Efficacy and safety of the glucagon receptor antagonist PF‐06291874: A 12‐week, randomized, dose‐response study in patients with type 2 diabetes mellitus on background metformin therapy

Kazierad, David J.; Chidsey, Kristin; Somayaji, Veena; Bergman, Arthur; Calle, Roberto A.

doi:10.1111/dom.13440

Cited by 23 publications

(19 citation statements)

References 31 publications

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“…In the current study, mean fasting glucagon increased relative to placebo with all three RVT-1502 doses, as has been reported with other GRAs (21,22,(30)(31)(32). In addition, there were increases in total and active GLP1 relative to baseline with some doses of RVT-1502, and a significant increase in total GLP1 with RVT-1502 10 mg compared with placebo.…”

Section: Discussionsupporting

confidence: 87%

“…Glucagon receptor antagonism to treat hyperglycemia in type 2 diabetes by reducing hepatic glucose production (5,6) has been pursued for several decades, but no drugs with this mechanism of action are currently available for clinical use. Despite promising efficacy results with previous compounds, adverse effects on lipids, BP, weight, and liver enzymes (particularly isolated ALT and AST) and increases in hypoglycemia have so far hampered clinical development of GRAs (5,6,(24)(25)(26)30). RVT-1502 shows similar reductions in HbA 1c at lower doses than other GRAs tested to date, which could potentially reduce the risk of off-target adverse effects during chronic therapy.…”

Section: Discussionmentioning

confidence: 99%

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Efficacy and Safety of the Glucagon Receptor Antagonist RVT-1502 in Type 2 Diabetes Uncontrolled on Metformin Monotherapy: A 12-Week Dose-Ranging Study

et al. 2019

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Evaluate the safety and efficacy of RVT-1502, a novel oral glucagon receptor antagonist, in subjects with type 2 diabetes inadequately controlled on metformin. RESEARCH DESIGN AND METHODS In a phase 2, double-blind, randomized, placebo-controlled study, subjects with type 2 diabetes (n 5 166) on a stable dose of metformin were randomized (1:1:1:1) to placebo or RVT-1502 5, 10, or 15 mg once daily for 12 weeks. The primary end point was change from baseline in HbA 1c for each dose of RVT-1502 compared with placebo. Secondary end points included change from baseline in fasting plasma glucose (FPG) and safety assessments. RESULTS Over 12 weeks, RVT-1502 significantly reduced HbA 1c relative to placebo by 0.74%, 0.76%, and 1.05% in the 5-, 10-, and 15-mg groups (P < 0.001), respectively, and FPG decreased by 2.1, 2.2, and 2.6 mmol/L (P < 0.001). The proportions of subjects achieving an HbA 1c <7.0% were 19.5%, 39.5%, 39.5%, and 45.0% with placebo and RVT-1502 5, 10, and 15 mg (P £ 0.02 vs. placebo). The frequency of hypoglycemia was low, and no episodes were severe. Mild increases in mean aminotransferase levels remaining below the upper limit of normal were observed with RVT-1502 but were reversible and did not appear to be dose related, with no other liver parameter changes. Weight and lipid changes were similar between RVT-1502 and placebo. RVT-1502-associated mild increases in blood pressure were not dose related or consistent across time. CONCLUSIONS Glucagon receptor antagonism with RVT-1502 significantly lowers HbA 1c and FPG, with a safety profile that supports further clinical development with longer-duration studies (NCT02851849). Glucagon stimulates gluconeogenesis and glycogenolysis through the glucagon receptor, thereby counteracting the role of insulin in the regulation of glucose homeostasis (1). In subjects with diabetes, the normal feedback system becomes imbalanced, and glucagon secretion is dysregulated, remaining elevated in both fasting

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of the Glucagon Receptor Antagonist RVT-1502 in Type 2 Diabetes Uncontrolled on Metformin Monotherapy: A 12-Week Dose-Ranging Study

et al. 2019

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“…Hyperglucagonemia is now known to be at least partly responsible for diabetic hyperglycemia [31,32], and therefore, clinical trials using glucagon receptor antagonists (GRAs) have been conducted in subjects with type 2 diabetes. GRA treatment improves diabetic hyperglycemia [21][22][23][24], but disturbing adverse effects including increased plasma concentrations of low-density lipoprotein and liver enzymes (aspartate-and alanine-transaminase) and hepatic fat accumulation halted further development of GRAs [33,34]. However, based on the observed changes in lipid metabolism and the possibility that glucagon may decrease food intake [35,36] and increase energy expenditure [37][38][39][40] (possibly through the sympathetic nervous system [41] or other indirect effects [42]), the focus has now shifted from glucagon receptor inhibition to glucagon receptor activation.…”

Section: The Glucagon Receptor As a Target In The Treatment Of Type 2mentioning

confidence: 99%

The Vicious Circle of Hepatic Glucagon Resistance in Non-Alcoholic Fatty Liver Disease

Galsgaard

2020

JCM

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A key criterion for the most common chronic liver disease—non-alcoholic fatty liver disease (NAFLD)—is an intrahepatic fat content above 5% in individuals who are not using steatogenic agents or having significant alcohol intake. Subjects with NAFLD have increased plasma concentrations of glucagon, and emerging evidence indicates that subjects with NAFLD may show hepatic glucagon resistance. For many years, glucagon has been thought of as the counterregulatory hormone to insulin with a primary function of increasing blood glucose concentrations and protecting against hypoglycemia. However, in recent years, glucagon has re-emerged as an important regulator of other metabolic processes including lipid and amino acid/protein metabolism. This review discusses the evidence that in NAFLD, hepatic glucagon resistance may result in a dysregulated lipid and amino acid/protein metabolism, leading to excess accumulation of fat, hyperglucagonemia, and increased oxidative stress contributing to the worsening/progression of NAFLD.

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“…Glucagon receptor expression has been reported in rat adipocytes (Svoboda et al, 1994; Hansen et al, 1995), where a lipolytic effect of glucagon may be of physiological relevance. As type 2 diabetic hyperglucagonaemia (Faerch et al, 2016) contributes to the hyperglycemic state of patients with type 2 diabetes (T2D) (Unger and Orci, 1975; Baron et al, 1987), inhibition of glucagon receptor signaling has been investigated as glucose-lowering therapy in T2D patients (Kazda et al, 2016; Kazierad et al, 2016, 2018; Vajda et al, 2017; Pettus et al, 2018). Interestingly, potential adverse effects of this therapeutic approach include increased low-density lipoprotein (LDL) plasma concentrations and increased hepatic fat accumulation (Guzman et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Glucagon Receptor Signaling and Lipid Metabolism

et al. 2019

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Glucagon is secreted from the pancreatic alpha cells upon hypoglycemia and stimulates hepatic glucose production. Type 2 diabetes is associated with dysregulated glucagon secretion, and increased glucagon concentrations contribute to the diabetic hyperglycemia. Antagonists of the glucagon receptor have been considered as glucose-lowering therapy in type 2 diabetes patients, but their clinical applicability has been questioned because of reports of therapy-induced increments in liver fat content and increased plasma concentrations of low-density lipoprotein. Conversely, in animal models, increased glucagon receptor signaling has been linked to improved lipid metabolism. Glucagon acts primarily on the liver and by regulating hepatic lipid metabolism glucagon may reduce hepatic lipid accumulation and decrease hepatic lipid secretion. Regarding whole-body lipid metabolism, it is controversial to what extent glucagon influences lipolysis in adipose tissue, particularly in humans. Glucagon receptor agonists combined with glucagon-like peptide 1 receptor agonists (dual agonists) improve dyslipidemia and reduce hepatic steatosis. Collectively, emerging data support an essential role of glucagon for lipid metabolism.

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Efficacy and safety of the glucagon receptor antagonist PF‐06291874: A 12‐week, randomized, dose‐response study in patients with type 2 diabetes mellitus on background metformin therapy

Abstract: In patients with T2DM, PF-06291874 significantly lowered HbA1c and glucose, was well tolerated and carried a low risk of hypoglycaemia. Small, non-dose-related increases in BP, lipids and hepatic transaminases were observed.

Cited by 23 publications

References 31 publications

Efficacy and Safety of the Glucagon Receptor Antagonist RVT-1502 in Type 2 Diabetes Uncontrolled on Metformin Monotherapy: A 12-Week Dose-Ranging Study

Efficacy and Safety of the Glucagon Receptor Antagonist RVT-1502 in Type 2 Diabetes Uncontrolled on Metformin Monotherapy: A 12-Week Dose-Ranging Study

The Vicious Circle of Hepatic Glucagon Resistance in Non-Alcoholic Fatty Liver Disease

Glucagon Receptor Signaling and Lipid Metabolism

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