Journal of Clinical Endocrinology & Metabolism最新文献

Context: Adrenal insufficiency from hypophysitis is a complication of immune checkpoint inhibitor (ICI) therapy. However, the risk associated with relatlimab, a lymphocyte activation gene 3 inhibitor, is unknown. Relatlimab was approved in 2022 in combination with nivolumab for the treatment of unresectable or metastatic melanoma.

Objective: To determine the prevalence, identify risk factors, and characterize the clinical presentation of central adrenal insufficiency in patients receiving relatlimab-nivolumab compared to nivolumab alone.

Methods: Retrospective analysis of Mass General Brigham healthcare system patients who received relatlimab-nivolumab from 2015 to 2023 matched by age, sex and race to individuals receiving monotherapy with nivolumab, an ICI with a risk of hypophysitis of <1%.

Results: Adrenal insufficiency was diagnosed in 10 patients (7.6%) after relatlimab-nivolumab administration and in 1 patient (0.8%) after nivolumab monotherapy (p=0.00056). Within the relatlimab-nivolumab group, median age and sex were comparable in patients who developed adrenal insufficiency compared to those who did not. The median number of doses received by subjects who developed adrenal insufficiency was 7 (4-10) compared to 3 (2-6) in those who did not (p=0.03). The most common presenting symptoms were fatigue, anorexia, nausea, and vomiting. No patients were diagnosed with additional anterior pituitary hormone deficiencies or AVP deficiency, though not all patients were evaluated for these diagnoses.

Conclusions: This study is the first cohort analysis of hypophysitis in patients treated with relatlimab-nivolumab compared to nivolumab monotherapy. Combination treatment with relatlimab-nivolumab confers a significantly higher risk of developing adrenal insufficiency, likely secondary to hypophysitis, compared to nivolumab alone.

Context: Complications of diabetes mellitus have significant impacts on morbidity, mortality, quality of life, and health costs for individuals. Setting and achieving glycemic targets to prevent these complications is a top priority when managing diabetes. However, patients often already have complications when diagnosed with diabetes mellitus. Therefore, methods to prevent disease progression become a crucial component of diabetes management. The purpose of this article is to review glycemic targets and methods of screening and managing diabetes-related complications.

Evidence acquisition: A PubMed review of the literature pertaining to diabetes mellitus, glycemic targets, microvascular complications, and macrovascular complications was conducted. We reviewed articles published between 1993 and 2024. Guidelines published by nationally recognized organizations in the fields of diabetes, nephrology, and cardiology were referenced. Public health statistics obtained by the Center for Disease Control and Prevention and the National Kidney Foundation were used.

Evidence synthesis: Achieving glycemic targets and screening for diabetes-related complications at appropriate intervals remains the key factor for early detection and intervention. An algorithmic approach to glycemic management based on individual risk factors is beneficial in choosing pharmacotherapy.

Conclusion: The consequences of diabetes-related complications can be detrimental. However, achieving and maintaining glycemic targets combined with diligent screening, reduction of risk factors, and prompt treatment can halt disease progression.

Aims: Sodium-glucose co-transporter 2 inhibitors (SGLT2i) enhance cardiovascular outcomes in individuals with type 2 diabetes mellitus (T2DM). Whether such effects also occur in T2DM patients with atrial fibrillation (AF) remains unknown. We aimed to investigate SGLT2i use on cardiovascular outcomes in patients with concomitant AF and T2DM.

Methods: Patients with both AF and T2DM were identified from TriNetX, an international electronic medical record. Participants were divided into 2 groups according to their use of SGLT2i, at a 1:1 distribution through propensity score matching (PSM). The hazard ratio (HR) for clinical outcomes was determined using multivariate Cox hazards regression model.

Results: We studied 339 792 patients with AF and T2DM, with 32 945 (9.70%) SGLT2i users. Following PSM, 17 011 patients aged 68.4 ± 7.9 years were included in each group. After a 3-year follow-up, patients treated with SGLT2i showed significantly reduced risks of stroke (adjusted HR: 0.830, P < .001), dementia (adjusted HR: 0.662, P < .001), long-standing persistent AF (adjusted HR: 0.917, P < .001), heart failure (adjusted HR: 0.833, P < .001), and all-cause mortality (adjusted HR: 0.532, P < .001).

Conclusion: The use of SGLT2i was associated with reduced risks of stroke, dementia, long-standing persistent AF, heart failure, and mortality in patients with both AF and T2DM. SGLT2i may be considered as a potential first-line therapy for this population.

Context: Establishing the genetic basis of early-onset primary ovarian insufficiency (EO-POI, <25 years) is important, but defining variant pathogenicity is challenging.

Objective: To elucidate the genetic architecture of EO-POI in a unique, large cohort.

Setting: Young women with EO-POI (n=149; n=31 familial, n=118 sporadic) attending a specialist reproductive unit.

Design: Exome sequencing was performed. After filtering, variants were retained which were 1) rare/novel (minor allele frequency <0.01%); 2) predicted pathogenic/likely pathogenic; and 3) enriched in the cohort. Each variant was assigned to a category: Category 1, variants in Genomics England Primary Ovarian Insufficiency PanelApp genes (n=69); Category 2, variants in other POI-associated genes (n=355) or Category 1 variants following unexpected inheritance patterns; and Category 3, homozygous variants in novel candidate POI genes.

Results: A total of 127 Category 1 or 2 variants were identified in 74 different genes (heterozygous 30.9%; homozygous 9.4%; polygenic 21.8%). In familial EO-POI, 64.7% (11/17 kindred) had a Category 1 or 2 variant identified (homozygous: STAG3, MCM9, PSCM3IP, YTHDC2, ZSWIM7; heterozygous: POLR2C, NLRP11, IGSF10, PRKD1, PLEC; polygenic: PDE3A, POLR2H, MSH6, CLPP). In sporadic EO-POI, 63.6% (n=75/118) women had a variant identified (21.2% (n=25) Category 1; 42.4% (n=50) Category 2). Novel POI candidate genes (Category 3) included PCIF1, DND1, MEF2A, MMS22L, RXFP3, C4orf33, and ARRB1.

Conclusions: The genetic basis of EO-POI is complex and affected genes span ovarian developmental processes from fetal life to adulthood. Establishing the pathogenicity of individual heterozygous variants can be challenging. However, some women have clear monogenic causes, particularly in familial POI with autosomal recessive inheritance. Others have potential polygenic causes. We describe novel candidate POI genes warranting further exploration.

Context: Current diabetes care and education programs and expert clinical diabetes management guidelines focus on diabetes self-care behaviors and have yet to incorporate complementary therapies. Complementary therapies, such as music therapy, yoga, mindfulness, and art therapy, have been used globally for centuries and have positive metabolic and glycemic outcomes. In this mini-review, we describe complementary therapies successfully used in diabetes, identify current evidence-based practice gaps, and provide recommendations for incorporating complementary therapies into diabetes care.

Evidence acquisition: We thoroughly searched relevant PubMed and Google Scholar studies from 2004 to 2024. Our inclusion criteria were clinical trial studies using the search terms "diabetes self-management" OR "metabolic outcomes" OR "diabetes" OR "type of complementary therapy (music therapy, mindfulness, yoga or art therapy) OR population (type 1 diabetes, type 2 diabetes, prediabetes, diabetes)."

Evidence synthesis: We synthesized the evidence to determine complementary therapies (music therapy, mindfulness, yoga, or art therapy) that benefit individuals with diabetes. Findings showed that complementary therapies support diabetes-related psychological and cardiometabolic outcomes and enhance the Association of Diabetes Care and Education Specialists 7 Self-Care Behaviors for diabetes self-management, specifically healthy coping, monitoring, reducing risks, and problem-solving. Critical gaps included the lack of large-scale randomized controlled trials in North American diabetes self-management education programs.

Conclusion: Complementary therapies have positive psychological and physiological health benefits for people living with diabetes, yet more randomized controlled trials are needed to assess their effectiveness on a large scale. In the interim, complementary therapies can be integrated into diabetes education, specifically as adjunctive hands-on therapies to enhance self-management behaviors and meet self-management goals.

Context: Diabetes mellitus is a global health burden, with factors contributing to its prevalence and costs. Educating people with diabetes improves outcomes and affects the economic burden on the individual and health systems.

Evidence acquisition: We included recent diabetes data from the Centers for Disease Control and Prevention and articles from PubMed and Ovid MEDLINE.

Evidence synthesis: Diabetes prevalence in the United States increased from 10.3% in 2001 to 14.7% in 2021. Factors contributing are an aging population, increased obesity, and social determinants of health. Total costs for diabetes in 2022 reached $412.9 billion, consisting of 74% direct medical and around 26% indirect costs. The highest medical expenses were hospital inpatient services ($96.2 billion), and indirect costs were decreased productivity while at work ($35.8 billion). The effect on the health economy in the United States and globally is only increasing. Interventions to improve disease outcomes such as diabetes education programs that teach self-management skills, healthy lifestyle behaviors, and coping strategies have improved glycated hemoglobin A1c and other outcomes. The economic effect of education is not well studied. However, the Diabetes Prevention Program demonstrated the benefits of lifestyle-based education in preventing or delaying the development of type 2 diabetes in high-risk people and in being cost-effective long term.

Conclusion: High direct and indirect costs and the prevalence of diabetes require urgent global awareness and interventions from many angles. We encourage clinicians and agencies to prioritize the education of people living with diabetes to prevent and treat diabetes and its complications.

Context: Patients affected by the classic form of congenital adrenal hyperplasia (CAH) need lifelong glucocorticoid therapy (GC). GC represents one of the primary causes of secondary osteoporosis, however the effect of steroid therapy on bone mineral density (BMD) in patients with CAH is still controversial.

Objective: To evaluate and compare the BMD of a group of prepubertal patients and a subgroup of young adult patients with CAH receiving chronic GC therapy, with healthy controls.

Design: retrospective observational study.

Setting: A referral center for pediatric endocrinology.

Patients and healthy controls: Fifty-six prepubertal children with CAH treated with GC from diagnosis and 60 prepubertal healthy children of comparable age. A subgroup of 36 young patients was studied after the completion of puberty, and their BMD was compared to that of 51 young adult healthy volunteers.

Methods: BMD was measured in the lumbar spine and in the whole body by dual-energy x-ray absorptiometry. Multivariate models were used for the comparison of BMD measurements between patients and control subjects.

Results: Whole-body BMD measurements of patients were significantly lower compared with healthy controls, both in boys and in girls. No differences were found in lumbar spine measurements. BMD expressed as Z-score decreased markedly in CAH patients from prepuberty to adulthood, particularly in young adult males. Men with CAH showed lumbar spine BMD values significantly lower than control subjects.

Conclusions: Boys and young adult men with classic form of CAH have lower bone mineral density values compared with healthy controls. This may put them at risk of developing osteoporosis early in life.

Context: The incidence of diabetes is growing at an alarming rate globally. Most of these projected individuals will develop type 2 diabetes (T2DM), raising their risk of cardiovascular disease and chronic kidney disease. This mini-review examines current noninsulin and noninjectable pharmacotherapy focused in T2DM, highlighting the effect on glycemic control and importance of cardiovascular and renal outcomes.

Evidence acquisition: We included population level data and searched the PubMed database for recent systematic reviews, meta-analyses, and original research articles.

Evidence synthesis: There is a pharmacologic menu of noninsulin-based medications for the treatment of diabetes. Through varying mechanisms, all agents ultimately lead to glycemic improvement to varying degrees. Only a select number of agents are shown to improve important clinical cardiovascular and renal outcomes. Of note, sodium-glucose cotransporter-2 inhibitors have improved cardiovascular mortality and time to dialysis in people with diabetes. Likewise, incretin-based therapies have improved important cardiovascular and renal composite outcomes in those with diabetes and cardiovascular disease. As a result, agents with proven cardiovascular and renal benefits should be prioritized based on patient risk.

Conclusion: Despite the availability of new medications and technology, published clinical guidelines, and treatment algorithms, most people with diabetes remain above glycemic targets. We encourage clinicians to follow the guidelines and use appropriate medications to lower cardiovascular risk, delay progression of chronic kidney disease, reach glycemic targets, and manage weight.

Context: Insulin therapy is first-line therapy for people with type 1 diabetes and often used for people with type 2 diabetes. Over the years, there has been a surge in insulin products available for use. As a result, clinicians need to have a strong understanding of the differences between insulin agents to provide proper patient care.

Evidence acquisition: We included population-level data and searched PubMed and Google Scholar databases for recent systematic reviews, meta-analyses, and original research articles.

Evidence synthesis: Patients who present with severe hyperglycemia or signs consistent with a catabolic state such as weight loss or ketonuria should be initiated on insulin. Furthermore, patients with a hemoglobin A1c (HbA1c) level >10% or an unclear diagnosis of type 1 diabetes should typically be treated with insulin. Insulin products differ mainly in their pharmacokinetic profiles and not mechanism of action. The literature suggests that differences in pharmacokinetics allow certain insulin products to be well equipped to address different clinical situations such as steroid-induced hyperglycemia, managing patients with severe chronic kidney disease or dialysis, and insulin pump therapy.

Conclusion: Understanding kinetic profiles of different insulin agents will allow clinicians to properly navigate options for either fasting or mealtime coverage. Furthermore, this foundational knowledge will be critical when applying insulin therapy in clinical scenarios such as steroid-induced hyperglycemia, kidney disease, and insulin pump management. Ultimately, this will allow clinicians and patients to create proper diabetes care plans and self-management skills.