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Exenatide
General information
Exenatide (synthetic exendin-4, from the saliva from a lizard) is an incretin mimetic [ ]. Incretins are compounds that increase insulin secretion from the pancreas in a glucose-dependent manner; they are therefore potential therapies for the treatment of diabetes mellitus. Glucagon-like peptide-1 (GLP-1; 30 amino acids) is a naturally occurring incretin. It is largely produced in the distal ileum and colon in response to food that contains carbohydrate and fat. Other incretins include gastric inhibitory polypeptide (GIP). The half life of endogenous GLP-1 is only minutes, as it is rapidly metabolized by dipeptidyl peptidase IV, which is another therapeutic target. Other actions of GLP-1 include delayed gastric emptying, appetite suppression, and increased beta cell mass. There is suppression of raised glucagon concentrations, but the counter-regulatory response remains intact. Subcutaneously administered GLP-1 also has a short half-life (about 30 minutes) and so longer-acting GLP-1 receptor agonists have been developed and are known as incretin mimetics.
Exenatide has a 53% overlap with glucagon-like peptide-1 and also binds to the glucagon-like peptide-1 receptor. It is injected subcutaneously into the thigh, abdomen, or upper arm. It is given twice daily. The pharmacokinetics of exenatide 10 micrograms subcutaneously are: C max 211 pg/ml, t max 2 hours, apparent volume of distribution 28 liters, clearance 9 liters/hour, terminal half-life 2.4 hours. Elimination is by glomerular filtration followed by proteolytic degradation. The clearance is not affected by mild or moderate renal impairment. However, clearance is reduced in patients with end-stage renal insufficiency and those who are on dialysis; it is recommended that exenatide should not be used in such patients.
General adverse effects and adverse reactions
Reviews have suggested that nausea and vomiting are adverse reactions common to all incretin mimetics [ ]. There may also be an increased risk of pancreatitis. The adverse reactions are transient and in association with peak plasma concentrations of glucagon-like peptide (GLP)-1. Because incretin mimetics slow gastric emptying they may alter the speed of absorption of other drugs [ ].
Drug studies
Observational studies
Exenatide in combination with insulin has been evaluated in 124 patients with type 2 diabetes mellitus over 1 year follow-up; 48 patients (36%) stopped taking exenatide, primarily because of gastrointestinal intolerance and 14 (10%) had hypoglycemia, mostly mild [ ].
Placebo-controlled studies
Exenatide has been investigated in a placebo-controlled study for 28 days in 116 patients with type 2 diabetes in addition to a sulfonylurea or metformin [ ]. The most common adverse effects were nausea (mostly only in the first week) and mild to moderate hypoglycemia, for which no treatment was needed.
Patients with type 2 diabetes treated with a sulfonylurea alone, aged 22–76 years, were randomized to placebo (n = 123) or subcutaneous exenatide 5 micrograms bd (n = 254); after 4 weeks 129 patients increased their dose to 10 micrograms bd [ ]. During the 30 weeks of the study 12 subjects had mild to moderate transient abnormalities of creatine kinase. Serious adverse events were no more frequent with exenatide (4% with 10 micrograms and 3% with 5 micrograms) than with placebo (8%). The adverse events that were related to treatment included nausea, which occurred in 49 patients (39%) of those who used 5 micrograms and 66 (51%) of those who used 10 micrograms, compared with 9 (7%) of those who used placebo. The nausea was worst during the first 8 weeks then abated. Other adverse effects and reactions included hypoglycemia, dizziness, and a jittery feeling. There was hypoglycemia in 36% of those taking 10 micrograms, 14% of those taking 5 micrograms, and 3% of those using placebo. One subject withdrew owing to hypoglycemia. Weight loss was progressive over 30 weeks and was most apparent in those taking 10 micrograms (− 1.6 kg). Those who did not report nausea also lost weight.
Systematic reviews
In a systematic review of 17 controlled trials of subjects with poorly controlled diabetes nausea was the most common adverse event in placebo-controlled trials. The rates of hypoglycemia were similar in comparisons of exenatide and insulin, but were more common with exenatide 10 micrograms bd than with placebo; hypoglycemia occurred predominantly when a sulfonylurea was co-administered with exenatide [ ].
In a meta-analysis of five comparisons of exenatide or liraglutide with insulin glargine, the studies lasted 16–52 weeks and included 1452 patients with a BMI of 30–35 kg/m 2 [ ]. Nausea, vomiting, diarrhea, dyspepsia, constipation, and upper abdominal pain were more common adverse events in those who used the incretin mimetics. The overall incidence of hypoglycemia was similar with incretin mimetics and insulin glargine (RR = 0.69; 95% CI = 0.4, 1.1). Nocturnal hypoglycemia was less frequent, although data were not available for all studies included.
In a meta-analysis of 21 trials lasting 12–52 weeks in 5429 patients using incretin mimetics and 3053 comparator/placebo patients, there were five deaths, two among those taking incretin mimetics and three in the comparator groups [ ]. There were cardiovascular events in 24 patients taking incretin mimetics compared with 18 in the comparator/placebo group, and the odds ratios were not significantly different.
Organs and systems
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