I need a power point about about a new medication study.
Tirzepatide Reduces Appetite, Energy Intake, and Fat Mass in
People With Type 2 Diabetes
Tim Heise, J. Hans DeVries, Shweta Urva, Jing Li, Edward J. Pratt, Melissa K. Thomas, Kieren J. Mather,
Chrisanthi A. Karanikas, Julia Dunn, Axel Haupt, Zvonko Milicevic, and Tamer Coskun
Diabetes Care 2023;46(5):998–1004 | https://doi.org/10.2337/dc22-1710
5
0
0
-5
**
#
**#
-10
-15
Baseline 5
**# **#
**#
##
** **##
9 13 17 21 25 28
Time (week)
Fat mass,
change from
baseline (kg)
Placebo
(n = 28)
Tirzepatide led to significant improvements over semaglutide and placebo on body
weight and fat mass.
y weight
g
Body
Fat mass
Body weight,
change from
baseline (kg)
Adults with type 2 diabetes
were randomized across
three groups and
monitored for 28 weeks
0 (0%)
-5
-15
**p < 0.001 vs placebo; #p < 0.05 and ##p < 0.001 tirzepatide vs semaglutide.
1400
80
1200
1000
800
600
*,†
Baseline
†
8
16
Time (week)
**,††
28
*p < 0.05 and **p < 0.001 tirzepatide vs placebo; †p < 0.05 and ††p < 0.001
semaglutide vs placebo.
Fasting satiety
VAS score
Tirzepatide
15 mg
(n = 48)
**p < 0.001 vs placebo.
Tirzepatide and semaglutide similarly reduced fasting appetite and energy intake
during ad libitum lunch.
y
Satiety
Calorie intake
Energy intake,
actual value (kcal)
Semaglutide
1 mg
(n = 45)
-5.9 (-16.1%)
**
-9.7 (-26.5%)
**
p = 0.002
-10
*,†
60
*
*,†
*
40
20
0
Baseline 5
9 13 17 21 25 28
Time (week)
Rating of satiety as measured by fasting visual analog score. *p < 0.05 tirzepatide vs
placebo; †p < 0.05 semaglutide vs placebo.
More work is needed to understand the mechanistic differences between tirzepatide and semaglutide
in promoting weight loss, reduced calorie intake, and reduced appetite. VAS, visual analog score.
ARTICLE HIGHLIGHTS
• The effects of once weekly glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 (GLP-1) receptor agonist tirzepatide were assessed on body weight and composition, appetite, and energy intake in a
phase 1 randomized, placebo-controlled study.
• At 28 weeks, tirzepatide (15 mg) demonstrated significant body weight reduction compared with selective GLP-1
receptor agonist, semaglutide (1 mg), which was mainly due to fat mass reduction.
• Both tirzepatide and semaglutide significantly reduced fasting appetite and ad libitum energy intake during lunch.
• These data highlight greater effects of tirzepatide than semaglutide on total body mass and fat mass reduction in
people with type 2 diabetes.
Downloaded from http://diabetesjournals.org/care/article-pdf/46/5/998/702102/dc221710.pdf by Eugenio Angueira on 30 April 2023
Tirzepatide reduces fat, calorie intake, and appetite in people with type 2 diabetes
998
Diabetes Care Volume 46, May 2023
Tirzepatide Reduces Appetite,
Energy Intake, and Fat Mass in
People With Type 2 Diabetes
Tim Heise,1 J. Hans DeVries,1
Shweta Urva,2 Jing Li,2 Edward J. Pratt,2
Melissa K. Thomas,2 Kieren J. Mather,2
Chrisanthi A. Karanikas,2 Julia Dunn,2
Axel Haupt,2 Zvonko Milicevic,2 and
Tamer Coskun 2
Downloaded from http://diabetesjournals.org/care/article-pdf/46/5/998/702102/dc221710.pdf by Eugenio Angueira on 30 April 2023
BRIEF REPORT
Diabetes Care 2023;46:998–1004 | https://doi.org/10.2337/dc22-1710
OBJECTIVE
To evaluate the effects of tirzepatide on body composition, appetite, and energy
intake to address the potential mechanisms involved in body weight loss with
tirzepatide.
RESEARCH DESIGN AND METHODS
In a secondary analysis of a randomized, double-blind, parallel-arm study, the
effects of tirzepatide 15 mg (N = 45), semaglutide 1 mg (N = 44), and placebo
(N = 28) on body weight and composition, appetite, and energy intake were assessed at baseline and week 28.
RESULTS
Tirzepatide treatment demonstrated significant reductions in body weight compared with placebo and semaglutide, resulting in greater fat mass reduction. Tirzepatide and semaglutide significantly reduced appetite versus placebo. Appetite
scores and energy intake reductions did not differ between tirzepatide and
semaglutide.
CONCLUSIONS
Differences in energy intake during ad libitum lunch were not sufficient to explain
the different weight outcomes. Further evaluation is needed to assess mechanistic differences related to tirzepatide actions on 24-h energy intake, substrate utilization, and energy expenditure.
1
Profil, Neuss, Germany
Eli Lilly and Company, Indianapolis, IN
Tirzepatide, a glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like
peptide 1 (GLP-1) receptor agonist, is approved for the treatment of type 2 diabetes (T2D). Tirzepatide causes robust body weight loss mainly by reduction in energy
intake and by increasing energy expenditure in preclinical models (1) and has demonstrated robust body weight reductions in people with T2D (2). We hypothesized
that body weight loss with tirzepatide is mainly driven by reduced energy intake.
2
RESEARCH DESIGN AND METHODS
This article contains supplementary material online
at https://doi.org/10.2337/figshare.21984596.
Study Design and Participants
Measurements of body composition, appetite, and energy intake were performed
as secondary assessments in a mechanism of action study, with main objectives
and safety results published (3). Eligible patients were randomized (3:3:2) to receive once weekly 15 mg tirzepatide (N 5 45), 1 mg semaglutide (N 5 44), or placebo (N 5 28) (Supplementary Material).
Corresponding author: Tamer Coskun, coskun_
tamer@lilly.com
Received 1 September 2022 and accepted 31
January 2023
Clinical trial reg. no. NCT03951753, clinicaltrials
.gov
© 2023 by the American Diabetes Association.
Readers may use this article as long as the
work is properly cited, the use is educational
and not for profit, and the work is not altered.
More information is available at https://www
.diabetesjournals.org/journals/pages/license.
diabetesjournals.org/care
Procedures
studied has been approved in the U.S. and
European Union and after primary publication acceptance, whichever is later. No expiration date of data requests is currently
set once data are made available. Access is
provided after a proposal has been approved by an independent review committee identified for this purpose and after
receipt of a signed data sharing agreement. Data and documents, including the
study protocol, statistical analysis plan,
clinical study report, and blank or annotated case report forms, will be provided in
a secure data sharing environment. For details on submitting a request, see the instructions provided at www.vivli.org.
Objectives
Energy metabolism objectives assessed
the effects of tirzepatide versus placebo
and semaglutide on body weight, body
composition, fasting appetite, and energy intake during ad libitum lunch.
Statistical Analysis
Analyses were conducted on data from
all randomized patients who received at
least one dose of the study drug and
had evaluable pharmacodynamic data
(pharmacodynamic analysis set). Analysis
of variance was conducted for baseline
comparisons across groups. Analysis of covariance was conducted for fat mass and
fat-free mass with study treatment as a
fixed effect and baseline measurement as
a covariate. Mixed-model repeated measures were conducted for body weight, fasting overall appetite, the four individual
VAS appetite scores, and energy intake using a restricted maximum likelihood–based
approach for parameter estimation. Analyses included fixed effects of study treatment, visit, treatment-by-visit interaction,
and baseline measurement as a covariate.
Significance tests were conducted at
a 5 0.05 (two-sided). Estimated treatment
differences were presented as least squares
mean and 95% CIs in brackets. We did not
imputefor missing data and multiplicity adjustment in this exploratory analysis. Statistical analyses were done using SAS version
9.4, unless otherwise specified. Additional
details are in Supplementary Material.
Data and Resource Availability
Eli Lilly and Company provides access to
all individual participant data collected
during the trial, after anonymization,
with the exception of pharmacokinetic
or genetic data. Data are available to
request 6 months after the indication
RESULTS
Baseline demographics and clinical characteristics were balanced, except for longer
T2D duration and more older patients randomly assigned to semaglutide (Table 1).
Safety outcomes were published (3); the
overall pattern of adverse events was consistent with incretin class molecules and
comparable between treatment groups.
Body Weight Assessment
Body weight significantly reduced from
baseline with tirzepatide and semaglutide (P < 0.001, all time points) (Fig. 1A).
Treatment differences were observed as
early as week 5 with tirzepatide ( 2.6 kg)
versus placebo ( 1.0 kg; estimated treatment differences [95% CI]: 1.5 kg [ 2.3,
0.8]; P < 0.001) and semaglutide
( 1.9 kg; 0.7 kg [ 1.4, 0.1]; P 5
0.029), and continued throughout the
trial. At week 28, tirzepatide-treated patients
achieved 11 kg of weight reduction, vs.
0 kg with placebo ( 11.2 kg [ 14.0, 8.4];
P < 0.001) and 7 kg with semaglutide
( 4.3 kg [ 6.8, 1.9]; P < 0.001) (Fig. 1B).
Body Composition Assessment
At week 28, fat mass and fat-free mass
significantly reduced from baseline with
tirzepatide and semaglutide, but not
with placebo (Fig. 1C and D). Fat mass
reductions differed in tirzepatide versus
placebo ( 9.6 kg [ 12.4, 6.9]; P <
0.001) and semaglutide ( 3.8 kg [ 6.2,
1.4]; P 5 0.002). Similarly, percentage
of fat mass loss was greater with tirzepatide ( 7.1%) versus semaglutide
( 4.0%) ( 3.1% [ 4.9, 1.2]; P 5
0.001) (Fig. 1C). Fat-free mass reductions differed in tirzepatide versus placebo ( 1.5 kg [ 2.3, 0.7]; P < 0.001)
999
and semaglutide ( 0.8 kg [ 1.5, 0.1];
P 5 0.018) (Fig. 1D). Body weight loss
with tirzepatide was predominantly driven
by fat mass reduction (Fig. 1B, D, E).
Fasting Appetite
At week 28, appetite reduced from baseline, as reflected by higher overall appetite
scores, with tirzepatide and semaglutide
(P < 0.001) but not placebo (P 5 0.241)
(Fig. 2A). This effect differed in tirzepatide
versus placebo (15.0 [4.1, 25.9]; P 5
0.007) but not versus semaglutide (5.3
[ 4.0, 14.6]; P 5 0.260). Longitudinal increases in component VAS scores for satiety and fullness and decreases in scores
for hunger and prospective food consumption were observed with tirzepatide and
semaglutide (Fig. 2B–E).
Energy Intake During Ad Libitum
Buffet-Style Lunch
Baseline energy intake was similar between groups. At week 8, energy intake
significantly reduced from baseline in all
groups (Fig. 3A). Reductions were greater
with tirzepatide versus placebo ( 185.3 kcal
[ 312.7, 57.8]; P 5 0.005), semaglutide
versus placebo ( 130.2 kcal [ 257.4, 3.0];
P 5 0.045), and were numerically, but not
significantly, higher with tirzepatide versus
semaglutide ( 55.1 kcal [ 165.0, 54.9];
P 5 0.323). At week 16, all groups consumed significantly fewer calories compared with baseline (Fig. 3A). Compared
with placebo, reductions from baseline
in energy intake were greater with semaglutide ( 143.4 kcal [ 282.4, 4.4]; P 5
0.043) and trended toward greater reductions with tirzepatide ( 129.9 kcal
[ 269.5, 9.7]; P 5 0.068). At week 28,
energy intake significantly reduced from
baseline with tirzepatide and semaglutide, but not with placebo. These reductions were greater with tirzepatide versus
placebo ( 309.8 kcal [ 423.0, 196.6];
P < 0.001) and were numerically, but not
significantly, greater with tirzepatide versus
semaglutide ( 64.3 kcal [ 160.3, 31.7];
P 5 0.187) (Fig. 3B).
CONCLUSIONS
Tirzepatide achieved significant weight reduction versus placebo in people with T2D.
Body composition analyses demonstrated
that the body weight loss was mainly due
to fat mass reduction. Semaglutide produced substantial, albeit smaller, weight
reduction that was also predominantly
Downloaded from http://diabetesjournals.org/care/article-pdf/46/5/998/702102/dc221710.pdf by Eugenio Angueira on 30 April 2023
Body weight was measured every 4 weeks,
and body composition (BOD POD measurement system; COSMED, Rome, Italy) was
assessed at baseline and week 28. Fasting
visual analog scale (VAS) ratings of hunger,
satiety, fullness, and prospective food consumption were completed, and a composite of the four scores was used to calculate
an overall appetite score (4–6). Energy intake was determined by measuring ad
libitum food intake during a 45-minute
buffet-style lunch performed at baseline
and weeks 8, 16, and 28 (Supplementary
Material).
Heise and Associates
1000
Tirzepatide Effects on People With T2D
Diabetes Care Volume 46, May 2023
Table 1—Patient demographics and clinical characteristics
Placebo, N 5 28
Semaglutide 1 mg, N 5 44
Tirzepatide 15 mg, N 5 45
60.4 ± 7.6
63.7 ± 5.9
61.1 ± 7.1
Sex, male, n (%)
21 (75.0)
34 (77.3)
31 (68.9)
Race, n (%)
Black or African American
White
0
28 (100.0)
0
44 (100.0)
1 (2.2)
44 (97.8)
Ethnicity, n (%)
Hispanic or Latino
Not Hispanic or Latino
0
28 (100.0)
0
44 (100.0)
0
45 (100.0)
HbA1c concentration
%
mmol/mol
7.9 ± 0.5
62.9 ± 5.5
7.7 ± 0.6
60.7 ± 6.6
7.8 ± 0.7
62.1 ± 7.9
Fasting glucose, mg/dL
126.6 ± 23.6
128.6 ± 25.0
139.3 ± 30.2
Diabetes duration, years
11.0 ± 6.8
12.7 ± 6.1
10.2 ± 5.8
a
109.2 ± 12.0
109.7 ± 9.2
113.5 ± 8.9
2
32.2 ± 4.0
30.8 ± 3.8
31.3 ± 5.0
Weight, kg
98.7 ± 14.6
92.7 ± 14.0
94.2 ± 14.0
Fat mass, kga
38.6 ± 10.7
35.3 ± 8.0
36.8 ± 11.5
59.1 ± 10.3
56.3 ± 10.3
57.7 ± 9.3
1,252.7 ± 483.2
1,131.0 ± 375.6
1,105.0 ± 343.7
Waist circumference, cm
BMI, kg/m
a
Fat-free mass, kg
Energy intake, kcal
a,b
Data are mean ± SD for the safety population, unless otherwise indicated. n, number of patients in the specified category; N, all randomly assigned
patients who took at least one dose of study drug. aTotal N 5 112 (tirzepatide 15 mg, n 5 43; semaglutide 1 mg, n 5 43; placebo, n 5 26) for
waist circumference and energy intake; total N 5 108 (tirzepatide 15 mg, n 5 41; semaglutide, n 5 43; placebo, n 5 24) for fat mass and fatfree mass from the pharmacodynamic analysis set. bEnergy intake during ad libitum buffet-style lunch.
explained by fat mass loss. Tirzepatide and
semaglutide significantly reduced fasting
appetite and energy intake during ad libitum lunch. Assessing the effect of tirzepatide on 24-h energy intake and energy
expenditure using respiratory chambers is
ongoing (clinical trial no. NCT04081337).
Tirzepatide and semaglutide decreased
weight primarily through a reduction in fat
mass. Nevertheless, the absolute changes
in total and fat mass were greater with tirzepatide, suggesting that the added efficacy of tirzepatide may be achieved by
utilizing body fat more effectively than
semaglutide. The underlying mechanisms
of this effect are unclear, and not explained by changes in energy intake during
lunch. Actions of tirzepatide to modulate
adipose lipid storage through actions at
GIP receptors have been described in preclinical and clinical studies (7) and may
contribute to such differential actions of
tirzepatide.
In a 12-week crossover trial, 1 mg
semaglutide significantly reduced total
energy intake across all ad libitum meals
by 24% versus placebo (8). The effect
was primarily observed during ad libitum
lunch (35% reduction with semaglutide
versus placebo) (8). Therefore, we focused on ad libitum lunch energy intake
assessment and observed similar reductions in energy intake for the two active
treatments versus placebo. At week 28, a
numerically, but not significantly, greater
reduction in energy intake during ad libitum lunch was observed with tirzepatide
versus semaglutide (64 kcal difference).
Such a difference during ad libitum lunch
may contribute to the differences in weight
reduction between tirzepatide and semaglutide, particularly if considering total
daily energy intake. Hence, up to week
16, reductions in energy intake during
lunch were similar for tirzepatide and
semaglutide, whereas weight reductions
started to separate as early as week 5.
Therefore, the differences in total energy
intake, in addition to other mechanisms,
may contribute to the differences in body
weight loss observed with tirzepatide versus semaglutide (8).
Study limitations include limited study
population diversity, thus limiting generalizability, and modest differences in baseline
characteristics between groups. Although
these analyses were prespecified and hypothesis driven, the study sample size was
not explicitly powered for these secondary and exploratory outcomes. The evaluation of energy intake was guided by
lunch-specific treatment effects observed
with semaglutide (8), which reflected a
single meal. However, this focused measurement of energy intake may not fully
reflect the treatment differences on total
energy intake. Animal data suggest that
food intake reduction is more prolonged
with tirzepatide compared with selective
GLP-1 receptor agonist (1), and maybe a
separation of energy intake may occur later.
The energy intake measures may have
been influenced by the artificial setting of
the research clinic, the specific food choices
provided in the buffet, and the assessment
being limited to only lunch. Overall, these
observations emphasize the value of including a placebo group, particularly where
the background treatment includes a
study-wide dietary intervention to explain treatment effect. The measurement
of appetite VAS under fasting conditions
prevented observations of treatment
group differences in meal-related appetite
Downloaded from http://diabetesjournals.org/care/article-pdf/46/5/998/702102/dc221710.pdf by Eugenio Angueira on 30 April 2023
Parameters
Age, years
diabetesjournals.org/care
Heise and Associates
A
Placebo
Semaglutide 1 mg
Tirzepatide 15 mg
B
Overall mean baseline body weight = 94.5 kg
5
0
0
**#
-5
**#
**#
**#
-10
**#
**##
**##
-15
Baseline
5
9
13
17
21
25
Semaglutide 1 mg
0.25 mg
0.5 mg
1 mg
mg
2.5
5 mg
C
-10
††
-11.2
p
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