Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: AstraZeneca AB, SE-151 85 Sodertalje, Sweden
Pharmacotherapeutic group: Glucagon-like peptide-1 (GLP-1) analogues
ATC code: A10BJ01
Exenatide is a glucagon-like peptide-1 (GLP-1) receptor agonist that exhibits several antihyperglycaemic actions of glucagon-like peptide-1 (GLP-1). The amino acid sequence of exenatide partially overlaps that of human GLP-1. Exenatide has been shown to bind to and activate the known human GLP-1 receptor in vitro, its mechanism of action mediated by cyclic AMP and/or other intracellular signalling pathways.
Exenatide increases, on a glucose-dependent basis, the secretion of insulin from pancreatic beta cells. As blood glucose concentrations decrease, insulin secretion subsides. When exenatide was used in combination with metformin alone, no increase in the incidence of hypoglycaemia was observed over that of placebo in combination with metformin which may be due to this glucose-dependent insulinotropic mechanism (see section 4.4).
Exenatide suppresses glucagon secretion which is known to be inappropriately elevated in type 2 diabetes. Lower glucagon concentrations lead to decreased hepatic glucose output. However, exenatide does not impair the normal glucagon response and other hormone responses to hypoglycaemia.
Exenatide slows gastric emptying thereby reducing the rate at which meal-derived glucose appears in the circulation.
Immediate-release exenatide improves glycaemic control through the immediate and sustained effects of lowering both postprandial and fasting glucose concentrations in patients with type 2 diabetes.
Studies of immediate-release exenatide with metformin, a sulphonylurea or both as background therapy
The clinical studies comprised 3945 subjects (2997 treated with exenatide), 56% men and 44% women, 319 subjects (230 treated with exenatide) were ≥70 years of age and 34 subjects (27 treated with exenatide) were ≥75 years of age.
Immediate-release exenatide reduced HbA1c and body weight in patients treated for 30 weeks in three placebo-controlled studies, whether the immediate-release exenatide was added to metformin, a sulphonylurea or a combination of both. These reductions in HbA1c were generally observed at 12 weeks after initiation of treatment. See Table 2. The reduction in HbA1c was sustained and the weight loss continued for at least 82 weeks in the subset of 10 mcg BID patients completing both the placebo-controlled studies and the uncontrolled study extensions (n=137).
Table 2. Combined results of the 30-week placebo-controlled studies (intent to treat patients):
| Placebo | Immediate-release exenatide 5 mcg BID | Immediate-release exenatide 10 mcg BID | |
|---|---|---|---|
| N | 483 | 480 | 483 |
| Baseline HbA1c (%) | 8.48 | 8.42 | 8.45 |
| HbA1c (%) change from base line | 0.08 | -0.59 | -0.89 |
| Proportion of patients () achieving HbA1c ≤7 | 7.9 | 25.3 | 33.6 |
| Proportion of patients () achieving HbA1c ≤7 (patients completing studies) | 10.0 | 29.6 | 38.5 |
| Baseline weight (kg) | 99.26 | 97.10 | 98.11 |
| Change of weight from baseline (kg) | -0.65 | -1.41 | -1.91 |
In insulin-comparator studies immediate-release exenatide (5 mcg BID for 4 weeks, followed by 10 mcg BID) in combination with metformin and sulphonylurea significantly (statistically and clinically) improved glycaemic control, as measured by decrease in HbA1c. This treatment effect was comparable to that of insulin glargine in a 26-week study (mean insulin dose 24.9 IU/day, range 4-95 IU/day, at the end of study) and biphasic insulin aspart in a 52-week study (mean insulin dose 24.4 IU/day, range 3-78 IU/day, at the end of study). Immediate-release exenatide lowered HbA1c from 8.21 (n=228) and 8.6% (n=222) by 1.13 and 1.01% while insulin glargine lowered from 8.24 (n=227) by 1.10% and biphasic insulin aspart from 8.67 (n=224) by 0.86%. Weight loss of 2.3 kg (2.6%) was achieved with immediate-release exenatide in the 26-week study and a loss of 2.5 kg (2.7%) in a 52-week study whereas treatment with insulin was associated with weight gain. Treatment differences (immediate-release exenatide minus comparator) were -4.1 kg in the 26-week study and -5.4 kg in the 52-week study. Seven-point self-monitored blood glucose profiles (before and after meals and at 3 am) demonstrated significantly reduced glucose values compared to insulin in the postprandial periods after immediate-release exenatide injection. Premeal blood glucose concentrations were generally
lower in patients taking insulin compared to immediate-release exenatide. Mean daily blood glucose values were similar between immediate-release exenatide and insulin. In these studies the incidence of hypoglycaemia was similar for immediate-release exenatide and insulin treatment.
Two placebo-controlled studies were conducted: one of 16 and one of 26 weeks duration, with 121 and 111 immediate-release exenatide and 112 and 54 placebo treated patients respectively, added to existing thiazolidinedione treatment, with or without metformin. Of the immediate-release exenatide patients, 12% were treated with a thiazolidinedione and immediate-release exenatide and 82% were treated with a thiazolidinedione, metformin and immediate-release exenatide. Immediate-release exenatide (5 mcg BID for 4 weeks, followed by 10 mcg BID) resulted in statistically significant reductions from baseline HbA1c compared to placebo (-0.7% versus +0.1%) as well as significant reductions in body weight (-1.5 versus 0 kg) in the 16 week study. The 26-week study showed similar results with statistically significant reductions from baseline HbA1c compared to placebo (-0.8% versus -0.1%). There was no significant difference in body weight between treatment groups in change from baseline to endpoint (-1.4 versus -0.8 kg).
When immediate-release exenatide was used in combination with a thiazolidinedione, the incidence of hypoglycaemia was similar to that of placebo in combination with a thiazolidinedione. The experience in patients >65 years and in patients with impaired renal function is limited. The incidence and type of other adverse events observed were similar to those seen in the 30-week controlled clinical trials with a sulphonylurea, metformin or both.
In a 30-week study, either immediate-release exenatide (5 mcg BID for 4 weeks, followed by 10 mcg BID) or a placebo was added to insulin glargine (with or without metformin, pioglitazone or both). During the study both treatment arms titrated insulin glargine using an algorithm reflecting current clinical practice to a target fasting plasma glucose of approximately 5.6 mmol/l. The mean age of subjects was 59 years and the mean duration of diabetes was 12.3 years.
At the end of the study, immediate-release exenatide (n=137) demonstrated a statistically significant reduction in the HbA1c and weight compared to placebo (n=122). Immediate-release exenatide lowered HbA1c by 1.7% from a baseline of 8.3% while placebo lowered HbA1c by 1.0% from a baseline of 8.5%. The proportion of patients achieving HbA1c <7% and HbA1c <6.5% was 56% and 42% with immediate-release exenatide and 29% and 13% with placebo. Weight loss of 1.8 kg from a baseline of 95 kg was observed with immediate-release exenatide whereas a weight gain of 1.0 kg from a baseline of 94 kg was observed with placebo.
In the immediate-release exenatide arm the insulin dose increased by 13 units/day compared to 20 units/day on the placebo arm. Immediate-release exenatide reduced fasting serum glucose by 1.3 mmol/l and placebo by 0.9 mmol/l. The immediate-release exenatide arm compared to placebo had significantly lowered postprandial blood glucose excursions at the morning meal (-2.0 versus -0.2 mmol/l) and evening meal (-1.6 versus +0.1 mmol/l), there was no difference between treatments at midday.
In a 24-week study, where either insulin lispro protamine suspension or insulin glargine was added to existing therapy of immediate-release exenatide and metformin, metformin and sulphonylurea or metformin and pioglitazone, HbA1c was lowered by 1.2% (n=170) and by 1.4% (n=167) respectively from a baseline of 8.2%. Weight increase of 0.2 kg was observed for patients on insulin lispro protamine suspension and 0.6 kg for insulin glargine treated patients from a baseline of 102 kg and 103 kg respectively.
In a 30-week, open-label, active comparator-controlled, noninferiority study, the safety and efficacy of immediate-release exenatide (n=315) versus titrated insulin lispro three times daily (n=312) on a background of optimized basal insulin glargine and metformin in patients with type 2 diabetes was evaluated.
Following a basal insulin optimization (BIO) phase, patients with HbA1c>7.0% were randomized to add either immediate-release exenatide or insulin lispro to their existing regimen of insulin glargine and metformin. In both treatment groups, subjects continued to titrate their insulin glargine doses using an algorithm reflecting current clinical practice.
All patients assigned to immediate-release exenatide initially received 5 mcg BID for four weeks. After four weeks, their dose was increased to 10 mcg BID. Patients in the immediate-release exenatide-treated group with an HbA1c <8.0% at the end of the BIO phase decreased their insulin glargine dose by at least 10%.
Immediate-release exenatide lowered HbA1c by 1.1% from a baseline of 8.3% and insulin lispro lowered HbA1c by 1.1% from a baseline of 8.2% and noninferiority of immediate-release exenatide to titrated lispro was demonstrated. The proportion of patients achieving HbA1c <7% was 47.9% with immediate-release exenatide and 42.8% with insulin lispro. Weight loss of 2.6 kg from a baseline of 89.9 kg was observed with immediate-release exenatide whereas a weight gain of 1.9 kg from a baseline of 89.3 kg was observed with insulin lispro.
Immediate-release exenatide has shown no adverse effects on lipid parameters. A trend for a decrease in triglycerides has been observed with weight loss.
Clinical studies with immediate-release exenatide have indicated improved beta-cell function, using measures such as the homeostasis model assessment for beta-cell function (HOMA-B) and the proinsulin to insulin ratio.
A pharmacodynamic study demonstrated in patients with type 2 diabetes (n=13) a restoration of first phase insulin secretion and improved second phase insulin secretion in response to an intravenous bolus of glucose.
A reduction in body weight was seen in patients treated with immediate-release exenatide irrespective of the occurrence of nausea although the reduction was larger in the group with nausea (mean reduction 2.4 kg versus 1.7 kg) in the long-term controlled studies of up to 52 weeks.
Administration of exenatide has been shown to reduce food intake, due to decreased appetite and increased satiety.
The European Medicines Agency has deferred the obligation to submit the results of studies with immediate-release exenatide in one or more subsets of the paediatric population in type 2 diabetes mellitus (see section 4.2 for information on paediatric use).
Following subcutaneous administration to patients with type 2 diabetes, exenatide reaches median peak plasma concentrations in 2 h. Mean peak exenatide concentration (Cmax) was 211 pg/ml and overall mean area under the curve (AUC0-inf) was 1036 pg h/ml following subcutaneous administration of a 10 mcg dose of exenatide. Exenatide exposure increased proportionally over the therapeutic dose range of 5 mcg to 10 mcg. Similar exposure is achieved with subcutaneous administration of exenatide in the abdomen, thigh, or arm.
The mean apparent volume of distribution of exenatide following subcutaneous administration of a single dose of exenatide is 28 l.
Nonclinical studies have shown that exenatide is predominantly eliminated by glomerular filtration with subsequent proteolytic degradation. In clinical studies the mean apparent clearance of exenatide is 9 l/h and the mean terminal half-life is 2.4 h. These pharmacokinetic characteristics of exenatide are independent of the dose.
In patients with mild (creatinine clearance 50 to 80 ml/min) or moderate renal impairment (creatinine clearance 30 to 50 ml/min), exenatide clearance was mildly reduced compared to clearance in individuals with normal renal function (13% reduction in mild and 36% reduction in moderate renal impairment). Clearance was significantly reduced by 84% in patients with end-stage renal disease receiving dialysis (see section 4.2).
No pharmacokinetic study has been performed in patients with hepatic insufficiency. Exenatide is cleared primarily by the kidney, therefore hepatic dysfunction is not expected to affect blood concentrations of exenatide.
Gender and race have no clinically relevant influence on exenatide pharmacokinetics.
Long-term controlled data in elderly are limited, but suggest no marked changes in exenatide exposure with increased age up to about 75 years old. In a pharmacokinetic study in patients with type 2 diabetes, administration of exenatide (10 mcg) resulted in a mean increase of exenatide AUC by 36% in 15 elderly subjects aged 75 to 85 years compared to 15 subjects aged 45 to 65 years likely related to reduced renal function in the older age group (see section 4.2).
In a single-dose pharmacokinetic study in 13 patients with type 2 diabetes and between the ages of 12 and 16 years, administration of exenatide (5 mcg) resulted in slightly lower mean AUC (16% lower) and Cmax (25% lower) compared to those observed in adults.
Non-clinical data reveal no special hazards for humans based on conventional studies of safety pharmacology, repeat-dose toxicity, or genotoxicity.
In female rats given exenatide for 2 years, an increased incidence of benign thyroid C-cell adenomas was observed at the highest dose, 250 mcg/kg/day, a dose that produced an exenatide plasma exposure 130-fold the human clinical exposure. This incidence was not statistically significant when adjusted for survival. There was no tumorigenic response in male rats or either sex of mice.
Animal studies did not indicate direct harmful effects with respect to fertility or pregnancy. High doses of exenatide during mid-gestation caused skeletal effects and reduced foetal growth in mice and reduced foetal growth in rabbits. Neonatal growth was reduced in mice exposed to high doses during late gestation and lactation.
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