Trulicity® (dulaglutid): Kardiovaskulära resultat jämfört med andra GLP-1 receptoragonister

Detailed Information

The Researching CV Events with a Weekly INcretin in Diabetes (REWIND) study was an event-driven, randomized, double-blind, phase 3 study evaluating once-weekly dulaglutide 1.5 mg treatment compared with placebo when added to standard of care on a composite endpoint of MACE-3 in adults with T2DM and established CV disease and/or risk factors.^1,2

Since the REWIND study did not include active comparators, there is no data available on how dulaglutide would compare with other GLP-1 receptor agonists in regards to cardiovascular outcomes.¹

Design

The study evaluated the risk of MACE with once-weekly dulaglutide 1.5 mg treatment compared with placebo when added to standard of care in patients 50 years of age and older with T2DM and CV risk factors.³

The primary CV outcome measure was the first occurrence of the composite MACE-3, which includes death due to CV causes, nonfatal MI, or nonfatal stroke.³

Results

Dulaglutide 1.5 mg significantly reduced MACE-3 when compared to 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.²

Other GLP-1 Receptor Agonists CV Outcome Trials

Per regulatory guidance, CV outcome trials were conducted for other marketed GLP-1 receptor agonists. The table below describes the CV outcomes across the GLP-1 receptor agonist class(Table 1). 

Table 1. Key Characteristics of GLP-1 Receptor Agonist CV Outcome Trials

	ELIXA4	LEADER5	SUSTAIN-66	EXSCEL7	Harmony8	REWIND1,2
GLP-1 RA	lixisenatide daily	liraglutide daily	semaglutide weekly	exenatide weekly	albiglutide weekly	dulaglutide weekly
Dose	20 mcg	1.8 mg	0.5 mg or 1 mg	2.0 mg	30-50 mg	1.5 mg
# of Patients	6068	9340	3297	14752	9463	9901
Mean age,  y	60	64	65	62 (median)	64	66
Female, %	31	36	39	38	31	46
Prior CVD,a %	100b	81c	83d	73e	100f	31g
BMI, kg/m2	30	33	33	32h	32	32
HbA1c, %	7.7	8.7	8.7	8.0h	8.7	7.3
# of CV eventsi	805	1302	254	1744	766	1257
Median follow-up, y	2.1	3.8	2.1	3.2	1.6	5.4
Primary Outcome	MACE-4	MACE-3	MACE-3	MACE-3	MACE-3	MACE-3

Abbreviations: BMI = body mass index; CAD = coronary artery disease; CHF = congestive heart failure; CKD = chronic kidney disease; CRF = chronic renal failure; CV = cardiovascular; CVD = cardiovascular disease; ELIXA = the Evaluation of Lixisenatide in Acute Coronary Syndrome trial; EXSCEL = the EXenatide Study of Cardiovascular Event Lowering; GLP-1 RA = glucagon-like peptide-1 receptor agonist; HbA1c = glycated hemoglobin; HF = heart failure; LEADER = the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; MACE = major adverse cardiovascular events; MACE-3 = 3-component MACE; MACE-4 = 4-component MACE; MI = myocardial infarction; p = p-value; PAD = peripheral artery disease; PVD = peripheral vascular disease; REWIND = Researching Cardiovascular Events with a Weekly INcretin in Diabetes; SUSTAIN 6 = the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes.

^a Definitions of prior CVD vary by study, thus making cross-trial comparisons difficult.

^b ELIXA: acute coronary event within 180 days before screening.

^c LEADER: CVD, cerebrovascular disease, PVD, CRF, CHF.

^d 83.0% established CVD including CKD of stage 3 or higher.

^e EXSCEL: 73% at least one prior CV event (70% CAD, 24% PAD, 22% cerebrovascular disease).

^f HARMONY: established CVD includes at least one of the following: CAD, cerebrovascular disease, or PAD.

^g REWIND: ≥1 of the following, prior MI, ischemic stroke, unstable angina, revascularization, hospitalization for ischaemia-related events, or documented myocardial ischemia.

^h Median.

ⁱ Composite endpoint.

GLP-1 Receptor Agonist CV Outcome Trials Compared to US T2DM Population

Boye et al examined the generalizability of results from CV outcome trials in the US T2DM population with results from the 4 GLP-1 receptor agonist CV outcome trials

• EXSCEL

• LEADER

• REWIND, and

• SUSTAIN-6.⁹

When inclusion and exclusion criteria for each trial were applied to the US T2DM population, eligibility were

• 42.6% for REWIND

• 15.9% for EXSCEL

• 13.0% for SUSTAIN-6, and

• 12.9% for LEADER.⁹

References

1. Gerstein 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

2. Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. The Lancet. 2019;394(10193):121-130. https://doi.org/10.1016/S0140-6736(19)31149-3

3. Gerstein 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

4. Pfeffer MA, Claggett B, Diaz R, et al. ELIXA Investigators. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373(23):2247-2257. https://doi.org/10.1056/NEJMoa1509225.

5. Marso SP, Daniels GH, Brown-Frandsen K, et al. LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311-322. https://doi.org/10.1056/NEJMoa1603827.

6. Marso SP, Bain SC, Consoli A, et al. SUSTAIN-6 Investigators. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834-1844. https://doi.org/10.1056/NEJMoa1607141

7. Holman RR, Bethel MA, Mentz RJ, et al. EXSCEL Study Group. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2017;377(13):1228-1239. https://doi.org/10.1056/NEJMoa1612917

8. Hernandez AF, Green JB, Janmohamed S, et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): A double-blind, randomised placebo-controlled trial. The Lancet. 2018;392(10157):1519-1529. https://doi.org/10.1016/S0140-6736(18)32261-X

9. Boye KS, Riddle MC, Gerstein HC, et al. Generalizability of glucagon-like peptide-1 receptor agonist cardiovascular outcome trials to the overall type 2 diabetes population in the United States [published online February 3, 2019]. Diabetes Obes Metab. https://doi.org/10.1111/dom.13649

Glossary

CV = cardiovascular

LEADER = Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results

EXSCEL = EXenatide Study of Cardiovascular Event Lowering

GLP-1 = glucagon-like peptide-1

HR = hazard ratio

MACE = major adverse cardiovascular event

MACE-3 = major adverse cardiovascular events (death due to cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke)

MI = myocardial infarction

REWIND = Researching cardiovascular Events with a Weekly INcretin in Diabetes

SUSTAIN-6 = trial to evaluate cardiovascular and other long-term outcomes with semaglutide in subjects with type 2 diabetes

T2DM = type 2 diabetes mellitus