Effects of lixisenatide once daily on gastric emptying in type 2 diabetes — Relationship to postprandial glycemia

Lorenz, Martin; Pfeiffer, Claudia; Steinsträßer, Axel; Becker, R. H. A.; Rütten, Hartmut; Ruus, Peter; Horowitz, Michael

doi:10.1016/j.regpep.2013.04.001

Cited by 139 publications

(177 citation statements)

References 29 publications

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“…Indeed, greater exposure to postprandial C‐peptide (and hence insulin) was observed in the sitagliptin group than in the lixisenatide group, which is consistent with the inverse association of C‐peptide levels with glycaemic variability and with post‐meal glucose rise in T2D (both of which were higher in the sitagliptin group) 38. In previous studies, there was a direct relationship between PPG AUC after breakfast and gastric emptying with lixisenatide 20 µg once daily,32, 39 which was not observed with placebo 39…”

Section: Discussionsupporting

confidence: 74%

Reduction of postprandial glucose by lixisenatide vs sitagliptin treatment in Japanese patients with type 2 diabetes on background insulin glargine: A randomized phase IV study (NEXTAGE Study)

Yamada

Senda

Naito

et al. 2017

Diabetes Obesity Metabolism

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AimTo evaluate the pharmacodynamics of lixisenatide once daily vs sitagliptin once daily in Japanese patients with type 2 diabetes receiving insulin glargine U100.Materials and methodsThis multicentre, open‐label, phase IV study (NEXTAGE Study; ClinicalTrials.gov number, NCT02200991) randomly assigned 136 patients to either lixisenatide once daily via subcutaneous injection (10 µg initially increased weekly by 5 up to 20 µg) or once‐daily oral sitagliptin 50 mg. The primary endpoint was the change in postprandial glucose (PPG) exposure 4 hours after a standardized breakfast (PPG area under the plasma glucose concentration–time curve [AUC0 :00‐4:00h]) from baseline to day 29.ResultsLixisenatide reduced PPG exposure to a statistically significantly greater extent than sitagliptin: least squares (LS) mean change from baseline in PPG AUC0 :00‐4:00h was −347.3 h·mg/dL (−19.3 h·mmol/L) in the lixisenatide group and −113.3 h·mg/dL (−6.3 h·mmol/L) in the sitagliptin group (LS mean between‐group difference −234.0 h·mg/dL [−13.0 h·mmol/L], 95% confidence interval −285.02 to −183.00 h·mg/dL [−15.8 to −10.2 h·mmol/L]; P < .0001). Lixisenatide led to significantly greater LS mean reductions in maximum PPG excursion than sitagliptin (−122.4 vs −46.6 mg/dL [−6.8 vs −2.6 h·mmol/L]; P < .0001). Change‐from‐baseline reductions in exposure to C‐peptide, fasting glycoalbumin levels, and the gastric emptying rate were greater in the lixisenatide than in the sitagliptin group. The incidence of treatment‐emergent adverse events was higher with lixisenatide (60.9%) than with sitagliptin (16.4%), with no serious events or severe hypoglycaemia reported.ConclusionLixisenatide reduced PPG significantly more than sitagliptin, when these agents were added to basal insulin glargine U100, and was well tolerated.

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Section: Discussionsupporting

confidence: 74%

Reduction of postprandial glucose by lixisenatide vs sitagliptin treatment in Japanese patients with type 2 diabetes on background insulin glargine: A randomized phase IV study (NEXTAGE Study)

Yamada

Senda

Naito

et al. 2017

Diabetes Obesity Metabolism

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“…Acute GLP-1 administration at pharmacological doses has been shown to dose-dependently relax the gastric fundus, increase gastric compliance, inhibit antral motility, and increase pyloric tone (28,29), thereby slowing gastric emptying and attenuating postprandial glycemic excursions (9). Similar effects have been reported with the commercially available "short-acting" GLP-1 agonists (11,30). The "long-acting" GLP-1 agonists, such as exenatide sustained release/long-acting release, compared with the "short-acting" GLP-1 agonists have diminished effect to slow emptying (31,32), which is thought to reflect the development of rapid tachyphylaxis to sustained exposure to supraphysiological concentrations of GLP-1 (33).…”

Section: Discussionmentioning

confidence: 66%

Hyperglycemia Potentiates the Slowing of Gastric Emptying Induced by Exogenous GLP-1

et al. 2015

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OBJECTIVEAcute hyperglycemia markedly slows gastric emptying. Exogenous GLP-1 also slows gastric emptying, leading to diminished glycemic excursions. The primary objective was to determine whether hyperglycemia potentiates the slowing of gastric emptying induced by GLP-1 administration. RESEARCH DESIGN AND METHODSTen healthy participants were studied on 4 separate days. Blood glucose was clamped at hyperglycemia using an intravenous infusion of 25% dextrose (∼12 mmol/L; hyper) on 2 days, or maintained at euglycemia (∼6 mmol/L; eu) on 2 days, between t = 215 and 240 min. During hyperglycemic and euglycemic days, participants received intravenous GLP-1 (1.2 pmol/kg/min) and placebo in a randomized double-blind fashion. At t = 0 min, subjects ingested 100 g beef mince labeled with 20 MBq technetium-99m-sulfur colloid and 3 g 3-O-methyl-glucose (3-OMG), a marker of glucose absorption. Gastric emptying was measured scintigraphically from t = 0 to 240 min and serum 3-OMG taken at regular intervals from t = 15 to 240 min. The areas under the curve for gastric emptying and 3-OMG were analyzed using one-way repeated-measures ANOVA with Bonferroni-Holm adjusted post hoc tests. RESULTSHyperglycemia slowed gastric emptying (eu/placebo vs. hyper/placebo; P < 0.001) as did GLP-1 (eu/placebo vs. eu/GLP-1; P < 0.001). There was an additive effect of GLP-1 and hyperglycemia, such that gastric emptying was markedly slower compared with GLP-1 administration during euglycemia (eu/GLP-1 vs. hyper/GLP-1; P < 0.01). CONCLUSIONSAcute administration of exogenous GLP-1 profoundly slows gastric emptying during hyperglycemia in excess of the slowing induced by GLP-1 during euglycemia. Studies are required to determine the effects of hyperglycemia on gastric emptying with the subcutaneously administered commercially available GLP-1 agonists in patients with type 2 diabetes.Gastric emptying is a major determinant of postprandial glycemia in health, as well as in type 1 and type 2 diabetes (1,2), and accounts for ;35% of the variance in the initial glycemic response to oral carbohydrate (1). Accordingly, dietary and pharmacological strategies that slow gastric emptying, including short-acting GLP-1 agonists, are useful interventions to attenuate postprandial glycemic excursions and overall glycemia in type 2 diabetes (3).

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“…The pronounced PPG reductions associated with lixisenatide make it particularly suitable for treatment intensification after basal insulin because this combination permits improvements in both PPG and FPG. Prandial GLP-1 RAs suppress glucagon and also delay gastric emptying, which reduces the rate of postmeal glucose absorption, resulting in robust PPG reductions associated with the meal after administration (7,22). Hence, future head-to-head studies comparing other GLP-1 RAs added to basal insulin would be of interest.…”

Section: Discussionmentioning

confidence: 99%

“…Lixisenatide (Lyxumia; Sanofi, Paris, France) is a oncedaily prandial GLP-1 RA with robust postprandial glucose (PPG)-lowering effect, predominantly via delayed gastric emptying and glucose-dependent reductions in glucagon release (6)(7)(8)(9).…”

mentioning

confidence: 99%

Prandial Options to Advance Basal Insulin Glargine Therapy: Testing Lixisenatide Plus Basal Insulin Versus Insulin Glulisine Either as Basal-Plus or Basal-Bolus in Type 2 Diabetes: The GetGoal Duo-2 Trial

et al. 2016

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OBJECTIVETo provide evidence-based options on how to intensify basal insulin, we explored head-to-head prandial interventions in overweight patients with type 2 diabetes inadequately controlled on basal insulin glargine with or without 1-3 oral antidiabetic agents (OADs). RESEARCH DESIGN AND METHODSPatients were randomized to lixisenatide once daily or insulin glulisine given once or thrice daily, added to glargine, with or without metformin, if HbA 1c remained ‡7 to £9% ( ‡53 to £75 mmol/mol) after 12 weeks of glargine optimization with OADs other than metformin stopped at the start of optimization. Coprimary end points at 26 weeks were 1) noninferiority (95% CI upper bound <0.4% [<4.4 mmol/mol]) in HbA 1c reduction with lixisenatide versus glulisine once daily, and either 2a) noninferiority in HbA 1c reduction for lixisenatide versus glulisine thrice daily or 2b) superiority in body weight change for lixisenatide versus glulisine thrice daily. Fasting and postprandial plasma glucose, composite efficacy/safety end points, and adverse events were also assessed. RESULTSBaseline characteristics were similar between arms (n = 298, diabetes and basal insulin duration of 12.2 and 3.2 years, respectively; BMI 32.2 kg/m 2 ). HbA 1c improved from 8.5% to 7.9% (69 to 63 mmol/mol) with glargine optimization and further to 7.2%, 7.2%, and 7.0% (55, 55, and 53 mmol/mol) with lixisenatide and glulisine once daily and thrice daily, respectively; all coprimary end points were met. Symptomatic hypoglycemia and body weight were lower in lixisenatide versus glulisine patients. More gastrointestinal events occurred with lixisenatide. CONCLUSIONSShort-acting glucagon-like peptide-1 receptor agonists as add-on to basal insulin may become a preferred treatment intensification option, attaining meaningful glycemic targets with fewer hypoglycemic events without weight gain versus basal-plus or basal-bolus in uncontrolled basal insulin-treated type 2 diabetes.

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Effects of lixisenatide once daily on gastric emptying in type 2 diabetes — Relationship to postprandial glycemia

Abstract: In this study, lixisenatide at a dose of 20 μg QD reduced postprandial glycemic excursions in patients with T2DM, possibly as a result of sustained slowing of gastric emptying.

Cited by 139 publications

References 29 publications

Reduction of postprandial glucose by lixisenatide vs sitagliptin treatment in Japanese patients with type 2 diabetes on background insulin glargine: A randomized phase IV study (NEXTAGE Study)

Reduction of postprandial glucose by lixisenatide vs sitagliptin treatment in Japanese patients with type 2 diabetes on background insulin glargine: A randomized phase IV study (NEXTAGE Study)

Hyperglycemia Potentiates the Slowing of Gastric Emptying Induced by Exogenous GLP-1

Prandial Options to Advance Basal Insulin Glargine Therapy: Testing Lixisenatide Plus Basal Insulin Versus Insulin Glulisine Either as Basal-Plus or Basal-Bolus in Type 2 Diabetes: The GetGoal Duo-2 Trial

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