A novel dual glucagon‐like peptide and glucagon receptor agonist SAR425899: Results of randomized, placebo‐controlled first‐in‐human and first‐in‐patient trials

Tillner, J.; Posch, Maximilian; Wagner, Frank; Teichert, Lenore; Hijazi, Youssef; Einig, Christine; Keil, Stefanie; Haack, Torsten; Wagner, Michael R.; Bossart, Martin; Larsen, Philip J.

doi:10.1111/dom.13494

Cited by 144 publications

(130 citation statements)

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“…This would suggest a higher effect of SAR425899 compared with sole GLP‐1R agonists on insulin action and β‐cell function. However, it is worth noting that in the GLP‐1R agonist was administered 30 minutes before the meal test, while in SAR425899 was administered 8 hours prior to meal ingestion, and therefore the different time of administration probably affects the comparison being made. Hence, further studies based on head‐to‐head comparisons are required to draw robust conclusions about comparisons being made with other treatments, either pure GLP‐1R or other dual GLP‐1R/GCGR agonists.…”

Section: Discussionmentioning

confidence: 99%

“…Among them, a novel dual GLP‐1R/GCGR agonist, SAR425899, showed significant reduction of body weight (BW), fasting plasma glucose (FPG) and HbA1c after 4 weeks of treatment in overweight to obese patients with type 2 diabetes . The safety profile was comparable with that of GLP‐1R agonists.…”

Section: Introductionmentioning

confidence: 99%

“…Here, we provide mechanistic insights into the effects of SAR425899 in type 2 diabetes by using the OMM method. In particular, we investigate SAR425899 effects in terms of insulin action, secretion and Ra, estimated by using data from a phase 1 clinical study in patients with type 2 diabetes …”

Section: Introductionmentioning

confidence: 99%

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Dual glucagon‐like peptide‐1 receptor/glucagon receptor agonist SAR425899 improves beta‐cell function in type 2 diabetes

Visentin

Schiavon

Göbel

et al. 2019

Diabetes Obesity Metabolism

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Aim To evaluate the change in insulin sensitivity, β‐cell function and glucose absorption after 28 days of treatment with high and low doses of SAR425899, a novel dual glucagon‐like peptide‐1 receptor/glucagon receptor agonist, versus placebo. Materials and Methods Thirty‐six overweight to obese subjects with type 2 diabetes were randomized to receive daily subcutaneous administrations of low‐dose SAR425899 (0.03, 0.06 and 0.09 mg) and high‐dose SAR425899 (0.06, 0.12 and 0.18 mg) or placebo for 28 days; dose escalation occurred after days 7 and 14. Mixed meal tolerance tests were conducted before treatment (day −1) and on days 1 and 28. Oral glucose and C‐peptide minimal models were used to quantify metabolic indices of insulin sensitivity, β‐cell responsiveness and glucose absorption. Results With low‐dose SAR425899, high‐dose SAR425899 and placebo, β‐cell function from day −1 to day 28 increased by 163%, 95% and 23%, respectively. The change in area under the curve for the rate of meal glucose appearance between 0 and 120 minutes was −32%, −20% and 8%, respectively. Conclusions After 28 days of treatment, SAR425899 improved postprandial glucose control by significantly enhancing β‐cell function and slowing glucose absorption rate.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dual glucagon‐like peptide‐1 receptor/glucagon receptor agonist SAR425899 improves beta‐cell function in type 2 diabetes

Visentin

Schiavon

Göbel

et al. 2019

Diabetes Obesity Metabolism

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“…Accordingly, dual agonism of GLP‐1 and glucagon receptors is likely to be useful in the management of obesity and T2DM. Emerging clinical trials have shown profound effects of novel GLP‐1/glucagon receptor dual agonists on body weight and glycaemic control in overweight/obese people with T2DM. Antagonism of the GLP‐1 receptor in people with T2DM, however, while increasing blood glucose, is associated with a favourable increase in energy expenditure; the latter may be protective against insulin resistance, as was seen in GLP‐1 receptor knockout mice …”

Section: Discussionmentioning

confidence: 99%

Role of endogenous glucagon‐like peptide‐1 enhanced by vildagliptin in the glycaemic and energy expenditure responses to intraduodenal fat infusion in type 2 diabetes

Xie

Wang

Jones

et al. 2019

Diabetes Obesity Metabolism

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Aim To evaluate the effects of the dipeptidyl peptidase‐4 (DPP‐4) inhibitor vildagliptin on glycaemic and energy expenditure responses during intraduodenal fat infusion, as well as the contribution of endogenous glucagon‐like peptide‐1 (GLP‐1) signalling, in people with type 2 diabetes (T2DM). Methods A total of 15 people with T2DM managed by diet and/or metformin (glycated haemoglobin 49.3 ± 2.1 mmol/mol) were studied on three occasions (two with vildagliptin and one with placebo) in a double‐blind, randomized, crossover fashion. On each day, vildagliptin 50 mg or placebo was given orally, followed by intravenous exendin (9–39) 600 pmol/kg/min, on one of the two vildagliptin treatment days, or 0.9% saline over 180 minutes. At between 0 and 120 minutes, a fat emulsion was infused intraduodenally at 2 kcal/min. Energy expenditure, plasma glucose and glucose‐regulatory hormones were evaluated. Results Intraduodenal fat increased plasma GLP‐1 and glucose‐dependent insulinotropic polypeptide (GIP), insulin and glucagon, and energy expenditure, and decreased plasma glucose (all P < 0.05). On the two intravenous saline days, plasma glucose and glucagon were lower, plasma intact GLP‐1 was higher (all P < 0.05), and energy expenditure tended to be lower after vildagliptin (P = 0.08) than placebo. On the two vildagliptin days, plasma glucose, glucagon and GLP‐1 (both total and intact), and energy expenditure were higher during intravenous exendin (9–39) than saline (all P < 0.05). Conclusions In well‐controlled T2DM during intraduodenal fat infusion, vildagliptin lowered plasma glucose and glucagon, and tended to decrease energy expenditure, effects that were mediated by endogenous GLP‐1.

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“…Another GLP1R/GCGR dual agonist, SAR425899 (Sanofi, Frankfurt, Germany) has recently been evaluated in single‐ascending dose and multiple‐ascending dose Phase 1 trials when given once a day over 28 days . At the highest maintenance doses tested, there was a reduction of HbA1c by 0.54%‐0.59% when given to overweight/obese diabetic patients, and mean weight losses of 2.37‐5.46 kg over the 28 days.…”

Section: Development Of Dual Agonistsmentioning

confidence: 99%

Cracking the combination: Gut hormones for the treatment of obesity and diabetes

Αλεξιάδου

Anyiam

Tan

2019

J Neuroendocrinology

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Obesity and type 2 diabetes are a veritable global pandemic. There is an imperative to develop new therapies for these conditions that can be delivered at scale to patients, which deliver effective and titratable weight loss, amelioration of diabetes, prevention of diabetic complications and improvements in cardiovascular health. Although agents based on glucagon‐like peptide‐1 (GLP‐1) are now in routine use for diabetes and obesity, the limited efficacy of such drugs means that newer agents are required. By combining the effects of GLP‐1 with other gut and metabolic hormones such as glucagon (GCG), oxyntomodulin, glucose‐dependent insulinotropic peptide (GIP) and peptide YY (PYY), we may obtain improved weight loss, increased energy expenditure and improved metabolic profiles. Drugs based on dual agonism of GLP1R/GCGR and GLP1R/GIPR are being actively developed in clinical trials. Triple agonism, for example with GLPR1/GCGR/GIPR unimolecular agonists or using GLP‐1/oxyntomodulin/PYY, is also being explored. Multi‐agonist drugs seem set to deliver the next generation of therapies for diabetes and obesity soon.

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A novel dual glucagon‐like peptide and glucagon receptor agonist SAR425899: Results of randomized, placebo‐controlled first‐in‐human and first‐in‐patient trials

Cited by 144 publications

References 40 publications

Dual glucagon‐like peptide‐1 receptor/glucagon receptor agonist SAR425899 improves beta‐cell function in type 2 diabetes

Dual glucagon‐like peptide‐1 receptor/glucagon receptor agonist SAR425899 improves beta‐cell function in type 2 diabetes

Role of endogenous glucagon‐like peptide‐1 enhanced by vildagliptin in the glycaemic and energy expenditure responses to intraduodenal fat infusion in type 2 diabetes

Cracking the combination: Gut hormones for the treatment of obesity and diabetes

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