With the addition of the CV indication, Trulicity is proven to do more1
Trulicity has proven MACE-3 risk reduction* in both primary and secondary prevention† patients1
CV = cardiovascular
*Trulicity 1.5 mg reduced the risk of MACE-3 (CV death, nonfatal MI, or nonfatal stroke) by 12% in patients without established CVD who have multiple CV risk factors and patients with established CVD.2
†Primary prevention: Reducing the risk of atherosclerotic cardiovascular disease (ASCVD) by preventing or managing risk factors. Secondary prevention: Reducing the risk of another event in people who have had a serious CV incident or procedure.3
A GLP-1 RA CVOT designed differently than any other2,4-10
REWIND is the only GLP-1 RA CVOT to include a majority of patients without established CVD*
No comparison can be made between GLP-1 RA CVOT outcomes due to differences in study design, population, and key inclusion/exclusion criteria.
*In REWIND, patients without established CV disease had multiple CV risk factors.
†In a study that evaluated the generalizability of the results of GLP-1 RA CVOTs to the overall population of type 2 diabetes patients in the US, key baseline characteristics of four GLP-1 RA CVOTs (EXSCEL, LEADER, REWIND, and SUSTAIN-6) were compared to the characteristics in a reference of the general type 2 diabetes population (primarily from IQVIA database). Based on its criteria, 42.6% of the reference population were eligible for enrollment in REWIND, versus 15.9% in EXSCEL, 13.0% in SUSTAIN-6, and 12.9% in LEADER. None of the trials were fully representative of the reference population, which included commercially insured patients <65 years of age, but may not be aligned to the general population.9
CVOT=cardiovascular outcomes trial; GLP-1 RA=glucagon-like peptide-1 receptor agonist; CVD=cardiovascular disease;
CV=cardiovascular; MI=myocardial infarction
Trulicity is the first and only GLP-1 RA to reduce the risk of CV death, nonfatal MI, or nonfatal stroke* in both primary and secondary prevention† patients1
*Trulicity 1.5 mg reduced the risk of MACE-3 (CV death, nonfatal MI, or nonfatal stroke) by 12% in patients without established CVD who have multiple CV risk factors and patients with established CVD.2
†Primary prevention: Reducing the risk of atherosclerotic cardiovascular disease (ASCVD) by preventing or managing risk factors. Secondary prevention: Reducing the risk of another event in people who have had a serious CV incident or procedure.3
CV indications for GLP-1 RAs‡
‡Indicated for risk reduction of major adverse CV events (CV death, nonfatal MI, or nonfatal stroke) for patients with type 2 diabetes.
MI=myocardial infarction
This chart includes oral or injectable GLP-1 RAs that are marketed in the US and have a CVOT.
Trulicity showed a significant reduction of MACE-3,* even with a majority primary prevention patient population†2
Median follow-up was 5.4 years with the Kaplan-Meier curves starting to diverge within the first year.
Trulicity is indicated to reduce the risk of major adverse CV events (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke) in adults with type 2 diabetes mellitus.1
- Without established CVD who have multiple CV risk factors
- With established CVD
The primary composite outcome (MACE-3) occurred in 594 (12.0%) participants assigned to Trulicity + standard of care and 663 (13.4%) participants assigned to placebo + standard of care (hazard ratio [HR] 0.88, 95% confidence interval [CI] 0.79-0.99; P=.026).
The safety profile of Trulicity was consistent with the GLP-1 receptor agonist class.2 The most common adverse events leading to the discontinuation of Trulicity were gastrointestinal events.15
*MACE-3 is a composite outcome comprising CV death, nonfatal MI, or nonfatal stroke.
†Primary prevention: Reducing the risk of ASCVD by preventing or managing risk factors.
Secondary prevention: Reducing the risk of another event in people who have had a serious CV incident or procedure.3
In the Trulicity CVOT, risk reduction was seen even with a relatively well-controlled mean baseline A1C for patients with type 2 diabetes2,4
REWIND participants had lower baseline A1C levels compared to other GLP-1 RA CVOTs 2,4-8,10,16
Mean Baseline A1C
No comparison can be made between GLP-1 RA CVOT outcomes due to differences in study design, population, and key inclusion/exclusion criteria.
Trulicity CVOT study description2,4
REWIND was a global, randomized, double-blind, placebo-controlled, event-driven study
REWIND did not include patients with a coronary or cerebrovascular event within 2 months prior to randomization or plans to revascularize, and an eGFR<15 mL/min/1.73m2 or on dialysis.
CV=cardiovascular; CVD=cardiovascular disease; OADs=oral antidiabetic drugs; MACE-3=major adverse cardiovascular events; MI=myocardial infarction
REWIND study description2,4
- Multicenter, randomized, double-blind, placebo-controlled, event-driven trial designed to assess whether once-weekly Trulicity 1.5 mg safely reduces the incidence of cardiovascular (CV) outcomes compared to placebo in adult patients with type 2 diabetes with and without CVD
- Key inclusion criteria: Established or newly detected type 2 diabetes with an A1C ≤9.5%; stable dose of up to 2 oral glucose-lowering drugs with or without basal insulin; BMI ≥23 kg/m2; age ≥50 years with established clinical vascular disease*, OR age ≥55 years and subclinical† vascular disease, OR age ≥60 years and at least 2 or more CV risk factors‡
- Key exclusion criteria: Uncontrolled diabetes; severe hypoglycemia in preceding year; coronary or cerebrovascular event in preceding 2 months; plans to revascularize; estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m2; on dialysis; gastric bypass or emptying abnormality; prior pancreatitis; liver disease; family or personal history of C-cell hyperplasia, medullary thyroid cancer, multiple endocrine neoplasia (MEN) 2A or 2B, or calcitonin ≥20 pg/mL; unwilling to stop GLP-1 RA, dipeptidyl peptidase-4 (DPP-4) inhibitor, or weight loss drug; cancer within preceding 5 years; possible pregnancy; life expectancy <1 year
- 9901 patients were randomized to receive Trulicity 1.5 mg or same volume of placebo in addition to standard of care treatments such as oral antidiabetic treatments, insulin, and antihypertensive, antiplatelet, and lipid-lowering therapies; patients were assessed every 6 months until 1200 confirmed primary outcomes had accrued
- Primary outcome was the first occurrence of the composite of either nonfatal MI, nonfatal stroke, or CV death (MACE-3). All outcomes occurring on or after randomization were included in analysis; Kaplan-Meier estimates were used to generate cumulative risks and Cox proportional hazard models were used to determine the effect of intervention on the outcome and to estimate HR and 95% CIs
Study results2
The primary composite outcome, major adverse cardiovascular events (MACE-3), occurred in 594 (12.0%) participants assigned to Trulicity and 663 (13.4%) participants assigned to placebo (hazard ratio [HR] 0.88, 95% confidence interval [CI] 0.79-0.99; P=.026).
Study Groups2,4
Placebo (n=4952)
Trulicity 1.5 mg QW, SC (n=4949)
*History of myocardial infarction (MI), ischemic stroke, revascularization, hospitalization for unstable angina with concordant new ischemic electrocardiogram changes, or a positive stress test with concordant imaging.4
†Myocardial ischemia, coronary, carotid, or lower extremity artery stenosis exceeding 50%, ankle to brachial index <0.9, hypertension with left ventricular hypertrophy, eGFR <60 mL/min per 1.73m2, or albuminuria.4
‡Tobacco use, dyslipidemia, hypertension, or abdominal obesity.2
Therapies at baseline
Most REWIND participants were taking various CV and antidiabetic medications at the beginning of the study2
CV therapies at baseline
Antidiabetic medications at baseline
ACE=angiotensin-converting enzyme; ARB=angiotensin-receptor blocker
Study Descriptions
REWIND2,4
- Multicenter, randomized, double-blind, placebo-controlled, event-driven trial designed to assess whether once-weekly Trulicity 1.5 mg safely reduces the incidence of cardiovascular (CV) outcomes compared to placebo in adult patients with type 2 diabetes with and without CVD
- Key inclusion criteria: Established or newly detected type 2 diabetes with an A1C ≤9.5%; stable dose of up to 2 oral glucose-lowering drugs with or without basal insulin; BMI ≥23 kg/m2; age ≥50 years with established clinical vascular disease*, OR age ≥55 years and subclinical† vascular disease, OR age ≥60 years and at least 2 or more CV risk factors‡
- Key exclusion criteria: Uncontrolled diabetes; severe hypoglycemia in preceding year; coronary or cerebrovascular event in preceding 2 months; plans to revascularize; estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m2; on dialysis; gastric bypass or emptying abnormality; prior pancreatitis; liver disease; family or personal history of C-cell hyperplasia, medullary thyroid cancer, multiple endocrine neoplasia (MEN) 2A or 2B, or calcitonin ≥20 pg/mL; unwilling to stop GLP-1 RA, dipeptidyl peptidase-4 (DPP-4) inhibitor, or weight loss drug; cancer within preceding 5 years; possible pregnancy; life expectancy <1 year
- 9901 patients were randomized to receive Trulicity 1.5 mg or same volume of placebo in addition to standard of care treatments such as oral antidiabetic treatments, insulin, and antihypertensive, antiplatelet, and lipid-lowering therapies; patients were assessed every 6 months until 1200 confirmed primary outcomes had accrued
- Primary outcome was the first occurrence of the composite of either nonfatal MI, nonfatal stroke, or CV death (MACE-3). All outcomes occurring on or after randomization were included in analysis; Kaplan-Meier estimates were used to generate cumulative risks and Cox proportional hazard models were used to determine the effect of intervention on the outcome and to estimate HR and 95% CIs
*History of myocardial infarction (MI), ischemic stroke, revascularization, hospitalization for unstable angina with concordant new ischemic electrocardiogram changes, or a positive stress test with concordant imaging.4
†Myocardial ischemia, coronary, carotid, or lower extremity artery stenosis exceeding 50%, ankle to brachial index <0.9, hypertension with left ventricular hypertrophy, eGFR <60 mL/min per 1.73m2, or albuminuria.4
‡Tobacco use, dyslipidemia, hypertension, or abdominal obesity.2
EXSCEL5
- Pragmatic, randomized, double-blind, placebo-controlled, parallel-group, event-driven trial to assess the long-term cardiovascular safety and efficacy of Bydureon in patients with type 2 diabetes
- Key inclusion criteria: ≥18 years of age with an A1C ≥6.5% to ≤10.0%; had been treated with ≤3 oral antihyperglycemic agents or insulin, alone or in combination with ≤2 oral antihyperglycemic agents; designed to have approximately 70% of patients with previous cardiovascular events defined as at least one of the following: history of major clinical manifestation of coronary artery disease (myocardial infarction, coronary revascularization, or coronary angiography showing at least one stenosis ≥50%); ischemic cerebrovascular disease (history of ischemic stroke or history of carotid disease with ≥50% stenosis); or atherosclerotic peripheral arterial disease (amputation, ankle to brachial index or toe to brachial index <0.9, or history of revascularization)
- 14752 patients were randomized to receive either Bydureon 2 mg (QW, SC) or matched placebo, in addition to standard of care
- Primary composite outcome was the first occurrence of nonfatal myocardial infarction, nonfatal stroke, or CV death
LEADER6
- Multicenter, randomized, double-blind, placebo-controlled, time- and event-driven trial to assess the long-term effects of Victoza on CV outcomes and other clinically important events in patients with type 2 diabetes
- Key inclusion criteria: Patients with type 2 diabetes with an A1C ≥7.0%, not previously treated with drugs for type 2 diabetes or had been treated with one or more antihyperglycemic agents with or without insulin, ≥50 years of age with at least one CV condition (coronary heart disease, cerebrovascular disease, peripheral vascular disease, chronic kidney disease of stage ≥3, or chronic heart failure [New York Heart Association class II or III]), ≥60 years of age with at least one CV risk factor (microalbuminuria or proteinuria, hypertension and left ventricular hypertrophy, left ventricular systolic or diastolic dysfunction, or an ankle to brachial index <0.9)
- 9340 patients were randomized to receive either Victoza 1.8 mg (or maximum tolerated dose QD, SC) or matched placebo, in addition to standard of care
- Primary composite outcome was the first occurrence of nonfatal myocardial infarction, nonfatal stroke, or CV death
SUSTAIN-67
- Randomized, double-blind, placebo-controlled, parallel-group, event-driven trial to assess the noninferiority of Ozempic as compared to placebo in terms of cardiovascular safety in patients with type 2 diabetes
- Key inclusion criteria: Type 2 diabetes and an A1C ≥7.0%; not previously treated for type 2 diabetes with an antihyperglycemic drug or had been treated with ≤2 oral antihyperglycemic agents with or without basal or premixed insulin; ≥50 years of age with established cardiovascular disease (previous cardiovascular, cerebrovascular, or peripheral vascular disease), chronic heart failure (New York Heart Association class II or III), or chronic kidney disease stage ≥3; ≥60 years of age with at least one CV risk factor (microalbuminuria or proteinuria, hypertension and left ventricular hypertrophy, left ventricular systolic or diastolic dysfunction, or an ankle to brachial index <0.9)
- 3297 patients were randomized to receive either Ozempic 0.5 mg or 1.0 mg (QW, SC) or volume-matched placebo, in addition to standard of care
- Primary composite outcome was the first occurrence of nonfatal myocardial infarction, nonfatal stroke, or CV death
PIONEER-68,9
- Randomized, double-blind, placebo-controlled, event-driven trial to assess the cardiovascular safety of Rybelsus in patients with type 2 diabetes
- Key inclusion criteria: Patients with type 2 diabetes, age ≥50 years with established CVD (prior myocardial infarction; prior stroke or transient ischemic attack; prior coronary, carotid or peripheral arterial revascularization; >50% stenosis of coronary, carotid, or lower extremity arteries; documented history of symptomatic coronary heart disease; documented asymptomatic cardiac ischemia or chronic heart failure [New York Heart Association class II or III]) or moderate (stage 3) chronic kidney disease; age ≥60 years with at least one cardiovascular risk factor (microalbuminuria or proteinuria, hypertension and left ventricular hypertrophy, left ventricular systolic or diastolic dysfunction, or ankle to brachial index <0.9)
- 3183 patients were randomized to receive either Rybelsus (target dose of 14 mg QD, PO) or placebo, in addition to standard of care
- Primary composite outcome was the first occurrence of nonfatal myocardial infarction, nonfatal stroke, or CV death
ELIXA10
- Multicenter, randomized, double-blind, placebo-controlled, event-driven trial to assess the effect of Adlyxin on cardiovascular outcomes in patients with type 2 diabetes who had had a recent acute coronary syndrome, defined as an ST-segment elevation myocardial infarction (STEMI), non-STEMI, or unstable angina
- Key inclusion criteria: Patients with type 2 diabetes who had had an acute coronary event ≤180 days prior to screening
- Key exclusion criteria: Age less than 30 years, A1C less than 5.5% or greater than 11%
- 6068 patients were randomized to receive either Adlyxin 10-20ug (QD, SC) or placebo, in addition to standard of care
- Primary composite outcome was the first occurrence of nonfatal myocardial infarction, nonfatal stroke, CV death or hospitalization for unstable angina
Indications and Limitations of Use
Trulicity1
Indication: Trulicity (dulaglutide) is indicated:
- as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
- to reduce the risk of major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) in adults with type 2 diabetes mellitus who have established cardiovascular disease or multiple cardiovascular risk factors.
Limitations of Use
- Has not been studied in patients with a history of pancreatitis. Consider other antidiabetic therapies in these patients.
- Not for the treatment of type 1 diabetes mellitus.
- Has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis and is therefore not recommended in these patients.
Rybelsus11
Indication: Rybelsus is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Limitations of Use
- Rybelsus is not recommended as a first-line therapy for patients who have inadequate glycemic control on diet and exercise because of the uncertain relevance of rodent C-cell tumor findings to humans.
- Rybelsus has not been studied in patients with a history of pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis.
- Rybelsus is not indicated for use in patients with type 1 diabetes mellitus or for the treatment of patients with diabetic ketoacidosis, as it would not be effective in these settings.
Ozempic12
Indication: Ozempic is indicated:
- as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
- to reduce the risk of major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction or nonfatal stroke) in adults with type 2 diabetes mellitus and established cardiovascular disease.
Limitations of Use
- Ozempic has not been studied in patients with a history of pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis.
- Ozempic is not a substitute for insulin. Ozempic is not indicated for use in patients with type 1 diabetes mellitus or for the treatment of patients with diabetic ketoacidosis, as it would not be effective in these settings.
Victoza13
Indication: Victoza is indicated:
- as an adjunct to diet and exercise to improve glycemic control in patients 10 years and older with type 2 diabetes mellitus,
- to reduce the risk of major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) in adults with type 2 diabetes mellitus and established cardiovascular disease.
Limitations of Use
- Victoza should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.
- The concurrent use of Victoza and prandial insulin has not been studied.
Bydureon14
Indication: Bydureon is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Limitations of Use
- Bydureon is not recommended as first-line therapy for patients who have inadequate glycemic control on diet and exercise because of the uncertain relevance of the rat thyroid C-cell tumor findings to humans.
- Bydureon is not a substitute for insulin. Bydureon is not indicated for use in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.
- The concurrent use of Bydureon with prandial insulin has not been studied.
- Bydureon is an extended-release formulation of exenatide. Bydureon should not be used with other products containing the active ingredient exenatide.
- Bydureon has not been studied in patients with a history of pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis.
References
- Trulicity [Prescribing Information]. Indianapolis, IN: Lilly USA, LLC.
- Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double‐blind, randomised placebo‐controlled trial. Lancet. 2019;394(10193):121‐130.
- Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;139(25):e1082-e1143.
- Gerstein HC, Colhoun HM, Dagenais GR, et al. Design and baseline characteristics of participants in the Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial on the cardiovascular effects of dulaglutide. Diabetes Obes Metab. 2018;20(1):42‐49.
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Holman RR, Bethel MA, Mentz RJ, et al. Effects of once‐weekly exenatide on cardiovascular outcomes in type 2 diabetes.
N Engl J Med. 2017;377(13):1228‐1239. - Marso SP, Daniels GH, Brown‐Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311‐322.
- Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834‐1844.
- Husain M, Birkenfeld AL, Donsmark M, et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2019;381(9):841‐851.
- Bain SC, Mosenzon O, Arechavaleta R, et al. Cardiovascular safety of oral semaglutide in patients with type2 diabetes: rationale, design and patient baseline characteristics for the PIONEER 6 trial. Diabetes Obes Metab. 2019;21(3):499‐508.
- Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373(23):2247‐2257.
- Rybelsus [Prescribing Information]. Bagsvaerd, Denmark: Novo Nordisk A/S.
- Ozempic [Prescribing Information]. Bagsvaerd, Denmark: Novo Nordisk A/S.
- Victoza [Prescribing Information]. Bagsvaerd, Denmark: Novo Nordisk A/S.
- Bydureon [Prescribing Information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP.
- Data on file, Lilly USA, LLC. DOF-DG-US-0105.
- Bentley‐Lewis R, Aguilar D, Riddle MC, et al. Rationale, design, and baseline characteristics in Evaluation of LIXisenatide in Acute Coronary Syndrome, a long‐term cardiovascular end point trial of lixisenatide versus placebo. Am Heart J. 2015;169(5):631‐638.