The incretin mimetics are medications that mimic the action of incretins, peptide hormones that originate in the gastrointestinal tract.
3-7 The two major incretins in humans are GLP-1 and glucose-dependent insulinotropic peptide (GIP). Incretins are released during nutrient absorption, augmenting insulin secretion.
Incretin mimetics also reduce postprandial glucagon secretion and delay gastric emptying time. As a result, patients using these medications can have improved postprandial glucose excursions and early satiety.
3-7 The improved sense of satiety is most likely a separate effect induced by activation of GLP-1 receptors in the brain.
5 Exenatide, a synthetic GLP-1 agonist and polypeptide originally isolated from the salivary secretions of the Gila monster, has approximately 53% homology to human GLP-1.
12-14 Unlike natural incretins, however, exenatide is resistant to degradation by DPP-IV. Thus, it shows much promise for treating patients with T2DM.
Figure 1 displays results of three 30-week clinical trials that examined the effects of exenatide in patients with T2DM who were also using metformin (N = 336),
12 sulfonylurea (N = 377),
13 or metformin plus sulfonylurea (N = 733).
14 Exenatide was given to patients 15 to 60 minutes before two large meals. Patients using metformin who were also treated with 10 μg of exenatide twice a day had a further reduction of HbA
1c of approximately 0.8%, compared with patients using metformin and placebo (
P < .001).
12 The sulfonylurea-exenatide group
13 and the metformin-sulfonylurea-exenatide group
14 also had further reductions in their HbA
1c levels of about 0.8% compared with their corresponding placebo groups (
P < .001). The percentages of patients who completed the study using 10 μg of exenatide and who reached the target HbA
1c level of less than 7.0% were the following: approximately 46% in the metformin-exenatide group, 41% in the sulfonylurea-exenatide group, and 34% in the metformin-sulfonylurea-exenatide group (
Figure 2).
12-14 The lesser reduction in the latter, combined group might be explained by the fact that T2DM was longer standing in those patients, thereby resulting in greater loss of endogenous insulin secretion.
Blonde et al
15 studied 314 overweight patients with T2DM who used exenatide for 82 weeks. The first 30 weeks of the study were placebo-controlled. Fifty-two additional weeks were an open-label uncontrolled extension. At week 30, patients using 10 μg of exenatide twice a day had an average reduction in body weight of 2 kg from baseline, in conjunction with an improvement in HbA
1c levels. At week 82, these patients had an average weight reduction of 4.4 kg. Approximately 50% of the patients using exenatide had a weight-neutral response. Therefore, this study suggests that about half of the patients using exenatide can expect to achieve a significant weight loss with the drug.
Blonde et al
15 also demonstrated that the body mass index (BMI) of patients with T2DM predicts their degree of weight loss when using exenatide. Patients with the greatest BMI (>40) also had the greatest weight loss during the 82-week course of the study—approximately 8 kg.
Heine et al
16 conducted a 26-week randomized controlled trial to compare glargine insulin (one daily dose to maintain fasting glucose levels) with exenatide (10 μg twice a day). Patients with suboptimally controlled T2DM and a mean baseline HbA
1c level of 8.2% were randomly assigned to receive either glargine insulin (n = 260) or exenatide (n = 275). At week 26, the average dose of glargine insulin was 25 units per day, a relatively small dose of insulin for most patients with T2DM.
Heine et al
16 found that the patients' average HbA
1c levels fell to just above 7% in both groups (1.1% drop from the baseline). The body weight of patients using glargine insulin increased an average of 1.8 kg during the study, while that of patients using exenatide decreased an average of 2.3 kg. Thus, the study suggested that glargine insulin and exenatide produce similar benefits in HbA
1c levels, but exenatide has the added benefit of weight loss. In addition, measurements of preprandial glycemic and postprandial glycemic excursions indicated a tendency for patients using exenatide to have reduced postprandial glycemic excursions.
The differences in adverse effects between glargine insulin and exenatide are striking. Heine et al
16 found that nausea occurred in about 9% of patients using glargine insulin, while it occurred in 57% of patients using exenatide. Vomiting occurred in about 4% of patients using glargine insulin and 17% of patients using exenatide (
P < .001). The hypoglycemia rate in both groups was comparable, with 6.3 events per patient-year in the glargine group and 7.3 events per patient-year in the group using exenatide. However, the occurrence of nocturnal hypoglycemia was slightly higher in the group using glargine.