Kanika Ballani, Pharm.D.
Diana Hubulasvili, Pharm.D.
Developed by Amylin Pharmaceuticals, Exenatide (Byetta®) is an incretin mimetic that is used as an adjunctive therapy with metformin, a sulfonylurea or a thiazolidinedione to improve glycemic control in type 2 diabetic patients. Mechanistically, Exenatide mimics the actions of endogenous incretin hormone, glucagon-like peptide (GLP-1), causing an increase in insulin secretion which slows gastric emptying and leads to a decrease in food intake. On November 3rd 2009, the FDA issued a safety warning on Exenatide associating it with the incidence of renal failure. This FDA warning was based on 78 postmarketing cases reported between April 2005 and October 2008. The average patient age in the case reports was 60 years. The FDA approved revisions to the drug label for exenatide due to the temporal-causal relationship that was observed with the initiation of exenatide and the occurrence of serious potential consequences of altered kidney function.1
Sixty-two of the cases reported were classified as acute renal failure and the remaining 16 cases were categorized as renal insufficiency. The postmarketing surveillance data of these cases reported that after the initiation of exenatide, hospitalization was required in 91% (71/78) of the patients. Two patients needed kidney transplantation and there were 4 fatalities. Dialysis had to be initiated in eighteen patients, of which, 2 patients had a known prior history of altered kidney function. Upon discontinuation, 39 patients reported improved signs and symptoms after the discontinuation of the drug. Recurrence in kidney dysfunction was reported in one patient who was reinitiated on exenatide.1
Forty-two patients (54%) reported symptoms associated with volume depletion, such as diarrhea, vomiting, and dehydration. These common gastrointestinal manifestations of exenatide are believed to be the risk factors for the development of altered kidney function. Weiss et al. reported the incidence of exenatide induced ischemic renal failure in 4 patients and established a temporal causal relationship between exenatide and the incidence of renal dysfunction. The induction of nausea and vomiting associated with exenatide use contributes to extracellular volume contraction, which when combined with concomitant therapy with diuretics and ACEIs, leads to an exaggerated decline in glomerular filtration rate. GLP-1 has also been proposed to cause natriuresis decreasing renal perfusion; an effect believed to be shared by exenatide as well.2,3
It must be noted that the time frame for the development of acute renal insufficiency was wide, ranging from 3 days to up to 2 years after the initiation of exenatide. Moreover, pre-existing kidney disease or risk factors for developing renal dysfunction such as- cardiac insufficiency, hypertension, pancreatitis, rhabdomyolysis, urinary tract infections and concomitant use of NSAIDs, antiretrovirals, and diuretics, were evident in 95% (74/78) of patient cases reported. It is plausible that the incidence of renal dysfunction noted in these patients could also have precipitated secondary to the independent risk factors initially present in these patients. In addition, 14 of the cases had a prior medical history of chronic kidney disease, and 4 cases with chronic renal failure, despite recommendations against the use of Byetta in these patients in the current prescribing information.1
Interestingly, Exenatide was approved as a first line agent, in conjunction with diet and exercise to improve glycemic control in type 2 diabetes mellitus on the same day this warning regarding the incidence of renal insufficiency was issued. Based on this warning, practitioners must weigh out risks and benefits before prescribing exenatide as monotherapy for the management of diabetes and exert precaution in administering it concomitantly with other nephrotoxic agents.
References:
1. www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyRelatedDrugLabelingChanges/ucm106696.htm
2. Weiss et al. Exenatide-Associated Ischemic Renal Failure. Diabetes Care. 2009;32(2):e22-23
3. Gutzwiller JP et al. Glucagon-like peptide 1 induces natriuresis in healthy subjects and in insulin-resistant obese men. J Clin Endocrinol Metab. 2004;89:3055-3061