What's new in endocrinology and diabetes mellitus

The following represent additions to UpToDate from the past six months that were considered by the editors and authors to be of particular interest. The most recent What's New entries are at the top of each subsection.

ADRENAL DISORDERS

Monitoring after negative confirmatory testing for primary aldosteronism (February 2024)

After a positive screening test for primary aldosteronism, confirmatory testing is required for diagnosis. In individuals with a positive screening test but negative confirmatory testing, the optimal monitoring strategy is uncertain. In a study that prospectively followed 184 individuals with a positive screening test for primary aldosteronism but negative confirmatory testing, a screening test was repeated after at least two years of follow-up [1]. If positive, confirmatory testing was performed again. Over a mean follow-up of five years, 20 percent of participants were diagnosed with primary aldosteronism. Those who developed primary aldosteronism exhibited higher blood pressure between initial and repeat testing despite similarly aggressive antihypertensive therapy. These findings support repeat testing for primary aldosteronism in individuals with initially negative confirmatory testing, particularly in those with progressively treatment-refractory blood pressure. (See "Diagnosis of primary aldosteronism", section on 'Negative confirmatory testing'.)

Cardiometabolic features of adrenal incidentaloma with mild autonomous cortisol secretion (December 2023)

In some individuals with adrenal incidentaloma, mild autonomous cortisol secretion (MACS) is evident in the absence of clinical features of Cushing syndrome. The long-term risks of MACS and optimal management strategies are not well defined. In a meta-analysis of 47 observational studies in 17,156 patients with adrenal incidentaloma, individuals with MACS (defined as serum cortisol >1.8 mcg/dL after a 1 mg overnight dexamethasone suppression test) exhibited a higher prevalence of diabetes, hypertension, and dyslipidemia compared with individuals with nonfunctioning adrenal adenomas [2]. Further, patients with MACS who underwent adrenalectomy showed greater improvement in cardiometabolic parameters than those who did not undergo surgery. These findings demonstrate the potential cardiometabolic risks of MACS and support our preference for adrenalectomy in patients with MACS and younger age or evidence of cardiometabolic dysregulation. (See "Evaluation and management of the adrenal incidentaloma", section on 'Clinical manifestations'.)

DIABETES MELLITUS

Glucagon-like peptide 1 receptor agonist use and thyroid cancer risk (April 2024)

Preclinical studies suggest that glucagon-like peptide 1 (GLP-1) receptor agonists may increase risk of thyroid neoplasia, but whether clinical use of these agents increases thyroid cancer risk is uncertain. A recent cohort study evaluated thyroid cancer incidence in individuals initiating treatment with a GLP-1 receptor agonist (predominantly liraglutide and semaglutide) compared with a dipeptidyl peptidase 4 (DDP-4) inhibitor. After a mean follow-up of 3.9 years, GLP-1 receptor agonist use was not associated with an increased risk of any thyroid cancer or medullary thyroid cancer [3]. DPP-4 inhibitors raise endogenous GLP-1 levels and therefore may not be an optimal comparator. Until more data are available, this study does not change our practice of avoiding GLP-1-based therapies in individuals with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia type 2A or 2B. (See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Other'.)

Extended-interval intravitreal aflibercept dosing for diabetic macular edema (April 2024)

For individuals with diabetic macular edema (DME) and impaired visual acuity, vascular endothelial growth factor (VEGF) inhibitors are often used as initial therapy. However, anti-VEGF therapy requires repeated intravitreal injections, contributing to nonadherence and undertreatment. In a 48-week trial of aflibercept in 660 adults (mean age 62 years) with type 1 or type 2 diabetes and center-involved DME, participants were randomly assigned to one of the following regimens after completing initial monthly dosing: 2 mg every 8 weeks (standard dosing), 8 mg every 12 weeks, or 8 mg every 16 weeks [4]. Improvement in visual acuity was similar among treatment groups (mean change +9.2, +8.8, and +7.9 letters, respectively). In individuals with center-involved DME,higher doses of aflibercept at extended intervals appear effective and may substantially reduce treatment burden. (See "Diabetic retinopathy: Prevention and treatment", section on 'Anti-VEGF agents'.)

Continuous glucose monitoring in individuals with type 2 diabetes (April 2024)

In individuals with type 2 diabetes, the utility of continuous glucose monitoring (CGM) is uncertain. In a meta-analysis of 14 trials in 1647 people with type 2 diabetes not meeting glycemic goals (variably defined, usually A1C ≥7, 7.5, or 8 percent), use of either flash or real-time CGM modestly reduced A1C compared with fingerstick blood glucose monitoring (BGM; mean difference -0.32 percentage points) [5]. Most participants were taking oral glucose-lowering medications with or without insulin, and trial duration varied from 10 to 52 weeks. In a separate meta-analysis with similar trial durations, CGM similarly reduced A1C [6]. In individuals with type 2 diabetes and A1C above target, CGM provides modest glycemic benefit. In this population, CGM may be helpful in identifying glycemic patterns that direct changes in behaviors and/or pharmacologic therapy. (See "Glucose monitoring in the ambulatory management of nonpregnant adults with diabetes mellitus", section on 'Insulin treated'.)

Noninsulin antidiabetic medications and pregnancy (February 2024)

Noninsulin antidiabetic medications such as glucagon-like peptide 1 (GLP-1) agonists, sodium-glucose cotransporter 2 (SGLT-2) inhibitors, and dipeptidyl peptidase 4 (DPP-4) inhibitors are commonly used in nonpregnant individuals but avoided in pregnancy because of lack of safety data in humans and harms observed in animal studies. However, in a multinational population-based cohort study including nearly 2000 individuals with preconception/first trimester exposure to these medications, the frequency of congenital anomalies was not increased compared with insulin [7]. A limitation of the study is that it did not adjust for potential differences in A1C, diabetes severity, or diabetes duration, which could obscure true effects on risk for congenital anomalies. We continue to avoid use of GLP-1 agonists, SGLT-2 inhibitors, and DPP-4 inhibitors in females planning to conceive and in pregnancy. (See "Pregestational (preexisting) diabetes: Preconception counseling, evaluation, and management", section on 'Patients on preconception noninsulin antihyperglycemic agents'.)

Effect of short-term sleep restriction on insulin sensitivity in females (January 2024)

Short sleep duration has been associated with risk of type 2 diabetes, but whether this reflects a causal relationship is uncertain. In a crossover study in 38 females aged 20 to 75 years with baseline sleep duration of seven to nine hours nightly, participants underwent sequential, six-week phases of sleep maintenance (usual sleep time maintained) and sleep restriction (sleep time reduced by 1.5 hours nightly) [8]. Sleep restriction led to increases in fasting insulin concentration and homeostasis model assessment of insulin resistance (HOMA-IR), indicating diminished insulin sensitivity. These changes were independent of changes in adiposity and were more pronounced in postmenopausal compared with premenopausal participants. Further studies are needed to verify the findings in a larger cohort of patients, including males, and to determine whether prolonged sleep restriction causes progressive worsening of glucose homeostasis. (See "Type 2 diabetes mellitus: Prevalence and risk factors", section on 'Sleep duration'.)

Janus kinase inhibition to preserve insulin secretion in early onset type 1 diabetes (January 2024)

In type 1 diabetes, the janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway has been implicated in immune-mediated beta cell destruction. In a trial in 91 individuals (aged 10 to 30 years) with new-onset type 1 diabetes (diagnosed within 100 days), participants were randomly assigned to daily treatment with the oral JAK1/2 inhibitor baricitinib (n = 60) or placebo (n = 31) [9]. After 48 weeks of therapy, insulin secretion was greater with baricitinib compared with placebo (median stimulated mean C-peptide level 0.65 versus 0.43 nmol/L per minute, respectively). A1C, frequency of hypoglycemia, and the percentage of time spent in the target glucose range (70 to 180 mg/dL [3.9 to 10 mmol/L]) were not significantly different between groups. JAK/STAT pathway inhibition is a promising strategy for preserving insulin secretion in new-onset type 1 diabetes. (See "Type 1 diabetes mellitus: Prevention and disease-modifying therapy", section on 'Cytokine-directed therapies'.)

Prenatal genetic testing for monogenic diabetes due to glucokinase deficiency (December 2023)

In pregnant individuals with monogenic diabetes due to glucokinase (GCK) deficiency, management depends on the fetal genotype. If the fetus inherits the maternal GCK variant, maternal hyperglycemia will not cause fetal hyperinsulinemia and excessive growth, and maternal hyperglycemia does not require treatment. However, if the fetus does not inherit the pathogenic variant, maternal insulin therapy is indicated to prevent excessive fetal growth. Fetal ultrasound has been used to predict fetal genotype but has limited diagnostic utility. In a cohort of 38 pregnant individuals with GCK deficiency, fetal genetic testing using cell-free DNA in maternal blood had higher sensitivity (100 versus 53 percent) and specificity (96 versus 61 percent) for prenatal diagnosis of GCK deficiency compared with ultrasound measurement of fetal abdominal circumference [10]. When available, noninvasive prenatal genotyping should be used to guide management of GCK deficiency during pregnancy. (See "Classification of diabetes mellitus and genetic diabetic syndromes", section on 'Glucokinase'.)

OBESITY

Tirzepatide for weight loss in adults (March 2024)

The US Food and Drug Administration recently approved subcutaneous tirzepatide, a dual glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, for chronic weight management [11]. Two randomized trials in adults with obesity demonstrated mean losses of 15 to 21 percent body weight with the highest dose of tirzepatide (15 mg weekly) [12,13]. In the larger of the two trials, over 80 percent of participants in all tirzepatide treatment groups (5 to 15 mg weekly) lost ≥5 percent of body weight, compared with 35 percent of those assigned to placebo [12]. Dose-related gastrointestinal side effects (nausea, diarrhea, constipation) were common but generally mild. Although direct comparisons are limited, the magnitude of weight loss with tirzepatide appears greater than that with other agents; thus, we consider tirzepatide a preferred medication for chronic weight management. (See "Obesity in adults: Drug therapy", section on 'Efficacy for weight loss'.)

Effects of tirzepatide discontinuation on weight (February 2024)

Glucagon-like peptide 1-based therapies for the treatment of obesity result in substantial weight loss. Although earlier data suggested that stopping treatment with semaglutide results in weight regain, it was unclear whether the same occurs with tirzepatide. Among adults with obesity who had previously lost weight (21 percent mean weight reduction) during a 36-week, open-label trial of tirzepatide, those randomly assigned to continue tirzepatide for 52 weeks experienced additional weight loss, whereas those assigned to placebo partially regained (-5.5 versus +14 percent mean weight change, respectively) [14]. These results, in line with those of previous studies, suggest that most individuals with obesity who opt for pharmacotherapy will require long-term treatment for weight loss maintenance. (See "Obesity in adults: Drug therapy", section on 'Duration of therapy'.)

Semaglutide and cardiovascular outcomes (January 2024)

Semaglutide and other glucagon-like peptide 1 receptor agonists can reduce rates of adverse cardiovascular events in individuals with type 2 diabetes who have established cardiovascular disease or are at high risk of cardiovascular disease. In a newly published trial of 17,604 individuals with overweight or obesity and cardiovascular disease but not diabetes, once-weekly subcutaneous semaglutide 2.4 mg reduced rates of adverse cardiovascular outcomes compared with placebo (6.5 versus 8.0 percent) [15]. Discontinuation of the study drug due to side effects occurred more often with semaglutide (17 versus 8 percent). For individuals with overweight or obesity and established cardiovascular disease, semaglutide is a particularly attractive option for chronic weight management. (See "Obesity in adults: Drug therapy", section on 'Cardiovascular benefits'.)

OSTEOPOROSIS

Proposed formal diagnostic criteria for hypophosphatasia in children and adults (March 2024)

Hypophosphatasia is a rare form of osteomalacia caused by pathogenic variants in the tissue nonspecific alkaline phosphatase gene (ALPL). Missed or delayed diagnosis is common, in part due to lack of formal diagnostic criteria. An international working group has proposed diagnostic criteria for hypophosphatasia in both children and adults [16]. Two major criteria or one major and two minor criteria are considered sufficient for diagnosis. For both children and adults, major criteria include a pathogenic (or likely pathogenic) variant in ALPL and elevated natural substrate concentrations (eg, pyridoxal 5'-phosphate). Additional major criteria for adults are atypical femoral fracture and recurrent metatarsal fractures and, for children, early loss of primary teeth and radiographic evidence of rickets. These criteria highlight the variable phenotypic expression of hypophosphatasia and the importance of considering this diagnosis in individuals with metabolic bone disease. (See "Clinical manifestations, diagnosis, and treatment of osteomalacia in adults", section on 'Low alkaline phosphatase (hypophosphatasia)' and "Skeletal dysplasias: Specific disorders", section on 'Hypophosphatasia'.)

Severe hypocalcemia with denosumab therapy in dialysis-treated patients (February 2024)

Denosumab use is not restricted in individuals with osteoporosis who have advanced kidney disease. However, concerns remain regarding the risk of severe hypocalcemia in such patients. In a cohort study of 2804 female patients (aged ≥65 years) with osteoporosis and undergoing dialysis, severe hypocalcemia (serum calcium <7.5 mg/dL [1.9 mmol/L] or hypocalcemia requiring emergency care) occurred in a higher proportion of patients who initiated denosumab compared with those who initiated an oral bisphosphonate (12-week weighted cumulative incidence 41.1 versus 2 percent, respectively) [17]. Denosumab also was associated with a higher incidence of very severe hypocalcemia (serum calcium <6.5 mg/dL [1.6 mmol/L]). A boxed warning about risk of severe hypocalcemia in individuals with advanced kidney disease, especially patients on dialysis, has been added for brand name denosumab (Prolia) [18], underscoring the need for greater caution and increased monitoring during treatment. (See "Denosumab for osteoporosis", section on 'Hypocalcemia'.)

PITUITARY DISORDERS

Risk of autoimmune disease after surgical cure of Cushing disease (February 2024)

In patients with a corticotropin (ACTH)-secreting pituitary tumor (Cushing disease), transsphenoidal surgery with adenomectomy provides a high rate of initial cure. Surgical cure of Cushing disease improves skeletal and cardiometabolic health, but it also may contribute to increased risk of autoimmune disorders. In a retrospective study in predominantly female adults (mean age approximately 44 years) with pituitary adenoma who underwent successful surgical management, patients with Cushing disease (n = 194) had a higher rate of new-onset autoimmune disease following surgery compared with patients with a nonfunctioning adenoma (n = 92; cumulative three-year incidence 10.4 versus 1.6 percent, respectively) [19]. Autoimmune thyroid disease was most common, and family history of autoimmune disease was associated with higher risk of developing an autoimmune disorder. These findings support the need for long-term monitoring of patients with Cushing disease, even after curative surgical treatment. (See "Primary therapy of Cushing disease: Transsphenoidal surgery and pituitary irradiation", section on 'Long-term health risks'.)

THYROID DISORDERS

Epidemiology of myxedema coma in the United States (May 2024)

Myxedema coma is a rare presentation of hypothyroidism. A 2024 analysis of a national inpatient database in the United States provides new information on the epidemiology and prognosis of myxedema coma [20]. The estimated incidence in the United States is 2.6 cases per million persons per year. The estimated in-hospital mortality was 6.8 percent, compared with 0.7 percent for patients hospitalized for hypothyroidism without myxedema coma. This mortality rate is substantially lower than prior mortality estimates, which ranged from 30 to 50 percent. The reason for the lower mortality rate in this analysis is uncertain but may be related to inclusion of patients with less severe myxedema coma or to recent improvements in intensive care unit management. (See "Myxedema coma", section on 'Prognosis'.)

Selenium deficiency and autoimmune thyroid disease (April 2024)

Selenium deficiency has been shown to exacerbate autoimmune thyroid disease. Reports of selenium supplementation for the treatment of Hashimoto thyroiditis are conflicting. In a recent meta-analysis evaluating selenium supplementation in individuals from selenium-deficient regions (eg, Europe and Asia) with Hashimoto thyroiditis, there was a reduction in thyroid-stimulating hormone in patients who were not receiving thyroid hormone replacement (seven trials; standard mean difference -0.21) [21]. This modest benefit is likely restricted to people from selenium-deficient regions of the world. In the United States, the soil in most states is rich in selenium, suggesting selenium deficiency is rare. (See "Treatment of primary hypothyroidism in adults", section on 'Selenium deficiency'.)

Hearing impairment after teprotumumab for thyroid eye disease (January 2024)

Teprotumumab, an insulin-like growth factor 1 receptor inhibitor, is a relatively new, effective treatment for moderate-to-severe thyroid eye disease. In the initial clinical trials, hearing abnormalities were reported in approximately 10 percent of patients, but audiograms were not routinely performed. In a subsequent prospective study evaluating hearing outcomes before and after teprotumumab therapy in 52 patients, 21 percent had a decline in hearing on audiometry immediately after completing therapy, which persisted after six months in 5 patients [22]. Most patients with hearing loss had baseline hearing dysfunction. It is important to discuss potential adverse hearing effects prior to initiating therapy and review symptoms at each visit. It is reasonable to obtain baseline audiometry in all patients and repeat in individuals who report any change in hearing. (See "Treatment of thyroid eye disease", section on 'Teprotumumab'.)