TouchREVIEWS in endocrinology最新文献

Short stature is a common reason for consulting a growth specialist during childhood. Normal height is a polygenic trait involving a complex interaction between hormonal, nutritional and psychosocial components. Genetic factors are becoming very important in the understanding of short stature. After exclusion of the most frequent causes of growth failure, clinicians need to evaluate whether a genetic cause might be taken into consideration. In fact, genetic causes of short stature are probably misdiagnosed during clinical practice and the underlying cause of short stature frequently remains unknown, thus classifying children as having idiopathic short stature (ISS). However, over the past decade, novel genetic techniques have led to the discovery of novel genes associated with linear growth and thus to the ability to define new possible aetiologies of short stature. In fact, thanks to the newer genetic advances, it is possible to properly re-classify about 25-40% of children previously diagnosed with ISS. The purpose of this article is to describe the main monogenic causes of short stature, which, thanks to advances in molecular genetics, are assuming an increasingly important role in the clinical approach to short children.

The treatment of obesity can no longer be reduced to a simplistic view of weight loss. Metabolic adaptation leads to systematic weight regain following weight-loss efforts, and new obesity treatments should therefore aim to induce long-standing double-digit weight loss, and thus improve and even reverse obesity-associated comorbidities such as type 2 diabetes. Until now, only metabolic surgery has been able to achieve such a goal, but this invasive procedure cannot be offered on a large scale. Among the alternatives, lifestyle interventions and drug therapies have often been disappointing. The recent availability of once-weekly subcutaneous 2.4 mg semaglutide (a glucagon-like peptide-1 receptor agonist; Wegovy™ Novo Nordisk A/S, Bagsværd, Denmark) has changed the scene, and semaglutide is considered a 'game changer' in the treatment of obesity. The results from the phase III STEP (Semaglutide treatment effect in people with obesity) clinical programme have shown that semaglutide provides clinically meaningful and sustained weight loss in ranges much higher than those achieved with previously available pharmacotherapies. These results led to the approval of semaglutide by regulatory authorities as an adjunct to a reduced-calorie diet and increased physical activity in people with obesity or overweight, with at least one weight-related comorbidity. With data from phase II and III clinical trials showing that newer drugs (i.e. the glucagon-like peptide-1 and gastric inhibitory polypeptide dual receptor agonist tirzepatide and the amylin agonist cagrilintide, either alone or combined) produce a greater sustained weight loss than semaglutide, an upstream 'weight-centric' strategy has emerged as a new standard for the treatment of type 2 diabetes.

There is an increasing prevalence of obesity worldwide, associated with significant morbidity and mortality, which frequently reduces quality of life and life expectancy. Consequently, there is a substantial and growing personal and economic burden necessitating the development of more effective therapies for obesity. Glucagon-like peptide-1 receptor analogues (GLP-1RAs) are licensed for the treatment of type 2 diabetes (T2D), and there is substantial evidence that these drugs not only improve cardiovascular outcomes but also promote weight loss. More recent evidence supports the use of the GLP-1RAs liraglutide and semaglutide in people with obesity without T2D. This article discusses the results of the major cardiovascular outcome trials for GLP-1RAs in people with T2D, the SCALE Obesity and Prediabetes study (Effect of liraglutide on body weight in non-diabetic obese subjects or overweight subjects with co-morbidities: SCALE™ - Obesity and Pre-diabetes; ClinicalTrials.gov identifier: NCT01272219; investigating liraglutide) and the STEP studies (Semaglutide treatment effect in people with obesity; assorted studies; investigating subcutaneous semaglutide). We also highlight the importance of a cost-effective approach to obesity pharmacotherapy. Clinicians should consider the use of GLP-1RAs in people with obesity, especially those with T2D or other obesity-related diseases, such as hypertension and dyslipidaemia. Ongoing trials, as well as clinical and cost-effectiveness appraisals, are anticipated over the next 12 months, and their findings may change the current landscape of obesity pharmacotherapy.

Imeglimin is a novel molecule currently under development for the treatment of type 2 diabetes mellitus, and is the first agent of the 'glimin' class of glucose-lowering medication. It has a unique mechanism of action that targets the three main pathophysiologic components of type 2 diabetes: impaired glucose uptake by muscle tissue, excess hepatic gluconeogenesis and increased β-cell apoptosis. To date, imeglimin has been evaluated in many preclinical and clinical trials and has shown to have notable antihyperglycaemic effects, such as statistically significant reductions in glycated haemoglobin, fasting plasma glucose and other glycaemic parameters. The encouraging tolerability profile, combined with its efficacy, could make it suitable as a monotherapy or in combination with other classes of antidiabetic agents, hopefully in the near future.

Craniopharyngiomas are rare benign neoplasms presenting in two different types, adamantinomatous (ACP) or papillary (PCP), which are molecularly and clinically distinct. Traditional treatment includes surgical resection and radiotherapy, which are accompanied by a number of debilitating complications because of the tumours' proximity to important brain structures. Recent advances in the understanding of molecular pathogenesis of craniopharyngiomas have opened horizons to medical therapeutic options. ACPs are mainly characterized by mutations of β-catenin, which activate Wingless/Int (Wnt), and alter the mitogen extracellular kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway, as well as inflammatory, cellular senescence, programmed cell death and sonic hedgehog (SHH) pathways. PCPs are mainly characterized by Ras/Raf/MEK/ERK pathway activation secondary to BRAF-V600E mutations. MEK inhibitors, such as binimetinib, or anti-inflammatory mediators, such as tocilizumab or interferon, have been administered to patients with ACP and the efficacy is mostly favourable. On the other hand, BRAF inhibitors, such as dabrafenib or vemurafenib, either alone or in combination with the MEK inhibitors trametinib and cobimetinib, have been administered to patients with PCP resulting in favourable responses. A number of ongoing trials will shed light on schemes, doses, combined treatments and safety issues of the new molecular-targeted treatments, changing the management of patients with craniopharyngiomas by launching the era of personalized medicine in these rare neoplasms. We conducted a systematic review to identify case series or case reports with patients currently treated with systemic medical therapy.

Non-alcoholic steatohepatitis (NASH) is becoming a global disease with significant associated comorbidities. To date, there are no commercialized drugs to treat NASH, outside of India; however, there is an abundance of new molecular entities which are in clinical development, some in phase III trials. Many of these trials have created an especially heavy demand for USA-based subjects. Hepatologists currently play a major role in the diagnosis, treatment and clinical-trial enrolment of patients with NASH. However, NASH has a strong metabolic component, with patients often carrying comorbid diseases, such as type 2 diabetes mellitus, obesity, hyperlipidaemia, hypothyroidism and sex steroid disorders. The primary care physician, internist and endocrinologist stand at a pivotal position in the NASH healthcare delivery system, as many of the diseases they commonly encounter are associated with a higher risk of developing NASH. Specialty society practice guidelines are evolving regarding the identification and care of patients with NASH. This review of the literature, and assessment of IQVIA's proprietary patient claims database of diagnosis codes, patient encounters and treatments, substantiates the importance of the primary care provider and endocrinologist in the clinical care and clinical research of patients with NASH.

Type 2 diabetes mellitus (T2DM) is a chronic disease with a constantly increasing prevalence worldwide. It is well established that T2DM affects both the macro- and microvasculature, and its presence is associated with a high risk of acute and chronic cardiovascular events. Traditionally, the management of T2DM has been mainly focused on the optimization of blood glucose levels with the use of antidiabetic medications. During recent years, however, an impressive accumulation of evidence has arisen from studies designed to explore the plausible effects of new antidiabetic drugs on cardiovascular outcomes in patients with diabetes. This review article aims to emphasize the findings of these studies and to highlight the substantial role of the newer classes of antidiabetic drugs in treating T2DM in a holistic, cardiorenal-metabolic approach, thus shifting the paradigm from the traditional, simplistic, glucose-lowering approach.

Gestational diabetes mellitus (GDM) complicates approximately 7% of pregnancies in the USA. Despite recognition of the benefits of diagnosing and treating GDM, there are several areas of controversy that remain unresolved. There is debate as to whether to screen for GDM with the one-step versus the two-step approach. While the former identifies more pregnancies with potential adverse outcomes, data are lacking as to whether treatment of these pregnancies will improve outcomes, while increasing costs by diagnosing more women. Though it is well established that the diagnosis of even mild GDM, and treatment with lifestyle recommendations and insulin, improves pregnancy outcomes, it is controversial as to which type and regimen of insulin is optimal, and whether oral agents can be used safely and effectively to control glucose levels. Finally, it is recommended that women with GDM get tested for type 2 diabetes within several months of delivery; however, many women do not undergo this testing and alternative approaches are needed. These controversies are discussed with data from both sides of the debate to enable clinicians to make patient-centered decisions until more definitive data are available.

Type 2 diabetes mellitus (T2DM) affects an estimated 463 million people worldwide, equivalent to 1 in 11 adults. Moreover, the rapid growth of this disease has resulted in a high incidence of diabetic kidney disease (DKD), which, together with hypertension, is the main cause of chronic kidney disease (CKD). Hyperglycaemia, low-grade inflammation, altered lipid metabolism and hyperactivation of the renin-angiotensin-aldosterone system (RAAS) seem to be interrelated mechanisms contributing to both T2DM and microvascular complications. The introduction of drugs such as sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists has improved the ability to slow the progression of DKD, and has also demonstrated benefits in cardiovascular disease. Beyond the effects of these novel antidiabetic drugs, a body of evidence suggests that the overactivation of the mineralocorticoid receptor also contributes to CKD progression. Moreover, new and ongoing trials have demonstrated that the selective nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone improves the risk of CKD progression and cardiovascular events in patients with CKD and T2DM and optimized RAAS blockade. We review the rationale for the development and use of MRA drugs to slow CKD progression in patients with DKD, as well as other pleiotropic effects, and highlight the warnings associated with these agents.