Takaisin

Eksenatidi ja kardiovaskulaaritapahtumat korkean kardiovaskulaaririskin omaavilla tyypin 2 diabetesta sairastavilla potilailla

Näytönastekatsaukset
Leo Niskanen ja Jorma Komulainen
7.2.2018

Näytön aste: C

Among patients with Type 2 Diabetes and high cardiovascular risk adding extended-release exenatide as compared to placebo does not seem to decrease the risk of major cardiovascular events.

A once-weekly, injectable, extended-release formulation of exenatide, an exendin-4–based GLP-1 receptor agonist approved for the treatment of type 2 diabetes, has been shown to lower blood glucose and induce modest decreases in body weight, blood pressure, and lipid level, but has also been shown to increase heart rate. In accordance with regulatory guidance the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) assessed the long-term cardiovascular safety and efficacy of exenatide, administered once weekly, in patients with type 2 diabetes who had a wide range of cardiovascular risk. A pragmatic, randomized, double-blind, placebo-controlled, event-driven trial was conducted at 687 sites in 35 countries. Patients with type 2 diabetes, with or without previous cardiovascular disease, were randomized to receive subcutaneous injections of extended-release exenatide at a dose of 2 mg or matching placebo once weekly. Adults with type 2 diabetes (defined as a glycated hemoglobin level of 6.5 to 10.0% [48 to 96 mmol per mole]) were eligible for participation in the trial. The trial was designed such that approximately 70% of enrolled patients would have had previous cardiovascular events and 30% would not have had previous cardiovascular events. Previous cardiovascular events were defined as a history of major clinical manifestation of coronary artery disease, ischemic cerebrovascular disease, or atherosclerotic peripheral arterial disease. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The coprimary hypotheses were that exenatide, administered once weekly, would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy. In all, 14,752 patients (of whom 10,782 [73.1%] had previous cardiovascular disease) were followed for a median of 3.2 years (interquartile range, 2.2 to 4.4). A primary composite outcome event occurred in 839 of 7356 patients (11.4%; 3.7 events per 100 person-years) in the exenatide group and in 905 of 7396 patients (12.2%; 4.0 events per 100 person-years) in the placebo group (hazard ratio, 0.91; 95% confidence interval [CI], 0.83 to 1.00), with the intention-to-treat analysis indicating that exenatide, administered once weekly, was noninferior to placebo with respect to safety (P<0.001 for noninferiority) but was not superior to placebo with respect to efficacy (P=0.06 for superiority). The rates of death from cardiovascular causes, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, hospitalization for heart failure, and hospitalization for acute coronary syndrome, and the incidence of acute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and serious adverse events did not differ significantly between the two groups. Among patients with type 2 diabetes with or without previous cardiovascular disease, the incidence of major adverse cardiovascular events did not differ significantly between patients who received exenatide and those who received placebo. (Funded by Amylin Pharmaceuticals; EXSCEL ClinicalTrials.gov number, NCT01144338 «http://clinicaltrials.gov/show/NCT01144338»1)

  • Study quality: Moderate
  • Applicability: Safety results may be generalized to T2D patients with lower cardiovascular risk.
  • Comment:
    • The study design did not include run-in-phase. Nearly half of the patients discontinued similarly from the placebo and exenatide group, most likely due to difficult (outdated) injection device and thus intention-to-treat-analysis may differ from on-treatment analysis (pending). Total mortality was lower (hazard ratio, 0.86 95% CI, 0.77 to 0.97); this difference was not considered to be statistically significant on the basis of the hierarchical testing plan.
    • The level of evidence is downgraded to C because of serious inaccuracy of the primary outcome measure.

Kirjallisuutta

  1. Holman RR, Bethel MA, Mentz RJ ym. Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2017;377:1228-1239 «PMID: 28910237»PubMed