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EXSCEL

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

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Year of Publication: 2017

Authors: Rury R. Holman, M. Angelyn Bethel, Robert J. Mentz, ..., for the EXSCEL Study Group

Journal: New England Journal of Medicine

Citation: N Engl J Med 2017;377:1228–1239. DOI: 10.1056/NEJMoa1612917

Link: https://www.nejm.org/doi/full/10.1056/NEJMoa1612917

PDF: https://www.nejm.org/doi/pdf/10.1056/NEJMoa1612917

Clinical Question

Does once-weekly exenatide reduce major cardiovascular events compared to placebo in patients with type 2 diabetes with or without established cardiovascular disease?

Bottom Line

Exenatide was noninferior but not superior to placebo for cardiovascular safety in patients with type 2 diabetes, and showed no statistically significant reduction in major adverse cardiovascular events (MACE).

        Major Points
        Large pragmatic RCT (N=14,752) assessing once-weekly exenatide vs. placebo in type 2 diabetes.
Median follow-up 3.2 years; 73% had prior cardiovascular disease.
Primary MACE outcome occurred in 11.4% (exenatide) vs. 12.2% (placebo); HR 0.91 (95% CI 0.83–1.00); P<0.001 for noninferiority, P=0.06 for superiority.
No significant difference in cardiovascular death, MI, stroke, or hospitalization for heart failure.
Exenatide showed modest reductions in HbA1c, weight, SBP, but increased heart rate.
No excess in severe hypoglycemia, pancreatitis, or cancer, including thyroid carcinoma.

      

Design

Study Type: Multicenter, double-blind, placebo-controlled, randomized trial

Randomization: 1

Blinding: Double-blind

Enrollment Period: June 2010 – September 2015

Follow-up Duration: Median 3.2 years (up to 6.8 years)

Centers: 687

Countries: 35 countries including USA, UK, India, China, Australia, Europe, Latin America

Sample Size: 14752

Analysis: Intention-to-treat and per-protocol; Cox regression stratified by CV disease history

Inclusion Criteria

Adults with type 2 diabetes
HbA1c 6.5–10.0%
± history of major cardiovascular disease
Allowed up to 3 oral agents or insulin ± 2 oral agents

Exclusion Criteria

≥2 severe hypoglycemia episodes in past year
eGFR <30 ml/min/1.73m²
Personal/family history of medullary thyroid carcinoma or MEN2
Prior GLP-1 receptor agonist use

Baseline Characteristics

Characteristic	Comorbidities	Qualifying Event
Diabetes	100

Arms

Field	Exenatide	Control
Intervention	Extended-release exenatide 2 mg SC weekly	Matching placebo SC weekly
Duration	Median 2.4 years	Median 2.3 years

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
First occurrence of MACE (CV death, nonfatal MI, nonfatal stroke)	Primary	12.2%	11.4%	0.91	0.06
Death from any cause \| 95% CI: 0.77–0.97	Secondary	7.9%	6.9%	0.86	NS
CV death \| 95% CI: 0.76–1.02	Secondary	5.2%	4.6%	0.88	NS
Nonfatal MI \| 95% CI: 0.85–1.10	Secondary	6.7%	6.6%	0.97	NS
Nonfatal stroke \| 95% CI: 0.70–1.03	Secondary	2.9%	2.5%	0.85	NS
Acute pancreatitis	Adverse		0.4% vs. 0.3%
Pancreatic cancer	Adverse		0.2% vs. 0.2%
Medullary thyroid carcinoma	Adverse		<0.1% in both groups
Severe hypoglycemia	Adverse		3.4% vs. 3.0%; not statistically significant

Subgroup Analysis

No significant heterogeneity except by age <65 vs ≥65 (P=0.005); most subgroups showed consistent direction of effect

Criticisms

High discontinuation rate (24%)
Modest treatment effect on metabolic parameters
Placebo group had more use of other cardioprotective agents (SGLT-2, GLP-1RA)
Shorter exposure time and lower baseline HbA1c than LEADER/SUSTAIN-6

Funding

Amylin Pharmaceuticals (subsidiary of AstraZeneca)

Based on: EXSCEL (New England Journal of Medicine, 2017)