Incretins and cardiovascular disease: to the heart of type 2 diabetes? DOI Creative Commons
Anna Solini, Domenico Tricò, Stefano Del Prato

et al.

Diabetologia, Journal Year: 2023, Volume and Issue: 66(10), P. 1820 - 1831

Published: Aug. 5, 2023

Major cardiovascular outcome trials and real-life observations have proven that glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs), regardless of structural GLP-1 homology, exert clinically relevant protection. GLP-1RAs provide cardioprotective benefits through glycaemic non-glycaemic effects, including improved insulin secretion action, body-weight loss, blood-pressure lowering lipid profile, as well via direct effects on the heart vasculature. These actions are likely combined with anti-inflammatory antioxidant properties translate into robust consistent reductions in atherothrombotic events, particularly people type 2 diabetes established atherosclerotic CVD. may also an impact obesity chronic kidney disease, conditions for which risk-reducing options limited. The available evidence has prompted professional medical societies to recommend mitigation risk diabetes. This review summarises clinical protection use main mechanisms underlying this effect. Moreover, it looks how availability upcoming dual triple incretin might expand possibility

Language: Английский

Efficacy and Safety of GLP-1 Medicines for Type 2 Diabetes and Obesity DOI Open Access
Daniel J. Drucker

Diabetes Care, Journal Year: 2024, Volume and Issue: unknown

Published: June 6, 2024

The development of glucagon-like peptide 1 receptor agonists (GLP-1RA) for type 2 diabetes and obesity was followed by data establishing the cardiorenal benefits GLP-1RA in select patient populations. In ongoing trials investigators are interrogating efficacy these agents new indications, including metabolic liver disease, peripheral artery Parkinson Alzheimer disease. success GLP-1–based medicines has spurred molecular entities combinations with unique pharmacokinetic pharmacodynamic profiles, exemplified tirzepatide, a GIP-GLP-1 coagonist. Simultaneously, investigational molecules such as maritide block GIP activate GLP-1 receptor, whereas retatrutide survodutide enable simultaneous activation glucagon receptors. Here I highlight evidence medicines, while discussing that inform safety, focusing on muscle strength, bone density fractures, exercise capacity, gastrointestinal motility, retained gastric contents anesthesia, pancreatic biliary tract disorders, risk cancer. Rapid progress highly efficacious anticipated differentiation newer subsets will provide greater opportunities use personalized medicine approaches to improve health people living cardiometabolic disorders.

Language: Английский

Citations

83
GIPR/GLP-1R dual agonist therapies for diabetes and weight loss—chemistry, physiology, and clinical applications DOI Creative Commons
Jonathan E. Campbell, Timo D. Müller, Brian Finan

et al.

Cell Metabolism, Journal Year: 2023, Volume and Issue: 35(9), P. 1519 - 1529

Published: Aug. 16, 2023

Language: Английский

Citations

58
The benefits of GLP-1 drugs beyond obesity DOI
Daniel J. Drucker

Science, Journal Year: 2024, Volume and Issue: 385(6706), P. 258 - 260

Published: July 18, 2024

Glucagon-like peptide–1–based medicines have weight loss–independent actions

Language: Английский

Citations

44
Efficacy and safety of SGLT2 inhibitors with and without glucagon-like peptide 1 receptor agonists: a SMART-C collaborative meta-analysis of randomised controlled trials DOI
Ellen M. Apperloo, Brendon L. Neuen, Robert A. Fletcher

et al.

The Lancet Diabetes & Endocrinology, Journal Year: 2024, Volume and Issue: 12(8), P. 545 - 557

Published: July 8, 2024

Citations

42
Diabetes mellitus—Progress and opportunities in the evolving epidemic DOI
E. Dale Abel, Anna L. Gloyn, Carmella Evans‐Molina

et al.

Cell, Journal Year: 2024, Volume and Issue: 187(15), P. 3789 - 3820

Published: July 1, 2024

Language: Английский

Citations

34
GLP-1 physiology in obesity and development of incretin-based drugs for chronic weight management DOI Creative Commons
Jens J. Holst

Nature Metabolism, Journal Year: 2024, Volume and Issue: 6(10), P. 1866 - 1885

Published: Aug. 19, 2024

The introduction of the highly potent incretin receptor agonists semaglutide and tirzepatide has marked a new era in treatment type 2 diabetes obesity. With normalisation glycated haemoglobin levels weight losses around 15-25%, therapeutic goals that were previously unrealistic are now within reach, clinical trials have documented these effects associated with reduced risk cardiovascular events premature mortality. Here, I review this remarkable development from earliest observations glucose lowering modest native glucagon-like peptide (GLP)-1 short acting compounds, to recent active formulations molecules. will classify agents as GLP-1-based therapies understanding compounds or combinations may actions on other receptors well. physiology GLP-1 is discussed well its mechanisms obesity, particular, role sensory afferents brain. provide details regarding for anti-obesity therapy discuss possible mechanism behind their beneficial adverse events. Finally, highlight pharmacological developments, including oral agents, important questions maintenance therapy.

Language: Английский

Citations

24
Prevention of cardiorenal complications in people with type 2 diabetes and obesity DOI Creative Commons
Daniel J. Drucker

Cell Metabolism, Journal Year: 2024, Volume and Issue: 36(2), P. 338 - 353

Published: Jan. 9, 2024

Language: Английский

Citations

22
A comprehensive spatio-cellular map of the human hypothalamus DOI Creative Commons
John A. Tadross, Lukas Steuernagel, Georgina K.C. Dowsett

et al.

Nature, Journal Year: 2025, Volume and Issue: 639(8055), P. 708 - 716

Published: Feb. 5, 2025

Abstract The hypothalamus is a brain region that plays key role in coordinating fundamental biological functions 1 . However, our understanding of the underlying cellular components and neurocircuitries have, until recently, emerged primarily from rodent studies 2,3 Here we combine single-nucleus sequencing 433,369 human hypothalamic cells with spatial transcriptomics, generating comprehensive spatio-cellular transcriptional map hypothalamus, ‘HYPOMAP’. Although conservation neuronal cell types between humans mice, as based on transcriptomic identity, generally high, there are notable exceptions. Specifically, significant disparities identity pro-opiomelanocortin neurons expression levels G-protein-coupled receptors two species carry direct implications for currently approved obesity treatments. Out 452 types, find 291 clusters significantly enriched body mass index (BMI) genome-wide association study genes. This enrichment driven by 426 ‘effector’ Rare deleterious variants six these ( MC4R , PCSK1 POMC CALCR BSN CORO1A ) associate BMI at population level, has not been linked previously to BMI. Thus, HYPOMAP provides detailed atlas context serves an important resource identify new druggable targets treating wide range conditions, including reproductive, circadian metabolic disorders.

Language: Английский

Citations

5
Renal effects of GLP-1 receptor agonists and tirzepatide in individuals with type 2 diabetes: seeds of a promising future DOI Creative Commons
Irene Caruso, Francesco Giorgino

Endocrine, Journal Year: 2024, Volume and Issue: 84(3), P. 822 - 835

Published: March 12, 2024

Abstract Purpose Chronic kidney disease (CKD) is one of the most common complications type 2 diabetes (T2D), and CKD-related disability mortality are increasing despite recent advances in management. The dual GIP/GLP-1 receptor agonist tirzepatide among furthest developed multi-agonists for care has so far displayed promising nephroprotective effects. This review aims to summarize evidence regarding effects glucagon-like peptide-1 agonists (GLP-1RA) putative mechanisms underlying favorable renal profile tirzepatide. Methods A comprehensive literature search was performed from inception July 31st 2023 select research papers addressing GLP-1RA Results pathogenesis CKD patients with T2D likely involves many contributors besides hyperglycemia, such as hypertension, obesity, insulin resistance glomerular atherosclerosis, exerting damage through metabolic, fibrotic, inflammatory, hemodynamic mechanisms. Tirzepatide an unprecedented glucose body weight lowering potential, presenting also ability increase sensitivity, reduce systolic blood pressure inflammation ameliorate dyslipidemia, particularly by reducing triglycerides levels. Conclusion counteract pathogenetic factors contributing T2D, potentially representing a step forward incretin-based therapy towards nephroprotection. Further needed understand its role hemodynamics, fibrosis, cell well conclusively show reduction hard outcomes.

Language: Английский

Citations

14
Recent advances in peptide-based therapies for obesity and type 2 diabetes DOI Creative Commons
Clifford J. Bailey, Peter R. Flatt, J. Michael Conlon

et al.

Peptides, Journal Year: 2024, Volume and Issue: 173, P. 171149 - 171149

Published: Jan. 5, 2024

Options for the treatment of type 2 diabetes mellitus (T2DM) and obesity have recently been expanded by results several large clinical trials with incretin-based peptide therapies. Most these studies conducted glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide, which is available as a once weekly subcutaneous injection daily tablet, injected dual tirzepatide, interacts receptors GLP-1 glucose-dependent insulinotropic polypeptide (GIP). In individuals T2DM therapies achieved reductions glycated haemoglobin (HbA1c) > 2% lowered body weight 10%. some studies, agents tested in non-diabetic, obese at much higher doses 15%. Emerging evidence suggests can also offer cardio-protective potentially reno-protective effects. Other early development, notably triple GLP-1/GIP/glucagon (retatrutide) combination semaglutide amylin analogue cagrilintide (CagriSema), shown strong efficacy. Although incretin incur adverse gastrointestinal effects are most patients mild-to-moderate transient but result cessation cases. Thus, efficacy new enhancing opportunity to control blood glucose improve obesity.

Language: Английский

Citations

11