Efficacy of lixisenatide in patients with type 2 diabetes: A post hoc analysis of patients with diverse β-cell function in the GetGoal-M and GetGoal-S trials

Yabe, Daisuke; Ambos, Anu; Cariou, Bertrand; Duvnjak, Lea; Evans, Marc; González-Gálvez, Guillermo; Lin, Jay; Nikonova, Elena; Pablos-Velasco, Pedro de; Yale, Jean-François; Åhrén, Bo

doi:10.1016/j.jdiacomp.2016.05.018

Cited by 16 publications

(15 citation statements)

References 39 publications

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“…A large body of clinical research has demonstrated that GLP-1-based drugs provide excellent control of blood glucose levels without dramatic side effects [12–14]. Furthermore, GLP-1 analogs can improve β-cell function, especially in regards to insulin secretion and glucose sensitivity, while promoting β-cell survival by inhibiting apoptosis and enhancing cell proliferation [3, 15, 16].…”

Section: Discussionmentioning

confidence: 99%

The albumin-exendin-4 recombinant protein E2HSA improves glycemic control and β-cell function in spontaneous diabetic KKAy mice

Hou

Liu

et al. 2017

BMC Pharmacol Toxicol

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BackgroundE2HSA is a genetic fusion protein that consists of two tandem exendin-4 molecules that are covalently bonded to recombinant human serum albumin via a peptide linker. Previous studies have demonstrated that E2HSA significantly decreased blood glucose levels, improved β-cell function and promoted β-cell proliferation in diabetic db/dB mice. This study aimed to evaluate the benefits of E2HSA on glucose and lipid metabolism in a spontaneous diabetes animal model, KKAy mice.MethodsE2HSA was acutely administered at doses of 1, 3 and 9 mg/kg by subcutaneous injection in diabetic KKAy mice with exendin-4 (2 μg/kg) as a positive reference, and then the non-fasting blood glucose and food intake levels were dynamically monitored. In addition, different doses of E2HSA were injected once daily, as well as with exendin-4 twice daily, for 7 weeks to evaluate the effect on glucose and lipid metabolism, as well as the body weight, food and water intake.ResultsSingle injection of E2HSA decreased non-fasting blood glucose and food intake levels in a dose-dependent manner for 4 days and 2 days, respectively. Repeated injections with E2HSA significantly decreased variations in blood glucose levels with a reduction of HbA1c levels by 1.6% at a 9 mg/kg dose, simultaneously increased fasting blood insulin levels, inhibited fasting blood glucagon levels, improved the impaired oral glucose tolerance and enhanced glucose infusion rate, which is the gold standard for evaluating β-cell function. Moreover, repeated injections with E2HSA also ameliorated the dyslipidemia and reduced body weight, food and water intake in diabetic KKAy mice.ConclusionsE2HSA significantly reduced blood glucose levels over a prolonged duration, enhanced β-cell function, and ameliorated dyslipidemia and obesity in diabetic KKAy mice. Thus, E2HSA may be a new candidate for the treatment of type 2 diabetes.Electronic supplementary materialThe online version of this article (doi:10.1186/s40360-017-0143-8) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

The albumin-exendin-4 recombinant protein E2HSA improves glycemic control and β-cell function in spontaneous diabetic KKAy mice

Hou

Liu

et al. 2017

BMC Pharmacol Toxicol

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“…7 Similarly, in an observational study, patients with a lower urinary C-peptide creatinine ratio were associated with reduced glycaemic response to liraglutide. 8 In contrast, lixisenatide improved glycaemic control irrespective of beta-cell function, as measured by the secretory units of islets in transplantation index 9 and by homeostatic model assessment for beta-cell function, HOMA2-%B. 10 In comparison to reduced glycaemic response to GLP-1RA therapies in patients with islet autoantibodies, 7 in a condition frequently called latent autoimmune diabetes in the adult (LADA), characterised by impaired beta-cell function-dulaglutide appears to remain effective.…”

Section: Introductionmentioning

confidence: 99%

Effect of once weekly dulaglutide by baseline beta‐cell function in people with type 2 diabetes in the AWARD programme

Mathieu

Prato

Botros

et al. 2018

Diabetes Obesity Metabolism

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Glucagon‐like peptide‐1 receptor agonists lower blood glucose in type 2 diabetes (T2D) partially through glucose‐dependent stimulation of insulin secretion. The aim of this study was to investigate whether beta‐cell function (as measured by HOMA2‐%B) at baseline affects the glycaemic response to dulaglutide. Dulaglutide‐treated patients from AWARD‐1, AWARD‐3 and AWARD‐6 clinical studies were categorised based on their homeostatic model assessment of beta‐cell function (HOMA2‐%B) tertiles. Changes in glycaemic measures in response to treatment with once‐weekly dulaglutide were evaluated in each HOMA2‐%B tertile. Patients with low HOMA2‐%B had higher baseline glycated haemoglobin (HbA1c), fasting and postprandial blood glucose, and longer duration of diabetes (P < .001, all) (mean low, middle and high tertiles with dulaglutide 1.5 mg: HOMAB‐2%B, 31%, 58%, 109%; HbA1c, 8.7%, 7.7%, 7.3%, respectively). At 26 weeks, the low tertile experienced larger reductions in HbA1c compared to the high tertile with dulaglutide 1.5 mg (mean; −1.55% vs. −0.98% [−16.94 vs. −10.71 mmol/mol]). Differences between low and high tertiles disappeared when adjusted for baseline HbA1c (LSM; −1.00 vs. −1.18% [−10.93 vs. −12.90 mmol/mol]). Greater decreases in fasting blood glucose and greater increases in fasting C‐peptide were observed in the low tertile. Similar increases in HOMA2‐%B were observed in all tertiles. Dulaglutide demonstrated clinically relevant HbA1c reduction irrespective of estimated baseline beta‐cell function.

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“…A post hoc analysis of the GetGoal‐M and ‐S trials indicated that when patients were stratified according to baseline β‐cell function (as measured by the secretory units of islet in transplantation index), reductions in Hb A1c and PPG levels from baseline with lixisenatide were similar across all strata . A second post hoc analysis of pooled data from these two studies showed that changes in postprandial glucagon levels induced by lixisenatide correlated with Hb A1c and PPG reductions, suggesting that glucagon lowering contributes to the glycemic improvement effects of lixisenatide …”

Section: Clinical Evaluationmentioning

confidence: 99%

Lixisenatide, a Once‐Daily Prandial Glucagon‐Like Peptide‐1 Receptor Agonist for the Treatment of Adults with Type 2 Diabetes

Trujillo

Goldman

2017

Pharmacotherapy

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Lixisenatide, a short-acting glucagon-like peptide-1 receptor agonist (GLP-1 RA), has been available in Europe since 2013 and was recently approved in the United States for the treatment of type 2 diabetes (T2D) as an adjunct to diet and exercise. The objective of this systematic review is to describe the pharmacology, pharmacokinetics, safety, and efficacy of lixisenatide in patients with T2D. We conducted a search of the EMBASE database, limited to human studies with abstracts available in English. Published conference abstracts, limited to the American Diabetes Association (ADA) and the European Association for the Study of Diabetes meetings in 2015, as well as abstracts presented at the ADA meeting in 2016, were also screened. The abstracts retrieved were assessed for relevance; review articles and meta-analyses focusing on GLP-1 RAs as a class were excluded. Lixisenatide induced mean reductions of 0.46-0.99% in glycated hemoglobin A (Hb ), 55.86-143.43 mg/dl in 2-hour postprandial glucose (PPG) levels, and 56.58-127.75 mg/dl in mealtime glucose level variations. Changes in fasting plasma glucose (FPG) levels and weight ranged from -21.98 to +5.41 mg/dl and from -2.96 to +0.3 kg, respectively, in patients with T2D enrolled in the GetGoal clinical program (a program of clinical trials that established the efficacy and safety profile of lixisenatide 20 μg once/day across patients with T2D with differing background therapies). Lixisenatide was well tolerated, demonstrating rates of symptomatic hypoglycemia of 0.8-42.9% and a very low rate of severe hypoglycemia (< 1.5%) as well as no increased risk of cardiovascular events. The most common adverse events were gastrointestinal in nature, mainly transient nausea and vomiting of mild-to-moderate severity. Lixisenatide effectively lowers Hb levels in patients with T2D through a mechanism of action complementary to that of agents that mainly target FPG, with the additional benefit of weight loss. Its once-daily administration schedule and effect on PPG levels make it an attractive option as add-on treatment to basal insulin therapy or oral antidiabetic agents.

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Efficacy of lixisenatide in patients with type 2 diabetes: A post hoc analysis of patients with diverse β-cell function in the GetGoal-M and GetGoal-S trials

Abstract: Lixisenatide treatment resulted in reductions in HbA1c and PPG levels across all SUIT quartiles. This suggests that non-insulin-related actions of lixisenatide contribute to improved glycemic control in T2D.

Cited by 16 publications

References 39 publications

The albumin-exendin-4 recombinant protein E2HSA improves glycemic control and β-cell function in spontaneous diabetic KKAy mice

The albumin-exendin-4 recombinant protein E2HSA improves glycemic control and β-cell function in spontaneous diabetic KKAy mice

Effect of once weekly dulaglutide by baseline beta‐cell function in people with type 2 diabetes in the AWARD programme

Lixisenatide, a Once‐Daily Prandial Glucagon‐Like Peptide‐1 Receptor Agonist for the Treatment of Adults with Type 2 Diabetes

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