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Safety-focused summary of GLP-1 receptor agonists in diabetes, obesity, and beyond

Safety-focused summary of GLP-1 receptor agonists in diabetes, obesity, and beyond


In a recent review published in the journal Diabetes Care, Daniel J. Drucker of Lunenfeld-Tanenbaum Research Institute, University of Toronto, evaluated the efficacy and safety of glucagon-like peptide 1 receptor agonists (GLP-1RA) for type 2 diabetes and obesity and explored their potential for new indications.

GLP-1 receptor, inactivated and surrounded by an agonist (semaglutide, red) and G-proteins. Image Credit: Juan Gaertner / Shutterstock. Review Article: Efficacy and Safety of GLP-1 Medicines for Type 2 Diabetes and Obesity

Background 

More than 19 years after the first GLP1RA was introduced for type 2 diabetes and 10 years after its approval for obesity, innovations are expanding the use of GLP-1 medicines for metabolic disorders. New developments include orally administered GLP1RA, unimolecular glucagon receptor (GCGR)-GLP1R coagonists like survodutide, and GCGR- Gastric Inhibitory Polypeptide Receptor (GIPR)-GLP1R triagonists like retatrutide. Additionally, new indications such as addiction, peripheral vascular disease, type 1 diabetes, metabolic liver disease, and neurodegenerative disorders are under clinical evaluation. Further research is needed to explore the full therapeutic potential and long-term safety of GLP-1RAs across a broader range of metabolic and neurodegenerative disorders.

Overview of modern GLP-1–based medicines and type 2 diabetes

GLP1RAs like exenatide, liraglutide, semaglutide, and tirzepatide are widely used for type 2 diabetes and obesity, offering significant benefits in glucose control, weight loss, and cardiovascular health. They reduce hemoglobin A1c (HbA1c), weight, major cardiovascular events, and renal decline. New GLP-1RAs and combinations, including oral options and multi-agonists like retatrutide and maritide, show promise. Safety concerns include gastrointestinal issues, potential aspiration risk, and rare anaphylactic reactions. Ongoing research explores their broader therapeutic potential, including in metabolic liver disease and neurodegenerative disorders, aiming to improve personalized medicine approaches for cardiometabolic health further.

GLP-1 medicines and the treatment of obesity

GLP-1RAs led to weight loss investigations, with liraglutide 3 mg daily approved for weight loss in 2014, followed by semaglutide 2.4 mg weekly in 2021, and tirzepatide in 2023. The Semaglutide Treatment Effect in People with Obesity (STEP) trials showed 12%-15% weight loss with semaglutide, less in type 2 diabetes patients. Semaglutide 2.4 mg weekly, assessed in 17,604 individuals with body mass index (BMI) ≥27 kg/m² and cardiovascular disease (CVD), resulted in 8.51% weight loss at 104 weeks and a 20% reduction in nonfatal Myocardial Infarction (MI), stroke, and cardiovascular death. Tirzepatide showed up to 20% weight loss in obese individuals and significant HbA 1c reduction in type 2 diabetes patients. The A Study of Tirzepatide on the Reduction on Morbidity and Mortality in Adults with Obesity (SURMOUNT-MMO) trial assesses tirzepatide’s impact on mortality and cardiovascular events in overweight or obese individuals.

Investigational GLP-1 medicines in the clinic

Late-stage investigational GLP-1 medicines for type 2 diabetes and obesity include new molecules like retatrutide and orforglipron, showing potential differentiation from semaglutide and tirzepatide through better tolerability, greater weight loss, Hb A1c reduction, and targeted outcomes. Retatrutide activates GIPR and GCGR, achieving over 20% weight loss in phase 2 trials. Orforglipron, an oral GLP-1RA, demonstrated significant Hb A1c reduction and weight loss. GLP-1 medicines incorporating GIPR blockade, like maritide, also show promise. AMG-133 (maridebart cafraglutide) produced substantial weight loss in phase 2 trials. These advances have renewed interest in small-molecule oral GLP-1RAs.

Metabolic liver disease

Real-world registry data from Sweden, Denmark, and Norway (2007–2020) showed a reduced incidence of acute liver events in individuals with type 2 diabetes initiating GLP-1RA therapy compared to dipeptidyl peptidase 4 (DPP-4) inhibitors. Clinical trials have also demonstrated the therapeutic utility of GLP-1RAs in metabolic liver disease, with liraglutide and semaglutide showing improvements in steatohepatitis and fibrosis.

Special considerations: children and adolescents

Several GLP-1RAs, including liraglutide and dulaglutide, are approved for treating children and adolescents with type 2 diabetes. Studies have shown reductions in Hb A1c and weight loss in this population. Semaglutide 2.4 mg weekly demonstrated significant weight loss in adolescents with obesity in the STEP TEENS trial.

Tirzepatide is being studied in the Study of Tirzepatide in Pediatric Participants with Type 2 Diabetes (SURPASS-PEDS) trial for children and adolescents with type 2 diabetes and the SURPASS-2 trial for those with obesity or overweight and related comorbidities.

Adverse events linked to GLP-1 medicines

The most common side effects of GLP-1RAs are gastrointestinal, including nausea, diarrhea, constipation, and vomiting. These usually occur during dose initiation and escalation and generally subside over time. GLP-1RAs may also delay gastric emptying, potentially leading to retained gastric contents and aspiration risk. To mitigate these risks, professional societies recommend discontinuing once-weekly GLP-1RAs at least one week prior to surgery.

Risks related to anesthesia, aspiration, and retained gastric contents

Reports of retained gastric contents and aspiration risk have increased with the widespread use of GLP-1RAs. Studies have shown a higher prevalence of residual gastric contents in GLP-1RA users, prompting professional societies to issue perioperative management guidelines.

Allergic and anaphylactic reactions

Antidrug antibodies (ADA) are reported with all injectable GLP-1RAs but generally do not impact drug efficacy. Anaphylactic reactions are rare but have been observed with all GLP-1 medicines. Exendin-based GLP-1RAs, such as exenatide, may have higher immunogenicity. ADA rates with semaglutide are low, while tirzepatide showed ADA in a minority of patients without affecting its pharmacokinetics or efficacy.

Conclusions 

To summarize, more than 19 years after exenatide’s approval, newer once-weekly GLP-1 medicines like semaglutide and tirzepatide have shown long-term efficacy and safety for type 2 diabetes and obesity. These medicines reduce Major Adverse Cardiovascular Events (MACE), cardiovascular death, and chronic kidney disease rates. While extensive data reassure their use, more trials are needed, particularly for populations like children, older adults, and those with severe illness. Numerous new GLP-1 medicines are in development, requiring a thorough evaluation to ensure the benefits outweigh the risks. Investing in cost-effective manufacturing and equitable access is essential to maximize global health impact.





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