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Potential Effects of Exenatide Once-Weekly on Glycemic Control and CV Risk

Injectable extended-release formulation of exenatide in patients with T2DM at a wide range of heart disease risk appeared not to cause increase in overall risk.

Patients with type 2 diabetes mellitus (T2DM) often exhibit several comorbidities such as obesity, hypertension, and dyslipidemia that are associated with an increased probability of cardiovascular (CV) disease. Although diet and exercise intervention can improve hyperglycemia and the comorbidities associated with T2DM, most patients eventually require pharmacotherapy to control hyperglycemia. Many antihyperglycemia agents are associated with weight gain, which may exacerbate hypertension and dyslipidemia. Thus, additional therapy is often needed to treat associated comorbidities. Studies have been done to find an agent that can improve glycemic control without increased CV risk. Exenatide is a glucagon-like peptide-1 receptor agonist (GLP-1RA) that approved for T2DM therapy in a twice-daily formulation and recently was approved as once-weekly formulation that provides sustained exenatide concentrations for greater glucose control. It has been shown to improve glycemic control in patients with T2DM through multiple mechanisms of action including increased glucose-dependent insulin secretion, attenuated postprandial glucagon secretion, slowed gastric emptying and increased satiety.

In a recent randomized, double-blind, placebo-controlled, event-driven trial at 687 sites in 35 countries, the multinational exenatide study of cardiovascular event lowering (EXSCEL) assessed the long-term cardiovascular safety and efficacy of exenatide once-weekly formulation in 14,752 patients who had a wide range of cardiovascular risk and a median duration of 12 years with T2DM. Out of the 14,752 patients, 7,356 patients were randomly assigned to receive subcutaneous injections of extended-release exenatide at a dose of 2 mg and 7396 patients to receive placebo once weekly. Both groups have a well-balanced baseline characteristics and about three-quarters of the patients (73.1%, n=10,782) had history of cardiovascular disease. Most of the patients were obese with mean body mass index of 32 kg/m2. The median duration of follow up was 3.2 years (interquartile range, 2.2 to 4.4; maximum, 6.8).

Other medications for diabetes were permitted, except for GLP-1 receptor agonists. Three-quarters of patients were using metformin, one-third were taking sulfonylureas, 45% were also using insulin, 12% dipeptidyl peptidase-4 inhibitors, and a small number were using sodium glucose cotransporter-2 (SGLT2) inhibitors.

According to the study results that were published on September 14, 2017 in New England Journal of Medicine, exenatide once-weekly formulation 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 primary outcome was defined as the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (three-component MACE outcome). A primary outcome event occurred in 11.4% of patients taking exenatide over a median of 3.2 years (in 839 of 7356 patients, 3.7 events per 100 person-years) and in 12.2% of patients taking placebo (in 905 of 7396 patients, 4.0 events per 100 person-years); (hazard ratio, 0.91; 95% confidence interval [CI], 0.83 to 1.00). The secondary outcome was that exenatide would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy. The risk of death from any cause was 6.9% in the exenatide group and 7.9% in the placebo group (hazard ratio, 0.86; 95% CI, 0.77 to 0.97), this difference was not considered to be statistically significant. Events of acute pancreatitis, pancreatic cancer, and medullary thyroid carcinoma were uncommon, with similar rates in the two groups.

A major limitation of the trial was short median follow up and duration of drug exposure. Other possible limitations included researchers used a lower level of baseline glycated hemoglobin and a large number of patients in placebo group were receiving SGLT-2 inhibitors and GLP-1 receptor agonists which can reduce cardiovascular risk.

Practice Pearls:

  • Once-weekly administration of extended-release exenatide in patients with T2DM at a wide range of cardiovascular risk appeared not to cause an increase in overall cardiovascular risk.
  • Exenatide once-weekly formulation was noninferior to placebo with respect to safety, but was not superior to placebo with respect to efficacy.
  • Rates of death from cardiovascular causes, fatal or nonfatal MI, fatal or nonfatal stroke, hospitalization for heart failure, and hospitalization for acute coronary syndrome, did not differ significantly between the two groups.


Rury R. Holman, F.Med.Sci., M. Angelyn Bethel, M.D., Robert J. Mentz. Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes. The new england journal of medicine. 2017 Sep 28.

Kay Lynn Tran, Doctor of Pharmacy Candidate: Class of 2018; LECOM College of Pharmacy