Article

Lixisenatide, a novel GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus.

Amager Hospital, Department of Internal Medicine, University of Copenhagen, Denmark.
IDrugs: the investigational drugs journal (Impact Factor: 2.33). 09/2009; 12(8):503-13.
Source: PubMed

ABSTRACT Lixisenatide, under development by sanofi-aventis, is a novel human glucagon-like peptide-1 receptor (GLP-1R) agonist for the treatment of type 2 diabetes mellitus (T2DM; non-insulin dependent diabetes). The structure of lixisenatide, based on exendin-4(1-39) modified C-terminally with six Lys residues, is able to withstand physiological degradation by dipeptidyl peptidase IV. In vitro, lixisenatide bound to human GLP-1R with a greater affinity than native human GLP-1 (7-36 amide). In various in vitro and in vivo models of T2DM, lixisenatide improved glycemic measures and demonstrated promising pancreatic beta-cell-preserving actions. In patients with T2DM, subcutaneously administered lixisenatide displayed linear pharmacokinetics. In two phase II clinical trials, lixisenatide improved glucose tolerance, resulted in weight loss and lowered HbA1C, thereby causing significantly more patients to achieve target HbA1C levels compared with placebo. Lixisenatide exhibited well-established GLP-1-related gastrointestinal side effects, with mild nausea occurring most frequently; a low frequency of hypoglycemia was also reported. The results of phase III trials are awaited for confirmation of the anticipated effects of lixisenatide on glycemic measures and weight; favorable results would place lixisenatide for consideration among other GLP-1R agonists in the treatment armamentarium for T2DM.

4 Bookmarks
 · 
366 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Glucagon-like peptide 1 receptor (GLP-1R) agonists provide good glycemic control combined with low hypoglycemia risk and weight loss. Here, we summarize the recently published data for this therapy class, focusing on sustainability of action, use in combination with basal insulin, and the efficacy of longer acting agents currently in development. The safety profile of GLP-1R agonists is also examined. GLP-1R agonists provide sustained efficacy and their combination with basal insulin is well tolerated, providing additional glycemic control and weight benefits compared with basal insulin alone. Data suggest that the convenience of longer acting agents may be at the expense of efficacy. Despite the initial concerns, most evidence indicates that GLP-1R agonists do not increase the risk of pancreatitis or thyroid cancer. However, the extremely low incidence of these events means further investigations are required before a causal link can be eliminated. Large-scale clinical trials investigating the long-term cardiovascular safety of this therapy class are ongoing and may also provide important insights into pancreatic and thyroid safety. GLP-1R agonists offer sustained glycemic efficacy, weight loss benefits, and a low risk of hypoglycemia. The results of ongoing trials should help to clarify the safety of this therapy class.
    Current opinion in endocrinology, diabetes, and obesity 04/2013; 20(2):87-97. · 3.77 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Type 2 diabetes mellitus (T2DM) is a complex, progressive disease affecting an estimated 257 million people worldwide. A number of unmet needs exist with traditional T2DM therapies, which can lead to insufficient glycaemic control and increased risk of diabetes-associated complications. An emerging class of diabetes therapeutics, the glucagon-like peptide-1 (GLP-1) receptor agonists, appear to address many of the unmet needs of patients with T2DM. This review summarises the recent findings and current clinical guidelines of the currently approved GLP-1 receptor agonists and explores the new GLP-1 receptor agonists in development. It also concentrates on the physiological basis for early use of GLP-1 receptor agonists, their use as an alternative to insulin therapy, the rationale for combining them with insulin and their cost-effectiveness.
    Diabetes research and clinical practice 07/2011; 93(3):317-27. · 2.74 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Glucagon-like peptide-1 (GLP-1) receptor agonists are a new class of hypoglycemic drugs, including exenatide, liraglutide, albiglutide, lixisenatide, and taspoglutide. Insulin glargine is a standard agent used to supplement basal insulin in type 2 diabetes mellitus (T2DM). Objective: The aim of this study was to review the efficacy and safety profiles of GLP-1 receptor agonists versus insulin glargine in type 2 diabetic patients who have not achieved treatment goals with oral hypoglycemic agents. Methods: The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, and the database of ongoing trials were searched from inception through April 2010. Additional data were sought from relevant Web sites, the American Diabetes Association, reference lists of included trials and related (systematic) reviews, and industry. Randomized controlled trials (RCTs) were selected if they were ≥3 months in duration, compared GLP-1 receptor agonists with insulin glargine in patients with T2DM, and included ≥1 of the following outcomes: mortality, complications of T2DM, glycemie control, weight, lipids, blood pressure, adverse effects, and health-related quality of life. Quasirandomized controlled trials were excluded. The quality of the eligible studies was assessed on the basis of the following aspects: randomization procedure, allocation concealment, blinding, incomplete outcome data (intent-to-treat [ITT] analysis), selective outcome reporting, and publication bias. Results: A total of 410 citations were retrieved; 5 multicenter RCTs that met the inclusion criteria were identified. They were all open-label designs with an insulin glargine arm, predefined outcomes reported, and ITT analysis. One trial had an unclear randomization procedure and allocation concealment. Publication bias was not able to be determined. No data wete found with regard to mortality or diabetes-associated complications, and few data were found on quality of life. The results of the metaanalysis suggest that insulin glargine was significantly better in reducing the fasting blood glucose (mean difference [MD] [95% CI], 1.31 [1.04 to 1.58]; P < 0.001), but exhibits greater incidence of nocturnal hypoglycemia (risk ratio [RR] [95% CI], 0.40 [0.23 to 0.71]; P = 0.002) and influenza (RR [95% CI], 0.56 [0.32 to 0.98]; P = 0.04). GLP-1 receptor agonists are more conducive to reducing weight (MD [95% CI], -3.96 [-5.14 to -2.77]; P < 0.001), postprandial blood glucose (after breakfast, P < 0.001; after dinner, P < 0.001), and LDL-C (MD [95% CI], -0.18 [-0.28 to -0.08]; P < 0.001), but have significantly more gastrointestinal adverse effects (eg, nausea/ vomiting, P < 0.001). There were no significant differences between GLP-1 receptor agonists and insulin glargine in reducing glycosylated hemoglobin (HbA1c) levels (MD [95% CI], -0.03 [-0.13 to 0.08]) and the overall incidence of hypoglycemia (RR [95% CI], 0.69 [0.42 to 1.14]). Conclusions: Compared with insulin glargine, GLP-1 receptor agonists did not have a significant difference in regard to reducing HbA1c levels and they were significantly associated with decreased weight but increased gastrointestinal adverse events. It remains unclear whether GLP-1 receptor agonists influence mortality or diabetes-associated complications in patients with T2DM. More trials with longer follow-up are needed to determine the exact long-term efficacy and safety profiles of this new class of hypoglycemic drugs.
    Current Therapeutic Research 08/2010; 71(4):211-238. · 0.45 Impact Factor

Full-text (2 Sources)

View
1,172 Downloads
Available from
May 28, 2014

Similar Publications