Heterogeneity and Similarities in GLP-1 Receptor Agonist Cardiovascular Outcomes Trials

Caruso, Irene; Cignarelli, Angelo; Giorgino, Francesco

doi:10.1016/j.tem.2019.07.004

Cited by 48 publications

(42 citation statements)

References 58 publications

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“…A recent meta‐analysis of GLP‐1RAs suggests that their CV benefits should be regarded as a class effect, and that timing of exposure is the most prominent factor in trial heterogeneity, with increased exposure associated with improved outcomes . The benefits of GLP‐1RAs on CV outcomes in subjects with T2D have also recently been confirmed in an analysis of the seven GLP‐1RA CVOTs described above, and are consistent irrespective of CVD at baseline …”

Section: Discussionmentioning

confidence: 84%

Semaglutide (SUSTAIN and PIONEER) reduces cardiovascular events in type 2 diabetes across varying cardiovascular risk

Husain

Bain

Jeppesen

et al. 2020

Diabetes Obesity Metabolism

125

106

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Aim To investigate the effects of semaglutide versus comparators on major adverse cardiovascular events (MACE: cardiovascular [CV] death, nonfatal myocardial infarction [MI] and nonfatal stroke) and hospitalization for heart failure (HF) in the SUSTAIN (subcutaneous semaglutide) and PIONEER (oral semaglutide) trials across subgroups of varying CV risk. Methods Post hoc analyses of individual patient‐level data combined from SUSTAIN 6 and PIONEER 6 were performed to assess MACE and HF. MACE were analysed in subjects with and without: established CV disease and/or chronic kidney disease; prior MI or stroke; and prior HF. MACE in the SUSTAIN and PIONEER glycaemic efficacy trials were also assessed. Results In SUSTAIN 6 and PIONEER 6 combined, the hazard ratio (HR) for effect of semaglutide versus placebo on overall MACE was 0.76 (95% CI 0.62, 0.92), which was mainly driven by the effect on nonfatal stroke (HR 0.65 [95% CI 0.43, 0.97]). The HR for hospitalization for HF was 1.03 (95% CI 0.75, 1.40). The HRs for MACE were <1.0 in all subgroups, except for those with prior HF (HR 1.06 [95% CI 0.72, 1.57]); P‐values for interaction of subgroup on treatment effect were >0.05, except for HF (0.046). In the combined glycaemic efficacy trials, the HR for effect of semaglutide versus comparators on MACE was 0.85 (95% CI 0.55, 1.33). Conclusions In SUSTAIN and PIONEER combined, glucagon‐like peptide‐1 analogue semaglutide showed consistent effects on MACE versus comparators across varying CV risk. No effect of semaglutide on MACE was observed in subjects with prior HF.

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Section: Discussionmentioning

confidence: 84%

Semaglutide (SUSTAIN and PIONEER) reduces cardiovascular events in type 2 diabetes across varying cardiovascular risk

Husain

Bain

Jeppesen

et al. 2020

Diabetes Obesity Metabolism

125

106

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“…Recent efforts have continued to focus on the development of once‐weekly GLP‐1 RAs, with the intention of improving patient compliance. Moreover, there is increasing evidence of the cardiovascular benefits of GLP‐1 RAs 5 . Hence, GLP‐1 RAs are emerging as a new approach for T2D treatment.…”

Section: Introductionmentioning

confidence: 99%

Efficacy and safety of polyethylene glycol loxenatide monotherapy in type 2 diabetes patients: A multicentre, randomized, double‐blind, placebo‐controlled phase 3a clinical trial

Shi

Yang

Zhang

et al. 2020

Diabetes Obesity Metabolism

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Aim To evaluate the efficacy and safety of polyethylene glycol loxenatide (PEX168) monotherapy in type 2 diabetes (T2D) patients in China. Materials and Methods In a multicentred, randomized, double‐blinded, placebo‐controlled phase 3a clinical trial, 361 patients with inadequate glycaemic control (HbA1c 7.0%‐10.5%, fasting plasma glucose <13.9 mmol/L) were randomized (1:1:1) for weekly subcutaneous injections: placebo, PEX168/100 μg or PEX168/200 μg. The 24‐week treatment was followed by a 28‐week extension, during which placebo‐treated patients were randomly assigned to PEX168/100 μg or PEX168/200 μg. The primary efficacy endpoint was the HbA1c change from baseline to week 24. Results The three groups had similar demographics and baseline characteristics. The HbA1c least‐square mean (95% CI) change from baseline to week 24 was greater for PEX168/100 μg (−1.02% [−1.21%, −0.83%]) and PEX168/200 μg (−1.34% [−1.54%, −1.15%]) than for placebo (−0.17% [−0.36%, 0.02%]); (superiority: P < .0001). The proportions of patients with less than 7% HbA1c in the placebo, PEX168/100 μg and PEX168/200 μg groups were 15.7%, 34.7% and 46.6%, respectively. Common gastrointestinal adverse events (AEs) were nausea (5.6%, 10.0% and 0% for PEX168/100 μg, PEX168/200 μg and placebo, respectively) and vomiting (2.4%, 8.3% and 0% for PEX168/100 μg, PEX168/200 μg and placebo, respectively). Six (1.6%) patients (PEX168/100 μg: N = 2 [1.6%], PEX168/200 μg: N = 3 [2.5%] and placebo: N = 1 [0.8%]) discontinued treatment because of AEs. Four (1.2%) patients (PEX168/100 μg: N = 3 [2.5%] and PEX168/200 μg: N = 1 [0.9%]) developed PEX168 antidrug antibodies. Conclusion PEX168 monotherapy significantly improved glycaemic control in T2D patients with a safety profile resembling that of other glucagon‐like peptide‐1 receptor agonists.

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“…Exenatide is equipotent with native GLP-1 for activating the GLP-1R (6) and displays beneficial effects on glucose control and body weight reduction at plasma concentrations in the 40 to 70 pmol/L range (7,8). Similarly, other highly potent GLP-1R agonists, including liraglutide (9), dulaglutide (10), and semaglutide (11), are approved T2DM medications, each with proven cardiovascular health benefits (12). While these medicines provide improved treatment outcomes for patients, all of them are large-molecular weight peptide-based agents that require administration by subcutaneous (s.c.) injection.…”

mentioning

confidence: 99%

Structural basis for GLP-1 receptor activation by LY3502970, an orally active nonpeptide agonist

Kawai¹,

Sun

Yoshino³

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Glucagon-like peptide-1 receptor (GLP-1R) agonists are efficacious antidiabetic medications that work by enhancing glucose-dependent insulin secretion and improving energy balance. Currently approved GLP-1R agonists are peptide based, and it has proven difficult to obtain small-molecule activators possessing optimal pharmaceutical properties. We report the discovery and mechanism of action of LY3502970 (OWL833), a nonpeptide GLP-1R agonist. LY3502970 is a partial agonist, biased toward G protein activation over β-arrestin recruitment at the GLP-1R. The molecule is highly potent and selective against other class B G protein–coupled receptors (GPCRs) with a pharmacokinetic profile favorable for oral administration. A high-resolution structure of LY3502970 in complex with active-state GLP-1R revealed a unique binding pocket in the upper helical bundle where the compound is bound by the extracellular domain (ECD), extracellular loop 2, and transmembrane helices 1, 2, 3, and 7. This mechanism creates a distinct receptor conformation that may explain the partial agonism and biased signaling of the compound. Further, interaction between LY3502970 and the primate-specific Trp33 of the ECD informs species selective activity for the molecule. In efficacy studies, oral administration of LY3502970 resulted in glucose lowering in humanized GLP-1R transgenic mice and insulinotropic and hypophagic effects in nonhuman primates, demonstrating an effect size in both models comparable to injectable exenatide. Together, this work determined the molecular basis for the activity of an oral agent being developed for the treatment of type 2 diabetes mellitus, offering insights into the activation of class B GPCRs by nonpeptide ligands.

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Heterogeneity and Similarities in GLP-1 Receptor Agonist Cardiovascular Outcomes Trials

Cited by 48 publications

References 58 publications

Semaglutide (SUSTAIN and PIONEER) reduces cardiovascular events in type 2 diabetes across varying cardiovascular risk

Semaglutide (SUSTAIN and PIONEER) reduces cardiovascular events in type 2 diabetes across varying cardiovascular risk

Efficacy and safety of polyethylene glycol loxenatide monotherapy in type 2 diabetes patients: A multicentre, randomized, double‐blind, placebo‐controlled phase 3a clinical trial

Structural basis for GLP-1 receptor activation by LY3502970, an orally active nonpeptide agonist

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