Long-term management of type 2 diabetes with glucagon-like peptide-1 receptor agonists

Abstract

Continuously reducing excess blood glucose is a primary goal for the management of type 2 diabetes (T2D). Most patients with T2D require glucose-lowering medications to achieve and maintain adequate glycemic control; however, treatment failure may occur, limiting treatment options. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are an emerging therapeutic class that can be prescribed for patients instead of basal insulin after the failure of oral therapies. Recent studies have focused on the durability and tolerability of long-term GLP-1RA therapy. This review summarizes the key efficacy and safety findings from prospective phase 3 clinical studies of at least 76 weeks’ duration for the GLP-1RAs currently approved in the United States and the European Union (albiglutide, dulaglutide, exenatide twice daily [BID], exenatide once weekly [QW], liraglutide, and lixisenatide). Currently, most of the long-term data are from uncontrolled extension studies, and continuous patient benefit has been observed for up to 3 years with multiple GLP-1RAs. Four-year comparative data demonstrated a longer time to treatment failure for exenatide BID than for sulfonylurea, and 3-year comparative extension data demonstrated greater glycated hemoglobin (HbA1c) reductions and weight loss with exenatide QW than with insulin glargine. Currently, the longest extension study for a GLP-1RA is the DURATION-1 study of exenatide QW, with >7 years of clinical data available. Data from DURATION-1 demonstrated that continuous HbA1c reductions and weight loss were observed for the patients continuing on the treatment, with no unexpected adverse events. Taken together, these data support GLP-1RAs as a long-term noninsulin treatment option after the failure of oral therapies.

Predictive factors associated with three years of response to HbA1c goals with exenatide QW or insulin glargine: Post‐hoc analysis of the DURATION‐3 study

“…Long‐term data with glucose‐lowering therapies for type 2 diabetes are limited, particularly for recently available agents . Most phase 3 clinical studies are 26 or 52 weeks in duration and cannot predict clinical outcomes over several years, although they often have open‐label extensions.…”

“…Most phase 3 clinical studies are 26 or 52 weeks in duration and cannot predict clinical outcomes over several years, although they often have open‐label extensions. Among glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs), follow‐up periods have extended to 2 years for albiglutide, dulaglutide and liraglutide and to 7 years for exenatide once weekly (QW) . Whereas cardiovascular outcome trials for the GLP‐1RAs exenatide, liraglutide and semaglutide and the sodium–glucose cotransporter‐2 inhibitors empagliflozin and canagliflozin had relatively long follow‐up periods, patient populations generally comprised those at high cardiovascular risk and were not representative of all patients in real‐world practice …”

“…2,3 Long-term data with glucose-lowering therapies for type 2 diabetes are limited, particularly for recently available agents. 5 Most phase 3 clinical studies are 26 or 52 weeks in duration and cannot predict clinical outcomes over several years, although they often have openlabel extensions. Among glucagon-like peptide-1 receptor agonists (GLP-1RAs), follow-up periods have extended to 2 years for albiglutide, dulaglutide and liraglutide and to 7 years for exenatide once weekly (QW).…”

“…Among glucagon-like peptide-1 receptor agonists (GLP-1RAs), follow-up periods have extended to 2 years for albiglutide, dulaglutide and liraglutide and to 7 years for exenatide once weekly (QW). [5][6][7][8][9] Whereas cardiovascular outcome trials for the GLP-1RAs exenatide, liraglutide and semaglutide and the sodium-glucose cotransporter-2 inhibitors empagliflozin and canagliflozin had relatively long follow-up periods, patient populations generally comprised those at high cardiovascular risk and were not representative of all patients in real-world practice. 10 The DURATION-3 study was a randomized open-label study that compared exenatide QW with insulin glargine in 467 adults with type 2 diabetes (Supporting Information Figure S1).…”

MiR-7, miR-9 and miR-375 contribute to effect of Exendin-4 on pancreatic β-cells in high-fat-diet-fed mice

“…This defect in insulin secretion is accompanied by a deficit in β-cell mass [1,2]. Recently, a glucagon-like peptide-1 (GLP-1) mimetic class of drugs, widely referred to as incretins, has shown promise as a therapeutic for treatment of T2DM [3,4]. A growing body of evidence has shown that GLP-1 can enhance glucose-stimulated insulin secretion (GSIS) and insulin synthesis, inhibit glucagon secretion, confer glucose sensitivity to glucose-resistant β-cell, stimulate β-cell proliferation and neogenesis and inhibit β-cell apoptosis [5][6][7].…”