Genetic architecture of obesity and advances in precision pharmacotherapy: a comprehensive review.

Hypothalamic obesity (HO) is a rare, complex disorder characterized by disruption of brain pathways regulating energy intake, expenditure, autonomic function, and hormonal signaling. It occurs in rare monogenic obesity syndromes affecting central leptin-melanocortin pathways or can be acquired (aHO) as a consequence of hypothalamic injury due to a tumor (e.g., craniopharyngioma), its treatment, or trauma. In this narrative review, we focus on aHO. Damage to specific hypothalamic nuclei leads to hyperphagia, central insulin and leptin resistance, decreased sympathetic activity, reduced energy expenditure, and rapid weight gain. Traditional obesity treatments, including lifestyle interventions, often fail to achieve sustained weight loss in patients with aHO. Recent advances in pharmacotherapy show promise by targeting the distinct pathophysiology of aHO. Effective treatment requires personalized approaches due to the heterogeneity of hypothalamic dysfunction and associated comorbidities. Early intervention may improve outcomes, as rapid postoperative weight gain frequently occurs. Emerging therapies target mechanisms of disturbed energy homeostasis pathways. These agents include stimulants, incretin-based therapies (e.g., glucagon-like peptide-1 receptor agonists), insulin modulators, and melanocortin receptor agonists such as setmelanotide. While monotherapies often fail in long-term treatment, combination therapies hold potential to restore energy balance and reduce or eliminate the need for bariatric surgery. Future research should focus on identifying clinical and biomarker profiles of aHO subtypes and evaluating combination therapies. Although challenging, aHO is no longer untreatable. Patients should be referred and managed at specialized centers, with pharmacological treatment preferably conducted within research settings to optimize and personalize care, and to develop evidence-based protocols for this debilitating condition.

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome with increasing prevalence and substantial morbidity and mortality. Recent advances in pharmacotherapy have transformed its management. This review summarizes current evidence supporting the use of sodium–glucose cotransporter 2 inhibitors, non-steroidal mineralocorticoid receptor antagonists, and glucagon-like peptide-1 receptor agonists, alongside selected use of angiotensin receptor–neprilysin inhibitors. Emphasis is placed on early initiation of disease-modifying therapies, phenotypic tailoring, and comorbidity-targeted strategies, especially in obese and diabetic patients. Together, these approaches define a new era of guideline-directed, personalized care for patients with HFpEF.

21 - Diabetes mellitus

Recent advances in pharmacotherapy for dyspnea in COPD

Ulcerative colitis is a form of chronic inflammatory bowel disease (IBD) that produces inflammation and ulcers along the inside of the colon, which can interfere with the normal function of the colon. The disease typically starts to manifest in patients as young adults. Ulcerative colitis is an intermittent disease with periods of exacerbated symptoms, or flares, and periods that are relatively symptom-free. According to the Cohn’s and Colitis Foundation of America, several millions people suffer from ulcerative colitis worldwide. Current therapeutic approaches for ulcerative colitis are partially successful despites advances in GIT research. A significant proportion of patients with ulcerative colitis undergo colectomy. Nearly 50% patients do not achieve sustained remission, leading to impairment of physical and mental health, social life, employment issues and sexual activity. Budesonide is an oral, extended release synthetic corticosteroid that is recently approved for UC. Enteric-coated budesonide formulations resist gastric-acid degradation, delivering active drug to the small intestine and proximal colon. Budesonide is specifically indicated for the induction of remission in patients with active, mild to moderate ulcerative colitis. Budesonide has a high first-pass metabolism with minimal systemic absorption. This review describes recent advances in the pharmacotherapy of ulcerative colitis and outlines why future studies targeting sustained suppression of inflammation could have an enormous impact on the natural course of the disease. Ulcerative colitis needs intense therapy and it should be maintained until sustained remission and mucosal healing has been reached.

Introduction Recent advances in anti-diabetic medications and glucose monitoring have led to a paradigm shift in diabetes care. Newer anti-diabetic medications such as DPP-4 inhibitors, GLP-1 receptor agonists (GLP-1RAs), and SGLT2 inhibitors have enabled optimal glycemic control to be achieved without increasing the risk of hypoglycemia and weight gain. Treatment with GLP-1RAs and SGLT2 inhibitors has been demonstrated to improve cardiorenal outcomes, positioning these agents as the mainstay of treatment for patients with type 2 diabetes (T2DM). The development of these newer agents has also prompted a paradigm shift in the concept of T2DM, highlighting the importance of beta cell dysfunction in the pathophysiology of T2DM. Areas covered Recent advances in pharmacotherapy for diabetes are summarized with a focus on the role of incretin-based drugs and SGLT2 inhibitors. The importance of a paradigm shift from a glucose-centric to a beta cell-centric concept of T2DM is also discussed, given from an Asian perspective. Expert opinion Management of T2DM including lifestyle modification as well as pharmacotherapy should be focused on reducing beta cell workload, to preserve functional beta cell mass. A paradigm shift from a glucose-centric to a beta cell-centric concept of T2DM enhances the implementation of person-centered diabetes care.

Chronic heart failure (CHF) is frequently complicated by chronic kidney disease (CKD), a comorbidity that profoundly influences disease progression, therapeutic decision-making, and clinical outcomes. The management of CHF in patients with advanced CKD presents substantial challenges, often requiring dose adjustments or even discontinuation of standard therapies. Effective therapeutic strategies must prioritize cardiorenal protection during the early stages of disease progression. Recent advancements in pharmacotherapy, including angiotensin receptor-neprilysin inhibitors, sodium-glucose cotransporter 2 inhibitors, non-steroidal mineralocorticoid receptor antagonists, and glucagon-like peptide-1 receptor agonists, have demonstrated remarkable dual cardiorenal protective effects. These therapies not only reduce the risk of de novo heart failure in high-risk populations and improve clinical outcomes in CHF patients, but also slow the progression of renal dysfunction by targeting critical pathophysiological processes, such as glomerular hyperfiltration, inflammation, ischemia, and endothelial dysfunction. Although transient declines in estimated glomerular filtration rate may occur upon initiating these agents, renal function typically stabilizes over time, facilitating sustained clinical benefits, particularly in patients with diabetes mellitus, albuminuric CKD, and CHF. This review focuses on the latest advancements in heart failure pharmacotherapy, emphasizing the cardiorenal protective mechanisms and clinical efficacy of novel therapeutic agents. It underscores the importance of bridging knowledge gaps and personalizing therapy to enhance cardiorenal benefits avoiding adverse effects.

Obstructive sleep apnea (OSA) is a prevalent global health issue, with recent advances in pharmacotherapy expanding treatment options. Tirzepatide, a dual GLP-1 and GIP receptor agonist, has been newly approved by the FDA for managing moderate to severe OSA, following promising results from major randomized trials. Initially indicated for type 2 diabetes mellitus, Tirzepatide promotes glycemic control and weight loss through incretin-mediated insulin secretion and appetite suppression. As its use becomes more widespread, perioperative physicians and head-neck surgeons must be familiar with its pharmacokinetics and associated risks. Notably, delayed gastric emptying, a dose-dependent side effect, raises concerns of pulmonary aspiration during general anesthesia. Preoperative gastric ultrasound, diet modification, and individualized glycemic management are recommended strategies. Given the limited high-quality data, a multidisciplinary, institution-specific approach remains essential in managing patients on Tirzepatide in the perioperative setting.

Should preimplantation genetic testing for polygenic disease be offered to all – or none?

IntroductionWeight gain and obesity are important health problems associated with psychiatric disorders and/or with psychotropic drug treatments. There is a high inter-individual variability in the susceptibility to drug induced weight gain and/or other cardiometabolic disorders.ObjectivesTo study the genetic, clinical and environmental risk factors for weight gain and onset of metabolic syndrome during psychotropic treatment.MethodsAnalysis in PsyMetab, a large (n>3000) ongoing longitudinal prospective cohort study investigating cardiometabolic disorders in psychiatric patients.ResultsAside from well-known clinical risk factors for metabolic worsening (e.g. young age, first episode status, rapid weight gain during the first month of treatment and/or low initial BMI), we recently identified additional risk factors, such as the socio-economic status, a low status being associated with increased worsening of cardiometabolic parameters. Results from ongoing studies on the moderate dose dependencies of the metabolic effects of antipsychotics will be shown, as well as the clinical consequences. An epigenome-wide association study (EWAS) performed in 78 patients before and after one month of treatment (Dubath et al., submitted) and a genome-wide association study (GWAS) in 1924 patients (Sjaarda et al. submitted) will also be presented, as well as the use of polygenic risk scores to predict patients at risks for dyslipidemia (Delacretaz-Reymond et al., in preparation)ConclusionsMany factors contribute to the differences in weight gain and metabolic disorders induced by psychotropic drugs. The use of specific algorithms and/or polygenic risk scores can help to identify patients at risks. However, when starting a psychotropic drug at risk, a prospective monitoring of clinical (e.g. weight and blood pressure) and biochemical (fasting glucose, lipid levels) parameters is essential.Disclosure of InterestNone Declared

A genetic condition known as sickle cell disease (SCD) is marked by the abnormal production of haemoglobin, which results in the formation of sickle-shaped red blood cells. This can lead to vaso-occlusive events, causing a variety of clinical complications. While traditional management strategies have focused on symptom relief and supportive care, recent years have witnessed remarkable advancements in pharmacotherapeutic approaches targeting the underlying genetic and molecular mechanisms of SCD. The aim of this review article is to provide an in-depth analysis of the emerges trends and development in pharmacotherapeutic strategies for SCD, including gene therapy, gene editing, fetal hemoglobin induction, nitric oxide pathway modulation, adhesion molecule inhibition, and novel anti-sickling agents. It reviews innovative pharmacotherapeutic interventions, including gene editing technologies, novel drug targets, and advanced therapies, emphasizing their potential in alter the course of the illness, minimize complications, and enhance the quality lifespan for individuals with sickle cell disease. We also discuss the challenges, limitations, and future directions in the development and implementation of these strategies are addressed. Background: Sickle cell disease is a genetic hemoglobinopathy characterized by the production of abnormal hemoglobin S (HbS), which causes red blood cells to deform into a sickle shape. These sickled cells are prone to hemolysis, causing anemia, and they obstruct small blood vessels, leading to vaso-occlusive crises and resultant pain, organ damage, and increased mortality. The disease predominantly affects individuals of African, Mediterranean, Middle Eastern, and Indian ancestry, with millions of people worldwide suffering from its debilitating effects. The pathophysiology of SCD is intricate and involves a series of events initiated by the polymerization of deoxygenated HbS. This polymerization causes red blood cells to deform, adhere to the vascular endothelium, and subsequently trigger inflammation, oxidative stress, and activation of blood clotting pathway. These processes collectively contribute to the acute and chronic complications seen in SCD patients, including acute pain episodes, chronic pain, stroke, acute chest syndrome, and multi-organ damage. Historically, treatment options for SCD have been limited and focused primarily on symptom management and the prevention of complications. The mainstays of therapy have included blood transfusions, hydroxyurea, and, more recently, L-glutamine. Blood transfusions help decrease the proportion of sickled cells but come with risks such as iron overload and all immunization. Hydroxyurea, a chemotherapeutic agent, stimulate the production of fetal hemoglobin (HbF), which reduce HbS polymerization. However, its use is limited by side effects and variable patient response. In 2017, FDA approved L-glutamine which helps reduce oxidative stress but does not address all the underlying pathophysiological mechanisms of SCD. In recent years, significant advancements in our understanding of the molecular and cellular mechanisms underlying SCD have paved the way for novel therapeutic approaches. These advancements include gene therapy, novel pharmacologic agents targeting specific pathways involved in the disease process, and approaches aimed at modifying the genetic defect itself. The advent of these innovative therapies holds the promise of transforming SCD from a previously life-threatening illness to a now manageable chronic disease. This article aims to explore recent advances in pharmacotherapy for SCD, focusing on novel approaches that offer hope for more effective and comprehensive management of this challenging disorder. By examining the mechanisms, efficacy, and safety of these emerging treatments, we seek to highlight their potential to improve the standard of life and outcomes for those affected by SCD.

Urinary tract infections, including cystitis, acute pyelonephritis, and prostatitis, are among the most common diagnoses prompting antibiotic prescribing. The rise in antimicrobial resistance over the past decades has led to the increasing challenge of urinary tract infections because of multidrug-resistant and "difficult-to-treat resistance" among Gram-negative bacteria. Recent advances in pharmacotherapy and medical microbiology are modernizing how these urinary tract infections are treated. Advances in pharmacotherapy have included not only the development and approval of novel antibiotics, such as ceftazidime/avibactam, meropenem/vaborbactam, imipenem/relebactam, ceftolozane/tazobactam, cefiderocol, plazomicin, and glycylcyclines, but also the re-examination of the potential role of legacy antibiotics, including older aminoglycosides and tetracyclines. Recent advances in medical microbiology allow phenotypic and molecular mechanism of resistance testing, and thus antibiotic prescribing can be tailored to the mechanism of resistance in the infecting pathogen. Here, we provide a narrative review on the clinical and pre-clinical studies of drugs that can be used for difficult-to-treat resistant Gram-negative bacteria, with a particular focus on data relevant to the urinary tract. We also offer a pragmatic framework for antibiotic selection when encountering urinary tract infections due to difficult-to-treat resistant Gram-negative bacteria based on the organism and its mechanism of resistance.

Introduction: ‘Female sexual dysfunction’ (FSD) is an umbrella term comprising a range of common disorders, including hypoactive sexual desire, reduced subjective and/or physical genital arousal (poor sensation, vasocongestion, lubrication), sexual pain and inability to achieve orgasm/satisfaction, which are multidimensional by nature and often coexisting. Psychological and contextual factors have a significant influence on organic components of sexual response and behavior and a tailored medical approach to sexual symptoms is inevitably limited.Areas covered: The paper reports the most recent advances in pharmacotherapy for women taking into account the biopsychosocial model. Hormone therapy, including estrogens, testosterone, tibolone and dehydroepiandrosterone, are discussed in term of efficacy and safety in postmenopausal women both for female sexual interest/arousal disorder (FSIAD) and genito-pelvic pain/penetration disorder. Ospemifene, a selective estrogen receptor modulator, approved to treat dyspareunia at menopause, is also discussed. Data on psychoactive agents for treatment of FSIAD in premenopausal women are discussed, including the potential use of on-demand combined hormonal (testosterone) and non-hormonal (buspirone or sildenafil) treatments to address possible neurophysiological profiles of women.Expert opinion: We are still waiting for an approved pharmacotherapy for FSD. This is not the result of gender inequality in sexual medicine, but it reflects the need of balancing benefits and risks in order to provide effective and safe treatments to women of any age.

Heart failure is a common entity encountered in healthcare with a vast socioeconomic impact. Recent advances in pharmacotherapy have led to the development of novel therapies with mortality benefits, improvement in heart failure symptoms and hospitalizations. This article is intended to explore those newer pharmacotherapies and summarize the evidence behind guideline directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF). It has been several years since any significant advances in pharmacotherapy of heart failure have resulted in survival benefit. Angiotensin-neprilysin inhibitors through the PARADIGM-HF and PIONEER-HF trials have shown mortality benefits and a reduction in heart failure hospitalizations and are considered landmark trials in heart failure. Vericiguat is an oral guanylate cyclase stimulator that through the recent VICTORIA trial showed a 10% relative difference in death from cardiovascular cause or hospitalization for heart failure. The sodium-glucose transport protein 2 (SGLT2) inhibitors are another class of medications that have shown promise in the treatment of patients with HFrEF and diabetes mellitus. The CANVAS and EMPA-REG OUTCOME trials showed the potential benefit of SGLT2 inhibitors on cardiovascular mortality, DECLARE-TIMI 58 trial showed that treatment with dapagliflozin reduced the risk of cardiovascular death or hospitalization for heart failure to a greater extent in patients with reduced ejection fraction (EF). Although novel pharmacotherapy is the current focus of intense research, there have been numerous studies on potential benefit of iron supplementation in ferropenic patients with heart failure. Another rapidly expanding area of research in the realm of heart failure is precision medicine and its impact on the development, progression, and treatment of heart failure. The field of heart failure is dynamic and with the influx of data from recent and ongoing trials, newer therapies with morbidity and mortality benefits in HFrEF are now available, nonetheless, much work is still needed.

Glucagon-Like Peptide-1 Receptor Agonists and Dual Glucose-Dependent Insulinotropic Polypeptide/Glucagon-Like Peptide-1 Receptor Agonists in the Treatment of Obesity/Metabolic Syndrome, Prediabetes/Diabetes and Non-Alcoholic Fatty Liver Disease-Current Evidence.