Recent developments in <scp>GLP‐1RA</scp> therapy: A review of the latest evidence of efficacy and safety and differences within the class

Bain, Evie; Bain, Stephen C.

doi:10.1111/dom.14487

Cited by 13 publications

(13 citation statements)

References 70 publications

(95 reference statements)

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“…More gradual doseescalation schemes over longer treatment durations are anticipated to result in lower incidence rates of gastrointestinal AEs. 9 However, both the overall and gastrointestinal safety profiles of danuglipron are generally consistent with those described for peptidic GLP-1R agonists, 10,11 including the recent oral formulation of semaglutide. [12][13][14][15] In this study, increases in heart rate were observed in danuglipron dose groups after 8 weeks of dosing, which was observed in the previous study in Western participants 8 and in other studies with peptidic GLP-1R agonists.…”

Section: Discussionsupporting

confidence: 59%

“…More gradual dose‐escalation schemes over longer treatment durations are anticipated to result in lower incidence rates of gastrointestinal AEs 9 . However, both the overall and gastrointestinal safety profiles of danuglipron are generally consistent with those described for peptidic GLP‐1R agonists, 10,11 including the recent oral formulation of semaglutide 12‐15 …”

Section: Discussionmentioning

confidence: 91%

“…In Japanese participants with T2DM, multiple doses of the novel, oral small‐molecule GLP‐1R agonist danuglipron showed a favourable safety profile that was consistent with phase 1 studies of danuglipron in Western participants 7 , 8 and with the peptidic GLP‐1R agonist class overall. 10 , 11 , 15 Approximately dose‐proportional increases in danuglipron plasma exposure were observed at steady state. Danuglipron robustly reduced plasma glucose levels, HbA1c and body weight after 8 weeks of dosing in Japanese adults with T2DM.…”

Section: Discussionmentioning

confidence: 96%

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A phase 1 study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of danuglipron (PF‐06882961), an oral small‐molecule glucagon‐like peptide‐1 receptor agonist, in Japanese adults with type 2 diabetes mellitus

Ono

Furihata

Ichikawa

et al. 2022

Diabetes Obesity Metabolism

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Aims: This study investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of danuglipron (PF-06882961), which is a novel, oral small-molecule glucagon-like peptide-1 receptor agonist, in Japanese participants with type 2 diabetes mellitus (T2DM). Materials and Methods:This phase 1, randomized, double-blind, placebo-controlled, parallel-group study enrolled adult Japanese participants with T2DM inadequately controlled on diet and exercise. Participants received twice-daily oral doses of placebo or multiple ascending doses of danuglipron titrated to 40, 80 or 120 mg twice daily over 8 weeks. The primary outcome was the safety and tolerability of danuglipron. Secondary and exploratory outcomes included plasma pharmacokinetics, glycaemic parameters and body weight.Results: In the 37 participants randomized, the most common treatment-emergent adverse events were nausea, vomiting, abdominal discomfort, diarrhoea and headache. Most treatment-emergent adverse events were of mild or moderate intensity. Dose-proportional increases in danuglipron exposure parameters were observed at steady state (Day 56). Significant reductions from baseline were observed with danuglipron on Day 56 for mean daily glucose [least squares mean (90% confidence interval) placebo-adjusted difference of up to À67.89 (À88.98, À46.79) mg/dl] and on Day 57 for fasting plasma glucose [up to À40.87 (À53.77, À27.98) mg/dl], glycated haemoglobin [up to À1.41% (À2.01%, À0.82%)] and body weight [up to À1.87 (À3.58, À0.17) kg].Conclusions: In Japanese adults with T2DM, danuglipron exhibited dose-proportional increases in plasma exposure at steady state and robustly reduced glycaemic

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Section: Discussionsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 96%

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A phase 1 study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of danuglipron (PF‐06882961), an oral small‐molecule glucagon‐like peptide‐1 receptor agonist, in Japanese adults with type 2 diabetes mellitus

Ono

Furihata

Ichikawa

et al. 2022

Diabetes Obesity Metabolism

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“…[9][10][11][12][13] As such, glucose-lowering medications have been shown to be efficacious for improving HF outcomes in diabetic patients, especially in diabetic patients with high risk or established cardiovascular disease. 14,15 Furthermore, results from multiple meta-analyses have also showed the superiority of glucose-lowering medications over placebo in improving outcomes for diabetic HF patients. GLP1-RA and SGLT2i demonstrated significant cardiovascular benefits, 16,17 while SGLT2i were more superior for improving HF outcomes and reduce hospitalizations for HF.…”

Section: Introductionmentioning

confidence: 99%

Can glucose‐lowering medications improve outcomes in non‐diabetic heart failure patients? A Bayesian network meta‐analysis

et al. 2022

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AimsThe cardioprotective effects of glucose-lowering medications in diabetic patients with heart failure (HF) are well known. Several large randomized controlled trials (RCTs) have recently suggested that the cardioprotective effects of glucose-lowering medications extend to HF patients regardless of diabetic status. The aim of this study was to conduct a Bayesian network meta-analysis to evaluate the impact of various glucose-lowering medications on the outcomes of non-diabetic HF patients. Methods and results Medline and Embase were searched for RCTs investigating the use of glucose-lowering medications in non-diabetic HF patients in August 2021. Studies were included in accordance with the inclusion and exclusion criteria, and data were extracted with a pre-defined datasheet. Primary outcomes include serum N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels, left ventricular ejection fraction (LVEF), and maximal oxygen consumption (PVO 2 ). A Bayesian network meta-analysis was performed to compare the effectiveness of different classes of glucose-lowering medications in improving HF outcomes. Risk-of-bias was assessed using Cochrane Risk-of-Bias tool 2.0 for randomized trials (ROB2). Seven RCTs involving 2897 patients were included. Sodium-glucose transporter 2 inhibitor (SGLT2i) was the most favourable in lowering NT-proBNP, with the significant reduction in NT-proBNP when compared with glucagon-like peptide-1 receptor agonists (GLP1-RA) [mean differences (MD): À229.59 pg/mL, 95%-credible intervals (95%-CrI): À238.31 to À220.91], metformin (MD: À237.15 pg/mL, 95%-CrI: À256.19 to À218.14), and placebo (MD: À228.00 pg/mL, 95%-CrI: À233.99 to À221.99). SGLT2i was more effective in improving LVEF for HF with reduced ejection fraction patients relative to GLP1-RA (MD: 8.09%, 95%-CrI: 6.30 to 9.88) and placebo (MD: 6.10%, 95%-CrI: 4.37 to 7.84). SGLT2i and GLP1-RA were more favourable to placebo in improving PVO 2 , with significant increase of PVO 2 at a MD of 1.60 mL/kg/min (95%-CrI: 0.63 to 2.57) and 0.86 mL/kg/min (95%-CrI: 0.66 to 1.06), respectively. All three drugs had comparable safety profiles when compared with placebo. Conclusions This Bayesian network meta-analysis demonstrated that SGLT2i, when compared with GLP1-RA and metformin, was superior in improving LVEF in HF with reduced ejection fraction patients, as well as improving PVO 2 and NT-proBNP in non-diabetic HF patients. Further large-scale prospective studies are needed to confirm these preliminary findings.

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“…postprandial insulin secretion, reduce glucagon secretion, delay gastric emptying, and decrease appetite, leading to improvements in glycaemic control and weight reduction. 4 The United States Food and Drug Administration (FDA) has approved two GLP-1RAs, liraglutide 1.8 mg/d and exenatide extended-release (ER), for T2D in youth aged 10 years or older. 2 However, little is known about GLP-1RA prescribing patterns in youth.…”

mentioning

confidence: 99%

Glucagon‐like peptide‐1 receptor agonist prescribing patterns in adolescents with type 2 diabetes

Bensignor

Wolf

Rudser

et al. 2022

Diabetes Obesity Metabolism

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Type 2 diabetes (T2D) in youth is a more aggressive disease that is associated with earlier co-morbidities compared with T2D in adulthood. 1 Treatment guidelines for paediatric T2D first recommend lifestyle management and metformin, which rarely achieve meaningful body mass index (BMI) reduction. 2,3 Because of limited options for treatment, medications approved for adult T2D have been used in an 'off-label' fashion in adolescents. One such medication class is glucagon-like peptide-1 receptor agonists (GLP-1RAs), which stimulate

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Recent developments in GLP‐1RA therapy: A review of the latest evidence of efficacy and safety and differences within the class

Cited by 13 publications

References 70 publications

A phase 1 study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of danuglipron (PF‐06882961), an oral small‐molecule glucagon‐like peptide‐1 receptor agonist, in Japanese adults with type 2 diabetes mellitus

A phase 1 study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of danuglipron (PF‐06882961), an oral small‐molecule glucagon‐like peptide‐1 receptor agonist, in Japanese adults with type 2 diabetes mellitus

Can glucose‐lowering medications improve outcomes in non‐diabetic heart failure patients? A Bayesian network meta‐analysis

Glucagon‐like peptide‐1 receptor agonist prescribing patterns in adolescents with type 2 diabetes

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