INDIANAPOLIS, May 20, 2021 /PRNewswire/ -- Tirzepatide led to
superior A1C and body weight reductions from baseline across all
three doses in adults with type 2 diabetes who have increased
cardiovascular (CV) risk compared to titrated insulin glargine in
topline results from Eli Lilly and Company's (NYSE: LLY)
SURPASS-4 clinical trial. For the efficacy estimandi,
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]) at 52 weeks.
The overall safety profile of tirzepatide was consistent with
the glucagon-like peptide-1 (GLP-1) receptor agonist class in this
patient population. Gastrointestinal side effects were the most
commonly reported adverse events, usually occurring during the
escalation period and then decreasing over time.
SURPASS-4 is the largest and longest trial of the program to
date and is the fifth and final global registration study for
tirzepatide in type 2 diabetes to be completed. The study
completion was driven by the accrual of major adverse
cardiovascular events (MACE) in order to meet the regulatory
submission requirements for evaluating CV risk for type 2 diabetes
therapies. The primary endpoint was measured at 52 weeks, and many
participants continued treatment beyond 52 weeks, some up to two
years.
A CV safety meta-analysis was conducted across the clinical
program once the predefined number of MACE events occurred. The
meta-analysis consisted of 116 participants with adjudicated
MACE-4, a composite endpoint of death from cardiovascular or
undetermined causes, myocardial infarction, stroke and
hospitalization for unstable angina. Comparing pooled tirzepatide
versus pooled comparators, a hazard ratio of 0.81 (97.85%
confidence interval [CI], 0.52 to 1.26) was attained. SURPASS-4
contributed the majority of the MACE-4 events for the CV safety
meta-analysis, and within SURPASS-4, a hazard ratio of 0.74 (95%
CI, 0.51 to 1.08) was observed. Lilly intends to submit the full
registration package to regulatory authorities by the end of
2021.
Tirzepatide is a novel investigational once-weekly dual
glucose-dependent insulinotropic polypeptide (GIP) and GLP-1
receptor agonist that integrates the actions of the GIP and GLP-1
incretins into a single molecule, representing a new class of
medicines being studied for the treatment of type 2 diabetes.
"Tirzepatide delivered impressive results in this study,
providing superior A1C reductions compared to insulin glargine – as
well as the addition of significant weight loss – in people with
type 2 diabetes who have increased cardiovascular risk," 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. "Type 2
diabetes is a complex condition that requires personalized
approaches to treatment, and results from SURPASS-4 demonstrate the
potential of tirzepatide to be an important option to help reduce
A1C and weight for people with type 2 diabetes on one or up to
three oral medicines."
SURPASS-4 is 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 more than 2,000 people with type 2
diabetes who have increased CV risk and are treated with between
one and three oral antihyperglycemic medicines (metformin, a
sulfonylurea or an SGLT-2 inhibitor).
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 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 superior A1C and body weight reductions compared to insulin
glargine for both estimandsii. At the highest dose of
tirzepatide, 91 percent of participants achieved an A1C less than 7
percent – the American Diabetes Association's recommended target
for people with diabetes – and 43 percent achieved an A1C less than
5.7 percent – the level seen in people without diabetes.
Specifically, results at 52 weeks showed:
Efficacy Estimand
Results
|
|
Tirzepatide
5 mg
|
Tirzepatide
10
mg
|
Tirzepatide
15
mg
|
Insulin
Glargine
|
A1C reduction
from
baseline of 8.52%
|
-2.24%*
|
-2.43%*
|
-2.58%*
|
-1.44%
|
Weight reduction
from
baseline of 90.3 kg
|
-7.1 kg*
(-8.1%)
|
-9.5 kg*
(-10.7%)
|
-11.7 kg*
(-13.0%)
|
+1.9 kg
(+2.2%)
|
Percent of
participants
achieving A1C <7%
|
81.0%*
|
88.2%*
|
90.7%*
|
50.7%
|
Percent of
participants
achieving A1C <5.7%
|
23.0%†
|
32.7%†
|
43.1%†
|
3.4%
|
*Denotes
statistical significance compared to insulin
glargine
|
†Not
controlled for type I error
|
For the treatment-regimen estimandiii, all
doses of tirzepatide led to superior A1C and body weight reductions
compared to insulin glargine. 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%: 75.1% (5 mg),
82.9% (10 mg), 84.9% (15 mg), 48.8% (insulin glargine)
Hypoglycemia less than 54 mg/dL at 52 weeks was reported in 6.7
percent (5 mg), 5.5 percent (10 mg) and 6.5 percent (15 mg) of
participants in the tirzepatide arms and in 15.0 percent of
participants in the insulin glargine arm. Episodes of hypoglycemia
were seen more often in participants who had a background therapy
of a sulfonylurea.
The most commonly reported adverse events in the tirzepatide
arms at 52 weeks 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 (11.9
percent, 15.9 percent, 22.2 percent), diarrhea (12.2 percent, 19.5
percent, 20.4 percent) and vomiting (4.9 percent, 8.2 percent, 8.3
percent) were more frequently experienced compared to insulin
glargine (1.6 percent [nausea], 3.2 percent [diarrhea], 1.1 percent
[vomiting]). Treatment discontinuation rates due to adverse events
at 52 weeks were 8.2 percent (tirzepatide 5 mg), 7.3 percent
(tirzepatide 10 mg) and 8.9 percent (tirzepatide 15 mg), compared
to 2.9 percent (insulin glargine).
"These strong results reinforce our belief that tirzepatide has
the potential to be an exciting treatment for people living with
type 2 diabetes," said Mike Mason,
president, Lilly Diabetes. "We look forward to meeting our goal of
bringing an important new therapy to people living with this
condition, including sharing more detailed results at scientific
congresses and submitting to regulatory authorities later this
year."
The complete SURPASS-4 study data are being evaluated and
additional results will be presented at the 57th Annual
Meeting of the European Association for the Study of Diabetes and
published in a peer-reviewed journal.
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 receptor agonists. 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 and for chronic weight
management. It is also being studied as potential treatments for
non-alcoholic steatohepatitis (NASH) and heart failure with
preserved ejection fraction (HFpEF).
About SURPASS-4 and the SURPASS clinical trial
program
SURPASS-4 (NCT03730662) is a 52-week, 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 assessed at 52 weeks, with
some participants continuing treatment for up to two years. Study
participants had a mean A1C between 7.5 percent and 10.5 percent
and a BMI greater than or equal to 25 kg/m2. 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 13,000 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 people in the U.S.1 (just over
1 in 10) and an estimated 463 million adults worldwide2
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 alone1. 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 data releases,
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 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.
1 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.
2 International Diabetes Federation. IDF Diabetes
Atlas, 9th edn. Brussels,
Belgium: International Diabetes Federation, 2019. Available
at: http://diabetesatlas.org.
i Efficacy estimand used when the treatment effect prior to
discontinuation of study drug or initiating rescue therapy for
persistent severe hyperglycemia, is of interest.
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.
iii Treatment-regimen estimand used when the treatment effect
irrespective of adherence to the investigational medicine or
introduction of rescue therapy for persistent severe hyperglycemia,
is of interest.
Refer to:
|
Maggie Pfeiffer;
monson_maggie@lilly.com; 317-650-5939 (Media)
|
|
Kevin Hern;
hern_kevin_r@lilly.com; 317-277-1838 (Investors)
|
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