INDIANAPOLIS, Oct. 19, 2021 /PRNewswire/ -- Adults with type 2
diabetes with increased cardiovascular (CV) risk experienced
superior A1C and body weight reductions from baseline across all
three doses of tirzepatide compared to titrated insulin glargine in
detailed results from Eli Lilly and Company's (NYSE: LLY)
SURPASS-4 clinical trial, which were published today in The
Lancet. At 52 weeks, the highest dose of tirzepatide led to an
A1C reduction of 2.58 percent and reduced body weight by 11.7 kg
(-25.8 lb., -13.0 percent) compared to results for those treated
with insulin glargine (A1C reduction of 1.44 percent and weight
gain of 1.9 kg [+4.2 lb., +2.2 percent]) for the efficacy
estimand.i,1
SURPASS-4 is the largest and longest clinical trial completed to
date of the phase 3 program studying tirzepatide as a potential
treatment for type 2 diabetes. The primary endpoint was measured at
52 weeks, with participants continuing treatment up to 104 weeks or
until study completion. The completion of the study was triggered
by the accrual of major adverse cardiovascular events (MACE) to
assess CV risk. In newly published data from the treatment period
after 52 weeks, participants taking tirzepatide maintained A1C and
weight control for up to two years.
The overall safety profile of tirzepatide, assessed over the
full study period, was consistent with the safety results measured
at 52 weeks, with no new findings up to 104 weeks. Gastrointestinal
side effects were the most commonly reported adverse events,
usually occurring during the escalation period and then decreasing
over time.
"We are encouraged by the continued A1C and weight control that
participants experienced past the initial 52 week treatment period
and up to two years as we continue to explore the potential impact
of tirzepatide for the treatment of type 2 diabetes," said
John Doupis, M.D., Ph.D., Director,
Diabetes Division and Clinical Research Center, Iatriko Paleou
Falirou Medical Center, Athens,
Greece and Senior Investigator for SURPASS-4.
Tirzepatide is a novel investigational once-weekly dual
glucose-dependent insulinotropic polypeptide (GIP)
and glucagon-like peptide-1 (GLP-1) receptor agonist that
integrates the actions of both incretins into a single molecule,
representing a new class of medicines being studied for the
treatment of type 2 diabetes.
SURPASS-4 was an open-label global trial comparing the safety
and efficacy of three tirzepatide doses (5 mg, 10 mg and 15 mg) to
titrated insulin glargine in 2,002 adults with type 2 diabetes with
increased CV risk who were treated with between one and three oral
antihyperglycemic medicines (metformin, a sulfonylurea or an SGLT-2
inhibitor). Of the total participants randomized, 1,819 (91%)
completed the primary 52-week visit and 1,706 (85%) completed the
study on treatment. The median study duration was 85 weeks and 202
participants (10%) completed two years.
Study participants had a mean duration of diabetes of 11.8
years, a baseline A1C of 8.52 percent and a baseline weight of 90.3
kg. More than 85 percent of participants had a history of
cardiovascular events. In the insulin glargine arm, the insulin
dose was titrated following a treat-to-target algorithm with the
goal of fasting blood glucose below 100 mg/dL. The starting dose of
insulin glargine was 10 units per day, and the mean dose of insulin
glargine at 52 weeks was 43.5 units per day.
SURPASS-4 achieved each of its primary and key secondary
endpoints. All three doses of tirzepatide (5 mg, 10 mg and 15 mg)
led to statistically significant and superior A1C and body weight
reductions compared to insulin glargine for both
estimandsii at 52 weeks (the primary endpoint).
Specifically, the efficacy estimand results showed:
- A1C reduction: -2.24% (5 mg), -2.43% (10 mg), -2.58% (15 mg),
-1.44% (insulin glargine)
- Weight change: -7.1 kg (-8.1%, 5 mg), -9.5 kg (-10.7%, 10 mg),
-11.7 kg (-13.0%, 15 mg), +1.9 kg (+2.2%, insulin glargine)
- Percent of participants achieving A1C <7%: 81% (5 mg), 88%
(10 mg), 91% (15 mg), 51% (insulin glargine)
- Percent of participants achieving A1C <5.7% (not controlled
for type 1 error): 23% (5 mg), 33% (10 mg), 43% (15 mg), 3%
(insulin glargine)
For the treatment-regimen estimandiii, all three
doses of tirzepatide led to superior A1C and weight reductions at
52 weeks. Specifically, results showed:
- A1C reduction: -2.11% (5 mg), -2.30% (10 mg), -2.41% (15 mg),
-1.39% (insulin glargine)
- Weight change: -6.4 kg (5 mg), -8.9 kg (10 mg), -10.6 kg (15
mg), +1.7 kg (insulin glargine)
- Percent of participants achieving A1C <7%: 75% (5 mg), 83%
(10 mg), 85% (15 mg), 49% (insulin glargine)
Participants taking tirzepatide maintained A1C and weight
control for up to two years in exploratory analyses.
- The mean A1C values at 52 and 104 weeks were:
-
- At 52 weeks (N=1,750): 6.3% (5 mg), 6.1% (10 mg), 6.0% (15 mg),
7.1% (insulin glargine)
- At 104 weeks (N=199): 6.4% (5 mg), 6.1% (10 mg), 6.1% (15 mg),
7.5% (insulin glargine)
- The changes in body weight at 52 and 104 weeks were:
-
- At 52 weeks (N=1,755): -7.1 kg (-8.1%, 5 mg), -9.5 kg (-10.7%,
10 mg), -11.7 kg (-13.0%, 15 mg), +1.9 kg (+2.2%, insulin
glargine)
- At 104 weeks (N=202): -5.8 kg (-8.6%, 5 mg), -10.4 kg (-10.8%,
10 mg), -11.1 kg (-12.8%, 15 mg), +2.3 kg (+2.3%, insulin
glargine)
Hypoglycemia less than 54 mg/dL was reported in 8.8 percent (5
mg), 6.1 percent (10 mg) and 8.0 percent (15 mg) of
participants in the tirzepatide arms and in 19.1 percent of
participants in the insulin glargine arm over the full study
period. Episodes of hypoglycemia were seen more often in
participants who had a background therapy of a sulfonylurea.
In an additional exploratory endpoint, all three doses of
tirzepatide led to favorable changes from baseline in fasting
lipids at 52 weeks. Specifically, at the highest dose of
tirzepatide (15 mg): total cholesterol was reduced by 5.6 percent,
triglycerides were reduced by 22.5 percent, low-density lipoprotein
(LDL) cholesterol was reduced by 7.9 percent, very low-density
lipoprotein (VLDL) cholesterol was reduced by 21.8 percent, and
high-density lipoprotein (HDL) cholesterol was increased by 10.8
percent.
The most commonly reported adverse events over the full study
period in the tirzepatide arms were gastrointestinal-related
and generally mild to moderate in severity. For study participants
treated with tirzepatide (5 mg, 10 mg and 15 mg, respectively),
nausea (12 percent, 16 percent, 23 percent), diarrhea (13 percent,
20 percent, 22 percent) and vomiting (5 percent, 8 percent, 9
percent) were more frequently experienced compared to insulin
glargine (2 percent [nausea], 4 percent [diarrhea], 2 percent
[vomiting]). Treatment discontinuation rates due to adverse events
over the full study period were 7.3 percent (tirzepatide 5 mg), 7.9
percent (tirzepatide 10 mg) and 8.9 percent (tirzepatide 15 mg),
compared to 1.9 percent (insulin glargine).
A safety analysis evaluated adjudicated MACE-4, a composite
endpoint of death from cardiovascular causes, myocardial
infarction, stroke and hospitalization for unstable angina. Within
SURPASS-4, comparing pooled tirzepatide to insulin glargine, no
increased cardiovascular risk was identified with tirzepatide; a
hazard ratio of 0.74 (95% confidence interval, 0.51 to 1.08) was
observed.
"Given the progressive nature of type 2 diabetes, evaluating the
positive efficacy results we have seen with tirzepatide over longer
periods of time is important. Throughout the length of SURPASS-4,
tirzepatide delivered robust improvements in blood glucose levels,
significant weight loss and consistent safety results in adults
with type 2 diabetes and increased cardiovascular risk," said
Jeff Emmick, M.D., Ph.D., vice
president, Product Development.
About tirzepatide
Tirzepatide is a once-weekly dual
glucose-dependent insulinotropic polypeptide (GIP) and
glucagon-like peptide-1 (GLP-1) receptor agonist that integrates
the actions of both incretins into a single novel molecule. GIP is
a hormone that may complement the effects of GLP-1. In preclinical
models, GIP has been shown to decrease food intake and increase
energy expenditure therefore resulting in weight reductions, and
when combined with a GLP-1 receptor agonist, may result in greater
effects on glucose and body weight. Tirzepatide is in phase 3
development for blood glucose management in adults with type 2
diabetes, for chronic weight management and heart failure with
preserved ejection fraction (HFpEF). It is also being studied as a
potential treatment for non-alcoholic steatohepatitis (NASH).
About SURPASS-4 and the SURPASS clinical trial
program
SURPASS-4 (NCT03730662) is a randomized, parallel,
open-label trial comparing the efficacy and safety of tirzepatide 5
mg, 10 mg and 15 mg to insulin glargine in adults with type 2
diabetes inadequately controlled with at least one and up to three
oral antihyperglycemic medications (metformin, sulfonylureas or
SGLT-2 inhibitors), who have increased cardiovascular (CV) risk.
The trial randomized 2,002 study participants in a 1:1:1:3 ratio to
receive either tirzepatide 5 mg, 10 mg or 15 mg or insulin
glargine. Participants were located in the European Union,
North America (Canada and the
United States), Australia,
Israel, Taiwan and Latin
America (Brazil,
Argentina and Mexico). The primary objective of the study
was to demonstrate that tirzepatide (10 mg and/or 15 mg) is
non-inferior to insulin glargine for change from baseline A1C at 52
weeks in people with type 2 diabetes and increased CV
risk. The primary and key secondary endpoints were measured at
52 weeks, with participants continuing treatment up to 104 weeks or
until study completion. The completion of the study was triggered
by the accrual of major adverse cardiovascular events (MACE). Study
participants enrolled had to have a mean baseline A1C between 7.5
percent and 10.5 percent and a BMI greater than or equal to 25
kg/m2 at baseline. All participants in the
tirzepatide treatment arms started the study at a dose of
tirzepatide 2.5 mg once-weekly and then increased the dose in a
step-wise approach at four-week intervals to their final randomized
maintenance dose of 5 mg (via a 2.5 mg step), 10 mg (via steps at
2.5 mg, 5 mg and 7.5 mg) or 15 mg (via steps at 2.5 mg, 5 mg, 7.5
mg, 10 mg and 12.5 mg). All participants in the titrated insulin
glargine treatment arm started with a baseline dose of 10 units per
day and titrated following a treat-to-target algorithm to reach a
fasting blood glucose below 100 mg/dL.
The SURPASS phase 3 global clinical development program for
tirzepatide has enrolled more than 20,000 people with type 2
diabetes across 10 clinical trials, five of which are global
registration studies. The program began in late 2018, and all five
global registration trials have been completed.
About Diabetes
Approximately 34 million Americans2 (just over 1 in
10) and an estimated 463 million adults worldwide3 have
diabetes. Type 2 diabetes is the most common type internationally,
accounting for an estimated 90 to 95 percent of all diabetes cases
in the United States
alone2. Diabetes is a chronic disease that occurs when
the body does not properly produce or use the hormone insulin.
About Lilly Diabetes
Lilly has been a global leader in diabetes care since 1923, when
we introduced the world's first commercial insulin. Today we are
building upon this heritage by working to meet the diverse needs of
people with diabetes and those who care for them. Through research,
collaboration and quality manufacturing we strive to make life
better for people affected by diabetes and related conditions. We
work to deliver breakthrough outcomes through innovative
solutions—from medicines and technologies to support programs and
more. For the latest updates, visit http://www.lillydiabetes.com/
or follow us on Twitter: @LillyDiabetes and Facebook:
LillyDiabetesUS.
About Eli Lilly and Company
Lilly is a global
healthcare leader that unites caring with discovery to make life
better for people around the world. We were founded more than a
century ago by a man committed to creating high-quality medicines
that meet real needs, and today we remain true to that mission in
all our work. Across the globe, Lilly employees work to discover
and bring life-changing medicines to those who need them, improve
the understanding and management of disease, and give back to
communities through philanthropy and volunteerism. To learn more
about Lilly, please visit us at lilly.com and
lilly.com/newsroom. P-LLY
Lilly Cautionary Statement Regarding Forward-Looking
Statements
This press release contains forward-looking
statements (as that term is defined in the Private Securities
Litigation Reform Act of 1995) about tirzepatide as a potential
treatment for people with type 2 diabetes and the timeline for
future readouts, presentations and other milestones relating to
tirzepatide and its clinical trials and reflects Lilly's current
belief and expectations. However, as with any pharmaceutical
product, there are substantial risks and uncertainties in the
process of drug research, development, and commercialization. Among
other things, there can be no guarantee that the studies will be
completed as planned, that future study results will be consistent
with the results to date or that tirzepatide will receive
regulatory approvals. For further discussion of these and
other risks and uncertainties, see Lilly's most recent Form 10-K
and Form 10-Q filings with the United States Securities and
Exchange Commission. Except as required by law, Lilly undertakes no
duty to update forward-looking statements to reflect events after
the date of this release.
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1 Del
Prato, S, et. al. (2021). Tirzepatide versus insulin glargine in
type 2 diabetes and increased cardiovascular risk (SURPASS-4): a
randomised, open-label, parallel-group, multicentre, phase 3 trial.
The
Lancet, https://doi.org/10.1016/S0140-6736(21)02188-7.
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2 Centers for Disease Control and
Prevention. National Diabetes Statistics Report, 2020. Atlanta, GA:
Centers for Disease Control and Prevention, U.S. Dept. of Health
and Human Services; 2020.
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3 International Diabetes Federation.
IDF Diabetes Atlas, 9th edn. Brussels, Belgium:
International Diabetes Federation, 2019. Available at:
http://diabetesatlas.org.
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i Efficacy
estimand represents efficacy prior to discontinuation of study drug
or initiating rescue therapy for persistent severe
hyperglycemia.
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ii
Treatment differences for two estimands – efficacy and
treatment-regimen – were evaluated for three tirzepatide doses (5
mg, 10 mg and 15 mg) compared to insulin glargine.
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iii Treatment-regimen estimand
represents the efficacy irrespective of adherence to the
investigational medicine or introduction of rescue therapy for
persistent severe hyperglycemia.
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Refer to:
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Maggie Pfeiffer;
monson_maggie@lilly.com; 317-650-5939 (Media)
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Kevin Hern;
hern_kevin_r@lilly.com; 317-277-1838 (Investors)
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