Alogliptin after Acute Coronary Syndrome in Patients with Type 2 Diabetes

New England Journal of Medicine, Journal Year: 2013, Volume and Issue: 369(14), P. 1327 - 1335

Published: Sept. 2, 2013

To assess potentially elevated cardiovascular risk related to new antihyperglycemic drugs in patients with type 2 diabetes, regulatory agencies require a comprehensive evaluation of the safety profile antidiabetic therapies. We assessed outcomes alogliptin, inhibitor dipeptidyl peptidase 4 (DPP-4), as compared placebo diabetes who had recent acute coronary syndrome.We randomly assigned and either an myocardial infarction or unstable angina requiring hospitalization within previous 15 90 days receive alogliptin addition existing drug therapy. The study design was double-blind, noninferiority trial prespecified margin 1.3 for hazard ratio primary end point composite death from causes, nonfatal infarction, stroke.A total 5380 underwent randomization were followed up 40 months (median, 18 months). A end-point event occurred 305 (11.3%) 316 (11.8%) (hazard ratio, 0.96; upper boundary one-sided repeated confidence interval, 1.16; P<0.001 noninferiority). Glycated hemoglobin levels significantly lower than (mean difference, -0.36 percentage points; P<0.001). Incidences hypoglycemia, cancer, pancreatitis, initiation dialysis similar placebo.Among syndrome, rates major adverse events not increased DPP-4 placebo. (Funded by Takeda Development Center Americas; EXAMINE ClinicalTrials.gov number, NCT00968708.).

Language: Английский

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Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future

The Lancet, Journal Year: 2013, Volume and Issue: 383(9922), P. 1068 - 1083

Published: Dec. 3, 2013

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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Pharmacology, Physiology, and Mechanisms of Incretin Hormone Action

Cell Metabolism, Journal Year: 2013, Volume and Issue: 17(6), P. 819 - 837

Published: May 16, 2013

Language: Английский

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Clinical Update: Cardiovascular Disease in Diabetes Mellitus

Circulation, Journal Year: 2016, Volume and Issue: 133(24), P. 2459 - 2502

Published: June 13, 2016

Cardiovascular disease remains the principal cause of death and disability among patients with diabetes mellitus. Diabetes mellitus exacerbates mechanisms underlying atherosclerosis heart failure. Unfortunately, these are not adequately modulated by therapeutic strategies focusing solely on optimal glycemic control currently available drugs or approaches. In setting multifactorial risk reduction statins other lipid-lowering agents, antihypertensive therapies, antihyperglycemic treatment strategies, cardiovascular complication rates falling, yet remain higher for than those without. This review considers mechanisms, history, controversies, new pharmacological recent evidence current guidelines management in patient to support evidence-based care outside acute setting.

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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Ghrelin, CCK, GLP-1, and PYY(3–36): Secretory Controls and Physiological Roles in Eating and Glycemia in Health, Obesity, and After RYGB

Physiological Reviews, Journal Year: 2016, Volume and Issue: 97(1), P. 411 - 463

Published: Dec. 22, 2016

The efficacy of Roux-en-Y gastric-bypass (RYGB) and other bariatric surgeries in the management obesity type 2 diabetes mellitus novel developments gastrointestinal (GI) endocrinology have renewed interest roles GI hormones control eating, meal-related glycemia, obesity. Here we review nutrient-sensing mechanisms that secretion four these hormones, ghrelin, cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), peptide tyrosine [PYY(3–36)], their contributions to controls motor function, food intake, increases glycemia healthy-weight obese persons, as well RYGB patients. Their physiological classical endocrine locally acting signals are discussed. Gastric emptying, detection specific digestive products by small intestinal enteroendocrine cells, synergistic interactions among different loci all contribute CCK, GLP-1, PYY(3–36). While CCK has been fully established an endogenous eating persons following uncertain. Similarly, only GLP-1 clearly contributes glycemia. It is likely local signaling involved hormones' actions, but methods determine status effects lacking. Further research fresh approaches required better understand PYY(3–36) physiology; surgery; therapeutic potentials.

Language: Английский

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The pathophysiology of hypertension in patients with obesity

Nature Reviews Endocrinology, Journal Year: 2014, Volume and Issue: 10(6), P. 364 - 376

Published: April 15, 2014

Language: Английский

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