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Lixisenatide as add-on therapy to basal insulin.

ABSTRACT: Many patients with type 2 diabetes mellitus do not achieve target glycosylated hemoglobin A1c levels despite optimally titrated basal insulin and satisfactory fasting plasma glucose levels. Current evidence suggests that HbA1c levels are dictated by both basal glucose and postprandial glucose levels. This has led to a consensus that postprandial glucose excursions contribute to poor glycemic control in these patients. Lixisenatide is a once-daily, prandial glucagon-like peptide 1 (GLP-1) receptor agonist with a four-fold affinity for the GLP-1 receptor compared with native GLP-1. Importantly, lixisenatide causes a significant delay in gastric emptying time, an important determinant of the once-daily dosing regimen. An exendin-4 mimetic with six lysine residues removed at the C-terminal, lixisenatide has pronounced postprandial glucose-lowering effects, making it a novel incretin agent for use in combination with optimally titrated basal insulin. Lixisenatide exerts profound effects on postprandial glucose through established mechanisms of glucose-dependent insulin secretion and glucagon suppression in combination with delayed gastric emptying. This review discusses the likely place that lixisenatide will occupy in clinical practice, given its profound effects on postprandial glucose and potential to reduce glycemic variability.

SUBMITTER: Brown DX

PROVIDER: S-EPMC3865973 | biostudies-other | 2013 Dec

REPOSITORIES: biostudies-other

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Lixisenatide as add-on therapy to basal insulin.

Brown Dominique Xavier DX Butler Emma Louise EL Evans Marc M

Drug design, development and therapy 20131213

Many patients with type 2 diabetes mellitus do not achieve target glycosylated hemoglobin A1c levels despite optimally titrated basal insulin and satisfactory fasting plasma glucose levels. Current evidence suggests that HbA1c levels are dictated by both basal glucose and postprandial glucose levels. This has led to a consensus that postprandial glucose excursions contribute to poor glycemic control in these patients. Lixisenatide is a once-daily, prandial glucagon-like peptide 1 (GLP-1) recepto ...[more]

PMID: 24363554

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Project description:BackgroundWe assessed the cost-effectiveness of the glucagon-like peptide 1 receptor agonists liraglutide 1.8 mg and lixisenatide 20 μg (both added to basal insulin) in patients with type 2 diabetes (T2D) in Sweden.MethodsThe Swedish Institute for Health Economics cohort model for T2D was used to compare liraglutide and lixisenatide (both added to basal insulin), with a societal perspective and with comparative treatment effects derived by indirect treatment comparison (ITC). Drug prices were 2016 values, and all other costs 2015 values. The cost-effectiveness of IDegLira (fixed-ratio combination of insulin degludec and liraglutide) versus lixisenatide plus basal insulin was also assessed, under different sets of assumptions.ResultsFrom the ITC, decreases in HbA1c were -1.32% and -0.43% with liraglutide and lixisenatide, respectively; decreases in BMI were -1.29 and -0.65 kg/m2, respectively. An estimated 2348 cases of retinopathy, 265 of neuropathy and 991 of nephropathy would be avoided with liraglutide compared with lixisenatide in a cohort of 10,000 patients aged over 40 years. In the base-case analysis, total direct costs were higher with liraglutide than lixisenatide, but costs associated with complications were lower. The cost/quality-adjusted life-year (QALY) for liraglutide added to basal insulin was SEK30,802. Base-case findings were robust in sensitivity analyses, except when glycated haemoglobin (HbA1c) differences for liraglutide added to basal insulin were abolished, suggesting these benefits were driving the cost/QALY. With liraglutide 1.2 mg instead of liraglutide 1.8 mg (adjusted for efficacy and cost), liraglutide added to basal insulin was dominant over lixisenatide 20μg.IDegLira was dominant versus lixisenatide plus basal insulin when a defined daily dose was used in the model.ConclusionsThe costs/QALY for liraglutide, 1.8 or 1.2 mg, added to basal insulin, and for IDegLira (all compared with lixisenatide 20 μg added to basal insulin) were below the threshold considered low by Swedish authorities. In some scenarios, liraglutide and IDegLira were cost-saving.

Project description:IntroductionThis analysis investigated the efficacy and safety of add-on lixisenatide by disease duration in Asian people with type 2 diabetes inadequately controlled with basal insulin ± oral antidiabetic drugs.MethodsData for Asian participants in the GetGoal-Duo 1, GetGoal-L, and GetGoal-L-C studies were pooled and categorized by diabetes duration: < 10 years (group 1), 10 to < 15 years (group 2), and ≥ 15 years (group 3). Efficacy and safety of lixisenatide versus placebo were evaluated by subgroup. The potential influence of diabetes duration on efficacy was examined using multivariable regression analyses.ResultsA total of 555 participants were included (mean age 53.9 years, 52.4% male). No significant differences in treatment effect between the duration subgroups were observed for the changes from baseline to 24 weeks in glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), postprandial glucose (PPG), PPG excursion, body weight or body mass index, or the proportion of participants with HbA1c < 7% at 24 weeks (all P values for interaction > 0.1). Change in insulin dosage (U/day) was significantly different between subgroups (P = 0.038). Multivariable regression analysis showed participants in group 1 had a smaller change in body weight and basal insulin dose over the 24-week treatment period than participants in group 3 (P = 0.014 and 0.030, respectively) and were less likely to achieve an HbA1c < 7% than participants in group 2 (P = 0.047). No severe hypoglycemia was reported. A higher proportion of participants in group 3 versus the other groups had symptomatic hypoglycemia, for both lixisenatide and placebo, and T2D duration had a significant effect on hypoglycemia risk (P = 0.001).ConclusionsLixisenatide improved glycemic control in Asian individuals regardless of diabetes duration, without increasing the risk of hypoglycemia. Individuals with longer disease duration had a greater risk of symptomatic hypoglycemia than individuals with shorter disease duration regardless of treatment. No additional safety concerns were observed.Clinical trial registrationGetGoal-Duo 1, ClinicalTrials.gov record NCT00975286; GetGoal-L, ClinicalTrials.gov record NCT00715624; GetGoal-L-C, ClinicalTrials.gov record NCT01632163.

Project description:BackgroundBasal insulin reduces fasting blood glucose levels, but postprandial blood glucose levels may remain higher. Traditional strategies with rapid insulin intensification can cause hypoglycemic episodes and weight gain. Glucagon-like peptide-1 receptor agonists, such as the short-acting lixisenatide, are able to control postprandial excursions, without weight gain, and with a low risk of hypoglycemic events.ObjectiveDue to the limited data on the combination of lixisenatide with basal insulin (with or without oral antidiabetes drugs) in clinical practice, this study evaluated changes in parameters associated with glycemic control and anthropometric data after 24 weeks of this therapy intensification.MethodsThis was a multicenter, retrospective observational study of 129 patients with type 2 diabetes that was uncontrolled by basal insulin. Their treatment was intensified by the addition of lixisenatide at least 24 weeks before being included in the study. Data were retrospectively collected to determine changes in glycated hemoglobin (HbA1c) levels, blood glucose levels, weight, and body mass index. Adverse reactions and hypoglycemic events were also recorded.ResultsAfter 24 weeks of therapy intensification with lixisenatide, a significant reduction in HbA1c levels was observed (-1.1%; P < 0.001). An HbA1c <7% was achieved in 30.2% of patients, and 17.1% reached an HbA1c <6.5%. There was a reduction in fasting blood glucose (31.8 [60.3] mg/dL; P < 0.001) and postprandial blood glucose (55.0 [49] mg/dL; P < 0.001) levels, as well as body weight (4.0 [5.4] kg; P < 0.001) and body mass index (1.5 [1.9]; P < 0.001). The most commonly observed adverse reactions were nausea (n = 9), in line with previous studies. Hypoglycemia events were rare; only reported in 2 patients.ConclusionsIntensification strategy based on lixisenatide added to basal insulin (with or without oral antidiabetes drugs) can be an effective treatment option in patients with uncontrolled type 2 diabetes. In this small, selected population, glycemic control was significantly improved in terms of HbA1, fasting blood glucose levels, and postprandial glucose levels, with a reduction of body weight and low risk of hypoglycemic events. (Curr Ther Res Clin Exp. 2018; 79:XXX-XXX).

Project description:IntroductionTo prove the feasibility and safety of a conversion to once-daily injected GLP1 agonist (lixisenatide) and long-acting basal insulin analogue (glargine) in patients with T2DM and poorly controlled glycemia previously treated with multiple injections of premixed insulins (iPremix) in an outpatient setting.MethodsNine patients with T2DM currently receiving iPremix formulations and poor glycemic control were switched to once-daily injected lixisenatide (Lixi) and basal insulin analogue glargine (iGlar) for a 12-week period. Efficacy was defined as A1c reduction of at least 0.4% and weight loss of 0.5 kg or higher.ResultsFive of nine patients achieved A1c reductions of 0.4% (4 mmol/mol) or higher and six of nine patients a weight loss of 0.5 kg or higher. A mean A1C reduction of 0.5% ± 0.5% (6 mmol/mol) and mean weight loss of -1.4 ± 3.6 kg were observed in all patients. Total daily insulin dose after 12 weeks declined from 56 ± 26 IU with iPremix formulations to 47 ± 17 IU in patients taking combined iGlar and Lixi. Corrections with fast acting insulin glulisine (iGlu) were necessary in two patients on a regular basis and in four patients on an irregular basis (2.3 IU mean total daily dose). Two patients did not need additional iGlu. Postprandial glucose profiles were lower in the combined group compared with iPremix throughout the day, which resolved in the afternoon. No metabolic derangements occurred. Mild hypoglycemia and gastrointestinal symptoms were the most often reported adverse events affecting three patients.ConclusionThe conversion to once-daily injected GLP1 agonist Lixi and basal iGlar could safely be performed in an outpatient setting and was associated with better postprandial glycemic control throughout the day, except dinner, compared to iPremix.Clinical trial registrationEU clinical trials register EudraCT number 2013-005334-37 and ClinicalTrials.gov NCT02168491.FundingSponsored by the Medical University of Vienna and in part supported by Sanofi-Aventis.

Project description:There is currently a lack of evidence from direct comparisons of treatment outcomes with lixisenatide versus neutral protamine Hagedorn (NPH)-insulin in type 2 diabetes mellitus (T2DM) patients with suboptimal glycaemic control with oral antidiabetic drugs (OADs). Hence, the current analysis indirectly compared available evidence on the risk of hypoglycaemia and weight change between lixisenatide and NPH-insulin based on randomized controlled trial (RCT) data with exenatide, insulin glargine and placebo as common references.A systematic search of PubMed, Embase, the Cochrane database and clinical registries identified English- and German-language articles published from January 1980 to October 2012 reporting data from RCTs. Only publications of trials that reported outcomes from 24 to 30 weeks comparing glucagon-like peptide-1 receptor agonists or basal insulin versus another antidiabetic agent or placebo were included. Hypoglycaemia, patients at glycated haemoglobin (HbA1c) target and discontinuations due to adverse events (AEs) were treated as binary variables, with risk ratios and odds ratios (ORs) calculated. HbA1c and body weight were treated as continuous variables with difference in mean change from baseline (MD) calculated. Meta-analyses were performed with random effects models and indirect comparisons were performed according to Bucher's method.Seven RCTs (n=3,301 patients) comparing the efficacy and safety of lixisenatide, exenatide, insulin glargine and NPH-insulin with different antidiabetic treatments in adult patients with T2DM were included in the final analysis. In the adjusted indirect comparison, there was a significant difference in symptomatic hypoglycaemia (OR = 0.38; 95% CI = [0.17, 0.85]) and in confirmed hypoglycaemia (OR = 0.46; 95% CI = [0.22, 0.96]) favouring lixisenatide over NPH-insulin and comparable changes in HbA1c from baseline (MD = 0.07%; 95% CI = [-0.26%, 0.41%]). In contrast to NPH-insulin, there was a significant reduction in body weight with lixisenatide (MD = -3.62 kg; 95% CI = [-5.86 kg, -1.38 kg]) at study completion. The number of discontinuations due to AEs numerically favoured NPH-insulin over lixisenatide (OR = 2.64; 95% CI = [0.25, 27.96]), with a broad confidence interval.Lixisenatide treatment was associated with a lower risk of hypoglycaemia and a greater weight loss compared with NPH-insulin. Glycaemic control with lixisenatide treatment was comparable with NPH-insulin. These data suggest that lixisenatide is a beneficial treatment option for T2DM patients with inadequate glycaemic control on OADs, and is associated with reduced risk of hypoglycaemia and weight gain.

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Lixisenatide as add-on therapy to basal insulin.

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Lixisenatide as add-on therapy to basal insulin.

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