Lixisenatide Reduces Chylomicron Triacylglycerol by Increased Clearance

Whyte, Martin; Shojaee‐Moradie, Fariba; Sharaf, Sharaf E; Jackson, Nicola; Fielding, Barbara A.; Hovorka, Roman; Mendis, Jeewaka; Russell‐Jones, David; Umpleby, A. Margot

doi:10.1210/jc.2018-01176

Cited by 23 publications

(22 citation statements)

References 48 publications

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“…The improvement in lipid profiles with iGlarLixi over iGlar is probably provided by the short‐acting GLP‐1 RA component lixisenatide, as prior studies have showed the beneficial effects of lixisenatide and exenatide on lipid variables . The improvements observed with iGlarLixi may be partly mediated by its efficacy in correcting hyperglycaemia rather than by a direct effect on lipid levels, as the effect was clearly evident in patients who met glycaemic targets.…”

Section: Discussionmentioning

confidence: 69%

“…The improvement in lipid profiles with iGlarLixi over iGlar is probably provided by the short-acting GLP-1 RA component lixisenatide, as prior studies have showed the beneficial effects of lixisenatide and exenatide on lipid variables. 5,6,8 The improvements observed with iGlarLixi may be partly mediated by its efficacy in correcting hyperglycaemia rather than by a direct effect on lipid levels, as the effect was clearly evident in patients who met glycaemic targets. However, patients on iGlar who achieved glycaemic targets did not show improvement in lipid profiles, pointing to a possible alternative mechanism for the lipid-lowering effects of iGlarLixi, independent of its glycaemic effects.…”

Section: Discussionmentioning

confidence: 99%

“…Short‐acting glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs), such as exenatide and lixisenatide, have been shown to improve postprandial proatherogenic lipids and vascular endothelial function, as well as exert antihyperglycaemic activity . Furthermore, long‐term use of such GLP‐1 RAs is associated with favourable changes in the lipid profiles of patients with type 2 diabetes …”

Section: Introductionmentioning

confidence: 99%

“…3 Short-acting glucagon-like peptide-1 receptor agonists (GLP-1 RAs), such as exenatide and lixisenatide, have been shown to improve postprandial proatherogenic lipids and vascular endothelial function, as well as exert antihyperglycaemic activity. [5][6][7][8][9] Furthermore, longterm use of such GLP-1 RAs is associated with favourable changes in the lipid profiles of patients with type 2 diabetes. 10 iGlarLixi is a titratable fixed-ratio combination of insulin glargine U100 (iGlar) and lixisenatide available as a single-injection pen for once-daily use.…”

Section: Introductionmentioning

confidence: 99%

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Achievement of glycaemic control is associated with improvements in lipid profile with iGlarLixi versus iGlar: A post hoc analysis of the LixiLan‐L trial

Giorgino

Shaunik

Liu

et al. 2019

Diabetes Obesity Metabolism

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Diabetic dyslipidaemia is a major risk factor for accelerated atherosclerosis. Glycaemic treatments that improve dyslipidaemia may help reduce the burden of atherosclerosis. This analysis investigated the effect of iGlarLixi [insulin glargine U100 (iGlar) and lixisenatide] versus iGlar on lipid profiles in patients with type 2 diabetes uncontrolled on basal insulin. Data from LixiLan‐L were used to estimate changes in fasting lipid levels from baseline to week 30, overall and in patients stratified by achievement of glycaemic targets {2‐hour postprandial glucose [≤10, >10 mmoL/L], fasting plasma glucose [≤6.1, >6.1 mmoL/L], HbA1c [≤7, >7% (≤53, >53 mmol/mol)]}. At week 30, median percentage change in triglycerides remained nearly unchanged (0.3% increase) with iGlarLixi versus a 6.5% increase with iGlar (P = 0.035; overall); similarly, trends towards better total and LDL cholesterol levels were observed with iGlarLixi versus iGlar. In patient subgroups achieving glycaemic targets, all lipid variables except for HDL cholesterol improved with iGlarLixi but not with iGlar. In summary, patients with type 2 diabetes uncontrolled on basal insulin showed improved fasting lipid profiles with iGlarLixi compared with iGlar, particularly when achieving glycaemic targets.

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Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Achievement of glycaemic control is associated with improvements in lipid profile with iGlarLixi versus iGlar: A post hoc analysis of the LixiLan‐L trial

Giorgino

Shaunik

Liu

et al. 2019

Diabetes Obesity Metabolism

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“…We have previously reviewed the effects of incretin therapies on intestinal lipoprotein metabolism (93). When CM-TG kinetics were assessed in patients with T2D, lixisenatide reduced CM-TG appearance after a single meal likely via delayed gastric emptying (94,95). However, over the course of a 12-h feeding protocol lixisenatide reduced CM-TG through increased clearance with no effect on production rate (95).…”

Section: Effects Of Currently Approved Lipid Modifying and Antidiabetmentioning

confidence: 99%

Role of the Gut in Diabetic Dyslipidemia

et al. 2020

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Type 2 diabetes (T2D) is associated with increased risk of cardiovascular disease (CVD). In insulin resistant states such as the metabolic syndrome, overproduction and impaired clearance of liver-derived very-low-density lipoproteins and gut-derived chylomicrons (CMs) contribute to hypertriglyceridemia and elevated atherogenic remnant lipoproteins. Although ingested fat is the major stimulus of CM secretion, intestinal lipid handling and ultimately CM secretory rate is determined by numerous additional regulatory inputs including nutrients, hormones and neural signals that fine tune CM secretion during fasted and fed states. Insulin resistance and T2D represent perturbed metabolic states in which intestinal sensitivity to key regulatory hormones such as insulin, leptin and glucagon-like peptide-1 (GLP-1) may be altered, contributing to increased CM secretion. In this review, we describe the evidence from human and animal models demonstrating increased CM secretion in insulin resistance and T2D and discuss the molecular mechanisms underlying these effects. Several novel compounds are in various stages of preclinical and clinical investigation to modulate intestinal CM synthesis and secretion. Their efficacy, safety and therapeutic utility are discussed. Similarly, the effects of currently approved lipid modulating therapies such as statins, ezetimibe, fibrates, and PCSK9 inhibitors on intestinal CM production are discussed. The intricacies of intestinal CM production are an active area of research that may yield novel therapies to prevent atherosclerotic CVD in insulin resistance and T2D.

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The GLP-1 receptor agonist lixisenatide reduces postprandial glucose in patients with diabetes secondary to total pancreatectomy: a randomised, placebo-controlled, double-blinded crossover trial

et al. 2020

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Aims/hypothesis Treatment of diabetes secondary to total pancreatectomy remains a challenge and insulin constitutes the only glucose-lowering treatment for these patients. We hypothesised that the glucagon-like peptide 1 (GLP-1) receptor agonist lixisenatide would improve postprandial glucose tolerance in totally pancreatectomised patients. Methods In a double-blinded, randomised, crossover study, 12 totally pancreatectomised individuals (age: 65.0 ± 9.5 mean±SD years; BMI: 22.9 ± 3.9 kg/m 2 ) and 12 healthy control individuals (age 66.1 ± 7.6 years; BMI: 24.0 ± 2.9 kg/m 2 ) underwent two 3 h liquid mixed-meal tests (with paracetamol for assessment of gastric emptying) after single-dose injection of 20 μg of lixisenatide or placebo. Basal insulin was given the night before each experimental day; no insulin was given during study days. Results Compared with placebo, lixisenatide reduced postprandial plasma glucose excursions in the pancreatectomy group (baselinesubtracted AUC [bsAUC] [mean±SEM]: 548 ± 125 vs 1447 ± 95 mmol/l × min, p < 0.001) and in the control group (−126 ± 12 vs 222 ± 51 mmol/l × min, p < 0.001). In the pancreatectomy group a mean peak glucose concentration of 23.3 ± 1.0 mmol/l was reached at time point 134 ± 11 min with placebo, compared with a mean peak glucose concentration of 18 ± 1.4 mmol/l (p = 0.008) at time point 148 ± 13 min (p = 0.375) with lixisenatide. In the control group a mean peak concentration of 8.2 ± 0.4 mmol/l was reached at time point 70 ± 13 min with placebo, compared with a mean peak concentration of 5.5 ± 0.1 mmol/l (p < 0.001) at time point 8 ± 25 min (p = 0.054) with lixisenatide. Lixisenatide also reduced gastric emptying and postprandial glucagon responses in the pancreatectomy group (66 ± 84 vs 1190 ± 311 pmol/l × min, p = 0.008) and in the control group (141 ± 100 vs 190 ± 100 pmol/l × min, p = 0.034). In the pancreatectomy group, C-peptide was undetectable in plasma. In the control group, postprandial plasma C-peptide responses were reduced with lixisenatide (18 ± 17 vs 189 ± 31 nmol/l × min, p < 0.001). Conclusions/interpretationThe GLP-1 receptor agonist lixisenatide reduces postprandial plasma glucose excursions in totally pancreatectomised patients. The mode of action seems to involve deceleration of gastric emptying and reduced postprandial responses of gut-derived glucagon.

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Lixisenatide Reduces Chylomicron Triacylglycerol by Increased Clearance

Cited by 23 publications

References 48 publications

Achievement of glycaemic control is associated with improvements in lipid profile with iGlarLixi versus iGlar: A post hoc analysis of the LixiLan‐L trial

Achievement of glycaemic control is associated with improvements in lipid profile with iGlarLixi versus iGlar: A post hoc analysis of the LixiLan‐L trial

Role of the Gut in Diabetic Dyslipidemia

The GLP-1 receptor agonist lixisenatide reduces postprandial glucose in patients with diabetes secondary to total pancreatectomy: a randomised, placebo-controlled, double-blinded crossover trial

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