2 Diabetes (SURPASS-3)
Bernhard Ludvik1, Francesco Giorgino2, Esteban Jódar3,
Juan P. Frias4, Laura Fernández Landó5, Katelyn
Brown5, Ross Bray5, Ángel Rodríguez5
11st Medical Department and Karl Landsteiner Institute for Obesity and
Metabolic Disorders, Landstrasse Clinic, Vienna Health Association,
Vienna, Austria, 2University of Bari Aldo Moro, Bari, Italy, 3Hospital
Universitario Quirónsalud Madrid, Madrid, Spain, 4National Research
Institute, Los Angeles, CA, USA, 5Eli Lilly and Company, Indianapolis, IN,
USA
SURPASS-3
TIRZEPATIDE

Study Design
■ Type 2 diabetes
■ HbA1c ≥7.0% ≤10.5%)
■ BMI ≥25 kg/m2 with stable
weight
■ Naive to insulin therapy
(except short-term use or
treatment of gestational diabetes)
■ On stable dose of metformin,
with or without SGLT-2i
■ Type 1 diabetes
■ History of pancreatitis
■ eGFR <45 mL/min/1.73 m2
Participating Countries: Argentina, Austria, Greece, Hungary, Italy, Poland, Puerto Rico, Romania, South Korea, Spain, Taiwan, Ukraine, and the USA.
aStable doses of metformin (≥1500 mg/day) ± SGLT-2i for ≥3 months prior to Visit 1 and during the screening/lead-in period.
bThe starting dose of insulin degludec was 10 U/day ideally at bedtime, titrated to a FBG <5.0 mmol/L (<90 mg/dL), following a treat-to-target algorithm.
Abbreviations: BMI = body mass index; eGFR = estimated glomerular filtration rate; FBG = fasting blood glucose; HbA1c = haemoglobin A1c; QD = once daily; QW = once weekly; SGLT-2i = sodium-
glucose cotransporter-2 inhibitor.
Randomisation
SURPASS-3

Data on left panel are LSM (SE); MMRM analysis. Data on right panel are estimated mean; Logistic regression. mITT (efficacy analysis set). Arrows on X-axis in overtime plot indicate when the maintenance dose of tirzepatide 5 mg, 10 mg, and 15 mg was
initiated. Mean insulin degludec dose at Week 52 was 48.8 U/day. Estimated treatment difference (95% CI) of tirzepatide vs. insulin degludec was: i) 5 mg, -6.4* (-7.9, -4.9) mmol/mol (-0.59%* [-0.73, -0.45]); ii) 10 mg, -9.4* (-10.9, -7.9) mmol/mol (-0.86%* [-1.00,
-0.72]); and iii) 15 mg, -11.3* (-12.8, -9.8) mmol/mol (-1.04%* [-1.17, -0.90]). *p<0.001 vs. insulin degludec.
Abbreviations: CFB = change from baseline; CI = confidence interval; HbA1c = haemoglobin A1c; LSM = least-squares mean; mITT = modified Intent-to-Treat; MMRM = mixed model repeated measures; SE = standard error.
HbA1c
Overall mean baseline HbA1c = 8.18%
(-1.93%)
(-2.20%)
- (-2.37%)
(-1.34%)
Tirzepatide 5 mg Tirzepatide 15 mg
Tirzepatide 10 mg Insulin Degludec
% of Participants Achieving
HbA1c Goals at Week 52
HbA1c over Time and Change from Baseline at Week 52
CFB
T
Z
P
5
m
g
T
Z
P
1
0
m
g
T
Z
P
1
5
m
g
I
D
e
g
T
Z
P
5
m
g
T
Z
P
1
0
m
g
T
Z
P
1
5
m
g
I
D
e
g
T
Z
P
5
m
g
T
Z
P
1
0
m
g
T
Z
P
1
5
m
g
I
D
e
g
0
20
40
60
80
100
Proportion
of
Participants
(%)
*
93
61
*
90
*
82
*
71
*
80
*
85
44
*
26
*
39
*
48
5
HbA1c <53 mmol/mol
(<7.0%)
48 mmol/mol
(6.5%)
<39 mmol/mol
(<5.7%)
SURPASS-3

Peso
Overall mean baseline weight = 94.5 kg (BMI = 33.5 kg/m2)
-7.5
-10.7
-12.9
2.3
Data on left panel are LSM (SE); MMRM analysis. Data on right panel are estimated mean; Logistic regression. mITT (efficacy analysis set). Arrows on X-axis in overtime plot indicate when the maintenance dose of tirzepatide 5 mg, 10 mg, and 15 mg was initiated. Estimated treatment difference
(95% CI) of tirzepatide vs. insulin degludec was: i) 5 mg, -9.8 kg* (-10.8, -8.8); ii) 10 mg, -13.0 kg* (-14.0, -11.9); and iii) 15 mg, -15.2 kg* (-16.2, -14.2). *p<0.001 vs. insulin degludec.
Abbreviations: BMI = body mass index; CFB = change from baseline; CI = confidence interval; LSM = least-squares mean; mITT = modified Intent-to-Treat; MMRM = mixed model repeated measures; SE = standard error.
Tirzepatide 10 mg Insulin Degludec
Proportion of Participants with Body
Weight Loss Goals at Week 52
Body Weight over Time and Change from Baseline at Week 52
CFB
T
Z
P
5
m
g
T
Z
P
1
0
m
g
T
Z
P
1
5
m
g
I
D
e
g
T
Z
P
5
m
g
T
Z
P
1
0
m
g
T
Z
P
1
5
m
g
I
D
e
g
T
Z
P
5
m
g
T
Z
P
1
0
m
g
T
Z
P
1
5
m
g
I
D
e
g
0
20
40
60
80
100
Proportion
of
Participants
(%)
*
88
6
*
84
*
66
*
37
*
56
*
69
3
*
13
*
28
*
43
0
5% weight loss 10% weight loss 15% weight loss
SURPASS-3

Time Spent in Target Ranges 71-180 mg/dL
at Baseline and 52 Weeks
* p<0.05, ** p<0.01, *** p<0.001 versus insulin degludec. 3.9-10 mmol/L = 71-180 mg/dL. TZP = tirzepatide.
TZP 5mg TZP 10mg TZP 15mg Insulin degludec
48% 52%
0.3%
Baseline
39% 61%
0.3% 0.3%
50% 50%
85%*
0.6%***
15%
Week
52
91%***
8%***
1%**
91%***
0.8%***
9%***
54%
0.3%
46%
75%
2%
23%
Hypoglycaemic < 3.9 mmol/L Time In Range 3.9-10 mmol/L Hyperglycaemic > 10 mmol/L

Average CGM Values Over 24 Hours at Baseline,
24 Weeks, and 52 Weeks
Values are in mg/dL. avg = average. cv = coefficient of variation. stdev = standard deviation. TZP = tirzepatide.

Liver Fat Content
Data are LSM (SE); ANCOVA analysis. mITT (MRI analysis set). Estimated treatment differences (ETD) are LSM (95% confidence interval) vs. insulin degludec. † p<0.05; ††† p<0.001 vs. baseline within
treatment group. ∝ represents the mean value at baseline for the respective group. Mean insulin degludec dose at Week 52 was 58.8 U/day (0.6 U/kg/day).
Abbreviations: ANCOVA = analysis of covariance; LFC = liver fat content; LSM = least-squares mean; mITT = modified Intent-to-Treat; MRI = magnetic resonance imaging; SE = standard error; TZP = tirzepatide.
Comparison Between Individual
Doses of Tirzepatide and
Insulin Degludec at Week 52
Comparison Between Pooled Data From Tirzepatide 10/15 mg
and Insulin Degludec at Week 52
-10
-8
-6
-4
-2
0
LFC
absolute
change
from
baseline
(%)
Insulin
Degludec
TZP pooled
10/15 mg
-8.09†††
-3.38†††
ETD -4.71 (-6.72, -2.70), p<0.001
15.67% 16.58%
-60
-40
-20
0
LFC
relative
change
from
baseline
(%)
-29.78†††
-47.11†††
-39.59†††
-11.17†
ETD -18.61 (-34.17, -3.04), p=0.019
ETD -28.42 (-43.85, -13.00), p<0.001
ETD -35.94 (-51.62, -20.27), p<0.001
Insulin
Degludec
TZP
5 mg
TZP
10 mg
TZP
15 mg
14.86% 14.78% 16.65% 16.58%

MRI Scan: Male, 59 Years, on Metformin + SGLT-2i
Randomised to Tirzepatide 5 mg
Abbreviations: BMI = body mass index; FSG = fasting serum glucose; HbA1c = haemoglobin A1c; LFC = liver fat content; SGLT-2i = sodium-glucose co-transporter-2 inhibitor; WC = waist circumference.
At Week 52
At Baseline
LFC
(%)
LFC
(%)
27.3
2.6
BMI: 44.8 kg/m2; body weight: 134.2 kg; WC: 139.7 cm
HbA1c: 9.3%
FSG: 186 mg/dL
BMI: 36.2 kg/m2; body weight: 108.4 kg; WC: 124.4 cm
HbA1c: 6.1%
FSG: 107 mg/dL

SURPASS-4
Tirzepatide Once Weekly
Versus Insulin Glargine
in Patients with Type 2
Diabetes and Increased
Cardiovascular Risk
SURPASS-4
TIRZEPATIDE

♦ T2D
♦ HbA1c ≥7.5% to ≤10.5%
♦ BMI ≥25 kg/m2
♦ Increased CV risk
♦ Use of 1-3 OAMs:
• metformin
• SGLT-2i
• sulfonylurea
♦ T1D
♦ History of pancreatitis
♦ Prior insulin use
Study Design
c The starting dose of insulin glargine will be 10 IU/day at bedtime, titrated to a FBG <5.6 mmol/L (100 mg/dL), following a treat-to-target algorithm (Riddle et al. 2003).
Study End Criteria
♦ ≥ 52 weeks for all
♦ ≥78 weeks for ≥300 on tirzepatide
♦ ~110 having MACE-4
SURPASS-4

HbA1c and FSG Change Over Time
mITT population (efficacy analysis set). Data are LSM (SE) over time, MMRM analysis up to 104 weeks. Arrows indicate time of primary endpoint. Dashed lines show baseline
values and dotted lines target values.
Tirzepatide 5 mg
Tirzepatide 10 mg
Tirzepatide 15 mg
Insulin Glargine
SURPASS-4

Body Weight Over Time
mITT population (efficacy analysis set). Data are LSM (SE) over time, MMRM analysis up to 104 weeks. Arrow indicates time of primary endpoint. Dashed line shows baseline value.
Tirzepatide 5 mg
Tirzepatide 10 mg
Tirzepatide 15 mg
Insulin Glargine
SURPASS-4

Lipid Profile at 52 Weeks and Over Time
mITT population (efficacy analysis set). Data are LSM (SE) at 52 weeks and up to 104 weeks from MMRM
analysis using log transformation. *p<0.001 vs. insulin glargine. Arrows indicate time of primary endpoint.
Tirzepatide 5 mg
Tirzepatide 10 mg
Tirzepatide 15 mg
Insulin Glargine

Blood Pressure Over Time
mITT population (safety analysis set). Data are LSM (SE) from MMRM analysis. Arrows indicate time of primary endpoint. Dashed lines show baseline values.
Systolic Blood Pressure Diastolic Blood Pressure
Tirzepatide 5 mg
Tirzepatide 10 mg
Tirzepatide 15 mg
Insulin Glargine

Tirzepatide, a Dual GIP/GLP-1
Receptor Agonist, is Effective
and Safe When Added to Basal
Insulin for Treatment of Type 2
Diabetes (SURPASS-5)
Dominik Dahl1, Yukiko Onishi2, Paul Norwood3, Ruth
Huh,4 Hiren Patel,4 Angel Rodriguez4
1Gemeinschaftspraxis für Inner Medizin und
Diabetologie, Hamburg, Germany, 2The Institute of
Medical Science, Asahi Life Foundation, Tokyo, Japan,
3Endocrine and Research, Fresno, USA, 4Eli Lilly and
Company, Indianapolis, USA
SURPASS-5
TIRZEPATIDE

Study Design
Participating Countries:Czech Republic, Germany, Japan, Poland, Puerto Rico, Slovakia, Spain, and the United States.
aRestricted insulin dose adjustments
Abbreviations: BMI = body mass index; eGFR = estimated glomerular filtration rate; HbA = haemoglobin A ; QW = once-weekly.
■ Type 2 diabetes
■ HbA1c ≥7.0% to ≤10.5% at screening
■ BMI ≥23 kg/m2 with stable weight
■ On stable dose of once-daily insulin
glargine (>0.25 U/kg/day or >20 U/day)
with or without metformin 3 months prior
to screening
■ Require further insulin glargine dose
increase at randomization
■ Type 1 diabetes
■ History of pancreatitis
■ eGFR <30 mL/min/1.73 m2
(<45 mL/min/1.73 m2 if on metformin)
Randomised, double-blind, placebo-controlled, parallel group, multicenter, multinational trial
SURPASS-5

HbA1c
Tirzepatide 10 mg Placebo
Data on left panel are LSM (SE); MMRM analysis. Data on right panel are estimated proportion; Logistic regression. mITT (efficacy analysis set). Arrows on X-axis in overtime plot indicate
when maintenance doses of tirzepatide 5 mg, 10 mg, and 15 mg were achieved. **p<0.001 vs placebo. Estimated treatment difference in mean change from baseline in HbA1c (95% CI) of
tirzepatide vs. placebo was (i) tirzepatide 5 mg: -14.2** (-16.6, -11.7), (ii) tirzepatide 10 mg: -18.1** (-20.6, -15.7); and (iii) tirzepatide 15 mg: -18.1** (-20.5, -15.6).
Abbreviations: CFB = change from baseline; CI = confidence interval; HbA1c = glycated haemoglobin A1c; LSM = least squares mean; mITT = modified Intent-to-Treat; MMRM = mixed model
repeated measures; SE = standard error.
HbA1c Overtime and Change from
Baseline at Week 40
% Participants Achieving HbA1c
Goals at Week 40
0
20
40
60
80
100
Proportion
of
participants
(%)
HbA1c <53 mmol/mol
(<7.0%)
HbA1c ≤48 mmol/mol
(≤6.5%)
HbA1c <39 mmol/mol
(<5.7%)
**
93
**
97
**
94
34
**
80
**
95
**
92
17
**
26
**
48
**
62
3
SURPASS-5

Body Weight
Body Weight Overtime and Change from Baseline at Week 40
Data on left panel are LSM (SE); MMRM analysis. Data on right panel are estimated proportion; Logistic regression. mITT (efficacy analysis set). Arrows on X-axis in overtime plot indicate when maintenance doses of tirzepatide 5 mg, 10 mg, and 15 mg were
achieved. *p<0.05, **p<0.001 vs placebo at Week 40. Estimated treatment difference (95% CI) of tirzepatide vs. placebo for mean change from baseline in weight at Week 40 was (i) tirzepatide 5 mg: -7.8** (-9.4, -6.3), (ii) tirzepatide 10 mg: -9.9** (-11.5, -8.3); and
(iii) tirzepatide 15 mg: -12.6** (-14.2, -11.0).
Abbreviations: CFB = change from baseline; CI = confidence interval; LSM = least squares mean; mITT = modified Intent-to-Treat; MMRM = mixed model repeated measures; SE = standard error.
SURPASS-5

Insulin Glargine Dose
Data are estimated means (SE). MMRM analysis using log-transformed data, mITT efficacy analysis set. Arrows on X-axis in overtime plot indicate when maintenance doses of tirzepatide 5 mg, 10 mg, and 15 mg were achieved. **p<0.001 vs placebo at Week 40. For left panel, estimated placebo-
adjusted percent change (95% CI) vs. placebo was: (i) tirzepatide 5 mg: -35.4** (-46.0, -22.8), (ii) tirzepatide 10 mg: -38.2** (-48.3, -26.1); and (iii) tirzepatide 15 mg: -49.3** (-57.7, -39.4).
Abbreviations: CI = confidence interval; ETD = estimated treatment difference; mITT = modified Intent-to-Treat; MMRM = mixed model repeated measures; SE = standard error.
Change from baseline
(in IU/kg/day)
0.08 0.07 0.00 0.26
Percent Change from Baseline Overtime
Change from Baseline at Week 40
SURPASS-5

GPGN-SURPASS CVOT
42+12
I8F-MC-GPGN -The Effect of Tirzepatide versus
Dulaglutide on Major Adverse Cardiovascular Events
in Patients with Type 2 Diabetes (SURPASS-CVOT)
@CristobMorales

SURPASS CVOT: Versus dulaglutide 1.5 mg
A study to compare the effect of tirzepatide (maximum tolerated dose) vs dulaglutide 1.5 mg on major
cardiovascular events in participants with T2D with established CVD
SURPASS-CVOT. Available at: https://clinicaltrials.gov/ct2/show/NCT04255433. Accessed May 2020
0 4 8 12 16 20 24 28 32 36 40 44
Week -2 -1
Screening
Randomization
(Estimated enrolment: N=12,500)
(≥1615 events)
DU 1.5 mg QW
Up to TZP 15 mg QW
2.5
mg
5
mg
7.5
mg
10
mg
12.5
mg
15
mg
Dose Escalation Period Maintenance Period

A Randomized, Phase 3, Open-label Trial Comparing the Effect of the Addition of
Tirzepatide Once Weekly versus Insulin Lispro (U100) Three Times Daily in
Participants with Type 2 Diabetes Inadequately Controlled on Insulin Glargine
(U100) with or without Metformin (SURPASS-6)Protocol Number:I8F-MC-GPHD
GPHD-SURPASS 6 VS LISPRO
CUALQUIER INSULINA BASAL ESTABLES 3M
(>30UI y >0,3 UI/KG/DÍA)
CON O SIN ADOS: MET /SU /DPP4 (NO SGLT2)
A1C 7,5-11%
IMC ≥ 23 Kg/m2
NO RETINOPATÍA NO PROLIFERATIVA QUE REQUIERA TRATAMIENTO, NO
RP PROLIFERATIVA O EDEMA MACULAR
@CristobMorales

-1.87*
-2.09*
-1.93*
-2.24* -2.23*
-1.89*
-2.37*
-2.20*
-2.43*
-2.59*
-2.07*
-2.46*
-2.37*
-2.58* -2.59*
0.04
-1.86
-1.34 -1.44
-0.93
-3
-2
-1
0
HbA1c
change
from
baseline
(%) HbA1c
Change From Baseline to Primary Endpoint. Efficacy Estimand
*P<.001 vs. placebo or active comparator.
Data are LSM (SE). mITT population (efficacy analysis set). MMRM analysis. Data labels are % HbA1c.
HbA1c = glycated hemoglobin; LSM = least squares mean; MET = metformin; mITT = modified intent-to-treat; MMRM = mixed model repeated measures; SEMA = semaglutide; SGLT2i = sodium-glucose co-transporter-2 inhibitor;
SU = sulfonylurea; TZP = tirzepatide.
TZP 5 mg
TZP 10 mg
TZP 15 mg
Active comparator
Placebo
Study SURPASS-11 SURPASS-22 SURPASS-33 SURPASS-44 SURPASS-55
Duration 40 Weeks 40 Weeks 52 Weeks 52 Weeks 40 Weeks
Baseline HbA1c 7.9% 8.3% 8.2% 8.5% 8.3%
N 478 1878 1437 1995 475
Superiority vs. Placebo SEMA 1 mg Insulin degludec Insulin glargine Placebo
Background therapy
Monotherapy Add-on to MET
Add-on to MET
or MET + SGLT2i
Add-on to MET,
SGLT2i, or SU
Add-on to insulin glargine ±
MET

Proportion of Patients Achieving HbA1c <7.0%
Efficacy Estimand
*
P<.001, †P<.05 vs. placebo or active comparator.
*P<.001, †P<.05 vs. placebo or active comparator.
Data are estimated mean; mITT population (efficacy analysis set). Logistic regression.
HbA1c = glycated hemoglobin; MET = metformin; mITT = modified intent-to-treat; SEMA = semaglutide; SGLT2i = sodium-glucose co-transporter-2 inhibitor; SU = sulfonylurea; TZP = tirzepatide.
87* 85†
82* 81*
93*
92*
89* 90* 88*
97*
88*
92* 93* 91*
94*
20
81
61
51
34
0
20
40
60
80
100
Patients
achieving
HbA1c
target
<7.0%
(53
mmol/mol)
TZP 5 mg
TZP 10 mg
TZP 15 mg
Active comparator
Placebo
Background
therapy
Add-on to MET
or MET + SGLT2i
Add-on to MET,
SGLT2i, or SU
Add-on to insulin
glargine ± MET
HbA1c <7.0%

Proportion of Patients Achieving HbA1c <5.7%
Efficacy Estimand
Data are estimated mean; mITT population (efficacy analysis set). Logistic regression.
HbA1c = glycated hemoglobin; MET = metformin; mITT = modified intent-to-treat; SEMA = semaglutide; SGLT2i = sodium-glucose co-transporter-2 inhibitor; SU = sulphonylurea; TZP = tirzepatide.
34*
29*
26*
23*
26*
31*
45*
39*
33*
48*
52* 51*
48*
43*
62*
1
20
5 3 3
0
20
40
60
80
100
Patients
achieving
HbA1c
target
<5.7%
(39
mmol/mol)
TZP 5 mg
TZP 10 mg
TZP 15 mg
Active comparator
Placebo
Background therapy
Add-on to MET
or MET + SGLT2i
Add-on to MET,
SGLT2i, or SU
Add-on to insulin
glargine ± MET
HbA1c <5.7%

Body Weight Change From Baseline to Primary Endpoint
Efficacy Estimand
Data are LSM (SE); mITT population (efficacy analysis set). MMRM analysis.
LSM = least squares mean; MET = metformin; mITT = modified intent-to-treat; MMRM = mixed model repeated measures; SEMA = semaglutide; SGLT2i = sodium-glucose co-transporter-2 inhibitor; SU = sulfonylurea; TZP = tirzepatide.
-7.0*
-7.8* -7.5*
-7.1*
-6.2*
-7.8*
-10.3*
-10.7*
-9.5*
-8.2*
-9.5*
-12.4* -12.9*
-11.7*
-10.9*
-0.7
-6.2
2.3
1.9
1.7
-15
-12
-9
-6
-3
0
3
Weight
change
from
baseline
(kg)
(-7.9%)
(-9.3%)
(-11.0%)
(-0.9%)
(-8.5%)
(-11.0%)
(-13.1%)
(-6.7%)
(-8.1%)
(-11.4%)
(-13.9%)
(2.7%)
(-6.6%)
(-8.9%)
(-11.6%)
(1.7%)
(-8.1%)
(-10.7%)
(-13.0%)
(2.2%)
TREATMENT
TZP 5 mg
TZP 10 mg
TZP 15 mg
Active comparator
Placebo
Baseline
Weight (kg)
85.9 93.7 94.3 90.3 95.3
Background
therapy
Add-on to MET
or MET + SGLT2i
Add-on to MET,
SGLT2i, or SU
Add-on to insulin glargine
± MET

Proportion of Patients Achieving Targeted Weight Loss
(SURPASS-2)
Efficacy Estimand
Company Confidential © 2021 Eli Lilly and Company
Note: mITT population (efficacy analysis set). Proportion of participants achieving weight loss ≤5%, ≤10% and ≤15% was obtained by dividing the number of participants reaching respective goals at Week 40 by the number of participants
with baseline value and at least one non-missing postbaseline value. Missing value at Week 40 was predicted from MMRM analysis.
mITT=Modified Intent-to-Treat; MMRM=Mixed Model Repeated Measures; SEMA = semaglutide.
Frias JP, et al. N Eng J Med. 2021;385(6):503-515.
T
Z
P
5
m
g
T
Z
P
1
0
m
g
T
Z
P
1
5
m
g
S
E
M
A
1
m
g
T
Z
P
5
m
g
T
Z
P
1
0
m
g
T
Z
P
1
5
m
g
S
E
M
A
1
m
g
T
Z
P
5
m
g
T
Z
P
1
0
m
g
T
Z
P
1
5
m
g
S
E
M
A
1
m
g
0
20
40
60
80
100
Participants
acheiving
body
weight
loss
target
(%) 86
58
82
69
36
53
65
25
15
28
40
9
5% weight loss 10% weight loss 15% weight loss
TZP 5 mg
TZP 10 mg
TZP 15 mg
SEMA 1 mg

2001: Odisea del Espacio, de Stanley Kubrick
¿ESTAMOS
EN UN
CAMBIO DE
ERA EN LA
DIABETES?
@CristobMorales

¿Es posible
alcanzar perdidas
de peso?
>10%?
>15%?
¿Es posible
reducir la HbA1c
< 6,5%?
< 5,7%?
@CristobMorales

TWIN-CRETINAS
COAGONISTAS
(GIP-GLP1)
LOS GEMELOS
GOLPEAN 2
VECES

@CristobMorales
MUCHAS
GRACIAS

MUCHAS
GRACIAS
@CristobMorales

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