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Expert Opinion on Pharmacotherapy Apr 2024Semaglutide, a glucagon-like peptide-1 receptor agonist, is associated with significant weight loss, yet its impact on lean body mass remains insufficiently understood.... (Review)
Review
INTRODUCTION
Semaglutide, a glucagon-like peptide-1 receptor agonist, is associated with significant weight loss, yet its impact on lean body mass remains insufficiently understood. This review investigates the effect of semaglutide on lean mass in the context of obesity management.
METHODOLOGY
This study investigates through different databases (PubMed, Elsevier, and Google Scholar) from 2016 for randomized control trials (RCTs) or observational studies that assessed the use of semaglutide in overweight or obese patients, regardless of whether they have type 2 diabetes or not. The studies compared semaglutide to a placebo or alternative medications.
RESULTS
Six studies with 1,541 overweight or obese adults were included, and significant weight reductions were observed primarily due to fat mass loss. While the lean mass remained stable in some cases, notable reductions ranging from almost 0% to 40% of total weight reduction were observed in others. Noteworthy decreases in lean mass were particularly evident in larger trials, yet the proportion of lean mass relative to total body mass increased, suggesting a positive overall outcome.
CONCLUSION
Semaglutide displays potential for weight loss primarily through fat mass reduction. However, concerns arise from notable reductions in lean mass, especially in trials with a larger number of patients.
Topics: Humans; Glucagon-Like Peptides; Weight Loss; Obesity; Randomized Controlled Trials as Topic; Overweight; Glucagon-Like Peptide-1 Receptor; Anti-Obesity Agents; Diabetes Mellitus, Type 2
PubMed: 38629387
DOI: 10.1080/14656566.2024.2343092 -
BMJ (Clinical Research Ed.) Apr 2024To investigate whether use of glucagon-like peptide 1 (GLP1) receptor agonists is associated with increased risk of thyroid cancer.
OBJECTIVE
To investigate whether use of glucagon-like peptide 1 (GLP1) receptor agonists is associated with increased risk of thyroid cancer.
DESIGN
Scandinavian cohort study.
SETTING
Denmark, Norway, and Sweden, 2007-21.
PARTICIPANTS
Patients who started GLP1 receptor agonist treatment were compared with patients who started dipeptidyl peptidase 4 (DPP4) inhibitor treatment, and in an additional analysis, patients who started sodium-glucose cotransporter 2 (SGLT2) inhibitor treatment.
MAIN OUTCOME MEASURES
Thyroid cancer identified from nationwide cancer registers. An active-comparator new user study design was used to minimise risks of confounding and time related biases from using real world studies of drug effects. Cox regression was used to estimate hazard ratios, controlling for potential confounders with propensity score weighting.
RESULTS
The mean follow-up time was 3.9 years (standard deviation 3.5 years) in the GLP1 receptor agonist group and 5.4 years (standard deviation 3.5 years) in the DPP4 inhibitor group. 76 of 145 410 patients (incidence rate 1.33 events per 10 000 person years) treated with GLP1 receptor agonists and 184 of 291 667 patients (incidence rate 1.46 events per 10 000 person years) treated with DPP4 inhibitors developed thyroid cancer. GLP1 receptor agonist use was not associated with increased risk of thyroid cancer (hazard ratio 0.93, 95% confidence interval 0.66 to 1.31; rate difference -0.13, 95% confidence interval -0.61 to 0.36 events per 10 000 person years). The hazard ratio for medullary thyroid cancer was 1.19 (0.37 to 3.86). In the additional analysis comparing the GLP1 receptor agonist group with the SGLT2 inhibitor group, the hazard ratio for thyroid cancer was 1.16 (0.65 to 2.05).
CONCLUSIONS
In this large cohort study using nationwide data from three countries, GLP1 receptor agonist use was not associated with a substantially increased risk of thyroid cancer over a mean follow-up of 3.9 years. In the main analysis comparing GLP1 receptor agonists with DPP4 inhibitors, the upper limit of the confidence interval was consistent with no more than a 31% increase in relative risk.
Topics: Humans; Thyroid Neoplasms; Glucagon-Like Peptide-1 Receptor; Male; Female; Middle Aged; Dipeptidyl-Peptidase IV Inhibitors; Aged; Denmark; Incidence; Sodium-Glucose Transporter 2 Inhibitors; Cohort Studies; Adult; Sweden; Hypoglycemic Agents; Risk Factors; Diabetes Mellitus, Type 2; Norway; Scandinavian and Nordic Countries; Proportional Hazards Models
PubMed: 38683947
DOI: 10.1136/bmj-2023-078225 -
Cytokine & Growth Factor Reviews Feb 2024CD40 is a member of the tumor necrosis factor (TNF) receptor superfamily of receptors expressed on a variety of cell types. The CD40-CD40L interaction gives rise to many... (Review)
Review
CD40 is a member of the tumor necrosis factor (TNF) receptor superfamily of receptors expressed on a variety of cell types. The CD40-CD40L interaction gives rise to many immune events, including the licensing of dendritic cells to activate CD8 effector T cells, as well as the facilitation of B cell activation, proliferation, and differentiation. In malignant cells, the expression of CD40 varies among cancer types, mediating cellular proliferation, apoptosis, survival and the secretion of cytokines and chemokines. Agonistic human anti-CD40 antibodies are emerging as an option for cancer treatment, and early-phase clinical trials explored its monotherapy or combination with radiotherapy, chemotherapy, immune checkpoint blockade, and other immunomodulatory approaches. In this review, we present the current understanding of the mechanism of action for CD40, along with results from the clinical development of agonistic human CD40 antibodies in cancer treatment (selicrelumab, CDX-1140, APX005M, mitazalimab, 2141-V11, SEA-CD40, LVGN7409, and bispecific antibodies). This review also examines the safety profile of CD40 agonists in both preclinical and clinical settings, highlighting optimized dosage levels, potential adverse effects, and strategies to mitigate them.
Topics: Humans; CD40 Antigens; CD40 Ligand; Neoplasms; T-Lymphocytes; Cytokines
PubMed: 38102001
DOI: 10.1016/j.cytogfr.2023.11.002 -
Dietary Exposure and Risk Assessment of Beta-Agonist Residues in Commercial Beef and Pork in Taiwan.Foods (Basel, Switzerland) Nov 2023Beta-agonists (β-agonists) in meat products in one's diet raise concerns about the possibility of foodborne illness. It may also lead to discomfort, such as headaches...
Beta-agonists (β-agonists) in meat products in one's diet raise concerns about the possibility of foodborne illness. It may also lead to discomfort, such as headaches and occasional irregular heartbeats, which might be linked to a heightened concern for cardiovascular issues. Taiwan's high demand for meat and reliance on imported meat products from certain countries where β-agonists are permitted has raised concerns. Recent import border checks and monitoring of meat products in the market have revealed the concentration of non-compliance with β-agonist residue regulations, which is ten ppb. This study aims to analyze the concentration of β-agonist residues in meat products sold in Taiwan and assess the current levels of exposure and dietary risk for consumers. The study analyzed 1415 samples of domestically produced and imported livestock products from supermarkets, traditional markets, and bulk stores in New Taipei City between 2019 and 2023. The samples were analyzed using the method for detecting 21 β-agonists based on the Taiwan Food and Drug Administration's specifications. Estimated daily intake (EDI) of β-agonists for different age groups and the target hazard quotient (THQ) were used to assess dietary exposure and risk. The results showed that all 1415 samples were compliant with regulations. Among them, 43 beef samples showed residues of ractopamine originating from the United States, with residue concentrations ranging from 1 to 10 μg/kg and an average residue concentration of 3.3 ± 1.9 μg/kg. Under average consumption, the highest EDI for the exposed population was observed in the 6-12 age group, with values of 0.1469 μg/kg/day, 0.0734 μg/kg/day, and 0.0242 μg/kg/day for the three residue concentrations (maximum detected residue, maximum allowable residue, and average detected residue, respectively). The THQs for ractopamine in imported beef samples were all less than 1, indicating no health hazards at the current intake levels of each age group and the residue concentrations in commercially available beef. Despite the findings, traders need to acknowledge regulatory variations between Taiwan and exporting countries when importing meat products. Traders should provide inspection reports to monitor β-agonist residue levels in imports or explore sourcing beef from countries with β-agonist bans.
PubMed: 38002110
DOI: 10.3390/foods12224052 -
Hypertension Research : Official... Aug 2023Diabetes and hypertension often coexist, with about half of patients with diabetes also having hypertension. The risk of cardiovascular disease increases by three to... (Review)
Review
Diabetes and hypertension often coexist, with about half of patients with diabetes also having hypertension. The risk of cardiovascular disease increases by three to six-fold with the coexistence of diabetes and hypertension; therefore, the management of blood pressure to prevent cardiovascular disease is a particularly important issue in patients with diabetes. Clinical trial findings have resulted in recommendations to control blood pressure to <130/80 mmHg in Japanese patients with diabetes. However, the target blood pressure and selection of anti-hypertensive medications should vary depending on the duration of diabetes and comorbidities, and guidelines and clinical trial results should be interpreted flexibly to provide anti-hypertensive treatment tailored to individual patients. In recent years, a number of drugs have emerged that have significant cardio-renal protective effects in patients with diabetes, and a typical example is sodium-glucose cotransporter 2 inhibitor (SGLT2i), glucagon-like peptide-1 receptor agonist (GLP-1RA), and nonsteroidal mineralocorticoid receptor antagonist, finerenone. They have also shown modest but significant blood pressure-lowering effects. In the future, beyond considering the thresholds for how far to lower blood pressure, blood pressure management in patients with diabetes will require understanding the additive cardioprotective value of drugs aimed at lowering blood pressure and the quality of blood pressure lowering. Clinical questions of blood pressure lowering in patients with diabetes GLP-1RA, glucagon-like peptide-1 receptor agonist; SGLT2i, sodium-glucose cotransporter 2 inhibitor.
Topics: Humans; Diabetes Mellitus, Type 2; Sodium-Glucose Transporter 2 Inhibitors; Hypoglycemic Agents; Glucagon-Like Peptide-1 Receptor; Cardiovascular Diseases; Antihypertensive Agents; Hypertension; Glucose; Sodium
PubMed: 37258623
DOI: 10.1038/s41440-023-01324-9 -
Current Opinion in Cardiology Nov 2023Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for the management of type 2 diabetes (T2D) and obesity, and some are recommended for cardiorenal risk... (Review)
Review
Glucagon-like peptide-1/glucose-dependent insulinotropic polypeptide receptor co-agonists for cardioprotection, type 2 diabetes and obesity: a review of mechanisms and clinical data.
PURPOSE OF REVIEW
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for the management of type 2 diabetes (T2D) and obesity, and some are recommended for cardiorenal risk reduction in T2D. To enhance the benefits with GLP-RA mono-agonist therapy, GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor co-agonists are in development to capitalize on the synergism of GLP-1 and GIP agonism. We review the mechanisms of action and clinical data for GLP-1/GIP receptor co-agonists in T2D and obesity and their potential role in cardiovascular protection.
RECENT FINDINGS
Tirzepatide, a first-in-class unimolecular GLP-1/GIP receptor co-agonist, is approved for T2D and is awaiting approval for obesity management. Phase 3 trials in T2D cohorts revealed significant reductions in glycemia and body weight and superiority compared with GLP-1R mono-agonism with semaglutide. Tirzepatide has demonstrated significant body weight reductions in individuals with obesity but not diabetes. It enhances lipid metabolism, reduces blood pressure, and lowers liver fat content. Pooled phase 2/3 data showed cardiovascular safety in T2D while a post hoc analysis suggested tirzepatide slows the decline of kidney function in T2D.
SUMMARY
GLP-1/GIP receptor co-agonists are a novel addition to the diabetes and obesity armamentarium. The cardiorenal-metabolic benefits position them as promising multiprong tools for metabolically complex individuals with chronic vascular complications.
Topics: Humans; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Receptors, Gastrointestinal Hormone; Obesity
PubMed: 37792556
DOI: 10.1097/HCO.0000000000001084 -
Proceedings of the National Academy of... Apr 2024G protein-coupled receptors (GPCRs) transduce the effects of many neuromodulators including dopamine, serotonin, epinephrine, acetylcholine, and opioids. The...
G protein-coupled receptors (GPCRs) transduce the effects of many neuromodulators including dopamine, serotonin, epinephrine, acetylcholine, and opioids. The localization of synthetic or endogenous GPCR agonists impacts their action on specific neuronal pathways. In this paper, we show a series of single-protein chain integrator sensors that are highly modular and could potentially be used to determine GPCR agonist localization across the brain. We previously engineered integrator sensors for the mu- and kappa-opioid receptor agonists called M- and K-Single-chain Protein-based Opioid Transmission Indicator Tool (SPOTIT), respectively. Here, we engineered red versions of the SPOTIT sensors for multiplexed imaging of GPCR agonists. We also modified SPOTIT to create an integrator sensor design platform called SPOTIT for all GPCRs (SPOTall). We used the SPOTall platform to engineer sensors for the beta 2-adrenergic receptor (B2AR), the dopamine receptor D1, and the cholinergic receptor muscarinic 2 agonists. Finally, we demonstrated the application of M-SPOTIT and B2AR-SPOTall in detecting exogenously administered morphine, isoproterenol, and epinephrine in the mouse brain via locally injected viruses. The SPOTIT and SPOTall sensor design platform has the potential for unbiased agonist detection of many synthetic and endogenous neuromodulators across the brain.
Topics: Animals; Receptors, G-Protein-Coupled; Humans; Mice; HEK293 Cells; Receptors, Dopamine D1; Receptors, Adrenergic, beta-2; Receptor, Muscarinic M2; Isoproterenol; Receptors, Opioid, mu; Morphine; Brain; Receptors, Opioid, kappa; Biosensing Techniques
PubMed: 38648487
DOI: 10.1073/pnas.2307090121 -
British Journal of Pharmacology May 2024GPR84 was first identified as an open reading frame encoding an orphan Class A G protein coupled receptor in 2001. Gpr84 mRNA is expressed in a limited number of cell... (Review)
Review
GPR84 was first identified as an open reading frame encoding an orphan Class A G protein coupled receptor in 2001. Gpr84 mRNA is expressed in a limited number of cell types with the highest levels of expression being in innate immune cells, M1 polarised macrophages and neutrophils. The first reported ligands for this receptor were medium chain fatty acids with chain lengths between 9 and 12 carbons. Subsequently, a series of synthetic agonists that signal via the GPR84 receptor were identified. Radioligand binding assays and molecular modelling with site-directed mutagenesis suggest the presence of three ligand binding sites on the receptor, but the physiological agonist(s) of the receptor remain unidentified. Here, we review the effects of GPR84 agonists on innate immune cells following a series of chemical discoveries since 2001. The development of highly biased agonists has helped to probe receptor function in vitro, and the remaining challenge is to follow the effects of biased signalling to the physiological functions of innate immune cell types. LINKED ARTICLES: This article is part of a themed issue GPR84 Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.10/issuetoc.
Topics: Receptors, G-Protein-Coupled; Signal Transduction; Macrophages; Ligands; Phagocytosis
PubMed: 38148720
DOI: 10.1111/bph.16310 -
American Journal of Physiology.... Nov 2023Dual amylin and calcitonin receptor agonists (DACRAs) are effective treatments for obesity and type 2 diabetes (T2D). They provide beneficial effects on body weight,...
Dual amylin and calcitonin receptor agonists (DACRAs) are effective treatments for obesity and type 2 diabetes (T2D). They provide beneficial effects on body weight, glucose control, and insulin action. However, whether DACRAs protect against diabetes-related kidney damage remains unknown. We characterize the potential of long-acting DACRAs (KBP-A, Key Bioscience Peptide-A) as a treatment for T2D-related pathological alterations of the kidney extracellular matrix (ECM) in Zucker diabetic fatty rats (ZDF). We examined levels of endotrophin (profibrotic signaling molecule reflecting collagen type VI formation) and tumstatin (matrikine derived from collagen type IVα3) in serum and evaluated kidney morphology and collagen deposition in the kidneys. We included a study in obese Sprague-Dawley rats to further investigate the impact of KBP-A on ECM biomarkers. In ZDF vehicles, levels of endotrophin and tumstatin increased, suggesting disease progression along with an increase in blood glucose levels. These rats also displayed damage to their kidneys, which was evident from the presence of collagen formation in the medullary region of the kidney. Interestingly, KBP-A treatment attenuated these increases, resulting in significantly lower levels of endotrophin and tumstatin than the vehicle. Levels of endotrophin and tumstatin were unchanged in obese Sprague-Dawley rats, supporting the relation to diabetes-related kidney complications. Furthermore, KBP-A treatment normalized collagen deposition in the kidney while improving glucose control. These studies confirm the beneficial effects of DACRAs on biomarkers associated with kidney fibrosis. Moreover, these antifibrotic effects are likely associated with improved glucose control, highlighting KBP-A as a promising treatment of T2D and its related late complications. These studies describe the beneficial effects of using a dual amylin and calcitonin receptor agonist (DACRA) for diabetes-related kidney complications. DACRA treatment reduced levels of serological biomarkers associated with kidney fibrosis. These reductions were further reflected by reduced collagen expression in diabetic kidneys. In general, these results validate the use of serological biomarkers while demonstrating the potential effect of DACRAs in treating diabetes-related long-term complications.
Topics: Animals; Rats; Amylin Receptor Agonists; Blood Glucose; Collagen; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Fibrosis; Islet Amyloid Polypeptide; Kidney; Obesity; Rats, Sprague-Dawley; Rats, Zucker; Receptors, Calcitonin
PubMed: 37792041
DOI: 10.1152/ajpendo.00245.2023 -
Peptides Mar 2024Options for the treatment of type 2 diabetes mellitus (T2DM) and obesity have recently been expanded by the results of several large clinical trials with incretin-based...
Options for the treatment of type 2 diabetes mellitus (T2DM) and obesity have recently been expanded by the results of several large clinical trials with incretin-based peptide therapies. Most of these studies have been conducted with the glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide, which is available as a once weekly subcutaneous injection and once daily tablet, and the once weekly injected dual agonist tirzepatide, which interacts with receptors for GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). In individuals with T2DM these therapies have achieved reductions of glycated haemoglobin (HbA1c) by > 2% and lowered body weight by > 10%. In some studies, these agents tested in non-diabetic, obese individuals at much higher doses have lowered body weight by > 15%. Emerging evidence suggests these agents can also offer cardio-protective and potentially reno-protective effects. Other incretin-based peptide therapies in early clinical development, notably a triple GLP-1/GIP/glucagon receptor agonist (retatrutide) and a combination of semaglutide with the amylin analogue cagrilintide (CagriSema), have shown strong efficacy. Although incretin therapies can incur adverse gastrointestinal effects these are for most patients mild-to-moderate and transient but result in cessation of treatment in some cases. Thus, the efficacy of new incretin-based peptide therapies is enhancing the opportunity to control body weight and blood glucose and improve the treatment of T2DM and obesity.
Topics: Humans; Diabetes Mellitus, Type 2; Incretins; Gastric Inhibitory Polypeptide; Obesity; Glucagon-Like Peptide 1; Body Weight; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents
PubMed: 38184193
DOI: 10.1016/j.peptides.2024.171149