Non‐glycaemic effects mediated via GLP‐1 receptor agonists and the potential for exploiting these for therapeutic benefit: focus on liraglutide

Vilsbøll, Tina; Garber, Alan J.

doi:10.1111/j.1463-1326.2012.01579.x

Cited by 26 publications

(21 citation statements)

References 85 publications

(181 reference statements)

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“…[67–69]), diet soda consumption and adverse cardiovascular events [67, 69–73], and adds to the known potential role of GLP-1 in modulating body weight and glucose homeostasis in humans (e.g. [40, 43, 59, 74–81]).…”

Section: Resultsmentioning

confidence: 99%

Experience with the high-intensity sweetener saccharin impairs glucose homeostasis and GLP-1 release in rats

Swithers¹,

Laboy²,

Clark³

et al. 2012

Behavioural Brain Research

100

120

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Previous work from our lab has demonstrated that experience with high-intensity sweeteners in rats leads to increased food intake, body weight gain and adiposity, along with diminished caloric compensation and decreased thermic effect of food. These changes may occur as a result of interfering with learned relations between the sweet taste of food and the caloric or nutritive consequences of consuming those foods. The present experiments determined whether experience with the high-intensity sweetener saccharin versus the caloric sweetener glucose affected blood glucose homeostasis. The results demonstrated that during oral glucose tolerance tests, blood glucose levels were more elevated in animals that had previously consumed the saccharin-sweetened supplements. In contrast, during glucose tolerance tests when a glucose solution was delivered directly into the stomach, no differences in blood glucose levels between the groups were observed. Differences in oral glucose tolerance responses were not accompanied by differences in insulin release; insulin release was similar in animals previously exposed to saccharin and those previously exposed to glucose. However, release of GLP-1 in response to an oral glucose tolerance test, but not to glucose tolerance tests delivered by gavage, was significantly lower in saccharin-exposed animals compared to glucose-exposed animals. Differences in both blood glucose and GLP-1 release in saccharin animals were rapid and transient, and suggest that one mechanism by which exposure to high-intensity sweeteners that interfere with a predictive relation between sweet tastes and calories may impair energy balance is by suppressing GLP-1 release, which could alter glucose homeostasis and reduce satiety.

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Section: Resultsmentioning

confidence: 99%

Experience with the high-intensity sweetener saccharin impairs glucose homeostasis and GLP-1 release in rats

Swithers¹,

Laboy²,

Clark³

et al. 2012

Behavioural Brain Research

100

120

View full text Add to dashboard Cite

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“…In addition, GLP-1 agonists are hypothesized to have effects on the cardiovascular system beyond glycaemic control, which may be exploited for therapeutic benefit [19,20]. …”

Section: Discussionmentioning

confidence: 99%

Cardioprotective effects of lixisenatide in rat myocardial ischemia-reperfusion injury studies

et al. 2013

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BackgroundLixisenatide is a glucagon-like peptide-1 analog which stimulates insulin secretion and inhibits glucagon secretion and gastric emptying. We investigated cardioprotective effects of lixisenatide in rodent models reflecting the clinical situation.MethodsThe acute cardiac effects of lixisenatide were investigated in isolated rat hearts subjected to brief ischemia and reperfusion. Effects of chronic treatment with lixisenatide on cardiac function were assessed in a modified rat heart failure model after only transient coronary occlusion followed by long-term reperfusion. Freshly isolated cardiomyocytes were used to investigate cell-type specific mechanisms of lixisenatide action.ResultsIn the acute setting of ischemia-reperfusion, lixisenatide reduced the infarct-size/area at risk by 36% ratio without changes on coronary flow, left-ventricular pressure and heart rate. Treatment with lixisenatide for 10 weeks, starting after cardiac ischemia and reperfusion, improved left ventricular end-diastolic pressure and relaxation time and prevented lung congestion in comparison to placebo. No anti-fibrotic effect was observed. Gene expression analysis revealed a change in remodeling genes comparable to the ACE inhibitor ramipril. In isolated cardiomyocytes lixisenatide reduced apoptosis and increased fractional shortening. Glucagon-like peptide-1 receptor (GLP1R) mRNA expression could not be detected in rat heart samples or isolated cardiomyocytes. Surprisingly, cardiomyocytes isolated from GLP-1 receptor knockout mice still responded to lixisenatide.ConclusionsIn rodent models, lixisenatide reduced in an acute setting infarct-size and improved cardiac function when administered long-term after ischemia-reperfusion injury. GLP-1 receptor independent mechanisms contribute to the described cardioprotective effect of lixisenatide. Based in part on these preclinical findings patients with cardiac dysfunction are currently being recruited for a randomized, double-blind, placebo-controlled, multicenter study with lixisenatide.Trial registration(ELIXA, ClinicalTrials.gov Identifier: NCT01147250)

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“…It is well recognized that overweight and obesity are significantly associated with an increased risk of diabetes in Chinese adults . Further, weight loss is associated with improvements in clinical symptoms and cardiovascular disease risk factors in individuals with T2DM .…”

Section: Introductionmentioning

confidence: 99%

Efficacy and safety of liraglutide versus sitagliptin, both in combination with metformin, in Chinese patients with type 2 diabetes: a 26‐week, open‐label, randomized, active comparator clinical trial

Zang

Liu

Luo

et al. 2016

Diabetes Obesity Metabolism

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AimsTo compare the efficacy and safety of liraglutide versus sitagliptin as add‐on to metformin after 26 weeks of treatment in Chinese patients with type 2 diabetes mellitus (T2DM).MethodsThis 26‐week open‐label, active comparator trial (NCT02008682) randomized patients (aged 18–80 years) with T2DM inadequately controlled with metformin [glycated haemoglobin (HbA1c) 7.0–10.0% (53–86 mmol/mol)] 1 : 1 to once‐daily subcutaneously administered liraglutide 1.8 mg (n = 184) or once‐daily oral sitagliptin 100 mg (n = 184), both as add‐on to metformin. The primary endpoint was change in HbA1c from baseline to week 26.ResultsLiraglutide was superior to sitagliptin in reducing HbA1c from baseline [8.1% (65 mmol/mol)] to 26 weeks, as evidenced by estimated mean HbA1c change of −1.65% (−18.07 mmol/mol) versus −0.98% (−10.72 mmol/mol), respectively [estimated treatment difference for liraglutide vs sitagliptin of −0.67% (95% CI −0.86, −0.48) or −7.35 mmol/mol (95% CI −9.43; −5.26); p < 0.0001]. More patients receiving liraglutide (76.5%) than sitagliptin (52.6%) achieved the HbA1c target of <7.0% (53 mmol/mol) at week 26 [odds ratio 3.65 (95% CI 2.18, 6.12); p < 0.0001]. Reductions in fasting plasma glucose, 7‐point self‐measured plasma glucose and body weight were greater with liraglutide than with sitagliptin (p < 0.0001 for all). More patients experienced nausea (14.8% vs 0.5%), diarrhoea (8.2% vs 2.2%) and decreased appetite (10.9% vs 0.5%) with liraglutide than sitagliptin. Two hypoglycaemic episodes were confirmed for liraglutide and one for sitagliptin; none were severe or nocturnal.ConclusionsLiraglutide provided better glycaemic control and greater body weight reduction than sitagliptin when administered as add‐on to metformin. More patients had nausea, diarrhoea and decreased appetite with liraglutide versus sitagliptin.

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Non‐glycaemic effects mediated via GLP‐1 receptor agonists and the potential for exploiting these for therapeutic benefit: focus on liraglutide

Cited by 26 publications

References 85 publications

Experience with the high-intensity sweetener saccharin impairs glucose homeostasis and GLP-1 release in rats

Experience with the high-intensity sweetener saccharin impairs glucose homeostasis and GLP-1 release in rats

Cardioprotective effects of lixisenatide in rat myocardial ischemia-reperfusion injury studies

Efficacy and safety of liraglutide versus sitagliptin, both in combination with metformin, in Chinese patients with type 2 diabetes: a 26‐week, open‐label, randomized, active comparator clinical trial

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