Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

New England Journal of Medicine, Journal Year: 2016, Volume and Issue: 375(4), P. 311 - 322

Published: June 13, 2016

The cardiovascular effect of liraglutide, a glucagon-like peptide 1 analogue, when added to standard care in patients with type 2 diabetes, remains unknown.In this double-blind trial, we randomly assigned diabetes and high risk receive liraglutide or placebo. primary composite outcome the time-to-event analysis was first occurrence death from causes, nonfatal myocardial infarction, stroke. hypothesis that would be noninferior placebo regard outcome, margin 1.30 for upper boundary 95% confidence interval hazard ratio. No adjustments multiplicity were performed prespecified exploratory outcomes.A total 9340 underwent randomization. median follow-up 3.8 years. occurred significantly fewer group (608 4668 [13.0%]) than (694 4672 [14.9%]) (hazard ratio, 0.87; [CI], 0.78 0.97; P<0.001 noninferiority; P=0.01 superiority). Fewer died causes (219 [4.7%]) (278 [6.0%]) 0.78; CI, 0.66 0.93; P=0.007). rate any cause lower (381 [8.2%]) (447 [9.6%]) 0.85; 0.74 P=0.02). rates stroke, hospitalization heart failure nonsignificantly group. most common adverse events leading discontinuation gastrointestinal events. incidence pancreatitis group.In analysis, stroke among mellitus (Funded by Novo Nordisk National Institutes Health; LEADER ClinicalTrials.gov number, NCT01179048.).

Language: Английский

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Glucagon-like peptide 1 (GLP-1)

Molecular Metabolism, Journal Year: 2019, Volume and Issue: 30, P. 72 - 130

Published: Sept. 30, 2019

Background: The glucagon-like peptide-1 (GLP-1) is a multifaceted hormone with broad pharmacological potential.Among the numerous metabolic effects of GLP-1 are glucose-dependent stimulation insulin secretion, decrease gastric emptying, inhibition food intake, increase natriuresis and diuresis, modulation rodent b-cell proliferation.GLP-1 also has cardio-and neuroprotective effects, decreases inflammation apoptosis, implications for learning memory, reward behavior, palatability.Biochemically modified enhanced potency sustained action, receptor agonists successfully in clinical use treatment type-2 diabetes, several GLP-1-based pharmacotherapies evaluation obesity.Scope review: In this review, we provide detailed overview on nature its pharmacology discuss therapeutic various diseases.Major conclusions: Since discovery, emerged as pleiotropic myriad functions that go well beyond classical identification an incretin hormone.The beneficial render interesting candidate development to treat obesity, neurodegenerative disorders

Language: Английский

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Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1

Cell Metabolism, Journal Year: 2018, Volume and Issue: 27(4), P. 740 - 756

Published: April 1, 2018

Language: Английский

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Effects of Liraglutide on Clinical Stability Among Patients With Advanced Heart Failure and Reduced Ejection Fraction

JAMA, Journal Year: 2016, Volume and Issue: 316(5), P. 500 - 500

Published: Aug. 2, 2016

Importance

Abnormal cardiac metabolism contributes to the pathophysiology of advanced heart failure with reduced left ventricular ejection fraction (LVEF). Glucagon-like peptide 1 (GLP-1) agonists have shown cardioprotective effects in early clinical studies patients failure, irrespective type 2 diabetes status.

Objective

To test whether therapy a GLP-1 agonist improves stability following hospitalization for acute failure.

Design, Setting, and Participants

Phase 2, double-blind, placebo-controlled randomized trial established LVEF who were recently hospitalized. Patients enrolled between August 2013 March 2015 at 24 US sites.

Interventions

The liraglutide (n = 154) or placebo 146) via daily subcutaneous injection; study drug was dosage 1.8 mg/d during first 30 days as tolerated continued 180 days.

Main Outcomes Measures

primary end point global rank score which all patients, regardless treatment assignment, ranked across 3 hierarchical tiers: time death, rehospitalization time-averaged proportional change N-terminal pro-B-type natriuretic level from baseline Higher values indicate better health (stability). Exploratory secondary outcomes included components, structure function, 6-minute walk distance, quality life, combined events.

Results

Among 300 (median age, 61 years [interquartile range {IQR}, 52-68 years]; 64 [21%] women; 178 [59%] diabetes; median 25% [IQR, 19%-33%]; 2049 pg/mL 1054-4235 pg/mL]), 271 completed study. Compared placebo, had no significant effect on (mean 146 group vs 156 group,P .31). There between-group differences number deaths (19 [12%] 16 [11%] group; hazard ratio, 1.10 [95% CI, 0.57-2.14];P .78) rehospitalizations (63 [41%] 50 [34%], respectively; 1.30 0.89-1.88];P .17) exploratory points. Prespecified subgroup analyses did not reveal any differences. investigator-reported hyperglycemic events (10%) 27 (18%) hypoglycemic infrequent (2 [1%] 4 [3%], respectively).

Conclusions Relevance

hospitalized LVEF, use lead greater posthospitalization stability. These findings do support this situation.

Trial Registration

clinicaltrials.gov Identifier:NCT01800968

Language: Английский

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Pharmacology, Physiology, and Mechanisms of Action of Dipeptidyl Peptidase-4 Inhibitors

Endocrine Reviews, Journal Year: 2014, Volume and Issue: 35(6), P. 992 - 1019

Published: Sept. 12, 2014

Dipeptidyl peptidase-4 (DPP4) is a widely expressed enzyme transducing actions through an anchored transmembrane molecule and soluble circulating protein. Both membrane-associated DPP4 exert catalytic activity, cleaving proteins containing position 2 alanine or proline. DPP4-mediated enzymatic cleavage alternatively inactivates peptides generates new bioactive moieties that may competing novel activities. The widespread use of selective inhibitors for the treatment type diabetes has heightened interest in molecular mechanisms which their pleiotropic actions. Here we review biology with focus on: 1) identification pharmacological vs physiological substrates; 2) elucidation studies employing genetic elimination chemical reduction activity. We data identifying roles key substrates glucoregulatory, anti-inflammatory, cardiometabolic both preclinical clinical studies. Finally, highlight experimental pitfalls technical challenges encountered designed to understand action downstream targets activated by inhibition DPP4.

Language: Английский

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The Cardiovascular Biology of Glucagon-like Peptide-1

Cell Metabolism, Journal Year: 2016, Volume and Issue: 24(1), P. 15 - 30

Published: June 25, 2016

Language: Английский

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Cardiovascular Actions and Clinical Outcomes With Glucagon-Like Peptide-1 Receptor Agonists and Dipeptidyl Peptidase-4 Inhibitors

Circulation, Journal Year: 2017, Volume and Issue: 136(9), P. 849 - 870

Published: Aug. 28, 2017

Potentiation of glucagon-like peptide-1 (GLP-1) action through selective GLP-1 receptor (GLP-1R) agonism or by prevention enzymatic degradation inhibition dipeptidyl peptidase-4 (DPP-4) promotes glycemic reduction for the treatment type 2 diabetes mellitus glucose-dependent control insulin and glucagon secretion. GLP-1R agonists also decelerate gastric emptying, reduce body weight food intake lower circulating lipoproteins, inflammation, systolic blood pressure. Preclinical studies demonstrate that both DPP-4 inhibitors exhibit cardioprotective actions in animal models myocardial ischemia ventricular dysfunction incompletely characterized mechanisms. The results cardiovascular outcome trials human subjects with increased risk have demonstrated a benefit (significant time to first major adverse event) liraglutide (LEADER trial [Liraglutide Effect Action Diabetes: Evaluation Cardiovascular Ourcome Results], −13%) semaglutide (SUSTAIN-6 [Trial Evaluate Other Long-term Outcomes Semaglutide], −24%). In contrast, examining safety shorter-acting agonist lixisenatide (ELIXA [Evaluation Lixisenatide Acute Coronary Syndrom]) saxagliptin (SAVOR-TIMI 53 [Saxagliptin Assessment Vascular Recorded Patients With Diabetes Mellitus-Thrombolysis Myocardial Infarction 53]), alogliptin (EXAMINE [Examination Alogliptin Versus Standard Care Type Mellitus Syndrome]), sitagliptin (TECOS Evaluating Sitagliptin]) found these agents neither nor decreased events. Here we review inhibitors, focus on translation mechanisms derived from preclinical complementary findings clinical studies. We highlight areas uncertainty requiring more careful scrutiny ongoing basic science As newer potent coagonists are being developed mellitus, obesity, nonalcoholic steatohepatitis, delineation potential underlie immediate relevance disease.

Language: Английский

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Effect of liraglutide, a glucagon‐like peptide‐1 analogue, on left ventricular function in stable chronic heart failure patients with and without diabetes (LIVE)—a multicentre, double‐blind, randomised, placebo‐controlled trial

European Journal of Heart Failure, Journal Year: 2016, Volume and Issue: 19(1), P. 69 - 77

Published: Oct. 28, 2016

Language: Английский

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Comprehensive Management of Cardiovascular Risk Factors for Adults With Type 2 Diabetes: A Scientific Statement From the American Heart Association

Circulation, Journal Year: 2022, Volume and Issue: 145(9)

Published: Jan. 10, 2022

Cardiovascular disease remains the leading cause of death in patients with diabetes. diabetes is multifactorial, and control cardiovascular risk factors leads to substantial reductions events. The 2015 American Heart Association Diabetes scientific statement, "Update on Prevention Disease Adults With Type 2 Mellitus Light Recent Evidence," highlighted importance modifying various responsible for At time, there was limited evidence suggest that glucose-lowering medications reduce present, several large randomized controlled trials newer antihyperglycemic agents have been completed, demonstrating safety reduction outcomes, including death, myocardial infarction, stroke, heart failure. This AHA statement update focuses (1) clinical utility improving glycemic reducing events diabetes; (2) impact blood pressure (3) role lipid-lowering therapies comprehensive management adults addresses continued lifestyle interventions, pharmacological therapy, surgical interventions curb epidemic obesity metabolic syndrome, important precursors prediabetes, diabetes, comorbid disease. Last, this explores critical social determinants health equity continuum care

Language: Английский

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The GLP-1 Analogs Liraglutide and Semaglutide Reduce Atherosclerosis in ApoE−/− and LDLr−/− Mice by a Mechanism That Includes Inflammatory Pathways

JACC Basic to Translational Science, Journal Year: 2018, Volume and Issue: 3(6), P. 844 - 857

Published: Nov. 21, 2018

The glucagon-like peptide-1 receptor agonists (GLP-1RAs) liraglutide and semaglutide reduce cardiovascular risk in type 2 diabetes patients. mode of action is suggested to occur through modified atherosclerotic progression. In this study, both the compounds significantly attenuated plaque lesion development apolipoprotein E-deficient (ApoE-/-) mice low-density lipoprotein receptor-deficient (LDLr-/-) mice. This attenuation was partly independent weight cholesterol lowering. aortic tissue, exposure a Western diet alters expression genes pathways relevant pathogenesis atherosclerosis, including leukocyte recruitment, rolling, adhesion/extravasation, metabolism, lipid-mediated signaling, extracellular matrix protein turnover, hemorrhage. Treatment with reversed these changes. These data suggest GLP-1RAs affect atherosclerosis an anti-inflammatory mechanism.

Language: Английский

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