Exenatide Study of Cardiovascular Event Lowering Trial (EXSCEL): A Trial To Evaluate Cardiovascular Outcomes After Treatment With Exenatide Once Weekly In Patients With Type 2 Diabetes Mellitus

Conditions

Type 2 Diabetes Mellitus

Keywords

exenatide once weekly, cardiovascular, Bydureon, Amylin

Brief summary

This study will compare the impact of including exenatide once weekly in addition to usual care vs. usual care without exenatide on major cardiovascular outcomes as measured by the primary composite endpoint of cardiovascular-related death, nonfatal myocardial infarction (MI), or nonfatal stroke.

Mahesh M. Umapathysivam, Elisa Araldi, Benoît Hastoy, Adem Y Dawed, Hasan Vatandaslar et al. (45 authors)

Genome Medicine2026-03-29

10.1186/s13073-026-01630-0

Inflammatory proteins associated with Alzheimer's disease reduced by a GLP1 receptor agonist: a post hoc analysis of the EXSCEL randomized placebo controlled trial.

Koychev I, Reid G, Nguyen M, Mentz RJ, Joyce D, Shah SH, Holman RR.

2024-10-0210 citations

10.1186/s13195-024-01573-x

Estimating Risk Factor Time Paths Among People with Type 2 Diabetes and QALY Gains from Risk Factor Management

Ni Gao, Helen Dakin, Rury R. Holman, Lee‐Ling Lim, José Leal et al. (6 authors)

PharmacoEconomics2024-06-264 citations

10.1007/s40273-024-01398-4

Effect of race on cardiometabolic responses to once-weekly exenatide: insights from the Exenatide Study of Cardiovascular Event Lowering (EXSCEL).

Davis TME, Giczewska A, Lokhnygina Y, Mentz RJ, Sattar N, Holman RR, EXSCEL Study Group.

2022-06-275 citations

10.1186/s12933-022-01555-z

Glucagon-like Peptide-1 Receptor Analogues for the Treatment of Obesity.

Williams DM, Staff M, Bain SC, Min T.

2022-03-185 citations

10.17925/ee.2022.18.1.43

Lifetime cost-effectiveness simulation of once-weekly exenatide in type 2 diabetes: A cost-utility analysis based on the EXSCEL trial.

Becker F, Dakin HA, Reed SD, Li Y, Leal J, Gustavson SM, Wittbrodt E, Hernandez AF, Gray AM, Holman RR.

2021-11-205 citations

10.1016/j.diabres.2021.109152

Generalizability of the Results of Cardiovascular Outcome Trials of Glucagon-Like Peptide 1 Receptor Agonists in Chinese Patients with Type 2 Diabetes Mellitus.

Cai X, Ji L.

2021-05-285 citations

10.1007/s13300-021-01079-x

Clinical Outcomes in Patients with Type 2 Diabetes Mellitus and Peripheral Artery Disease: Results from the EXSCEL Trial

Anish Badjatiya, Peter Merrill, John B. Buse, Shaun G. Goodman, Brian G. Katona et al. (13 authors)

UNC Libraries2020-10-278 citations

10.17615/ks7q-gz23

Effects of exenatide and open-label SGLT2 inhibitor treatment, given in parallel or sequentially, on mortality and cardiovascular and renal outcomes in type 2 diabetes: Insights from the EXSCEL trial

L.E. Clegg, R.C. Penland, S. Bachina, D.W. Boulton, M. Thuresson et al. (13 authors)

UNC Libraries2020-10-273 citations

10.17615/brjm-hg52

Rationale and design of the EXenatide Study of Cardiovascular Event Lowering (EXSCEL) trial

R.R. Holman, M.A. Bethel, J. George, H. Sourij, Z. Doran et al. (22 authors)

UNC Libraries2020-10-27

10.17615/psft-h469

Baseline characteristics of patients enrolled in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL)

R.J. Mentz, M.A. Bethel, S. Gustavson, V.P. Thompson, N.J. Pagidipati et al. (16 authors)

UNC Libraries2020-10-27

10.17615/wt81-5t92

Exploring the Possible Impact of Unbalanced Open-Label Drop-In of Glucose-Lowering Medications on EXSCEL Outcomes

M.A. Bethel, S.R. Stevens, J.B. Buse, J. Choi, S.M. Gustavson et al. (14 authors)

UNC Libraries2020-10-27

10.17615/mtwd-4906

Exploring the Possible Impact of Unbalanced Open-Label Drop-In of Glucose-Lowering Medications on EXSCEL Outcomes

M. Angelyn Bethel, Susanna R. Stevens, John B. Buse, Jasmine Choi, Stephanie M. Gustavson et al. (14 authors)

Circulation2020-03-1814 citations

10.1161/circulationaha.119.043353

Clinical Outcomes in Patients With Type 2 Diabetes Mellitus and Peripheral Artery Disease

Anish Badjatiya, Peter Merrill, John B. Buse, Shaun G. Goodman, Brian G. Katona et al. (13 authors)

Circulation Cardiovascular Interventions2019-11-2259 citations

10.1161/circinterventions.119.008018

Effects of exenatide and open-label SGLT2 inhibitor treatment, given in parallel or sequentially, on mortality and cardiovascular and renal outcomes in type 2 diabetes: insights from the EXSCEL trial.

Clegg LE, Penland RC, Bachina S, Boulton DW, Thuresson M, Heerspink HJL, Gustavson S, Sjöström CD, Ruggles JA, Hernandez AF, Buse JB, Mentz RJ, Holman RR.

2019-10-2267 citations

10.1186/s12933-019-0942-x

Effect of Once-Weekly Exenatide in Patients With Type 2 Diabetes Mellitus With and Without Heart Failure and Heart Failure–Related Outcomes

Marat Fudim, Jennifer A. White, Neha J. Pagidipati, Yuliya Lokhnygina, Julio Wainstein et al. (13 authors)

Circulation2019-09-2389 citations

10.1161/circulationaha.119.041659

Implications of cardiovascular outcome trials with injectable antidiabetic agents

Richard E. Pratley

Journal of Diabetes2018-07-044 citations

10.1111/1753-0407.12792

Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes

Rury R. Holman, M. Angelyn Bethel, Robert J. Mentz, Vivian P. Thompson, Yuliya Lokhnygina et al. (18 authors)

New England Journal of Medicine2017-09-142,052 citations

10.1056/nejmoa1612917

Baseline characteristics of patients enrolled in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL).

Mentz RJ, Bethel MA, Gustavson S, Thompson VP, Pagidipati NJ, Buse JB, Chan JC, Iqbal N, Maggioni AP, Marso SP, Ohman P, Poulter N, Ramachandran A, Zinman B, Hernandez AF, Holman RR.

2017-02-1244 citations

10.1016/j.ahj.2017.02.005

Efficacy and Tolerability of Exenatide Once Weekly Over 6 Years in Patients with Type 2 Diabetes: An Uncontrolled Open-Label Extension of the DURATION-1 Study

Robert R. Henry, E. Klein, Jenny Han, Nayyar Iqbal

Diabetes Technology & Therapeutics2016-08-1543 citations

10.1089/dia.2016.0107

Rationale and design of the EXenatide Study of Cardiovascular Event Lowering (EXSCEL) trial.

Holman RR, Bethel MA, George J, Sourij H, Doran Z, Keenan J, Khurmi NS, Mentz RJ, Oulhaj A, Buse JB, Chan JC, Iqbal N, Kundu S, Maggioni AP, Marso SP, Öhman P, Pencina MJ, Poulter N, Porter LE, Ramachandran A, Zinman B, Hernandez AF.

2015-12-2178 citations

10.1016/j.ahj.2015.12.009

Long-term changes in cardiovascular risk markers during administration of exenatide twice daily or glimepiride: results from the European exenatide study

Rafael Simó, Bruno Guerci, Guntram Schernthaner, Baptist Gallwitz, Juan Rosas-Guzmán et al. (9 authors)

Cardiovascular Diabetology2015-09-0348 citations

10.1186/s12933-015-0279-z

Adding liraglutide to the backbone therapy of biguanide in patients with coronary artery disease and newly diagnosed type-2 diabetes (the AddHope2 study): a randomised controlled study protocol

Christian Anholm, Preman Kumarathurai, Malene S Klit, Ole Peter Kristiansen, Olav Wendelboe Nielsen et al. (9 authors)

BMJ Open2014-07-0119 citations

10.1136/bmjopen-2014-005942

Treatment of patients with type 2 diabetes with exenatide once weekly versus oral glucose-lowering medications or insulin glargine: achievement of glycemic and cardiovascular goals.

Meloni AR, DeYoung MB, Han J, Best JH, Grimm M.

2013-03-2312 citations

10.1186/1475-2840-12-48

Interventions

DRUGExenatide Once Weekly

Subcutaneous injection, 2 mg, administered once weekly.

DRUGPlacebo

Subcutaneous injection, matching volume of placebo, administered once weekly.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to 130 Years

Healthy volunteers

No

Inclusion criteria

* Patient has type 2 diabetes mellitus * Patient has an HbA1c of ≥ 6.5 % and ≤ 10.0% and is currently using one of the following treatment regimens: A) Treatment with 0-3 oral antihyperglycemic agents B) Insulin therapy, either alone or in combination with up to two oral agents * Female patients must not be breast feeding and agree to use an effective method of contraception or must not otherwise be at risk of becoming pregnant.

Exclusion criteria

* Patient has a diagnosis of type 1 diabetes mellitus, or a history of ketoacidosis. * Patient has ever been treated with an approved or investigational GLP-1 receptor agonist. * Patient is enrolled in another experimental protocol which involves the use of an investigational drug or device, or an intervention that would interfere with the conduct of the trial. * Patient has a planned or anticipated revascularization procedure. * Pregnancy or planned pregnancy during the trial period. * Patient has end-stage renal disease or an estimated glomerular filtration rate (eGFR) of \<30 mL/min/1.73m2. * Patient has a history of gastroparesis or pancreatitis. * Personal or family history of medullary thyroid cancer or MEN2 (Multiple EndocrineNeoplasia Type 2) or calcitonin level of \>40 ng/L at baseline.

Design outcomes

Primary

Measure	Time frame	Description
Primary Efficacy Outcome MACE Events	Time to first event. Information collected during study period (anticipated to be up to 7.5 years).	The primary efficacy outcome variable is defined as the composite endpoint of cardiovascular death, nonfatal MI, or nonfatal stroke. The number of participants who had an event is reported in the results. The primary efficacy endpoint is the same as the primary safety endpoint, and the statistical analysis tests the superiority of exenatide against the placebo.
Primary Safety Outcome MACE Events	Time to first event. Information collected during study period (anticipated to be up to 7.5 years).	The primary safety outcome variable is defined as the composite endpoint of cardiovascular death, nonfatal MI, or nonfatal stroke. The number of participants who had an event is reported in the results. The primary safety endpoint is the same as the primary efficacy endpoints, and the statistical analysis tests the non-inferiority of exenatide against placebo.

Secondary

Measure	Time frame	Description
Secondary Efficacy Outcome MI	Time to first event. Information collected during study period (anticipated to be up to 7.5 years).	Component of primary efficacy outcome: fatal or non-fatal MI. The number of participants who had an event is reported in the results.
Secondary Efficacy Outcome Stroke	Time to first event. Information collected during study period (anticipated to be up to 7.5 years).	Component of primary efficacy outcome: fatal or non-fatal stroke. The number of participants who had an event is reported in the results.
Secondary Efficacy Outcome All-Cause Mortality	Time to first event. Information collected during study period (anticipated to be up to 7.5 years).	The secondary efficacy outcome variable is defined as the all-cause mortality (deaths). The number of participants who had an event is reported in the results.
Secondary Efficacy Outcome Hospitalization for HF	Time to first event. Information collected during study period (anticipated to be up to 7.5 years).	The secondary efficacy outcome variable is defined as hospitalization for heart failure. The number of participants who had an event is reported in the results.
Secondary Efficacy Outcome Hospitalization for ACS	Time to first event. Information collected during study period (anticipated to be up to 7.5 years).	The secondary efficacy outcome variable is defined as hospitalization for acute coronary syndrome. The number of participants who had an event is reported in the results.
Secondary Efficacy Outcome CV Death	Time to first event. Information collected during study period (anticipated to be up to 7.5 years).	Component of the primary efficacy outcome: cardiovascular death. The number of participants who had an event is reported in the results.

Countries

Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, China, Colombia, Czechia, Germany, Hong Kong, Hungary, Israel, Italy, Latvia, Lithuania, Malaysia, Mexico, Netherlands, New Zealand, Philippines, Poland, Romania, Russia, Slovakia, South Africa, South Korea, Spain, Taiwan, Thailand, Ukraine, United Kingdom, United States

Participant flow

Participants by arm

Arm	Count
Placebo Matching placebo subcutaneous injections	7,396
Exenatide Once Weekly Exenatide 2mg once weekly subcutaneous injections	7,356
Total	14,752

Baseline characteristics

Characteristic	Placebo	Exenatide Once Weekly	Total
Age, Continuous	61.9 Years STANDARD_DEVIATION 9.4	61.8 Years STANDARD_DEVIATION 9.4	61.9 Years STANDARD_DEVIATION 9.4
Prior CV Event No	2008 Participants	1962 Participants	3970 Participants
Prior CV Event Yes	5388 Participants	5394 Participants	10782 Participants
Race/Ethnicity, Customized ASIAN	727 Participants	725 Participants	1452 Participants
Race/Ethnicity, Customized BLACK OR AFRICAN AMERICAN	436 Participants	442 Participants	878 Participants
Race/Ethnicity, Customized HISPANIC	557 Participants	577 Participants	1134 Participants
Race/Ethnicity, Customized INDIAN (AMERICAN ) OR ALASKA NATIVE	35 Participants	38 Participants	73 Participants
Race/Ethnicity, Customized MISSING	3 Participants	2 Participants	5 Participants
Race/Ethnicity, Customized NATIVE HAWAIIAN OR OTHER PACIFIC ISLANDER	17 Participants	18 Participants	35 Participants
Race/Ethnicity, Customized WHITE	5621 Participants	5554 Participants	11175 Participants
Region of Enrollment Global ASIA PACIFIC	760 Participants	769 Participants	1529 Participants
Region of Enrollment Global EUROPE	3399 Participants	3389 Participants	6788 Participants
Region of Enrollment Global LATIN AMERICA	1363 Participants	1364 Participants	2727 Participants
Region of Enrollment Global NORTH AMERICA	1874 Participants	1834 Participants	3708 Participants
Sex: Female, Male Female	2809 Participants	2794 Participants	5603 Participants
Sex: Female, Male Male	4587 Participants	4562 Participants	9149 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	584 / 7,372	507 / 7,344
other Total, other adverse events	0 / 0	0 / 0
serious Total, serious adverse events	1,222 / 7,372	1,234 / 7,344

Outcome results

Primary

Primary Efficacy Outcome MACE Events

The primary efficacy outcome variable is defined as the composite endpoint of cardiovascular death, nonfatal MI, or nonfatal stroke. The number of participants who had an event is reported in the results. The primary efficacy endpoint is the same as the primary safety endpoint, and the statistical analysis tests the superiority of exenatide against the placebo.

Time frame: Time to first event. Information collected during study period (anticipated to be up to 7.5 years).

Population: ITT population: all patients consented and randomized in the study without a major GCP violation. ITT population is analyzed as randomized.

Arm	Measure	Category	Value (COUNT_OF_PARTICIPANTS)
Placebo	Primary Efficacy Outcome MACE Events	Number of patients who had a MACE event	905 Participants
Exenatide Once Weekly	Primary Efficacy Outcome MACE Events	Number of patients who had a MACE event	839 Participants

p-value: 0.06195% CI: [0.832, 1.004]Regression, Cox

Primary

Primary Safety Outcome MACE Events

The primary safety outcome variable is defined as the composite endpoint of cardiovascular death, nonfatal MI, or nonfatal stroke. The number of participants who had an event is reported in the results. The primary safety endpoint is the same as the primary efficacy endpoints, and the statistical analysis tests the non-inferiority of exenatide against placebo.

Time frame: Time to first event. Information collected during study period (anticipated to be up to 7.5 years).

Population: ITT population: all patients consented and randomized in the study without a major GCP violation. ITT population is analyzed as randomized.

Arm	Measure	Category	Value (COUNT_OF_PARTICIPANTS)
Placebo	Primary Safety Outcome MACE Events	Number of patients who had a MACE event	905 Participants
Exenatide Once Weekly	Primary Safety Outcome MACE Events	Number of patients who had a MACE event	839 Participants

Comparison: This analysis uses the same endpoint and cox regression method as the primary efficacy analysis. However, the statistical hypothesis is a non-inferiority test with a margin of HR=1.3.p-value: <0.00195% CI: [0.832, 1.004]Regression, Cox

Secondary

Secondary Efficacy Outcome All-Cause Mortality

The secondary efficacy outcome variable is defined as the all-cause mortality (deaths). The number of participants who had an event is reported in the results.

Time frame: Time to first event. Information collected during study period (anticipated to be up to 7.5 years).

Population: ITT population: all patients consented and randomized in the study without a major GCP violation. ITT population is analyzed as randomized.

Arm	Measure	Category	Value (COUNT_OF_PARTICIPANTS)
Placebo	Secondary Efficacy Outcome All-Cause Mortality	Number of patients who died	584 Participants
Exenatide Once Weekly	Secondary Efficacy Outcome All-Cause Mortality	Number of patients who died	507 Participants

p-value: 0.01695% CI: [0.77, 0.97]Regression, Cox

Secondary

Secondary Efficacy Outcome CV Death

Component of the primary efficacy outcome: cardiovascular death. The number of participants who had an event is reported in the results.

Time frame: Time to first event. Information collected during study period (anticipated to be up to 7.5 years).

Population: ITT population: all patients consented and randomized in the study without a major GCP violation. ITT population is analyzed as randomized.

Arm	Measure	Category	Value (COUNT_OF_PARTICIPANTS)
Placebo	Secondary Efficacy Outcome CV Death	Number of patients who had CV death	383 Participants
Exenatide Once Weekly	Secondary Efficacy Outcome CV Death	Number of patients who had CV death	340 Participants

p-value: 0.09695% CI: [0.76, 1.02]Regression, Cox

Secondary

Secondary Efficacy Outcome Hospitalization for ACS

The secondary efficacy outcome variable is defined as hospitalization for acute coronary syndrome. The number of participants who had an event is reported in the results.

Time frame: Time to first event. Information collected during study period (anticipated to be up to 7.5 years).

Population: ITT population: all patients consented and randomized in the study without a major GCP violation. ITT population is analyzed as randomized.

Arm	Measure	Category	Value (COUNT_OF_PARTICIPANTS)
Placebo	Secondary Efficacy Outcome Hospitalization for ACS	Num of pts with hospitalization due to ACS	570 Participants
Exenatide Once Weekly	Secondary Efficacy Outcome Hospitalization for ACS	Num of pts with hospitalization due to ACS	602 Participants

p-value: 0.40295% CI: [0.94, 1.18]Regression, Cox

Secondary

Secondary Efficacy Outcome Hospitalization for HF

The secondary efficacy outcome variable is defined as hospitalization for heart failure. The number of participants who had an event is reported in the results.

Time frame: Time to first event. Information collected during study period (anticipated to be up to 7.5 years).

Population: ITT population: all patients consented and randomized in the study without a major GCP violation. ITT population is analyzed as randomized.

Arm	Measure	Category	Value (COUNT_OF_PARTICIPANTS)
Placebo	Secondary Efficacy Outcome Hospitalization for HF	Number of patients who died	231 Participants
Exenatide Once Weekly	Secondary Efficacy Outcome Hospitalization for HF	Number of patients who died	219 Participants

p-value: 0.48595% CI: [0.78, 1.13]Regression, Cox

Secondary

Secondary Efficacy Outcome MI

Component of primary efficacy outcome: fatal or non-fatal MI. The number of participants who had an event is reported in the results.

Time frame: Time to first event. Information collected during study period (anticipated to be up to 7.5 years).

Population: ITT population: all patients consented and randomized in the study without a major GCP violation. ITT population is analyzed as randomized.

Arm	Measure	Category	Value (COUNT_OF_PARTICIPANTS)
Placebo	Secondary Efficacy Outcome MI	Number of patients who died	493 Participants
Exenatide Once Weekly	Secondary Efficacy Outcome MI	Number of patients who died	483 Participants

p-value: 0.62295% CI: [0.85, 1.1]Regression, Cox

Secondary

Secondary Efficacy Outcome Stroke

Component of primary efficacy outcome: fatal or non-fatal stroke. The number of participants who had an event is reported in the results.

Time frame: Time to first event. Information collected during study period (anticipated to be up to 7.5 years).

Population: ITT population: all patients consented and randomized in the study without a major GCP violation. ITT population is analyzed as randomized.

Arm	Measure	Category	Value (COUNT_OF_PARTICIPANTS)
Placebo	Secondary Efficacy Outcome Stroke	Number of patients who had stroke	218 Participants
Exenatide Once Weekly	Secondary Efficacy Outcome Stroke	Number of patients who had stroke	187 Participants

p-value: 0.09595% CI: [0.7, 1.03]Regression, Cox

Exenatide Study of Cardiovascular Event Lowering Trial (EXSCEL): A Trial To Evaluate Cardiovascular Outcomes After Treatment With Exenatide Once Weekly In Patients With Type 2 Diabetes Mellitus

Conditions

Keywords

Brief summary

Related papers

Interventions

Sponsors

Study design

Eligibility

Inclusion criteria

Exclusion criteria

Design outcomes

Primary

Secondary

Countries

Participant flow

Participants by arm

Baseline characteristics

Adverse events

Outcome results

Primary Efficacy Outcome MACE Events

Primary Safety Outcome MACE Events

Secondary Efficacy Outcome All-Cause Mortality

Secondary Efficacy Outcome CV Death

Secondary Efficacy Outcome Hospitalization for ACS

Secondary Efficacy Outcome Hospitalization for HF

Secondary Efficacy Outcome MI

Secondary Efficacy Outcome Stroke