Tirzepatide: a new low for bodyweight and blood glucose 
646 Vol 9 October 2021
national survey data from the Health Survey for England,
which also used EHRs. Additionally, the findings in this
study remained robust in rigorous sensitivity analyses
that supported the assumptions made regarding
imputation procedures and minimised confounding
by chronic morbidities. Finally, the platform presented
in this study could serve as an advantageous tool for
monitoring the effectiveness of future intervention
efforts for obesity prevention.
I declare no competing interests.
Gilad Twig
[email protected]
Israel Defense Forces Medical Corps and Department of Military Medicine,
Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel;
and School of Public Health, Sackler Faculty of Medicine, Tel Aviv University,
Tel Aviv, Israel; Institute of Endocrinology, Sheba Medical Center, Ramat-Gan,
52621, Israel
1 Ward ZJ, Bleich SN, Cradock AL, et al. Projected U.S. state-level prevalence
of adult obesity and severe obesity. N Engl J Med 2019; 381: 2440–50.
2 Würtz P, Wang Q, Kangas AJ, et al. Metabolic signatures of adiposity in
young adults: Mendelian randomization analysis and effects of weight
change. PLoS Med 2014; 11: e1001765.
3 Kyrgiou M, Kalliala I, Markozannes G, et al. Adiposity and cancer at major
anatomical sites: umbrella review of the literature. BMJ 2017; 356: 1–10.
4 Olshansky SJ, Passaro DJ, Hershow RC, et al. A potential decline in life
expectancy in the United States in the 21st century. N Engl J Med 2005;
352: 1138–45.
5 Katsoulis M, Lai AG, Diaz-Ordaz K, et al. Identifying adults at high-risk for
change in weight and BMI in England: a longitudinal, large-scale,
population-based cohort study using electronic health records.
Lancet Diabetes Endocrinol 2021; published online Sept 2. https://doi.
6 Twig G, Zucker I, Afek A, et al. Adolescent obesity and early-onset type 2
diabetes. Diabetes Care 2020; 43: 1487–95.
7 Saydah SH, Siegel KR, Imperatore G, Mercado C, Gregg EW.
The cardiometabolic risk profile of young adults with diabetes in the U.S.
Diabetes Care 2019; 42: 1895–902.
8 Lascar N, Brown J, Pattison H, Barnett AH, Bailey CJ, Bellary S. Type 2
diabetes in adolescents and young adults. Lancet Diabetes and Endocrinol
2018; 6: 69–80.
9 Ward ZJ, Long MW, Resch SC, Giles CM, Cradock AL, Gortmaker SL.
Simulation of growth trajectories of childhood obesity into adulthood.
N Engl J Med 2017; 377: 2145–53.
10 Patton GC, Sawyer SM, Santelli JS, et al. Our future: a Lancet commission on
adolescent health and wellbeing. Lancet 2016; 387: 2423–78.
Tirzepatide: a new low for bodyweight and blood glucose
The normal incretin effect—an enhanced prandial insulin
response—is mediated mostly by meal-stimulated release
of the intestinal hormones GLP-1 and glucose-dependent
insulinotropic peptide (GIP).1
Analogues of GLP-1 that
act as GLP-1 receptor agonists are established glucose￾lowering agents that potentiate insulin release and
suppress glucagon in a glucose-dependent manner. GLP-1
receptor agonists also facilitate weight loss via reduced
food intake, by creating a feeling of fullness through
delayed gastric emptying and by modulating central
hunger-satiety controls. GIP probably makes a greater
contribution to the normal prandial insulin response
than does GLP-1, but GIP was disregarded for therapeutic
purposes because its insulinotropic activity is greatly
reduced in type 2 diabetes.2
However, subsequent studies
noted that the insulinotropic potency of GIP is restored
in individuals with type 2 diabetes if the hyperglycaemia
is first reduced by another agent such as insulin.
This discovery has brought GIP back into therapeutic
consideration, and a new incretin mimetic, tirzepatide,
combines GIP receptor agonism with GLP-1 receptor
agonism in a single chimeric peptide.3
Beyond its insulinotropic effect, what does GIP bring
to the therapeutic party? Intriguingly, preclinical studies
have shown that both enhancement and inhibition of
GIP action can prevent or reverse non-insulin dependent
forms of diabetes in rodent models of obesity, but
species differences in GIP receptor responsiveness have
made it difficult to extrapolate preclinical evidence to
type 2 diabetes in humans. Moreover, pharmacological
concentrations of GIP can increase glucagon secretion
and promote adipose deposition, although these
effects can be countered by the suppression of glucagon
secretion and reduced food intake associated with
Indeed, tirzepatide has been designed to closely
mimic the physiological incretin balance of GIP and
GLP-1, and prolong activity with a structure that avoids
degradation from DPP-4 and attaches to albumin via
a C20 fatty di-acid (figure). Preclinical studies have
not identified a definite effect of GIP on food intake
and clinical studies are scarce, but GIP does seem to
synergise the central satiety effect and weight loss
associated with GLP-1. GIP might also improve bone
strength, cognitive function, and some aspects of the
lipid profile, but its effects on cardiovascular health are
yet to be established.
The efficacy and safety of tirzepatide in people with
type 2 diabetes have been studied in the SURPASS
programme of phase 3 trials. Tirzepatide was admini￾stered by once-weekly subcutaneous injection for 40 or
Published Online
August 19, 2021

Comment Vol 9 October 2021 647
52 weeks, and the findings summarised below all refer to
the group receiving dose escalation to 15 mg (the highest
dose tested). Monotherapy tirzepatide lowered HbA1c by
2·07% (23 mmol/mol) and bodyweight by 9·5 kg from
a baseline of 7·9% (63 mmol/mol) and a body-mass
index of 31·9 kg/m².5
Similarly, as add-on to metformin,
tirzepatide lowered HbA1c by 2·3% (25 mmol/mol)
and bodyweight by 11·2 kg from a baseline of 8·28%
(67 mmol/mol) and a body-mass index of 34·2 kg/m².
For comparison, the strongest currently available GLP-1
receptor agonist, semaglutide (1 mg once weekly) was
less effective than tirzepatide, reducing HbA1c by 1·86%
(20 mmol/mol) and bodyweight by 5·7 kg.
In two further SURPASS trials,7,8 tirzepatide was added
to existing treatment with metformin plus or minus a
SGLT2 inhibitor and compared with the addition of a
basal insulin. Tirzepatide reduced HbA1c by 2·37–2·58%
(25–28 mmol/mol) from baselines of 8·17–8·52%
(65–69 mmol/mol), exceeding the reductions in HbA1c
with degludec and glargine (1·34% [14 mmol/mol] and
1·44% [15 mmol/mol], respectively) and avoiding the
modest weight gain (2·3 kg and 1·9 kg, respectively)
associated with the basal insulins.7
When tirzepatide was
added to insulin-treated (glargine) patients with type 2
diabetes in another trial, HbA1c was reduced by 2·59%
(28 mmol/mol) compared with 0·98% (11 mmol/mol)
with insulin only, whereas bodyweight was reduced by
10·9 kg with tirzepatide compared with an increase of
1·7 kg with insulin.8
Because tirzepatide has recorded very substantial
reductions in HbA1c and bodyweight, exceeding the
glucose lowering effect of a GLP-1 receptor agonist and
basal insulin, one might ask whether and to what extent
tirzepatide could replace these established agents in
the treatment of type 2 diabetes. Insulin will remain
the default intervention for patients with otherwise
intractable hyperglycaemia, and companies that produce
GLP-1 receptor agonists will be examining the value of
higher doses and combinations with other beneficial
peptides. For example, higher doses of semaglutide
are already approved for the treatment of obesity and
produce greater reductions in HbA1c than the dose
tested in the SURPASS trials. Further, the combination
of semaglutide with the amylin analogue cagrilintide
(each with dose escalation to 2·4 mg by subcutaneous
injection once weekly over 20 weeks) reduced
bodyweight by 17·1 % in participants with overweight
or obesity but without diabetes.9
Appealing reductions
in bodyweight and glycaemia have also been seen
during pilot studies with combinations of peptides and
chimeric constructs with agonism at receptors for GLP-1,
oxyntomodulin, peptide YY, and other gastrointestinal
hormones. However, modified peptides carry the risk
of immunological reactions, and gastrointestinal side￾effects often restrict dose escalation of incretin-based
The tirzepatide trials provide a timely reminder that
weight control remains a key handle in the management
of type 2 diabetes. Caloric restriction that reduces weight
by 10–15 kg has achieved an HbA1c of less than 6·5%
(<48 mmol/mol) without antidiabetic medication in
57% of newly diagnosed people with overweight or
obesity and type 2 diabetes.10 However, losing weight
and maintaining a lower weight are more difficult for
people with (than without) type 2 diabetes, due in part
to reduced glucosuria and increased insulin sensitivity.
Nevertheless, long-term consolidation of weight loss and
maintenance of glycaemic control for people with type 2
diabetes has been achieved with bariatric surgery, often
Figure: Actions of GLP-1 and GIP incretin hormones
In response to a meal, GIP is secreted by enteroendocrine K-cells and GLP-1 is
secreted by enteroendocrine L-cells. Tirzepatide is a chimeric peptide with dual
agonism at both GLP-1 and GIP receptors, creating an accentuated incretin effect.
Upward arrows denote an increase, downward arrows denote a decrease,
and – denotes a neutralised effect in combination with GLP-1.
GIP=glucose-dependent insulinotropic peptide.
Combined effect
↓ bodyweight
↓ blood glucose
↑ satiety effect of GLP-1
↓ gastric acid secretion
↑ insulin secretion
↑/ – glucagon secretion
↑ / – adipose deposition
↑ satiety
↓ gastric emptying
↑ insulin secretion
↓ glucagon secretion
Initial nausea
K cells L cells
648 Vol 9 October 2021
enabling around 50% of patients to maintain an HbA1c
of less than 6·5% (<48 mmol/mol) without antidiabetic
medication for 5 years. This achievement cannot be
wholly attributed to caloric restriction and weight loss,
and might reflect increased production of incretins.
In the SURPASS trials, more than 80% of participants
who received the 15-mg dose of tirzepatide achieved a
HbA1c of less than 6·5% (<48 mmol/mol). This finding
suggests that incretin-based dual agonist glucose￾lowering pharmacotherapies might offer an alternative
to strict dietary restriction and could challenge the
antidiabetic achievements of bariatric surgery.
I report research support, honoraria, and ad-hoc advisory activities associated
with Eli Lilly, Novo Nordisk, and Sanofi.
Clifford J Bailey
[email protected]
Health and Life Sciences, Aston University, Birmingham B4 7ET, UK (CJB)
1 Drucker DJ, Nauck M. The incretin system: glucagon-like peptide-1 receptor
agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet
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2 Gasbjerg, LS, Helsted MM, Hartmann B, et al. Separate and combined
glucometabolic effects of endogenous glucose-dependent insulinotropic
polypeptide and glucagon-like peptide 1 in healthy individuals. Diabetes
2019; 68: 906–17.
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receptor agonist for the treatment of type 2 diabetes mellitus: From
discovery to clinical proof of concept. Molecular Metabolism 2018; 18: 3–14.
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6 Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus semaglutide once
weekly in patients with type 2 diabetes. N Engl J Med 2021; published online
June 25.
7 Ludvik B, Giorgino F, Jodar E, et al. Once-weekly tirzepatide versus once￾daily insulin degludec as add-on to metformin with or without SGLT2
inhibitors in patients with type 2 diabetes (SURPASS-3): a randomised,
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type 2 diabetes (SURPASS-5). Diabetes 2021; 70: 80–LB.
9 Enebo LB, Berthelsen KK, Kankam M, et al. Safety, tolerability,
pharmacokinetics, and pharmacodynamics of concomitant administration
of multiple doses of cagrilintide with semaglutide 2·4 mg for weight
management: a randomised, controlled, phase 1b trial. Lancet 2021;
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for remission of type 2 diabetes (DiRECT): an open-label, cluster￾randomised trial. Lancet 2018; 391: 541–51.