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Effects of Exenatide versus Sitagliptin on Postprandial Glucose, Insulin, and Glucagon Secretion, Gastric Emptying, and Caloric Intake: A Randomized, Crossover Study
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ffects of Exenatide versus Sitagliptin on Postprandial Glucose, Insulin, and Glucagon Secretion, Gastric Emptying, and Caloric Intake: A Randomized, Crossover Study
Alexander Julian, Doctor of Pharmacy Candidate
University of Florida College of Pharmacy
The clinical study entitled “Effects of exenatide versus sitagliptin on postprandial glucose, insulin, and glucagon secretion, gastric emptying, and caloric intake: a randomized, crossover study” compared the two newer treatment options in the management of Type 2 diabetes. The article was authored by Ralph Defronzo of the University of Texas Health Science Center. Co-authors included John H. Holcombe from Eli Lilly and Company as well as Ted Okerson, Prabhakar Viswanathan, Xuesong Guan, and Leigh MacConell who are affiliated with Amylin Pharmaceuticals, Inc. which is the company that manufactures the study drug exenatide (Byetta®). It may also be important to note that this study was also funded by Amylin pharmaceuticals. The study was published in 2008 in the journal Current Medical Research and Opinion.
This study was a double blind, randomized cross-over, multi-center study. The primary endpoint compared the effect of exenatide and sitagliptin on 2 hour post-prandial glucose. Secondary endpoints included postprandial insulin, glucagons, active GLP-1 and triglyceride concentrations, insulin secretion rate, acetaminophen absorption, exenatide pharmacokinetics, and safety. Other endpoints included caloric intake, fasting plasma glucose, insulinogenic index of insulin secretion, body weight, and sitagliptin pharmacokinetics.
This study was performed on Type 2 diabetes patients treated exclusively with metformin. There were 64 patients evaluated in this study, 54% of which were female. The mean age was 54 with a standard deviation of 9 years. Thirty percent were Caucasian, 8% were black, and 62% were Hispanic. The mean body weight of the patients was 91.5 kg with a standard deviation of 18.8 kg; the mean BMI was 32.6 with a standard deviation of 5.1. Patients had a past medical history of diabetes for a mean of 7 years with a standard deviation of 5 years. At baseline, the mean 2 hour postprandial glucose was 245mg/dL with a standard deviation of 65 mg/dL. Patients were excluded from the study if they had hepatic, renal, gastrointestinal, or cardiovascular disease. Other exclusion criteria included seizure disorders, active or untreated malignancies, fasting triglycerides of greater than or equal to 400 mg/dL, previous treatment with sitagliptin or exenatide, or current treatment with a sulfonylurea, thiazolidinedione, insulin, systemic corticosteroids, or any drug that affects gastric motility.
Patients underwent a 1-week placebo lead-in period in which no treatment was given for the management of their diabetes. Patients were randomly assigned to either exenatide treatment which consisted of 5 microgram subcutaneous dosing twice daily for 1 week then and increase to 10 micrograms twice daily for an additional week or sitagliptin 100mg by mouth every morning for 2 weeks. After the two weeks the patients were switched to the other treatment. All patients received an injection BID and an orally administered capsule daily to ensure blinding. Two hour postprandial glucose was assessed using a standardized meal tolerance test performed at baseline as well as after two weeks with a particular treatment. To determine caloric intake, a cohort of 25 patients were allowed to eat from free-choice variety of pre-weighed foods in which caloric intake was calculated using The Food Processor nutritional analysis software. Gastric emptying was determined by administering and measuring acetaminophen levels over a 4 hour period following a single 1,000 mg dose of acetaminophen given just prior to the standard meal. The insulin and glucagon secretion rates were determined by using computer programs using pharmacodynamic parameters such as AUC measured over a 240 minute timeframe. An insulinogenic index which measured acute phase insulin response to the meal was calculated by dividing pre and post (30 minutes between levels) insulin by pre and post glucagons (30 minute between levels).
The authors reported a significantly lower 2 hour postprandial glucose in exenatide (133 ± 6mg/dL) compared to sitagliptin (208mg/dL ± 6mg/dL). The authors also reported that caloric intake in the cohort of 25 patients was decreased by -134 ± 97k/cal in the exenatide treatment group and it was increased by +130 k/cal ± 97 k/cal in the sitagliptin treatment group. Gastric emptying was determined to be slowed because the plasma acetaminophen level was lower in the exenatide treatment group compared to the sitagliptin treatment group which did not deviate from baseline. The authors found clinically significant decreases in glucagons secretion as well as improved insulinogenic index and insulin secretion rate.
It may be important to note that the authors also found that the fasting plasma glucose concentrations were similar in both treatment groups. The authors stress that exenatide will likely put patients within the goal of a 2 hour postprandial glucose reading of <180 mg/dL set forth by the American Diabetes Association.
Reference:
Defronzo RA, Okerson T, et al. “Effects of exenatide versus sitagliptin on postprandial glucose, insulin, and glucagon secretion, gastric emptying, and caloric intake: a randomized, crossover study” Current Medical Research and Opinion Vol.2, No. 10, 2008, 2943-2952