Liraglutide, a Long-Acting Human Glucagon-Like Peptide-1 Analog, Given as Monotherapy Significantly Improves Glycemic Control and Lowers Body Weight Without Risk of Hypoglycemia in Patients With Type 2 Diabetes

Vilsbøll, Tina; Zdravković, Milan; Le-Thi, T.; Krarup, Thure; Schmitz, O.; Courrèges, J.P.; Verhoeven, Rob H.A.; Bugáňová, Ingrid; Madsbad, Sten

doi:10.2337/dc06-2593

Cited by 416 publications

(391 citation statements)

References 10 publications

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“…Prior studies have shown that administration of GLP‐1 agonists has an impact on lipid homeostasis 72, 73, 74, 75. Liraglutide administration appears to have beneficial effects on plasma lipids and lipoproteins, including a reduction in total cholesterol, triglycerides, and low‐density lipoprotein cholesterol, and an increase in high‐density lipoprotein cholesterol 76, 77, 78. Moreover, we have demonstrated that intravenous lipid infusion induces ER stress in endothelial cells 41.…”

Section: Discussionmentioning

confidence: 60%

Liraglutide Treatment Reduces Endothelial Endoplasmic Reticulum Stress and Insulin Resistance in Patients With Diabetes Mellitus

Bretón‐Romero

Weisbrod

Feng

et al. 2018

JAHA

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BackgroundPrior studies have shown that nutrient excess induces endoplasmic reticulum (ER) stress in nonvascular tissues from patients with diabetes mellitus (DM). ER stress and the subsequent unfolded protein response may be protective, but sustained activation may drive vascular injury. Whether ER stress contributes to endothelial dysfunction in patients with DM remains unknown.Methods and ResultsTo characterize vascular ER stress, we isolated endothelial cells from 42 patients with DM and 37 subjects without DM. Endothelial cells from patients with DM displayed higher levels of ER stress markers compared with controls without DM. Both the early adaptive response, evidenced by higher phosphorylated protein kinase–like ER eukaryotic initiation factor‐2a kinase and inositol‐requiring ER‐to‐nucleus signaling protein 1 (P=0.02, P=0.007, respectively), and the chronic ER stress response evidenced by higher C/EBPα‐homologous protein (P=0.02), were activated in patients with DM. Higher inositol‐requiring ER‐to‐nucleus signaling protein 1 activation was associated with lower flow–mediated dilation, consistent with endothelial dysfunction (r=0.53, P=0.02). Acute treatment with liraglutide, a glucagon‐like peptide 1 receptor agonist, reduced p‐inositol‐requiring ER‐to‐nucleus signaling protein 1 (P=0.01), and the activation of its downstream target c‐jun N‐terminal kinase (P=0.025) in endothelial cells from patients with DM. Furthermore, liraglutide restored insulin‐stimulated endothelial nitric oxide synthase activation in patients with DM (P=0.019).ConclusionsIn summary, our data suggest that ER stress contributes to vascular insulin resistance and endothelial dysfunction in patients with DM. Further, we have demonstrated that liraglutide ameliorates ER stress, decreases c‐jun N‐terminal kinase activation and restores insulin‐mediated endothelial nitric oxide synthase activation in endothelial cells from patients with DM.

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Section: Discussionmentioning

confidence: 60%

Liraglutide Treatment Reduces Endothelial Endoplasmic Reticulum Stress and Insulin Resistance in Patients With Diabetes Mellitus

Bretón‐Romero

Weisbrod

Feng

et al. 2018

JAHA

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“…Liraglutide also produced greater reductions in HbA1c compared with glimepiride (0.84 and 1.14% for liraglutide 1.2 and 1.8 mg respectively, vs. 0.51% for glimepiride 8 mg; p < 0.001) [111]. In a phase 2 monotherapy trial, liraglutide reduced body weight in all treatment groups, with a significant reduction of ∼3.0 kg in the 1.9 mg group after 14 weeks of treatment (p = 0.039) [113]. Liraglutide 1.9 mg reduced HbA1c by 1.74% compared with placebo (p < 0.0001) [113].…”

Section: Glp-1 Receptormentioning

confidence: 99%

“…In a phase 2 monotherapy trial, liraglutide reduced body weight in all treatment groups, with a significant reduction of ∼3.0 kg in the 1.9 mg group after 14 weeks of treatment (p = 0.039) [113]. Liraglutide 1.9 mg reduced HbA1c by 1.74% compared with placebo (p < 0.0001) [113]. Liraglutide combination therapy is also associated with reductions in body weight and HbA1c [92,112].…”

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confidence: 99%

Diabesity: therapeutic options

Colagiuri¹

2010

Diabetes Obesity Metabolism

102

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A pathogenic relationship exists between type 2 diabetes and obesity. Over the last decade, the escalation in diabetes cases has paralleled the rapid increase in obesity rates, constituting a global health crisis. Environmental risk factors attributed to the global increase in obesity include the consumption of high-calorie, high-fat foods and inadequate physical activity. Obese individuals may also have a genetic predisposition for obesity. Both diabetes and obesity confer an elevated risk of developing a range of complications and comorbidities, including cardiovascular disease, hypertension and stroke, which can complicate disease management. This review examines the aetiology of the linkages between diabetes and obesity and the range of available therapies. Recent clinical evidence substantiating the efficacy and safety of incretin-based antidiabetic therapies is analysed, in addition to data on antiobesity therapeutic strategies, such as antiobesity agents, behaviour modification and bariatric surgery. Glucose control is often accompanied by weight-neutral or modest weight reduction effects with DPP-4 inhibitor treatment (sitagliptin, vildagliptin, saxagliptin) and weight loss with GLP-1 receptor agonist therapy (exenatide, liraglutide). Studies of antiobesity agents including orlistat, sibutramine and rimonabant have shown attrition rates of 30-40%, and the long-term effects of these agents remain unknown. Bariatric surgical procedures commonly performed are laparoscopic adjustable banding of the stomach and the Roux-en-Y gastric bypass, and have produced type 2 diabetes remission rates of up to 73%. Therapeutic strategies that integrate glycaemic control and weight loss will assume greater importance as the prevalence of diabetes and obesity increase. Keywords: DPP-4, exenatide, GLP-1 analogue, human, incretin, liraglutide, once-daily, type 2 diabetes mellitus Date submitted 2 June 2009; date of first decision 2 November 2009; date of final acceptance 4 November 2009 IntroductionThe term 'diabesity', coined by Sims and colleagues [1] in the 1970s, describes the strong link between type 2 diabetes and obesity [1,2]. As evidence of this pathogenic interrelationship continues to accumulate, so does the appearance of the term in the clinical literature. A large body of clinical evidence attests to the relationship between being overweight or obese and being at an elevated risk for development of type 2 diabetes [3][4][5][6][7]. The risk escalates with the degree of excess weight, increasing threefold with a body mass index (BMI) of 25.0-29.9 kg/m 2 and 20-fold with a BMI over 30 kg/m 2 [4]. In particular, abdominal fat accumulation exacerbates insulin resistance and confers a strong, independent risk of developing diabetes [8]. Global diabetes prevalence is estimated at 171 million and is projected to more than double, to 366 million, by 2030 [9]. Countries with the highest numbers of diabetes cases include India, China, USA, Indonesia and Japan [9][10][11]. The greatest relative increases in diabetes incide...

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“…Treatment for 3 years or more was associated with significant improvements in cardiovascular risk Recently published data demonstrated that liraglutide as monotherapy is capable of decreasing fasting plasma glucose levels up to 3.4 mmol/l (1.90 mg dose) on average when compared to placebo (110). In the same study, a decrease in HbA 1c of up to 1.7 percentage points (baseline HbA 1c 8.0%) was seen, and almost 50% of the patients with T2DM managed to reached the goal level of <7% in HbA 1c.…”

Section: Glp-1 Receptor Agonistsmentioning

confidence: 99%

The incretin system and its role in type 2 diabetes mellitus

Holst

Vilsbøll

Deacon

2009

Molecular and Cellular Endocrinology

449

332

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The incretin hormones are released during meals from gut endocrine cells. They potentiate glucoseinduced insulin secretion and may be responsible for up to 70 % of postprandial insulin secretion.The incretin hormones include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), both of which may also promote proliferation/neogenesis of beta cells and prevent their decay (apoptosis). Both hormones contribute to insulin secretion from the beginning of a meal and their effects are progressively amplified as plasma glucose concentrations rise. The current interest in the incretin hormones is due to the fact that the incretin effect is severely reduced or absent in patients with type 2 diabetes mellitus (T2DM). In addition, there is hyperglucagonaemia, which is not suppressible by glucose. In such patients, the secretion of GIP is near normal, but its effect on insulin secretion, particularly the late phase, is severely impaired. The loss of GIP action is probably a consequence of diabetes, since it is also observed in patients with diabetes secondary to chronic pancreatitis, in whom the incretin effect is also lost. GLP-1 secretion, on the other hand, is also impaired, but its insulinotropic and glucagon-suppressive actions are preserved, although the potency of GLP-1 in this respect is decreased compared to healthy subjects. Introduction-The incretin effect.

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Liraglutide, a Long-Acting Human Glucagon-Like Peptide-1 Analog, Given as Monotherapy Significantly Improves Glycemic Control and Lowers Body Weight Without Risk of Hypoglycemia in Patients With Type 2 Diabetes

Cited by 416 publications

References 10 publications

Liraglutide Treatment Reduces Endothelial Endoplasmic Reticulum Stress and Insulin Resistance in Patients With Diabetes Mellitus

Liraglutide Treatment Reduces Endothelial Endoplasmic Reticulum Stress and Insulin Resistance in Patients With Diabetes Mellitus

Diabesity: therapeutic options

The incretin system and its role in type 2 diabetes mellitus

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