Therapy for Obesity Based on Gastrointestinal Hormones

Christensen, Mikkel B.; Knop, Filip K.; Vilsbøll, Tina

doi:10.1900/rds.2011.8.339

Cited by 10 publications

(12 citation statements)

References 107 publications

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“…Hyperglucagonaemia is a common feature of diabetes and is thought to be a direct result of loss of insulin‐induced suppression of glucagon secretion . Based on the fact that hyperglucagonaemia contributes to fasting and postprandial hyperglycaemia in people with type 2 diabetes (T2D), glucagon and the glucagon receptor have been investigated as potential targets for diabetes control . Clinical trials with small molecule glucagon receptor antagonists in patients with T2D treated for up to 24 weeks have demonstrated a significant decrease in fasting glucose, postprandial glucose and HbA1c, without significant hypoglycaemia .…”

Section: Introductionmentioning

confidence: 99%

“…postprandial hyperglycaemia in people with type 2 diabetes (T2D), glucagon and the glucagon receptor have been investigated as potential targets for diabetes control. 6 Clinical trials with small molecule glucagon receptor antagonists in patients with T2D treated for up to 24 weeks have demonstrated a significant decrease in fasting glucose, postprandial glucose and HbA1c, without significant hypoglycaemia. [7][8][9][10] Reversible increases in LDL-cholesterol and elevated serum hepatic aminotransferases levels have also been reported.…”

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confidence: 99%

“…Recombinant glucagon (Eli Lilly LLC, Indianapolis, Indiana) was administered intravenously at a dose of 0.8 mg. Blood samples were drawn from an indwelling catheter prior to and at6,15,20,25, 30, 45, 60, 75, 90, 120, 135, 150, 165, 180, 195, 210, 225 and 240 minutes after administration of glucagon for determination of plasma glucose levels.…”

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confidence: 99%

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A first‐in‐human pharmacodynamic and pharmacokinetic study of a fully human anti‐glucagon receptor monoclonal antibody in normal healthy volunteers

Kostić

King

Yang

et al. 2017

Diabetes Obesity Metabolism

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AimsGlucagon receptor (GCGR) blockers are being investigated as potential therapeutics for type 1 and type 2 diabetes. Here we report the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of REGN1193, a fully human glucagon receptor blocking monoclonal antibody from a first‐in‐human healthy volunteer randomized double‐blinded trial.MethodsHealthy men and women received single ascending doses of REGN1193 ranging from 0.05 to 0.6 mg/kg (n = 42) or placebo (n = 14) intravenously. Safety, tolerability and PK were assessed over 106 days. The glucose‐lowering effect of REGN1193 was assessed after induction of hyperglycaemia by serial glucagon challenges.ResultsREGN1193 was generally well tolerated. There were small (<3× the upper limit of normal) and transient dose‐dependent increases in hepatic aminotransferases. No increase in LDL‐C was observed. Hypoglycaemia, assessed as laboratory blood glucose ≤70 mg/dL, occurred in 6/14 (43%) subjects on placebo and 27/42 (57%) on REGN1193 across all dose groups. All episodes of hypoglycaemia were asymptomatic, >50 mg/dL, and did not require treatment or medical assistance. Concentration‐time profiles suggest a 2‐compartment disposition and marked nonlinearity, consistent with target‐mediated clearance. REGN1193 inhibited the glucagon‐stimulated glucose increase in a dose‐dependent manner. The 0.6 mg/kg dose inhibited the glucagon‐induced glucose area under the curve for 0 to 90 minutes (AUC0‐90 minutes) by 80% to 90% on days 3 and 15, while blunting the increase in C‐peptide. REGN1193 dose‐dependently increased total GLP‐1, GLP‐2 and glucagon, with plasma levels returning to baseline by day 29 in all dose groups.ConclusionREGN1193, a GCGR‐blocking monoclonal antibody, produced a safety, tolerability and PK/PD profile suitable for further clinical development. The occurrence of transient elevations in serum hepatic aminotransferases observed here and reported with several small molecule glucagon receptor antagonists suggests an on‐target effect of glucagon receptor blockade. The underlying mechanism is unknown.

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Section: Introductionmentioning

confidence: 99%

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A first‐in‐human pharmacodynamic and pharmacokinetic study of a fully human anti‐glucagon receptor monoclonal antibody in normal healthy volunteers

Kostić

King

Yang

et al. 2017

Diabetes Obesity Metabolism

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“…GLP-1 has several physiological functions, increasing insulin secretion and suppressing glucagon levels in a glucose-dependent manner, as well as decreasing food intake, slowing gastric emptying and increasing satiety [4,5]. Considering these actions, GLP-1 may represent a promising therapy for PWS, although there is still little evidence that this is the case.…”

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confidence: 99%

The glucagon-like peptide-1 analog liraglutide suppresses ghrelin and controls diabetes in a patient with Prader-Willi syndrome

et al. 2012

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“…Together with their ability to prevent or delay the progression to impaired glucose states, incretin mimetics have been suggested for use in obese patients who have a high risk of developing diabetes. These aspects of incretin-based therapy are discussed in the article by Bagger and coworkers [9]. In addition to incretin therapy, obesity is currently treated by interventions in peptideric systems using neuropeptides or peripheral gut peptides like the PP-fold peptide YY, pancreatic polypeptide, amylin, and the gastric hormone ghrelin.…”

Section: Treatment Of Diabetes Risk Factors and Complications -Differmentioning

confidence: 99%

The Continuing Need for Drug Development and Clinical Trials in Type 2 Diabetes and its Complications: Introduction to The RDS Special Issue

Gallwitz¹

2011

Rev Diabet Stud

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■ AbstractThe increased burden of type 2 diabetes (T2D) necessitates the need for effective and safe novel drugs to treat this epidemic disease and its complications. By compiling this RDS Special Issue, our aim was to provide a comprehensive and critical overview on recent, ongoing, and future developments in this field. In collaboration with distinguished and renowned experts, we analyzed and discussed the most important advances in the field of incretin-based therapies, their extraglycemic effects, cardiovascular actions, and specific properties of the central nervous system. Another important drug class currently in development, the SGLT-2 inhibitors, and the role of the kidney in T2D are topics also covered by this issue. In addition to drug developments, new physiological insights into the understanding of the organ pathophysiology in T2D are presented that may eventually lead to additional therapeutic targets for obesity, T2D, and chronic inflammation acting on the brain, cardiovascular system, and pancreatic islets. The outcome of this Special Issue is a comprehensive reference work including bundled knowledge and expert opinions on the various aspects of the disease and its possible therapy strategies available now and in the near future. However, despite the advances delivered by modern incretin-based therapies today, there are still many limitations associated with efficacy data, application routes, and safety issues, which prevent the decline in diabetes complication rates. We conclude that further drug development and clinical trials are required to overcome these limitations, and to counteract the movement towards higher incidence rates of T2D and its complications. Keywords: type 2 diabetes · incretin-based therapy · extraglycemic effects · antidiabetic · SGLT-2 inhibitorThe significance of new therapeutic developments in the treatment of type 2 diabetes and its complications ype 2 diabetes (T2D) is an increasing global health burden with estimated 350 million affected people and increasing incidence rates [1,2]. It is among the 5 principal sources of non-infectious diseases in industrialized and developing countries with an estimated global cost of treatment of 47 trillion US dollars [3]. The disease is adversely affecting health, life-expectancy, quality of life, and health care systems. Despite enormous efforts to develop new treatment strategies, more than 50% of patients are not at treatment target and rates for complications and mortality are still high. According to the National Institute of Health (NIH), incidence rates for diabetes complications between 2004 and 2008 in the US were: retinopathy 28.5%, nephropathy 44%, and an estimate of 60-70% with nerve damages [4]. This in-

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Therapy for Obesity Based on Gastrointestinal Hormones

Cited by 10 publications

References 107 publications

A first‐in‐human pharmacodynamic and pharmacokinetic study of a fully human anti‐glucagon receptor monoclonal antibody in normal healthy volunteers

A first‐in‐human pharmacodynamic and pharmacokinetic study of a fully human anti‐glucagon receptor monoclonal antibody in normal healthy volunteers

The glucagon-like peptide-1 analog liraglutide suppresses ghrelin and controls diabetes in a patient with Prader-Willi syndrome

The Continuing Need for Drug Development and Clinical Trials in Type 2 Diabetes and its Complications: Introduction to The RDS Special Issue

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