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Trulicity ® (dulaglutide) injection
0.75 mg/0.5 mL, 1.5 mg/0.5 mL, 3mg/0.5mL, 4.5mg/0.5mL
This information is provided in response to your request. Resources may contain information about doses, uses, formulations and populations different from product labeling. See Prescribing Information above, if applicable.
Does Trulicity® (dulaglutide) have cardiovascular benefits?
The REWIND study, dulaglutide's cardiovascular outcomes trial, showed that dulaglutide 1.5 mg significantly reduced MACE-3 when compared to placebo.
See important safety information, including boxed warning, in the attached prescribing information.
Dulaglutide and Cardiovascular Outcomes
Indication
Dulaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated
- as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes, and
- to reduce the risk of major adverse cardiovascular events (MACEs) in adults with type 2 diabetes who have established cardiovascular (CV) disease or multiple CV risk factors.1
REWIND: Cardiovascular Outcomes Trial
REWIND was an event-driven, randomized, double-blind, placebo-controlled study of dulaglutide.2
The study evaluated the effect on major adverse cardiovascular events (death due to cardiovascular causes or unknown causes, nonfatal myocardial infarction, or nonfatal stroke) (MACE-3) and other serious outcomes with once-weekly dulaglutide 1.5 mg treatment compared with placebo when added to standard of care in participants 50 years of age and older with type 2 diabetes and established CV disease and/or risk factors.3
Key Inclusion/Exclusion Criteria
Eligible patients had
- newly diagnosed or an established type 2 diabetes diagnosis
- a glycated hemoglobin (HbA1c) value of 9.5% or lower
- been on stable doses of up to 2 oral glucose-lowering drugs with or without basal insulin
- a body mass index of ≥23 kg/m2, and
- vascular diseases or CV risk factors depending on their age ().2,3
If the participant's age was... |
Then they had to have... |
50-54 years old |
established CVDa. |
55-59 years old |
established CVDa or evidence of subclinical vascular diseaseb. |
60 years or older |
established CVDa, evidence of subclinical vascular diseaseb, or at least 2 other CV risk factorsc. |
Abbreviations: CV = cardiovascular; CVD = cardiovascular disease; eGFR = estimated glomerular filtration rate; HDL = high-density lipoprotein; LDL = low-density lipoprotein; MI = myocardial infarction; REWIND = Researching cardiovascular Events with a Weekly INcretin in Diabetes.
aPrior MI; prior ischemic stroke; coronary revascularization ≥2 years earlier; carotid or peripheral revascularization ≥2 months earlier; unstable angina hospitalization; image-proven myocardial ischemia; or percutaneous coronary intervention.
bDocumented myocardial ischemia by stress test or imaging; >50% coronary, carotid or lower extremity artery stenosis; ankle–brachial index <0.9; eGFR persistently <60 mL/min/1.73 m2 ; hypertension with left ventricular hypertrophy; or persistent albuminuria.
cAny tobacco use; use of lipid-modifying therapy or a documented untreated LDL cholesterol ≥3.4 mmol/L (130 mg/dL) within the past 6 months; HDL cholesterol <1.0 mmol/L (40 mg/dL) for men and <1.3 mmol/L (50 mg/dL) for women or triglycerides ≥2.3 mmol/L (200 mg/dL) within the past 6 months; use of ≥1 blood pressure drug or untreated systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥95 mm Hg; or waist-to-hip ratio >1.0 (men) and >0.8 (women).
Patients were excluded if they had
- cancer in the previous 5 years
- severe hypoglycemia in the previous year
- uncontrolled diabetes
- life expectancy <1 year
- liver disease
- a history of pancreatitis
- gastric bypass or emptying abnormalities
- an estimated glomerular filtration rate (eGFR) of less than 15 mL/min/1.73 m2 or on dialysis
- a coronary or cerebrovascular event in the last 2 months or plans to revascularize, or
- history of medullary C-cell hyperplasia or medullary thyroid cancer.2,3
Additionally, female patients were excluded if they were pregnant or not using a reliable form of birth control.2
Primary Outcome Measures
The primary outcome was the first occurrence of the composite MACE-3 endpoint, which included
Baseline Characteristics
A total of 9901 patients in 24 countries were randomized ( and ).3
Clinical Characteristics |
Dulaglutide |
Placebo |
Age, y, mean (SD) |
66.2 (6.5) |
66.2 (6.5) |
Females, n (%) |
2306 (46.6) |
2283 (46.1) |
DM duration, y, mean (SD) |
10.5 (7.3) |
10.6 (7.2) |
HbA1c, %, mean (SD) |
7.3 (1.1) |
7.4 (1.1) |
BMI, kg/m2, mean (SD) |
32.3 (5.7) |
32.3 (5.8) |
BP, mm Hg, mean (SD) |
137.1 (16.6)/78.4 (9.8) |
137.3 (17.0)/78.5 (9.9) |
Pulse, beats/min, mean (SD) |
71.4 (10.7) |
71.6 (11.0) |
Cholesterol, mg/dL, mean (SD) |
174.79 (44.86) |
174.79 (44.86) |
LDL cholesterol, mg/dL, mean (SD) |
98.99 (37.90) |
98.99 (37.90) |
HDL cholesterol, mg/dL, mean (SD) |
45.63 (12.76) |
45.63 (13.92) |
Triglycerides, mg/dL, median (IQR) |
141.72 (101.86-194.86) |
141.72 (106.29-199.29) |
eGFR, mL/min/1.73 m2, median (IQR) |
75.3 (61.6-91.8) |
74.7 (61.2-90.6) |
eGFR<60, mL/min/1.73 m2, n (%) |
1081 (21.8) |
1118 (22.6) |
Serum creatinine, mg/dL, mean (SD) |
0.95 (0.31) |
0.96 (0.31) |
UACR, mg/g, median (IQR) |
15.93 (6.19-58.41) |
16.64 (6.19-65.31) |
Albuminuriaa, n (%) |
1707 (34.5) |
1760 (35.5) |
Prior CV diseaseb, n (%) |
1560 (31.5) |
1554 (31.4) |
Prior hypertension, n (%) |
4605 (93.0) |
4619 (93.3) |
Prior heart failure, n (%) |
421 (8.5) |
432 (8.7) |
Prior diabetic retinopathy, n (%) |
448 (9.1) |
443 (8.9) |
Current tobacco use, n (%) |
694 (14.0) |
713 (14.4) |
Abbreviations: BMI = body mass index; BP = blood pressure; CV = cardiovascular; DM = diabetes mellitus; eGFR = estimated glomerular filtration rate; HbA1c = glycated hemoglobin; HDL = high-density lipoprotein; IQR = interquartile range; LDL = low-density lipoprotein; REWIND = Researching cardiovascular Events with a Weekly INcretin in Diabetes; UACR = urinary albumin-to-creatinine ratio.
aUACR ≥30 mg/g.
bMyocardial infarction, ischemic stroke, unstable angina with electrocardiogram changes, myocardial ischemia on imaging or stress test, or coronary, carotid, or peripheral revascularization.
Parametera |
Dulaglutide |
Placebo |
Use of DM-specific drug classes |
||
Any insulin |
1189 (24.0) |
1174 (23.7) |
Metformin |
4022 (81.3) |
4015 (81.1) |
Sulfonylureas |
2270 (45.9) |
2282 (46.1) |
DPP-4 inhibitors |
266 (5.4) |
298 (6.0) |
Thiazolidinediones |
100 (2.0) |
68 (1.4) |
Other glucose-lowering drugs |
14 (0.3) |
18 (0.4) |
Use of CV-specific drug classes |
||
ACE inhibitors or ARBs |
4009 (81.0) |
4059 (82.0) |
Beta blockers |
2237 (45.2) |
2274 (45.9) |
Other blood pressure medications |
2767 (55.9) |
2833 (57.2) |
Antiplatelets |
2662 (53.8) |
2680 (54.1) |
Statins |
3279 (66.3) |
3268 (66.0) |
Fibrates |
452 (9.1) |
446 (9.0) |
Abbreviations: ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; CV = cardiovascular; DM = diabetes mellitus; DPP-4 = dipeptidyl peptidase-4; REWIND = Researching cardiovascular Events with a Weekly INcretin in Diabetes.
aData presented as n (%).
Statistical Analysis
The primary outcome was evaluated by time-to-event analyses.3
Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and calculate 95% CIs. The statistical significance of the effect of the intervention was based on the p value from the Cox model. To adjust for a prespecified interim analysis and to maintain an overall Type I error of 0.05, the final 2-sided p value for superiority was 0.0467.3
Key secondary objectives followed a prespecified graphical statistical approach for multiple comparisons to control the overall Type I error rate at a 2-sided α-level of 0.05 (adjusted for interim analysis). With this approach, allocating percentages of alpha to each hypothesis according to the prespecified scheme was used to determine statistical significance of the individual components of the primary endpoint and the other key secondary endpoints.3
Results
Dulaglutide 1.5 mg significantly reduced MACE-3 compared with placebo (HR=0.88 [95% CI, 0.79-0.99]; p=.026), demonstrating a decrease in CV events and showing safety in a population that included a majority of participants without established CV disease.3
Each component of MACE-3 is described in .3
CV Parameter |
HR (95% CI) |
Nonfatal MI |
0.96 (0.79-1.16) |
Nonfatal stroke |
0.76 (0.61-0.95) |
CV deatha |
0.91 (0.78-1.06) |
Abbreviations: CV = cardiovascular; HR = hazard ratio; MACE-3 = major adverse cardiovascular events (death due to cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke); MI = myocardial infarction.
aIncludes deaths of unknown cause.
Patients receiving dulaglutide had a lower incidence (HR=0.87 [95% CI, 0.79-0.95]; p=.002) of the composite microvascular outcome compared to patients receiving placebo ().3
Parameter |
HR (95% CI) |
Composite microvascular outcomea |
0.87 (0.79-0.95) |
Eye outcomesb |
1.24 (0.92-1.68) |
Renal outcomesc |
0.85 (0.77-0.93) |
Abbreviations: eGFR = estimated glomerular filtration rate; HR = hazard ratio.
aEye or renal outcome.
bPhotocoagulation, anti-vascular endothelial growth factor therapy, or vitrectomy.
cNew macroalbuminuria, a sustained decline in eGFR of 30% or more from baseline, or chronic renal replacement therapy.
The incidence of all-cause mortality, heart failure, revascularization, hospital admissions, fractures, or cholelithiasis were not significantly affected by dulaglutide treatment.3
Safety
The median follow-up time in REWIND was 5.4 years. Dulaglutide did not differ significantly from placebo in frequencies of prespecified adverse events of special interest including first study drug discontinuation, serious gastrointestinal events, severe hypoglycemia, cancers, or pancreatitis ().3
Parametera |
Dulaglutide |
Placebo |
P Value |
First study drug DC |
2092 (42.3) |
2171 (43.8) |
.38 |
Acute pancreatitisb |
23 (0.5) |
13 (0.3) |
.11 |
Any cancerc |
351 (7.1) |
348 (7.0) |
.98 |
Medullary thyroid carcinoma or C-cell hyperplasiad |
1 (<0.1) |
0 |
.32 |
Thyroid cancer |
7 (0.1) |
3 (0.1) |
.21 |
Pancreatic cancer |
19 (0.4) |
12 (0.2) |
.22 |
Serious GI event |
120 (2.4) |
117 (2.4) |
.87 |
Serious hepatic event |
25 (0.5) |
40 (0.8) |
.057 |
Serious renal or urinary evente |
84 (1.7) |
93 (1.9) |
.46 |
Immune reactions |
8 (0.2) |
20 (0.4) |
.022 |
Severe hypoglycemia |
64 (1.3) |
74 (1.5) |
.38 |
Supraventricular tachycardia or CV conduction disorders |
216 (4.4) |
192 (3.9) |
.26 |
Abbreviations: CV = cardiovascular; DC = discontinuation; GI = gastrointestinal; REWIND = Researching cardiovascular Events with a Weekly INcretin in Diabetes.
aData presented as n (%).
bBased on the first occurrence of acute pancreatitis, diagnosed on the basis of at least 2 of the 3 diagnostic criteria (symptoms, elevated pancreatic enzymes, or an abnormal pancreatic image).
cExcluding nonmelanoma skin cancers.
dThere were no cases of medullary thyroid carcinoma.
eBased on a search of the REWIND database for any reported adverse event linked to acute renal failure.
Enclosed Prescribing Information
References
The published references below are available by contacting 1-800-LillyRx (1-800-545-5979).
1Trulicity [package insert]. Indianapolis, IN: Eli Lilly and Company; 2021.
2Gerstein HC, Colhoun HM, Dagenais GR, et al; REWIND Trial Investigators. 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. https://doi.org/10.1111/dom.13028
3Gerstein HC, Colhoun HM, Dagenais GR, et al; REWIND Investigators. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019;394(10193):121-130. https://doi.org/10.1016/S0140-6736(19)31149-3
Date of Last Review: May 06, 2022