DURATION-1: Exenatide Once Weekly Produces Sustained Glycemic Control and Weight Loss Over 52 Weeks

Abstract

OBJECTIVEIn the Diabetes Therapy Utilization: Researching Changes in A1C, Weight and Other Factors Through Intervention with Exenatide Once Weekly (DURATION-1) study, the safety and efficacy of 30 weeks of treatment with the glucagon-like peptide-1 receptor agonist exenatide once weekly (exenatide QW; 2 mg) was compared with exenatide BID in 295 patients with type 2 diabetes. We now report the safety and efficacy of exenatide QW in 1) patients who continued treatment for an additional 22 weeks (52 weeks total) and 2) patients who switched from exenatide BID to exenatide QW after 30 weeks.RESEARCH DESIGN AND METHODSIn this randomized, multicenter, comparator-controlled, open-label trial, 258 patients entered the 22-week open-ended assessment phase (n = 128 QW-only; n = 130 BID→QW). A1C, fasting plasma glucose (FPG), body weight, blood pressure, fasting lipids, safety, and tolerability were assessed.RESULTSPatients continuing exenatide QW maintained A1C improvements through 52 weeks (least squares mean −2.0% [95% CI −2.1 to −1.8%]). Patients switching from exenatide BID to exenatide QW achieved further A1C improvements; both groups exhibited the same A1C reduction and mean A1C (6.6%) at week 52. At week 52, 71 and 54% of all patients achieved A1C <7.0% and ≤6.5%, respectively. In both treatment arms, FPG was reduced by >40 mg/dl, and body weight was reduced by >4 kg after 52 weeks. Nausea occurred less frequently in this assessment period and was predominantly mild. No major hypoglycemia was observed.CONCLUSIONExenatide QW elicited sustained improvements in glycemic control and body weight through 52 weeks of treatment. Patients switching to exenatide QW experienced further improvements in A1C and FPG, with sustained weight loss.

GLP-1 for type 2 diabetes

“…Within the GLP-1 receptor agonist group, the longer acting agonists seem more potent, as verified by head-to-head studies showing a larger reduction in HbA 1c by liraglutide than by exenatide [40] and by once weakly exenatide versus twice daily exenatide [15]. In regard to DPP-4 inhibitors, they seem all to have similar efficacy, which is supported by a head-to-head studies comparing sitagliptin with saxagliptin as add-on to metformin.…”

“…This long acting form is now in late clinical development and has been shown to have a better glycemic effect than conventional exenatide given twice daily in a study over 52 weeks [15]. The reduction in HbA 1c by exenatide LAR was 2.0% from a baseline of 8.3% and this was associated with a reduction in body weight by 4.1kg from 7…”

Rationale and design of the EXenatide Study of Cardiovascular Event Lowering (EXSCEL) trial

“…It improves hyperglycemia and 16 other cardiovascular risk factors such as blood pressure, lipids, and body weight without increasing the risk of hypoglycemia. [7][8][9][10][11] In addition, further pleiotropic effects on the cardiovascular system, both through GLP-1 receptor-mediated and other mechanisms, have been suggested. 29 Studies in animal models suggest beneficial effects of GLP-1 on atherogenesis, by inhibiting the inflammatory response in macrophages and endothelial adhesion 30 and modulating endothelial function.…”

“…Exenatide has also been shown to have beneficial effects on blood pressure, blood lipids, and to facilitate weight loss. [7][8][9][10][11] Mechanistic data suggest that exenatide can improve cardiac function in patients with chronic heart failure, 12 improve endothelial dysfunction, 13 and reduce infarct size after ST-segment elevation myocardial infarction. 12,14 A patient-level integrated meta-analysis showed no evidence for increased cardiovascular disease risk with use of exenatide in 6 subjects with T2DM, 15 while a retrospective analysis of a medical and pharmaceutical insurance claims database found a lower relative cardiovascular disease risk associated with exenatide treatment than with other glucose-lowering drugs.…”

The Current Status of Exenatide Once Weekly

“…24 In a 22 week open-ended extension of the above trial, subjects originally randomized to exenatide once weekly remained on weekly doses and those previously receiving twice daily converted to weekly doses. 25 Both groups experienced durable glycemic improvement and weight loss at the 52 week mark regardless of the original dosing regimen, but patients who switched from the twice daily to the once weekly dosing regimen were noted to have a temporary decline in glycemic control during the conversion. This is thought to be due to the long half-life of the once weekly formulation that may require 4-6 weeks to achieve steady state.…”