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

https://spiral.imperial.ac.uk/bitstream/10044/1/74273/2/Glucagon-like%20peptide%201%20%28GLP-1%29%20Molecular%20Metabolism.pdf

Glucagon-like peptide 1 (GLP-1)

Background Nonalcoholic steatohepatitis (NASH) is a common disease that is associated with increased morbidity and mortality, but treatment options are limited. The efficacy and safety of ...

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A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis

Non-alcoholic fatty liver disease

Background GLP-1 receptor agonists (GLP-1 RAs) with exenatide b.i.d. first approved to treat type 2 diabetes in 2005 have been further developed to yield effective compounds/preparations that have overcome the original problem of rapid elimination (short half-life), initially necessitating short intervals between injections (twice daily for exenatide b.i.d.). Scope of review To summarize current knowledge about GLP-1 receptor agonist. Major conclusions At present, GLP-1 RAs are injected twice daily (exenatide b.i.d.), once daily (lixisenatide and liraglutide), or once weekly (exenatide once weekly, dulaglutide, albiglutide, and semaglutide). A daily oral preparation of semaglutide, which has demonstrated clinical effectiveness close to the once-weekly subcutaneous preparation, was recently approved. All GLP-1 RAs share common mechanisms of action: augmentation of hyperglycemia-induced insulin secretion, suppression of glucagon secretion at hyper- or euglycemia, deceleration of gastric emptying preventing large post-meal glycemic increments, and a reduction in calorie intake and body weight. Short-acting agents (exenatide b.i.d., lixisenatide) have reduced effectiveness on overnight and fasting plasma glucose, but maintain their effect on gastric emptying during long-term treatment. Long-acting GLP-1 RAs (liraglutide, once-weekly exenatide, dulaglutide, albiglutide, and semaglutide) have more profound effects on overnight and fasting plasma glucose and HbA1c, both on a background of oral glucose-lowering agents and in combination with basal insulin. Effects on gastric emptying decrease over time (tachyphylaxis). Given a similar, if not superior, effectiveness for HbA1c reduction with additional weight reduction and no intrinsic risk of hypoglycemic episodes, GLP-1RAs are recommended as the preferred first injectable glucose-lowering therapy for type 2 diabetes, even before insulin treatment. However, GLP-1 RAs can be combined with (basal) insulin in either free- or fixed-dose preparations. More recently developed agents, in particular semaglutide, are characterized by greater efficacy with respect to lowering plasma glucose as well as body weight. Since 2016, several cardiovascular (CV) outcome studies have shown that GLP-1 RAs can effectively prevent CV events such as acute myocardial infarction or stroke and associated mortality. Therefore, guidelines particularly recommend treatment with GLP-1 RAs in patients with pre-existing atherosclerotic vascular disease (for example, previous CV events). The evidence of similar effects in lower-risk subjects is not quite as strong. Since sodium/glucose cotransporter-2 (SGLT-2) inhibitor treatment reduces CV events as well (with the effect mainly driven by a reduction in heart failure complications), the individual risk of ischemic or heart failure complications should guide the choice of treatment. GLP-1 RAs may also help prevent renal complications of type 2 diabetes. Other active research areas in the field of GLP-1 RAs are the definition of subgroups within the type 2 diabetes population who particularly benefit from treatment with GLP-1 RAs. These include pharmacogenomic approaches and the characterization of non-responders. Novel indications for GLP-1 RAs outside type 2 diabetes, such as type 1 diabetes, neurodegenerative diseases, and psoriasis, are being explored. Thus, within 15 years of their initial introduction, GLP-1 RAs have become a well-established class of glucose-lowering agents that has the potential for further development and growing impact for treating type 2 diabetes and potentially other diseases.

GLP-1 receptor agonists in the treatment of type 2 diabetes - state-of-the-art.

Obesity contributes to reduced life expectancy, impaired quality of life, and disabilities, mainly in those individuals who develop cardiovascular diseases, type 2 diabetes, osteoarthritis, and cancer. However, there is a large variation in the individual risk to developing obesity-associated comorbid diseases that cannot simply be explained by the extent of adiposity. Observations that a proportion of individuals with obesity have a significantly lower risk for cardiometabolic abnormalities led to the concept of metabolically healthy obesity (MHO). Although there is no clear definition, normal glucose and lipid metabolism parameters-in addition to the absence of hypertension-usually serve as criteria to diagnose MHO. Biological mechanisms underlying MHO lower amounts of ectopic fat (visceral and liver), and higher leg fat deposition, expandability of subcutaneous adipose tissue, preserved insulin sensitivity, and beta-cell function as well as better cardiorespiratory fitness compared to unhealthy obesity. Whereas the absence of metabolic abnormalities may reduce the risk of type 2 diabetes and cardiovascular diseases in metabolically healthy individuals compared to unhealthy individuals with obesity, it is still higher in comparison with healthy lean individuals. In addition, MHO seems to be a transient phenotype further justifying therapeutic weight loss attempts-even in this subgroup-which might not benefit from reducing body weight to the same extent as patients with unhealthy obesity. Metabolically healthy obesity represents a model to study mechanisms linking obesity to cardiometabolic complications. Metabolically healthy obesity should not be considered a safe condition, which does not require obesity treatment, but may guide decision-making for a personalized and risk-stratified obesity treatment.

Metabolically Healthy Obesity.

Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial.

Maria Kabisch

Papers

Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial.