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Keywords:

  • exenatide;
  • type 2 diabetes mellitus;
  • oral agents

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Future Developments
  6. Conclusions
  7. Acknowledgements
  8. References

Background:  Exenatide is an incretin mimetic that activates glucagon-like-peptide-1 receptors. It blunts the postprandial rise of plasma glucose by increasing glucose-dependent insulin secretion, suppressing inappropriately high glucagon secretion and delaying gastric emptying.

Methods:  In seven clinical trials performed in 2845 adult patients with type 2 diabetes mellitus who were inadequately controlled by a sulphonylurea and/or metformin (glycosylated haemoglobin, HbA1c ≤11%), or by thiazolidinediones (with or without metformin) and treated for periods from 16 weeks to 3 years, exenatide (5 μg b.i.d. s.c. for the first 4 weeks of treatment and 10 μg b.i.d. s.c. thereafter) reduced HbA1c, fasting and postprandial glucose, and body weight dose dependently, and was similar to insulin glargine and biphasic insulin aspart in reducing HbA1c. Body weight diminished with exenatide, whereas it increased with both insulin preparations. Positive effects on the lipid profile and a reduction in C-reactive protein were also recorded with exenatide. Treatment extensions up to 3 years showed that benefits were maintained in the long term. Adverse events were usually mild to moderate in intensity, and generally the frequency decreased with continued therapy. The most common was nausea (whose incidence may be reduced by gradual dose escalation from 5 μg b.i.d. to 10 μg b.i.d.), vomiting, diarrhoea, headache and hypoglycaemia (almost exclusively in patients treated with a sulphonylurea).

Results and conclusions:  Exenatide is a new, promising therapeutic option for type 2 diabetic patients inadequately controlled by oral agents, before insulin therapy, offering the added benefits of body weight reduction and tight postprandial glucose control.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Future Developments
  6. Conclusions
  7. Acknowledgements
  8. References

Glucagon-like peptide 1 (GLP-1), a gut-derived incretin hormone that stimulates insulin secretion, suppresses glucagon secretion and inhibits gastric emptying, thus reducing appetite and food intake, has a key role in the pathogenesis of type 2 diabetes mellitus (T2DM). Moreover, it has been reported that GLP-1 levels are reduced in diabetic patients after a mixed meal and after an oral glucose load [1]. It is still not clear whether the reduction in meal or oral glucose–stimulated GLP-1 levels in T2DM patients is because of impairment of secretion, increase in degradation or both [2,3]. Furthermore, GLP-1 is likely to have physiological effects on the heart and, after cardiac injury; GLP-1 has consistently increased myocardial performance both in experimental animals and in patients [4].

Exenatide (AC2993) is the synthetic form of naturally occurring exendin-4, a 39-amino acid–peptide hormone secreted by the salivary glands of the lizard Heloderma suspectum, otherwise known as the Gila monster. It is a potent agonist of mammalian GLP-1 receptors, which are located in pancreatic periductal cells and α- and β-cells, besides the kidney, heart, stomach and brain [5]. Nevertheless, it is not a GLP-1 analogue and the amino acid sequence overlap with GLP-1 is 53% [6,7].

GLP-1 is a gastrointestinal hormone that together with GIP (glucose-dependent insulinotropic polypeptide), stimulates insulin secretion after food intake and is responsible, along with GIP, for the ‘incretin effect’: the insulin response to an oral glucose load is higher than to an intravenous glucose infusion, as a result of GLP-1 and GIP secretion from the gastrointestinal tract. The incretin effect accounts for about 60% of total insulin release following a meal, mostly because of GLP-1 secretion [8].

In animal and in vitro T2DM models, exenatide has proved to share the glucose-regulating properties of GLP-1: glucose-dependent increase in insulin secretion and suppression of inappropriately high glucagon secretion, reduction in gastric emptying rate, centrally induced satiety associated with lower food intake and body weight loss, increase in pancreatic β-cell number, as a result of stimulation of cell formation from precursors and inhibition of their apoptosis. However, exenatide differs substantially from GLP-1 in terms of pharmacokinetics. The substitution of Gly2 amino acid for an Ala2 at the inactivation site makes exenatide more resistant to dipeptidyl peptidase-4 (responsible for GLP-1 degradation); this accounts for its much longer half-life (2.4 h vs. a few minutes), which enables its therapeutic use [6,7,9].

These pharmacological features are of considerable interest in T2DM and were addressed in recent reviews [10,11]: glucose-dependent regulation of insulin and glucagon secretion improves glycaemic control avoiding the risk of hypoglycaemia, body weight loss is highly desirable in T2DM patients, who are usually overweight/obese, and the potential increase in pancreatic β-cell mass would slow down the progression of disease, should this property be confirmed by further studies.

The purpose of this review is to summarize the properties of exenatide that have been documented in clinical pharmacology studies, as well as the evidence provided by the clinical trials in which its therapeutic efficacy and safety have been assessed in T2DM patients.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Future Developments
  6. Conclusions
  7. Acknowledgements
  8. References

Electronic searches of Medline/PubMed, EMBASE, from 1980 to November 2007 were conducted using ‘exenatide’ and ‘exendin-4’ as key words. A separate search was also run to complete the electronic search checking references reported in the selected articles to ensure all appropriate articles were included in this review. All retrieved articles were examined and only those reporting the results of clinical pharmacology, and clinical trials about on-label use of exenatide were included in this review, in addition to only one paper on the development of new exenatide formulations. Review articles or papers, including data already available in other studies were not included in this review.

Clinical Pharmacology

The designs of the five main clinical pharmacology studies on exenatide [12–16] are summarized in table 1. They were all randomized, blinded, placebo-controlled, crossover clinical trials, with one exception (a four-armed parallel group trial comparing placebo to three different dosage regimens) [14]. They were carried out in a total of 184 patients with T2DM; one trial also had a parallel group of 12 healthy volunteers. The included diabetes patient population was on treatment regimens based on diet and the use of oral antidiabetic agents.

Table 1.  Main features of the clinical pharmacology studies performed with exenatide
AuthorsDesignSubjectsDosage + duration exenatide adminAssessments
  1. BP, blood pressure; b.i.d., bis in die, twice daily; BMI, body mass index; HbA1c, glycosylated haemoglobin; OAA, oral antidiabetic agents; s.c., subcutaneous; t.i.d., tris in die, three times a day; T2DM, type 2 diabetes mellitus; VAS, visual analogue scale.

Kolterman et al. [13]Randomized stratified, single blind, placebo-control, two-period, four-strata crossoverT2DM, age: 55.8 ± 2.1 years, n = 24, BMI 28.8 ± 08 kg/m2, If OAA, stable for 6 months0.1 μg/kg sc b.i.d., before breakfast and dinner × 5 days + acetaminophen 20 mg/kgFasting plasma, glucose, insulin, glucagon, acetaminophen, day 1 and day 5
Kolterman et al. [13]Randomized sequence, double blind, placebo-control, four-period, crossoverT2DM, age: 49.0 ± 2 years, n = 13, BMI 32.8 ± 3.3, HbA1c 7.5–11%, If OAA, stable for 3 months0.05 μg/kg, 0.1 μg/kg, 0.2 μg/kg, placebo with 1 day wash-out periodsFasting value and 8h profile for plasma glucose, Insulin, Glucagon, On days 1, 3, 5, 7
Fehse et al. [15]Randomized, single blind, placebo control, two period, crossover, parallel control group with healthy volunteern = 13 T2DM, age: 35–70 years, BMI 25–35 kg/m2, HbA1c ≤8.5%, not on insulin, n = 12 matched volunteers300 min exenatide infusion or saline (volunteers only saline) i.v. glucose bolusPlasma glucose, insulin, C-peptide, glucagon, Exenatide
Kolterman et al. [12]Randomized, single-blind, placebo control, rising-dose, crossoverT2DM, male 35–65 years, HbA1c 8–10%, Diet + stable OAA for 3 months, n = 7 completersFour treatment sequences (placebo, 0,1 μg/kg s.c., 0.2 μg/kg s.c., 0,3 μg/kg s.c. and either 0,4 μg/kg s.c. or additional placebo) + acetaminophen (20 mg/kg) on days 1, 3, 5, 7 and 9Plasma exenatide, glucose, insulin and glucagon
Kolterman et al. [12]Randomized, single dose, single-blind, placebo control, crossover in two partsT2DM, Male 18–65 years, HbA1c 7–12%, Diet + stable OAA for 3 monthsPart 1 n = 6: 3 treatment sequences (placebo, 0.01 μg/kg sc and 0.1 μg/kg sc); Part 2 n = 8: 4 treatment sequences (placebo, 0.02 μg/kg sc, 0.05 μg/kg sc, 0.1 μg/kg sc) Acetaminophen 20 mg/kgPart 1 n = 6: Plasma glucose; Part 2: Plasma exenatide, glucose and acetaminophen
Linnebjerg et al. [16]Randomized, 3-period single-blind crossoverT2DM, n = 17, age 39–69 years, BMI 22.7–34.6 kg/m2, HbA1c 7–10%, oral agents3 treatment sequences (placebo b.i.d., 5 μg b.i.d. and 10 μg b.i.d. sc X 5 days each)Gastric emptying time; Plasma exenatide; Serum glucose and insulin; Perception of appetite on VAS
Calara et al. [17]Randomized 3-period, open-label, crossoverT2DM, n = 28, age 18–65 years, BMI 27–45 kg/m2, HbA1c ≤12%Single sc injection into the abdomen, arm or thighPlasma exenatide concentrations
Fineman et al. [14]Randomized, triple blind, parallel group, placebo controlled, four-armedT2DM, 18–65 years, diet + oral agents stable for ≥6 months, HbA1c 8–11%, BMI 27–40 kg/m2Placebo n = 28, exenatide 0.08 μg/kg/injection × 28 days, b.i.d. breakfast + dinner n = 26, b.i.d. breakfast + bedtime n = 27, t.i.d. breakfast, dinner and bedtime n = 28Fructosamine, postprandial plasma glucose, HbA1c, Fasting plasma glucose, body weight, fasting and postprandial lipids

A broad range of single subcutaneous doses of exenatide were investigated, ranging from 0.02 μg/kg up to 0.4 μg/kg. Doses were usually given immediately before a meal. In addition, repeated dose regimens (0.1 μg/kg b.i.d. and 5 μg/kg b.i.d. for 5 days; 5 μg/kg b.i.d. for 2 days + 10 μg/kg b.i.d. for 2 days; 0.08 μg/kg b.i.d. at breakfast and dinner, b.i.d. at breakfast and bedtime, t.i.d. at breakfast, dinner and bedtime) and a continuous infusion of 50 ng/min for 30 min, followed by the maintenance dosage of 25 ng/min for another 270 min, were investigated.

Plasma glucose

The postprandial rise in plasma glucose was not influenced significantly by the administration of 0.01 μg/kg exenatide. The lowest effective dose was 0.02 μg/kg, which produced a significantly lower area under the curve (AUC) (0–5 h) than placebo (p < 0.05), but not a significantly lower maximum concentration (Cmax) of blood glucose. The lowest dose that produced significant blunting of both AUC and Cmax was 0.05 μg/kg (p < 0.05 and p = 0.002 respectively) [12]. The blunting effect on the postprandial rise of plasma glucose was dose dependent between 0.02 and 0.1 μg/kg, while mean tmax did not vary significantly among doses (1.4–1.8 h). Dose dependency disappeared above 0.1 μg/kg, as the blunting effect was similar with the three higher doses tested (0.2, 0.3 and 0.4 μg/kg): they all produced a reduction in postprandial glucose levels (after a modest increase at 30–45 min) to values below baseline within 1.5–2 h vs. 5 h with placebo [12].

The course of fasting plasma glucose levels recorded in the study by Kolterman et al. [12] was consistent with the course of postprandial glucose levels: all the three tested doses (0.05, 0.1 and 0.2 μg/kg) reduced fasting glucose levels over 8 h compared with placebo (p < 0.0001), producing a nadir at 3–4 h post-dose, with a trend towards greater efficacy of 0.1 μg/kg over 0.05 μg/kg, but not of 0.2 μg/kg over 0.1 μg/kg.

The repeated dose investigations were performed with doses just over the lowest effective dose, that is, 0.08 and 0.1 μg/kg for 4–5 days. The blunting effect was maintained following repeated dosing (0.1 μg/kg) for 5 days. A breakdown into the four strata according to treatment [diet alone, oral antidiabetic agents and glycosylated haemoglobin (HbA1c) <8%, oral antidiabetic agents and HbA1c 8–12%, insulin ± oral antidiabetic agents] did not reveal any important differences [13].

Following repeated dosing of 0.08 μg/kg for 28 days, significant reductions in mean postprandial plasma glucose concentrations were maintained vs. placebo (p ≤ 0.004); differences were seen among the three dosage regimens, the most effective being the b.i.d. regimen at breakfast and dinner (−4.4 mmol/l vs. −3.2 mmol/l with the b.i.d. regimen at breakfast and bedtime, −3.4 mmol/l with the t.i.d. regimen and −0.6 mmol/l with placebo) [14].

Plasma Exenatide

Plasma concentrations of exenatide became detectable within 10–15 min after administration and reflected the course of pharmacodynamic effects. Tmax was achieved after 2–3 h vs. plasma glucose nadir at about 3 h, with similar bioavailability following subcutaneous injection in the abdomen, thigh or upper arm [17]. However, unlike pharmacodynamic effects, plasma levels were dose dependent throughout the whole range of doses tested, as shown by AUC values. Mean t½ values ranged from 3.3 to 4.0 h, independently of dose. Plasma levels remained detectable for up to 15 h after doses of 0.2 μg/kg and higher [12], allowing for b.i.d. administration.

After repeated administration of 0.08 μg/kg for 28 days notable lengthening of t½ and increase in Cmax were recorded in the presence of detectable anti-exenatide antibodies, whereas values remained unchanged in their absence [14].

Serum Insulin

A significant increase in fasting serum insulin concentrations during the first 3 h after exenatide administration was recorded in the study by Kolterman et al. [13]. The increase was dose dependent, once again with a much larger difference between 0.05 μg/kg and 0.1 μg/kg than between 0.1 and 0.2 μg/kg, as the peak mean incremental serum insulin concentrations turned out to be dose related.

No significant increase in postprandial serum insulin concentrations with exenatide (0.1–0.4 μg/kg s.c.) was recorded in the study by Kolterman et al. [12]; however, a change in its course was observed in terms of earlier rise in insulin concentrations and longer persistence, as after 8 h insulin concentrations had returned to baseline with placebo, but not with any of the doses of exenatide.

A specific study [10] was designed to assess the effects of exenatide (50 ng/min i.v. for 30 min followed by 25 ng/min for 270 min) on glucose-stimulated insulin secretion, including not only the comparison of T2DM patients given exenatide with patients given saline, but also the comparison of T2DM patients given exenatide with healthy subjects given saline. In T2DM subjects, exenatide proved to increase glucose-stimulated insulin secretion during the first phase (0–10 min) as compared with patients given saline (p = 0.0002), whereas during the second phase (10–120 min) the increase was significant not only as compared with T2DM patients given saline (p = 0.0002), but also compared with healthy subjects (p = 0.0029). The values coming from the calculation of the glucose disappearance constant were consistent with the results related to insulin secretion. The restoration of the first phase of insulin secretion (that is lost in T2DM) shows that exenatide improves β-cell function.

Plasma Gucagon

The postprandial rise in glucagon was suppressed with 0.1 μg/kg exenatide and all higher dosages tested [12]. The suppression was maintained also after repeated dosing for 5 days with 0.1 μg/kg [13].

Additionally, fasting plasma glucagon was suppressed for 3 h after 0.05–0.2 μg/kg exenatide vs. placebo; after 3 h, which coincided with the nadir of plasma glucose concentrations (see above), values no longer differed importantly from those with placebo, demonstrating that exenatide does not suppress glucagon secretion during euglycaemia or hypoglycaemia [13].

Gastric Emptying

Gastric emptying, assessed on the basis of the timing of appearance of acetaminophen plasma levels, was delayed by exenatide in a dose-dependent manner. The delay was statistically significant starting from the dose of 0.05 μg/kg [12]. The delay, expressed as AUC (0–300 min) of acetaminophen, was maintained after repeated administration of 0.1 μg/kg exenatide (p < 0.0001) [13]. Furthermore, labelled eggs took almost twice as long to progress by 50% into the duodenum after exenatide 5 μg b.i.d. and almost three times as long after exenatide 10μg b.i.d.; the corresponding values related to labelled water were nearly three times and nearly four times as long (all p < 0.01) [16].

The delay in gastric emptying is associated with a slower nutrient absorption rate and a reduction in the postprandial glucose excursion.

β-Cell Function

One specific study showed that exenatide 0.08 μg/kg increased pancreatic β-cell function, expressed by homeostasis model assessment (HOMA) scores, by 50–100% on days 14 and 28 vs. baseline, whereas no change was seen with placebo [14].

Therapeutic Efficacy

The designs of the main seven clinical trials assessing efficacy in patients with T2DM inadequately controlled by oral antidiabetic agents are described in table 2[18–25]. The first three trials (AMIGO studies) compared two dosage regimens of exenatide (5 and 10 μg b.i.d.) vs. placebo under triple-blind conditions (investigator, patients and sponsor were all blind) following almost identical protocols; the main difference was the kind of background therapy, namely metformin or sulphonylurea given at maximum tolerated dosages for 30 weeks, or their combination with randomization to maximum or minimum sulphonylurea starting dosage and subsequent adjustments according to glucose levels [18–20]. The subsequent three trials compared exenatide (10 μg b.i.d.) to various insulin preparations (namely insulin glargine and biphasic insulin aspart) in patients using also oral antidiabetic agents for periods ranging from 16 to 52 weeks [21–23]. In addition, another trial assessed the efficacy of exenatide 10 μg b.i.d. vs. placebo in combination with thiazolidinedione ± metformin treatment in a double-blinded study for 16 weeks [25].

Table 2.  Efficacy studies on exenatide in type 2 diabetes mellitus
AuthorsDesignSubjectsTreatment dosage + duration exenatide admin (n ITT pat)Assessments
  1. b.i.d., bis in die, twice daily; BMI, body mass index; DSC-R, Diabetes Symptom Checklist revised; EQ-5D, EuroQuality of Life; HbA1c, glycosylated haemoglobin; HOMA-B, homeostasis model assessment of β-cell function; ITT, intention to treat; MET, metformin; SFU, sulphonylurea; TZD, thiazolidines; SF-36, Short Form 36; VAS, visual analogue scale.

Buse et al. [18]Randomized, triple-blind, placebo-controlled, parallel group, 4-week single-blind run-in, stratification by HbA1c <9% or ≥9.0%377 patients of both sexes, 22–76 years, sulphonylurea monotherapy for ≥3 months, BMI 27–45 kg/m2, HbA1c 7.1–11%, stable body weight for ≥3 monthsPlacebo (n = 123), Exenatide 5 μg b.i.d. (n = 125), Exenatide 10 μg b.i.d. (n = 129), (first 4 weeks with 5 μg b.i.d.) for 26 weeksHbA1c, adverse events, body weight, fasting glucose, insulin, proinsulin, lipids
Kendall et al. [19]Randomized, triple-blind, placebo-controlled, parallel group, 4-week single-blind run-in, randomization to MAX or MIN dose sulphonylurea, stratification by HbA1c <9% or ≥9.0%, meal subset733 patients of both sexes, 22–77 years, metformin + sulphonylurea, BMI 27–45 kg/m2, HbA1c 7.5–11%, stable body weight for ≥3 months, meal subset (n = 77)Placebo (n = 247), Exenatide 5 μg b.i.d. (n = 245), Exenatide 10 μg/kg b.i.d. (n = 241), (first 4 weeks with 5 μg b.i.d.) for 26 weeksHbA1c, adverse events, body weight, fasting glucose, insulin, lipids, postprandial glucose (meal subset)
DeFronzo et al. [20]Randomized, triple-blind, placebo-controlled, parallel group, 4-week single-blind run-in, stratification by HbA1c < 9% ≥9.0%336 patients of both sexes, 19–78 years, metformin monotherapy for ≥3 months, BMI 27–45 kg/m2, HbA1c 7.1–11%, stable body weight for ≥3 monthsPlacebo (n = 113), exenatide 5 μg b.i.d. (n = 110), exenatide 10 μg b.i.d. (n = 113), (first 4 weeks with 5 μg b.i.d.) for 26 weeks.HbA1c, adverse events, body weight, fasting glucose, insulin, proinsulin, lipids, postprandial glucose and insulin (meal subset)
Heine et al. [21]Randomized, open-label, controlled vs. insulin glargine, meal subset549 patients of both sexes, metformin + sulphonylurea ≥3 months, 30–75 years, HbA1c 7-10%, BMI 25–45 kg/m2, stable body weight for ≥3 months, meal subset (n = 78)Exenatide 10 μg b.i.d. (n = 282) (first 4 weeks with 5 μg b.i.d.), insulin glargine (n = 267), initial dose 10 U daily titrated to fasting glucose <5.6 mmol/l for 26 weeksHbA1c, adverse events, fasting glucose, seven-point self-monitored blood glucose, body weight, postprandial glucose (meal subset)
Nauck et al. and Yurgin et al. [22,24]Randomized, open-label, parallel group vs. biphasic insulin aspart, meal subset501 patients, 58.7 ± 9.0 years, HbA1c 8.6 ± 1.0%, BMI 30.4 ± 4.1 kg/m2, On top of metformin and sulponylureaExenatide 10 μg b.i.d. (n = 253) (first 4 weeks with 5 μg b.i.d.), titrated biphasic insulin aspart 30/70 b.i.d. (n = 248) for 52 weeksHbA1c, adverse events, body weight, fasting glucose, postprandial glucose, quality of life, (EQ-5D, SF-36,DSC-R)
Barnett et al. [23]Randomized, open-label, two period crossover vs. insulin glargine, meal subset114 patients, 54 ± 9 years, HbA1c 8.9 ± 1.1%, monotherapy with oral antidiabetic agent, MET 56% SFU 44%Exenatide 10 μg b.i.d. (first 4 weeks with 5 μg b.i.d.), Insulin glargine titrated to fasting glucose <5.6 mmol/l, each for 16 weeksHbA1c, adverse events, body weight, fasting glucose, postprandial glucose
Zinman et al. [25]Randomized, double-blind, placebo-controlled, parallel group233 patients, 56 ± 10 years, on thiazolidinediones ± metformin, TZD 20%; TZD + MET 80%, HbA1c 7.9 ± 0.9%, BMI 34 ± 5 kg/m2Exenatide 10 μg b.i.d. (first 4 weeks with 5 μg b.i.d.) or placebo for 16 weeksHbA1c, adverse events, fasting and postprandial glucose, fasting insulin and proinsulin, body weight, self-monitored glucose HOMA-B

Overall, 2845 patients entered the seven studies; 1726 received exenatide.

They were all adult patients aged 19 years and older, of both sexes, with a body mass index (BMI) ranging from 25 to 45 kg/m2 and an HbA1c between 7 and 11%. All the parallel groups were similar at baseline both in terms of demographic data and values of glycaemic control parameters.

In the study 115-AMIGO [19], in which patients were randomly allocated to the maximally effective or minimum recommended dose of a sulphonylurea, subsequent adjustments led to 94% of maximum dosage in patients allocated to placebo vs. 79% in the exenatide group.

The results related to the main efficacy parameters (HbA1c, body weight and fasting plasma glucose) were highly consistent among studies and are shown in table 3.

Table 3.  Glycosylated haemoglobin (HbA1c) (%) at baseline and clinical outcomes related to main efficacy parameters at end of treatment (mean reduction ± s.d.)
StudyHbA1c (%) at baselineHbA1c (%) change vs. baseline% patients with HbA1c ≤7%Fasting glucose (mmol/l) change vs. baselineBody weight (kg) Change vs. baseline
  1. E, Exenatide; NS, not significant.

Buse et al. [18]E 10 μg 8.6 ± 1.2E 10 μg −0.86 ± 0.11E 10 μg 34.2%E 10 μg −0.6 ± 0.3E 10 μg −1.6 ± 0.3
E 5 μg 8.5 ± 1.1E 5 μg −0.46 ± 0.12E 5 μg 26.7%E 5 μg −0.3 ± 0.2E 5 μg −0.9 ± 0.3
Placebo 8.7 ± 1.2Placebo +0.12 ± 0.09Placebo 7.7%Placebo +0.4 ± 0.3Placebo −0.6 ± 0.3
 p ≤ 0.0002p < 0.0001p ≤ 0.05 E 10 vs. Plp ≤ 0.05 E 10 vs. Pl
Kendall et al. [19]E 10 μg 8.5 ± 1.1E 10 μg −0.8 ± 0.1E 10 μg 30%E 10 μg −0.6 ± 0.2E 5 and 10 μg −1.6 ± 0.2
E 5 μg 8.5 ± 1.0E 5 μg −0.6 ± 0.1E 5 μg 24%E 5 μg −0.5 ± 0.2 
Placebo 8.5 ± 1.0Placebo +0.2 ± 0.1Placebo 7%Placebo +0.8 ± 0.2Placebo −0.9 ± 0.2
 p ≤ 0.0001p < 0.0001p < 0.0001p ≤ 0.01
DeFronzo et al. [20]E 10 μg 8.2 ± 1.0E 10 μg −0.78 ± 0.10E 10 μg 40%E 10 μg −0.6 ± 0.2E 10 μg −2.8 ± 0.5
E 5 μg 8.3 ± 1.1E 5 μg −0.40 ± 0.11E 5 μg 27%E 5 μg −0.4 ± 0.3E 5 μg −1.6 ± 0.4
Placebo 8.2 ± 1.0Placebo +0.08 ± 0.10Placebo 11%Placebo +0.8 ± 0.2Placebo −0.3 ± 0.3
 p ≤ 0.002p < 0.01p = 0.0001p ≤ 0.05 E 5 vs. Pl; p < 0.001 E 10 vs. Pl
Heine et al. [21]E 10 μg 8.2 ± 1.0E 10 μg −1.11E 10 μg 46%E 10 μg −1.4E 10 μg −2.3
IG 8.3 ± 1.0IG −1.11IG 48%IG −2.9IG +1.8
 NSNSp < 0.001 G vs. Ep < 0.0001
Nauck et al. and Yurgin et al. [22,24]All patients 8.6 ± 1.0E 10 μg −1.04 ± 0.07E 10 μg 32%E 10 μg −1.8 ± 0.2E 10 μg −2.5 ± 0.2
 IA −0.89 ± 0.06IA 24%IA −1.6 ± 0.2IA +2.9 ± 0.2
 NSp = 0.07NSp < 0.001
Barnett et al. [23]All patients 8.9 ± 1.1E 10 μg −1.43 ± 0.1E 10 μg 40%E 10 μg −3.04 ± 0.23E 10 μg −1.95
 IG −1.41 ± 0.1IG 41%IG −4.2 ± 0.23IG +0.35
 NSNSp < 0.0001 G vs. Ep < 0.001
Zinman et al. [25]All patients 7.9 ± 0.9E 10 μg −0.89 ± 0.09E 10 μg 62%E 10 μg −1.5 lower than PlaceboE 10 μg −1.5 ± 3.1
 Placebo +0.09 ± 0.10Placebo 16% Placebo −0.2 ± 2.5
 p < 0.001p < 0.0001p < 0.0001p < 0.001
HbA1c

In the placebo-controlled studies [18–20,25], exenatide produced a dose-dependent reduction in HbA1c (the primary end-point) vs. baseline, which was significantly higher than that achieved with placebo, independently of the oral antidiabetic agents used as background therapy. Similarly, the proportion of patients, in whom adequate glucose control (HbA1c ≤7%) was achieved, was higher with exenatide (table 3). Stratification of patients accordingly to baseline HbA1c (<9% or ≥9%) revealed that the reductions were significant in both subgroups, but were larger in the patients with HbA1c ≥9% at baseline. The reduction in HbA1c was slightly higher in the subgroup allocated to the maximum dose of a sulphonylurea as compared with the subgroup allocated to the minimum dose (mean difference vs. placebo: 1.1% vs. 0.9%, p ≤ 0.0001) [19].

A total of 974 patients from the three placebo-controlled studies have entered a long-term open-label extension and, to date, 217 patients have completed 3 years of treatment with exenatide 10 μg b.i.d. [26]. The therapeutic effects of exenatide on HbA1c were fully maintained in the long term: a further slight improvement was recorded at week 104 vs. the end of the double-blind period (a further −0.2% reduction in mean HbA1c, which resulted in 50% of patients achieving HbA1c ≤7%) [27] and a sustained efficacy was confirmed after 3 years with a mean HbA1c reduction of −1.0% [26].

Considering the close relationship between weight and glycaemic control, an interim analysis over 82 weeks on the same population evaluated the dependency of HbA1c changes vs. baseline on BMI reduction: when weight changes were examined by weight change quartile (with patients in quartile 1 losing the most weight and those in quartile 4 losing the least or even gaining weight), patients in all four weight-change quartiles had reductions in HbA1c from baseline ranging from 1.7% for quartile 1 to 0.7% for quartile 4, demonstrating an exenatide antidiabetic effect that is independent of weight loss induction [28].

The reduction in HbA1c achieved with exenatide 10 μg b.i.d. was similar to that achieved with insulin glargine or biphasic insulin aspart in all insulin-controlled studies, as well as the proportion of patients in whom adequate glucose control was achieved (HbA1c ≤7%) (table 3) [21–23]. When the population was stratified on the basis of baseline BMI, exenatide achieved equivalent glycaemic control to insulin glargine, independently of baseline BMI [29].

Fasting Plasma Glucose

Exenatide produced a dose-dependent reduction in fasting glucose vs. baseline significantly higher than that achieved with placebo with both the tested dosage regimens (5 and 10 μg b.i.d.) in all placebo-controlled studies [18–20,25], independently of the oral antidiabetic agents used as background therapy (table 3). The reduction vs. placebo with exenatide 10 μg b.i.d. ranged from 1.0 to 1.4 mmol/l after 30 weeks and was sustained in the long-term after 3 years of treatment [18–20,27].

Exenatide 10 μg b.i.d. reduced fasting glucose also in the comparative trials vs. insulin, to a lesser extent than insulin glargine, but with no difference vs. biphasic insulin aspart (table 3) [21,23].

Fasting proinsulin and insulin

In the three studies in which fasting proinsulin and insulin were measured [18,20,25], the fasting proinsulin/insulin ratio diminished dose dependently vs. baseline and the reduction was always larger than in the placebo arm. This phenomenon indirectly indicates that exenatide treatment improves β-cell function.

Postprandial glucose and self-monitored blood glucose profile

The results related to postprandial glucose, in the subsets of patients in whom plasma glucose was recorded after a test meal, were consistent with those of the clinical pharmacology studies. Postprandial glucose AUC (15–180 min) geometric mean was reduced by exenatide to a greater degree than placebo after 30 weeks of treatment [19,20]. Exenatide also reduced the postprandial glucose rise to a greater extent than insulin glargine in the comparative study: the change in incremental glucose AUC (0–4 h) at week 26 vs. baseline was −8.6 mmol h/l with exenatide vs. −1.3 mmol h/l with insulin glargine (difference −7.3 mmol h/l, confidence interval (CI) −10.2 to 4.4 mmol h/l) [21]. Considering the self-monitored blood glucose profiles, in the comparative studies vs. insulins, exenatide 10 μg b.i.d. reduced the glucose levels after morning and evening meals (p < 0.001 vs. insulin glargine and biphasic insulin aspart) and also the 2 h postprandial glucose excursions after all three meals (p = 0.03 and p < 0.001 vs. insulin glargine (figure 1) and biphasic insulin aspart respectively) [21–23].

image

Figure 1. Self-monitored blood glucose profiles with exenatide 10 μg b.i.d. or insulin glargine [21].

Download figure to PowerPoint

Body Weight

Exenatide reduced body weight dose dependently vs. baseline at the end of treatment: the reduction was larger both vs. placebo and active comparators (table 3) [18–20,25]. On the contrary, in the comparative studies, the insulin groups showed a significant increase in body weight vs. baseline (table 3): the difference between the two treatment groups was always significant (p < 0.001) [21–23]. The reduction in body weight was achieved with exenatide also in patients who did not experience nausea (on average −1.9 kg in subjects without nausea vs. −2.3 kg in all patients treated with exenatide) [21]. In the crossover study by Barnett et al. [23], during the exenatide-insulin sequence, insulin neutralized the weight loss produced by exenatide (−2.35 kg completely regained with insulin), whereas during the insulin–exenatide sequence the weight gain with insulin (+0.75 kg) was subsequently overcome by exenatide (−2.3 kg).

The progressive reduction in body weight continued in the long-term open-label extension mentioned above [26,27]. At week 104, mean weight loss in subjects who completed the treatment more than doubled vs. week 30 (−4.7 ± 0.3 kg vs. −2.1 ± 0.2 kg) and 81% of patients lost weight. Additional data in the 217 patients who completed 3 years of treatment showed that body weight loss was still sustained (mean loss vs. baseline −5.3 ± 0.4 kg) [27].

In an interim analysis on the exenatide effects over 82 weeks, weight loss was strongly influenced by baseline BMI: patients with BMI ≥40 lost more than 7 kg (5.5% of their body weight), whereas patients with BMI <25 lost on average 2 kg (2.9% baseline body weight) [28]. Another factor influencing weight loss was the background oral antidiabetic agent. Patients taking metformin alone lost more body weight than patients taking a sulphonylurea either alone or in combination with metformin (−5.2% of baseline body weight vs. −4.0% and −4.1% respectively).

C-reactive Protein

A post hoc interim analysis [30] of serum high-sensitivity C-reactive protein (CRP) levels in 178 patients, entered into the first three placebo-controlled studies and followed up in the long term for 82 weeks, showed that long-term treatment with exenatide produced a reduction in median CRP concentrations by −1.35 mg/l from baseline median 3.21 mg/l (p < 0.0001). Multiple regression analysis showed that both change in HbA1c and change in body weight vs. baseline were correlated to CRP levels (p = 0.02 and p < 0.0001 respectively).

Lipid Profile

The lipid profile was studied in the efficacy studies listed above. In the study by Buse et al. [18], small, but significant reductions in low-density lipoproteins (LDL) and apolipoprotein B (p < 0.05) were noted. The long-term effects of exenatide 10 μg b.i.d. on the lipid profile were assessed in depth in a subgroup of 52 patients with T2DM belonging to the comparative trial vs. biphasic insulin aspart [31]. After 1 year of treatment, increases in LDL particle size (+0.33 ± 0.10 nm; p = 0.001), high-density lipoprotein (HDL) particle size (+0.11 ± 0.04 nm; p = 0.013), large LDL (+68.4 ± 27.3 nmol/l; p = 0.017) and large HDL (+0.69 ± 0.33 μmol/l; p = 0.042) were recorded with exenatide, as well as reductions in small LDL (−146.4 ± 67.7 nmol/l; p = 0.037) and very small LDL (−126.8 ± 53.9 nmol/l; p = 0.024). No significant changes were found with biphasic insulin aspart, except increases in total HDL (+2.5 ± 0.9 μmol/l; p = 0.01) and in large HDL (+1.0 ± 0.4 μmol/l; p = 0.01) [31]. Furthermore, a positive effect of exenatide on the lipid profile was confirmed also by a 2-year and 3.5-year observational study; it consisted in reduction in triglycerides (−12%), total cholesterol (−5%) and LDL cholesterol (−6%), and in an increase in HDL cholesterol (+24%) [32].

Blood Pressure

In the comparative study vs. insulin glargine, a mean reduction of −4.12 ± 17.77 mmHg in systolic blood pressure was observed, at the end-point, among exenatide-treated patients vs. a reduction of −0.57 ± 16.01 mmHg in glargine-treated subjects (p = 0.0215) [33].

Similar findings were observed in the comparative trial vs. biphasic insulin aspart, in which a statistically significant mean reduction in both systolic blood pressure (mean reduction −5 ± 15 mmHg, p < 0.001) and diastolic blood pressure (mean reduction −2 ± 10 mmHg, p = 0.03) in the exenatide group were recorded at end-point (52 weeks). Blood pressure did not change significantly with premixed insulin (systolic blood pressure change 1 ± 16 mmHg, p = not significant (NS); diastolic blood pressure change 1 ± 10 mmHg, p = NS) [21].

These results were confirmed also in the long-term open-label extension, in which a reduction in both mean systolic blood pressure (−2.6 mmHg, p = 0.003) and mean diastolic blood pressure (−1.9 mmHg, p < 0.001) was recorded vs. baseline in patients treated with exenatide 10 μg b.i.d. by week 104 [26].

Quality of Life

Health outcome questionnaires were collected during two of the above-mentioned seven clinical trials, in order to ascertain whether there are differences between the effects of exenatide and insulin that could have a significant impact on patient quality of life (QOL). During the head-to-head trial with insulin glargine, the improvement in five patient-reported outcomes was evaluated: vitality scale score of Short Form 36 (SF-36), Diabetes Treatment Satisfaction Questionnaire score, Revised Diabetes Symptom Checklist (DSC-R) scores, Euro QOL EQ-5D score and Treatment Flexibility Scale score [34]. Both treatments improved the first three parameters vs. baseline, without any significant differences. In the other study by Yurgin et al. [24] exenatide improved QOL scores, that is, the Euro QOL index (EQ-5D) score (+0.03 p = 0.03), the EQ-5D visual analogue scale score (+3.39 p = 0.0009), the DSC-R score (−0.13, p = 0.03) and the SF-36 Vitality Score (+3.89 p = 0.0019) vs. baseline, whereas biphasic insulin aspart did not.

Safety

Adverse Events

Exenatide was generally well tolerated.

The most common treatment-emergent adverse events affected the gastrointestinal tract, were usually mild to moderate, dose dependent and generally appeared during the first 8 weeks of treatment. Nausea was reported in 33–57.1% of patients treated with exenatide 10 μg b.i.d., was typically episodic and mild to moderate in intensity; its incidence tended to decrease during long-term open-label treatment [18–20,25,26]. Other commonly reported adverse events were vomiting (12–17.4%), diarrhoea (5.8–17.4%) and headache (4.7–8.9%). Discontinuation of therapy because of the gastrointestinal adverse events was low and consistent across studies (3–9% in the 10 μg b.i.d. arm) [18–20,25].

In view of the incidence of dose-limiting nausea and vomiting, a two-armed, triple-blind, placebo-controlled study [35] was performed in 123 patients with T2DM to ascertain whether gradual dose escalation could contain the phenomenon. Patients in the dose-escalation arm received exenatide 0.02 μg/kg t.i.d. on day 1; the dosage was increased by 0.02 μg/kg every 3 days up to the top dose of 24 μg/kg t.i.d., which was continued for 3 days. Patients in the placebo arm received placebo up to day 35, when exenatide was introduced at the dosage of 0.24 μg/kg t.i.d. and continued for 3 days. The incidence of nausea and vomiting was 27% in the dose-escalation arm vs. 56% in the placebo arm (p = 0.0018); in particular, severe nausea was experienced by 29 vs. 48% and vomiting by 10 vs. 31% respectively. No reduction in glucoregulating effects during dose escalation was observed.

Regarding hypoglycaemic episodes, in the placebo-controlled studies the phenomenon was common only in the two studies [18,19] using a sulphonylurea as background therapy (27.8 and 36%), because of the glucose-independent mechanism of action of that oral therapy. When the patients were allocated to the minimum recommended drug dose, the hypoglycaemia incidence was significantly reduced vs. the maximum dosage group (21 vs. 35% in exenatide 10 μg b.i.d.) [19]. There was no difference between exenatide and placebo arms when metformin was the background therapy [20]. This evidence was confirmed also in the crossover insulin glargine comparative study, in which a difference in the incidence of hypoglycaemia was found when exenatide and insulin treatments were given in combination with metformin (3% with exenatide and 17% with insulin glargine, p = 0.01) vs. a similar percentage between treatment arms when the two drugs were given in combination with a sulphonylurea (30% with exenatide and 35% with insulin glargine) [23]. In patients treated with adjunctive metformin, exenatide was associated also with less nocturnal hypoglycaemic episodes than insulin glargine [18], additional evidence supporting the data already generated in the insulin comparative trials (p < 0.0001 vs. glargine; p < 0.038 vs. biphasic insulin aspart) [22,33].

In view of the potential immunogenic properties of protein and peptide pharmaceuticals, patients may develop anti-exenatide antibodies when they are treated with exenatide. The antibody titres are generally low and diminish over time. Overall, the percentage of antibody-positive patients was consistent across clinical trials (40–50%) and antibody-positive subjects had similar rates and types of adverse events as compared to antibody-negative patients [9]. In the AMIGO studies, 38% of patients had low-titre anti-exenatide antibodies at 30 weeks and the level of glycaemic control (HbA1c) was generally comparable to that observed in those without antibody titres. An additional 6% of patients had higher titre antibodies at 30 weeks. In about half of these 6% patients (3% of the total patients given exenatide in placebo-controlled studies), the glycaemic response to exenatide appeared to be diminished; the remainder had a glycaemic response consistent with that of patients without antibodies [19,20]. In two insulin-comparator controlled trials, comparable efficacy and adverse events were observed in patients treated with exenatide regardless of antibody titre [21,23].

Finally, there have been rare spontaneous reports of acute pancreatitis [36]. Preclinical studies using exenatide doses that exceeded those used in clinical practice by a factor of more than 100 and were given for several months did not result in pathological changes in the pancreas [9]. However, patients should be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain. Resolution of pancreatitis has been observed with supportive treatment [9].

Laboratory Tests

No untoward changes in laboratory tests were reported during exenatide treatment. The lipid profile was already described above. Moreover, in the 104-week extension, exenatide treatment was also associated with an improvement of alanine aminotransferase (ALT) (−11 U/l; 95% CI: −14 to −8 U/l from baseline) and AST (−5 U/l; 95% CI: −7 to −3 U/l from baseline) in patients with elevated ALT at baseline (53%), but not in patients with normal ALT at baseline. The 25% of subjects who lost the most weight had the greatest reduction in ALT levels [26].

Future Developments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Future Developments
  6. Conclusions
  7. Acknowledgements
  8. References

A new exenatide formulation is now under clinical assessment.

A once-weekly formulation for subcutaneous injection was studied in a placebo-controlled trial for 15 weeks at the dosage of 0.8 and 2.0 mg once a week [37]. Type 2 diabetes patients, suboptimally controlled with metformin (60%) and/or diet and exercise (40%), showed, at a 2.0 mg dose, an HbA1c reduction of 1.7 ± 0.3% (p 0.0001), because of a reduction in fasting and postprandial plasma glucose. Subjects receiving 2.0 mg exenatide once weekly had significant body weight reductions (3.8 ± 1.4 kg) (p < 0.05). Mild nausea was the most frequent adverse event.

From a pharmacokinetic perspective, after ∼ 6 weeks of treatment with 2.0 mg exenatide once weekly, plasma exenatide concentrations were maintained at concentrations similar to the maximum concentration achieved with a single injection of 10 μg.

This formulation offers the potential of 24-h glycaemic control and merits longer-term, large-scale studies to gain further insight into the clinical application.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Future Developments
  6. Conclusions
  7. Acknowledgements
  8. References

In conclusion, clinical pharmacology studies have shown that exenatide exerts all the glucose-regulating properties of GLP-1 in humans (glucose-dependent increase in insulin secretion, suppression of inappropriately high glucagon secretion, reduction in gastric emptying rate) and suggest that it may also increase pancreatic β-cell function, enabling multifactorial T2DM control and management. This last possibility is of great importance, especially if we consider the fact that traditional secretagogues (sulphonylureas and glinides), on the contrary, may contribute to the progressive decline of β-cell mass described in the natural history of the disease. It has been shown in addition that exenatide has a much longer half-life than GLP-1, which enables b.i.d. dosing. The most effective dosage regimen appears to be b.i.d. at breakfast and dinner, at the recommended dosage of 5 μg b.i.d. for the first 4 weeks of treatment, followed by 10 μg b.i.d. [9]. In Europe exenatide is indicated for the treatment of T2DM in combination with metformin and/or sulphonylurea in patients who have not achieved adequate glycaemic control on maximum tolerated dosages of these oral drugs [9].

The use of exenatide produces a sustained reduction in HbA1c, which is significantly greater than with placebo and similar to what is achieved with insulin preparations. The reduction is clinically important and results in optimal glucose metabolic control, defined as HbA1c ≤7%, in 30–62% of patients. Exenatide-induced HbA1c improvement is produced by a significant action on fasting blood glucose, albeit to a lesser extent than with insulin preparations (indirectly suggesting a lower risk of hypoglycaemia), and on postprandial glucose levels, with a particularly marked effect on postprandial glucose excursions. In view of recent scientific evidence demonstrating the crucial pathophysiological role of postprandial hyperglycaemia in endothelial and vascular damage (and, consequently, in the appearance of micro- and macrovascular diabetic complications) [38–41], the contemporary effect of exenatide on fasting plasma glucose and postprandial plasma glucose is of particular interest.

Furthermore, patients using exenatide experience consistent weight loss, also in the long term, independently of baseline BMI, which becomes more evident when compared to the weight increase associated with insulin use.

The safety data collected during controlled clinical trials on 2845 T2DM patients not optimally controlled by oral antidiabetic agents show that the compound is generally safe and well tolerated. The most common adverse events are gastrointestinal disorders; they are usually mild or moderate in intensity and occur mainly at the beginning of treatment. A study focused on the issue of nausea and vomiting has shown that dose escalation can halve the incidence of this untoward reaction. Because of its glucose-dependent mechanism of action, exenatide does not increase hypoglycaemia risk when added on top of metformin; on the contrary, a sulphonylurea dose reduction at the beginning of treatment may reduce the risk of hypoglycaemia associated with this oral drug [9].

An additional finding is that exenatide appears to have positive effects on blood pressure, a cardiovascular risk factor. This effect, together with the improvement in glucose metabolism control, the reduction in body weight and CRP, and the positive changes in lipids, may contribute to cardiovascular risk profile improvement in patients with T2DM and seems to be associated also with improved QOL [34].

Because of the recent introduction in the market, official guidelines from Scientific International Societies still need to update the treatment algorithms for type 2 diabetes with the new incretin-based therapies (incretin mimetics and Dipeptidyl peptidase-4 (DPP-IV) inhibitors). The only exceptions are the guidelines from National Institute for Health and Clinical Excellence (NICE) [42], the Road Map to achieve glycaemic goals by American Association of Clinical Endocrinologist (AACE) [43] and the Guidelines on Postprandial Glucose Control by International Diabetes Federation (IDF) [44]. In these documents, Exenatide is considered a valuable therapeutic option when type 2 diabetic patients are not optimally controlled by oral drugs.

Further studies on the chronic effects and on the new once-weekly formulation of exenatide are warranted to assess which T2DM patients might particularly benefit from its use and to verify the hypothesis that it may have long-term effects on β-cell function (and potentially β-cell mass) and may reduce the rate of long-term diabetic complications, as a result of better and multifactorial disease control.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Future Developments
  6. Conclusions
  7. Acknowledgements
  8. References

The authors thank Dr Jennifer Hartwig for her contribution to the drafting and editing of this article, and Dr Francesco Cremasco for manuscript review.

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  3. Introduction
  4. Methods
  5. Future Developments
  6. Conclusions
  7. Acknowledgements
  8. References
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