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Effects of Exenatide (Exendin-4) on Glycemic Control Over 30 Weeks in Sulfonylurea-treated Patients With Type 2 Diabetes

Background: Over time, sulfonylurea treatment will eventually fail to provide sufficient blood glucose control in the majority of patients with type 2 diabetes. In addition, hypoglycemia and weight gain are common problems associated with sulfonylurea treatment. The addition of exenatide may improve glycemic control in patients who are beginning to fail sulfonylurea therapy while minimizing hypoglycemia and weight gain by mimicking the effects of glucagon like peptide.

Objective: The purpose of this study is to verify that patients with type 2 diabetes who are failing monotherapy on a maximally effective dose of a sulfonylurea will increase blood glucose control over a 30-week period with exenatide treatment.

Methods: This was a randomized, triple-blind, placebo-controlled, parallel group trial. General inclusion criteria were a screening fasting plasma glucose concentration of <240 mg/dl, BMI 27-45 kg/m2, and HbA1c 7.1-11.0%. Patients had to be treated with the maximally effective dose of a sulfonylurea as monotherapy and maintain a stable weight for at least three months prior to screening and have type 2 diabetes. Exclusion criteria were using metformin, thiazolidinediones, meglitinides, alpha-glucosidase inhibitors, exogenous insulin therapy, or weight-loss drugs within the prior three months before screening, as well as, using corticosteroids, drugs known to affect gastrointestinal motility, transplantation medications, or any investigational drug. There were 377 patients enrolled. Prior to the start of the study, patients had their sulfonylurea dose adjusted to the maximally effective dose to standardize its use. Study drug dosages included 5 mcg of exenatide, 10 mcg of exenatide, or an equivalent volume of placebo. Study medication was self-administered subcutaneously twice daily over a 30-week duration. Primary outcome measures were to evaluate glycemic control, mainly assessed by HbA1c, and safety. Secondary measures included examining the effects of exenatide on fasting plasma glucose concentrations, body weight, and fasting concentrations of circulating insulin, proinsulin, and lipids. About 90% power was used to identify a difference of 0.6% in the change from baseline HbA1c values between at least one treatment arm and placebo. All safety and efficacy analyses were done using the intent-to-treat (ITT) population, except the percentage of patients attaining HbA1c values of less than or equal to 7% at 30 weeks. For this analysis, the population of evaluable subjects was used.

Results: Overall, there were 260 (69.0%) patients who completed the study. In the 10 mcg arm 91 (70.5%) patients completed the study, 95 (76.0%) in the 5 mcg arm, and 74 (60.2%) in the placebo arm. At week 30, the HbA1c change from baseline was -0.86 +/- 0.11% in the 10 mcg arm and -0.46 +/- 0.12% in the 5 mcg arm compared with an increase of 0.12 +/- 0.09% in the placebo arm (P≤0.0002). For the ITT patients at week 30 who had baseline HbA1c >7%, 41 subjects (34.2%) in the 10 mcg arm and 31 subjects (26.7%) in the 5 mcg arm reached an HbA1c of ≤7%, compared with placebo (9 subjects [7.7%]; P< 0.0001). For the evaluable patients at week 30 who had baseline HbA1c >7%, 33 subjects (41.3%) in the 10 mcg arm and 28 subjects (32.6%) in the 5 mcg arm reached an HbA1c of less than or equal to 7%, compared with placebo (6 subjects [8.8%]; P≤0.0002). Subjects in the 10 mcg arm had an end-of-study weight loss of -1.6 +/- 0.3 kg from baseline (P <0.05 vs. placebo). There was no significant difference in weight loss between the 5 mcg exenatide group and placebo. By week 30, fasting plasma glucose concentrations in the 10 and 5 mcg arms were reduced by -0.6 +/- 0.3 and -0.3 +/- 0.2 mmol/l from baseline, respectively, compared with an increase of 0.4 +/- 0.3 mmol/l in the placebo arm (P <0.05 vs. placebo for the 10 mcg arm only). There were no significant changes in fasting plasma insulin concentrations over the course of the study. However, there was a significant drop in fasting proinsulin concentrations in the 10 mcg arm from baseline (-16 pmol/l, 95% CI -26.1 to -6.0) (P <0.01 compared to placebo). The most common adverse events were mild or moderate and included nausea, hypoglycemia, dizziness, and other GI complaints. The prevalence of severe nausea was low (5% in the 10 mcg arm, 6% in the 5 mcg arm, and 2% in placebo arm). Withdrawals due to nausea were also low (4% in the 10 mcg arm, 2% in the 5 mcg arm, and 0% in placebo arm). There were no cases of severe hypoglycemia. Furthermore, there were no undesirable trends evident in vital sign measurements, physical examination findings, heart rate, or blood pressure between the treatment arms. The author’s concluded that long-term exenatide treatment at fixed subcutaneous doses of 5 and 10 mcg twice daily appears to have potential for the treatment of patients with type 2 diabetes whose blood glucose levels are inadequately controlled with sulfonylurea agents alone.

Strengths: Since exenatide’s indication is adjunctive therapy for uncontrolled type 2 diabetes, the study’s objective is rational. The parallel study design is appropriate for determining the efficacy of a drug, provided the patients in the experimental and control groups are truly comparable which is accurate for this study. The inclusion and exclusion criteria for this study were representative of the patient population of interest (overweight, reasonably healthy patients with uncontrolled type 2 diabetes). However, reasonably healthy was not well defined in the study. These criteria will help determine the ability of exenatide to be used as adjunctive therapy with a sulfonylurea for improved glycemic control.

Weaknesses: Potential conflicts of interest may exist since a major supporter of the study is the pharmaceutical company that manufactures exenatide. Also, the pharmaceutical company employs four of the article’s authors. All safety and efficacy analyses were done using the ITT population which provides more true-to-life data; however, the population of evaluable patients was used to report the percentage of patients attaining HbA1c values of less than or equal to 7% by the end of the trial. This was done since the percentage of patients achieving this HbA1c goal in the 10 mcg arm was higher in the evaluable population than in the ITT population (41% vs. 34%), so it made the data appear stronger. This occurred because the evaluable population reports the absolute change that can be expected with optimal patient compliance. Although this may not be a true weakness of the study, it was deceiving since the conclusion stressed the results found in the evaluable population without mentioning the ITT population. The results were given as mean +/- standard error not standard deviation in an effort to make the data appear more impressive. Since the study medication was self-injected there may have been an unreported compliance problem. Although precautions were taken, the occurrence of known adverse events could indirectly lead to unblinding. Also an important factor, the patient’s diet during the study, was not noted.

Conclusion: The majority of the study’s findings are clinically significant in regards to decreasing HbA1c levels in both exenatide treatment groups. However, due to its subcutaneous administration, exenatide is probably not a practical alternative to the existing oral antidiabetic agents or to the effectiveness of insulin. At this point adverse events do not seem to be a limiting factor since they are usually mild to moderate and diminish after the first few weeks of treatment. Future studies could compare exenatide with other adjunctive therapies such as metformin.

Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD; Exenatide-113 Study Group. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care. 20004 Nov;27(11):2628-35.

Heather B. Fouse, Pharm.D. Candidate