Drug Topics’ Post

GLP-1 receptor agonist therapies have been used mainly to treat type 2 diabetes mellitus and obesity. More recently, new medications (e.g., semaglutide- “Ozempic® and Wegovy®”) have become popular because of their efficacy in reducing body weight in obese patients with and without diabetes. At present, there are seven GLP-1 receptor agonists approved as medications for type 2 diabetes, cardiovascular disease, and obesity: albiglutide, dulaglutide, exenatide, extended-release exenatide, liraglutide, lixisenatide, and semaglutide. The latter was the most recent, receiving FDA approval in 2019. In 2021, the FDA approved high-dose semaglutide injections for chronic weight management. GLP-1 receptor agonist pharmacotherapies are being evaluated for other clinical uses . For example, they are promising neuroprotective agents, preventing neuroinflammation and supporting cognitive improvement. Herein, the latest information about how GLP-1 interacts with the human brain.

Beyond the pancreas: contrasting cardiometabolic actions of GIP and GLP1 Rola Hammoud 1, Daniel J Drucker 2 Affiliations expand PMID: 36509857 DOI: 10.1038/s41574-022-00783-3 Abstract Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP1) exhibit incretin activity, meaning that they potentiate glucose-dependent insulin secretion. The emergence of GIP receptor (GIPR)-GLP1 receptor (GLP1R) co-agonists has fostered growing interest in the actions of GIP and GLP1 in metabolically relevant tissues. Here, we update concepts of how these hormones act beyond the pancreas. The actions of GIP and GLP1 on liver, muscle and adipose tissue, in the control of glucose and lipid homeostasis, are discussed in the context of plausible mechanisms of action. Both the GIPR and GLP1R are expressed in the central nervous system, wherein receptor activation produces anorectic effects enabling weight loss. In preclinical studies, GIP and GLP1 reduce atherosclerosis. Furthermore, GIPR and GLP1R are expressed within the heart and immune system, and GLP1R within the kidney, revealing putative mechanisms linking GIP and GLP1R agonism to cardiorenal protection. We interpret the clinical and mechanistic data obtained for different agents that enable weight loss and glucose control for the treatment of obesity and type 2 diabetes mellitus, respectively, by activating or blocking GIPR signalling, including the GIPR-GLP1R co-agonist tirzepatide, as well as the GIPR antagonist-GLP1R agonist AMG-133. Collectively, we update translational concepts of GIP and GLP1 action, while highlighting gaps, areas of uncertainty and controversies meriting ongoing investigation

Functions of Neprilysin, what happens if its level goes down? The impact of NARI, 5 years down the line. Neprilysin is an endopeptidase that cleaves a variety of peptides such as natriuretic peptides, 1. bradykinin, 2. adrenomedullin, 3. substance P, 4. angiotensin I and II, and 5. endothelin. 6. ANP, BNP, CNP 7. Neprilysin removes ß amyloid from brain, reducing risk of dementia. 8. Endothelin levels are higher in pulmonary hypertension, 9. AT-2 level control aldosterone and posterior pituitary hormones. 10. It has a broad role in cardiovascular, renal, pulmonary, gastrointestinal, endocrine, and neurologic functions. However, because neprilysin breaks down angiotensin II, inhibiting neprilysin will accumulate angiotensin II. For this reason, a neprilysin inhibitor cannot be used alone; it must always be combined with an ARB to block the effect of the excess angiotensin II. Breaks Down natriuretics This action of neprilysin is associated with increased natriuresis, diuresis, and systemic vasodilation, since these peptides have been shown to have potent diuretic, natriuretic, and vasodilating effects Neprilysin also metabolizes natriuretic peptides. However, despite the potential therapeutic benefit of increased natriuretic peptide and bradykinin levels, neprilysin inhibitor therapy has only modest efficacy in essential hypertension and heart failure Patients receiving ARNI had significantly lower rates of cardiovascular death than ACEI and ARB users [HR for ARNI vs. ACEI: 0.37, (95%CI, 0.18–0.79), HR for ARNI vs. ARB: 0.41. Cardiovascular death contributed most to the primary outcome benefits. The mechanism for the increased risk in angioedema is likely attributable to an increase in circulating bradykinins caused by inhibition of both ACE and neprilysin. ACEI/ARB group overall and across the eGFR spectrum, including in advanced chronic kidney disease. Angiotensin receptor blockers inhibit the renin-angiotensin-aldosterone system. Sacubitril/valsartan, a first-in-class angiotensin receptor-neprilysin inhibitor (ARNI), has been shown to improve cardiovascu- lar outcomes in HFrEF and delay the progression of chronic kidney disease (CKD) in patients with HFrEF. The angiotensin receptor neprilysin inhibitor sacubitril/valsartan has been shown to be superior to ACE inhibition for reduction of HF hospitalization or cardiovascular death in patients with HF with reduced ejection fraction (HFrEF),5 among whom sacubitril/valsartan has also been associated with greater improvements

An interesting and surprising finding in a small study with semaglutide in Type 1 diabetes. Between 2020 and 2022 UB's Clinical Research Center in the Division of Endocrinology studied 10 patients that were diagnosed with Type 1 diabetes in the past 3-6 months with a mean HbA1c level of 11. The patients were started on a low dose of semaglutide while they were also taking meal-time bolus insulin and basal (background) insulin. Semaglutide dosing was gradually increased while mealtime insulin was reduced to avoid hypoglycemia. Within 3 months, all of the mealtime insulin were discontinued for all patients and within 6 months basal insulin was eliminated in 7 of the 10 patients. This was maintained until the end of 12-month follow-up. Mean HbA1c fell to 5.9 at 6 months and to 5.7 at 12 months. It is unknown whether this is limited to newly diagnosed Type 1 diabetes (due to possible available reserve of insulin in the beta cells of their pancreas) or all Type 1 diabetics. #type1diabetes #semaglutide

GLP-1 receptor agonists surged in 2023, with a 352% rise in prescriptions. With these treatments reshaping the obesity and diabetes landscape, hepatology experts IHEP (International Hepatology Education Program) ask what the impact could be for metabolic dysfunction-associated steatohepatitis. Learn their insights and find out how the treatment landscape is changing: https://bit.ly/3vLfgJM #AvalereHealth #Hepatology #MedicalInnovation #MASH #NASH #GLP1

Testosterone induces erythrocytosis via increased erythropoietin and suppressed hepcidin: evidence for a new erythropoietin/hemoglobin set point Eric Bachman 1, Thomas G Travison 2, Shehzad Basaria 3, Maithili N Davda 2, Wen Guo 2, Michelle Li 2, John Connor Westfall 3, Harold Bae 3, Victor Gordeuk 2, Shalender Bhasin 4 Affiliations expand PMID: 24158761 PMCID: PMC4022090 DOI: 10.1093/gerona/glt154 Abstract Background: The mechanisms by which testosterone increases hemoglobin and hematocrit remain unclear. Methods: We assessed the hormonal and hematologic responses to testosterone administration in a clinical trial in which older men with mobility limitation were randomized to either placebo or testosterone gel daily for 6 months. Results: The 7%-10% increase in hemoglobin and hematocrit, respectively, with testosterone administration was associated with significantly increased erythropoietin (EPO) levels and decreased ferritin and hepcidin levels at 1 and 3 months. At 6 months, EPO and hepcidin levels returned toward baseline in spite of continued testosterone administration, but EPO levels remained nonsuppressed even though elevated hemoglobin and hematocrit higher than at baseline, suggesting a new set point. Consistent with increased iron utilization, soluble transferrin receptor (sTR) levels and ratio of sTR/log ferritin increased significantly in testosterone-treated men. Hormonal and hematologic responses were similar in anemic participants. The majority of testosterone-treated anemic participants increased their hemoglobin into normal range. Conclusions: Testosterone-induced increase in hemoglobin and hematocrit is associated with stimulation of EPO and reduced ferritin and hepcidin concentrations. We propose that testosterone stimulates erythropoiesis by stimulating EPO and recalibrating the set point of EPO in relation to hemoglobin and by increasing iron utilization for erythropoiesis. Keywords: Erythropoietin; Ferritin.; Hepcidin; Testosterone.

GLP-1 receptor agonists surged in 2023, with a 352% rise in prescriptions. With these treatments reshaping the obesity and diabetes landscape, hepatology experts IHEP (International Hepatology Education Program) ask what the impact could be for metabolic dysfunction-associated steatohepatitis. Learn their insights and find out how the treatment landscape is changing: https://bit.ly/3vLfgJM #AvalereHealth #Hepatology #MedicalInnovation #MASH #NASH #GLP1

GLP-1 receptor agonists surged in 2023, with a 352% rise in prescriptions. With these treatments reshaping the obesity and diabetes landscape, hepatology experts IHEP (International Hepatology Education Program) ask what the impact could be for metabolic dysfunction-associated steatohepatitis. Learn their insights and find out how the treatment landscape is changing: https://bit.ly/3vLfgJM #AvalereHealth #Hepatology #MedicalInnovation #MASH #NASH #GLP1

Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future The balance between continual Aβ generation and efficient clearance is important for Aβ homeostasis to prevent its toxic aggregation into misfolded assemblies.19 Similar to other brain metabolites, Aβ clearance depends on different pathways including enzyme degradation, crossing the blood–brain barrier (BBB), interstitial fluid (ISF) bulk-flow and CSF absorption.19,20 The BBB is composed of endothelial cells connected by tight junctions to form a selectively permeable system.21 The transport of soluble Aβ across brain endothelial cells to the peripheral circulation is mainly via low density lipoprotein receptor-related protein 1(LRP-1) and ABC transporter sub-family A and B member 1 (ABCA1 and ABCB1),22,23 while receptors for advanced glycosylation end-products (RAGE) is responsible for circulating Aβ entering into the brain.24 It has been identified that the expressions of the two blood efflux transporters LRP1 and ABCB1 were reduced during AD, whereas the expression of the blood influx transporter RAGE is elevated.21,25 The perivascular drainage pathway plays a vital role in ISF bulk-flow clearance of Aβ.26 Failure of perivascular drainage of Aβ altered Aβ homeostasis associated with synaptic dysfunction and cognitive impairment, leading to the development of AD.27 CSF absorption clearance of Aβ depends on factors including CSF production by the choroid plexus, integrity of the blood-CSF barrier, relevant transporters and CSF lymphatic absorption.28 In AD, the structural integrity of the blood-CSF barrier is destroyed, resulting in aberrant Aβ clearance.29 Enzymatic pathways for Aβ degradation include the zinc metalloendopeptidases, insulin-degrading enzyme (IDE), matrix metalloproteinase (MMPs), angiotensin converting enzyme (ACE), and endothelin-converting enzyme (ECE), serine proteases, cystein proteases, and kallikrein-related peptidase 7.30,31 In the hippocampus of AD patients, the enzymes IDE, ACE and NEP had decreased activity.30 AD model mice also showed the impaired Aβ degradation system.21,32 In GWAS, many genetic risk factors for AD (e.g. RIN3, CLU and PTK2B) are linked to Aβ degradation.33,34

Safety and efficacy of #faecalmicrobiota transplantation in patients with mild to moderate #Parkinson's disease (GUT-PARFECT): a double-blind, placebo-controlled, randomised, phase 2 trial https://lnkd.in/eckQ-P8f The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication https://lnkd.in/eU_rwJp4 The Potential Role of Fecal Microbiota Transplantation in Parkinson’s Disease: A Systematic Literature Review https://lnkd.in/eU_rwJp4