Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial

The Lancet, Journal Year: 2019, Volume and Issue: 394(10192), P. 39 - 50

Published: June 8, 2019

Language: Английский

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Glucagon-like peptide 1 in health and disease

Nature Reviews Endocrinology, Journal Year: 2018, Volume and Issue: 14(7), P. 390 - 403

Published: May 4, 2018

Language: Английский

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Semaglutide lowers body weight in rodents via distributed neural pathways

JCI Insight, Journal Year: 2020, Volume and Issue: 5(6)

Published: March 25, 2020

Semaglutide, a glucagon-like peptide 1 (GLP-1) analog, induces weight loss, lowers glucose levels, and reduces cardiovascular risk in patients with diabetes. Mechanistic preclinical studies suggest loss is mediated through GLP-1 receptors (GLP-1Rs) the brain. The findings presented here show that semaglutide modulated food preference, reduced intake, caused without decreasing energy expenditure. Semaglutide directly accessed brainstem, septal nucleus, hypothalamus but did not cross blood-brain barrier; it interacted brain circumventricular organs several select sites adjacent to ventricles. induced central c-Fos activation 10 areas, including hindbrain areas targeted by semaglutide, secondary direct GLP-1R interaction, such as lateral parabrachial nucleus. Automated analysis of access, activity, distribution, connectivity revealed may involve meal termination controlled neurons Transcriptomic microdissected from semaglutide-treated rats showed upregulation prolactin-releasing hormone tyrosine hydroxylase area postrema. We body interaction diverse populations indirectly affecting activity neural pathways involved reward,

Language: Английский

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SGLT2 inhibitors and GLP-1 receptor agonists: established and emerging indications

The Lancet, Journal Year: 2021, Volume and Issue: 398(10296), P. 262 - 276

Published: June 30, 2021

Language: Английский

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From NASH to diabetes and from diabetes to NASH: Mechanisms and treatment options

JHEP Reports, Journal Year: 2019, Volume and Issue: 1(4), P. 312 - 328

Published: July 19, 2019

The worldwide prevalence of non-alcoholic fatty liver disease (NAFLD) is estimated to have reached 25% or more in adults. NAFLD prevalent obese individuals, but may also affect non-obese insulin-resistant individuals. associated with a 2- 3-fold increased risk developing type 2 diabetes (T2D), which be higher patients severe – fibrosis increases this risk. In NAFLD, not only the close association obesity, impairment many metabolic pathways, including decreased hepatic insulin sensitivity and secretion, increase T2D related comorbidities. Conversely, steatohepatitis, end-stage disease. Genetics mechanisms involving dysfunctional adipose tissue, lipotoxicity glucotoxicity appear play role. review, we discuss altered pathophysiological that underlie development vice versa. Although there no approved therapy for treatment NASH, pharmacological agents currently available treat could potentially useful management NASH.

Language: Английский

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Oral Semaglutide Versus Empagliflozin in Patients With Type 2 Diabetes Uncontrolled on Metformin: The PIONEER 2 Trial

Diabetes Care, Journal Year: 2019, Volume and Issue: 42(12), P. 2272 - 2281

Published: Sept. 17, 2019

Efficacy and safety of the glucagon-like peptide 1 (GLP-1) analog oral semaglutide sodium-glucose cotransporter 2 inhibitor empagliflozin were compared in patients with type diabetes uncontrolled on metformin.Patients randomized to once-daily open-label treatment 14 mg (n = 412) or 25 410) a 52-week trial. Key end points change from baseline week 26 HbA1c (primary) body weight (confirmatory secondary). Two estimands addressed efficacy-related questions: policy (regardless trial product discontinuation rescue medication) (on without all patients.Four hundred (97.1%) group 387 (94.4%) completed Oral provided superior reductions versus at (treatment -1.3% vs. -0.9% [-14 -9 mmol/mol], estimated difference [ETD] -0.4% [95% CI -0.6, -0.3] [-5 mmol/mol (-6, -3)]; P < 0.0001). The significantly favored for estimand (-1.4% [-15 ETD -0.5% -0.7, -0.4] [-6 (-7, -5)]; 0.0001) 52 both (P Superior loss was not confirmed policy), but better than (trial -4.7 -3.8 kg; 0.0114). Gastrointestinal adverse events more common semaglutide.Oral reducing weeks metformin. At 52, estimand) reduced empagliflozin. well tolerated within established profile GLP-1 receptor agonists.

Language: Английский

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Efficacy and safety of once-weekly semaglutide 1.0 mg vs once-daily liraglutide 1.2 mg as add-on to 1–3 oral antidiabetic drugs in subjects with type 2 diabetes (SUSTAIN 10)

Diabetes & Metabolism, Journal Year: 2019, Volume and Issue: 46(2), P. 100 - 109

Published: Sept. 17, 2019

Language: Английский

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Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist

JCI Insight, Journal Year: 2020, Volume and Issue: 5(17)

Published: July 30, 2020

Tirzepatide (LY3298176) is a dual GIP and GLP-1 receptor agonist under development for the treatment of type 2 diabetes mellitus (T2DM), obesity, nonalcoholic steatohepatitis. Early phase trials in T2DM indicate that tirzepatide improves clinical outcomes beyond those achieved by selective agonist. Therefore, we hypothesized integrated potency signaling properties provide unique pharmacological profile tailored improving broad metabolic control. Here, establish methodology calculating occupancy each clinically efficacious doses drug. This analysis reveals greater degree engagement than receptor, corroborating an imbalanced mechanism action. Pharmacologically, studies demonstrate mimics actions native at but shows bias to favor cAMP generation over β-arrestin recruitment, coincident with weaker ability drive internalization compared GLP-1. Experiments primary islets reveal β-arrestin1 limits insulin response GLP-1, not or tirzepatide, suggesting biased agonism enhances secretion. Imbalance toward combined distinct together may account promising efficacy this investigational agent.

Language: Английский

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Semaglutide once weekly as add-on to SGLT-2 inhibitor therapy in type 2 diabetes (SUSTAIN 9): a randomised, placebo-controlled trial

The Lancet Diabetes & Endocrinology, Journal Year: 2019, Volume and Issue: 7(5), P. 356 - 367

Published: March 2, 2019

Language: Английский

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GLP-1 Analogs and DPP-4 Inhibitors in Type 2 Diabetes Therapy: Review of Head-to-Head Clinical Trials

Frontiers in Endocrinology, Journal Year: 2020, Volume and Issue: 11

Published: April 3, 2020

The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released from enteroendocrine cells in response to the presence of nutrients small intestines. These homones facilitate glucose regulation by stimulating insulin secretion a dependent manner while suppressing glucagon secretion. In patients with type 2 diabetes (T2DM), an impaired GLP-1 GIP contributes hyperglycemia. Dipeptidyl peptidase-4 (DPP-4) inhibitors block breakdown increase levels active hormones. clinical trials, DPP-4 have modest impact on glycemic control. They generally well-tolerated, weight neutral do not risk hypoglycemia. receptor agonists (GLP-1 RA) peptide derivatives either exendin-4 or human designed resist activity therefore, prolonged half-life. they demonstrated superior efficacy many oral antihyperglycemic drugs, improved loss low However, GI adverse events, particularly nausea, vomiting, diarrhea seen. Both RAs safety robust cardiovascular outcome several been shown significantly reduce major events persons T2DM pre-existing disease (CVD). Several trials directly compared RAs. studies that RA provided control relative inhibitor. treatments were associated comparable incidence hypoglycemia, but treatment invariably higher events. A few evaluated switching GLP-1RA and, as expected, seen following switch. According current guidelines, both indicated for management across spectrum disease. may be preferred over DPP- 4 because greater reductions hemoglobin A1c observed trials. Among preexisting CVD, proven benefit add-on metformin therapy.

Language: Английский

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