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What's new in endocrinology and diabetes mellitus

What's new in endocrinology and diabetes mellitus
Literature review current through: Jan 2024.
This topic last updated: Feb 01, 2024.

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

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 [1]. 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

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) [2]. 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) [3]. 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 [4]. 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'.)

Investigational once-weekly basal insulin therapy (insulin icodec) for the treatment of adults with type 1 diabetes (November 2023)

Ultra-long-acting insulin icodec is an investigational basal insulin therapy that requires only once-weekly dosing. In a trial in 655 adults with type 1 diabetes (mean A1C approximately 7.6 percent), participants were randomly assigned to basal insulin therapy with once-weekly insulin icodec or once-daily insulin degludec [5]. After 26 weeks, the mean reduction in A1C was similar in the icodec and degludec groups (-0.47 and -0.51 percentage points, respectively). However, insulin icodec led to a nearly twofold higher combined rate of clinically significant (<54 mg/dL [<3 mmol/L]) or severe hypoglycemia (2836 versus 1495 events with insulin degludec). Additional studies are needed to determine whether risk of hypoglycemia will limit the use of ultra-long-acting insulin in individuals with type 1 diabetes. (See "General principles of insulin therapy in diabetes mellitus", section on 'Basal insulin analogs'.)

Automated insulin delivery in pregnant patients with type 1 diabetes (October 2023)

Hybrid closed-loop insulin therapy is associated with improved glucose control in nonpregnant adults and in children, but little information is available in pregnant people. In the first randomized trial in this population, hybrid closed-loop insulin delivery beginning at 11 weeks gestation improved glycemic control compared with standard insulin therapy in 124 patients with type 1 diabetes, without increasing their risk of severe hypoglycemia [6]. The system allowed customization of glycemic targets appropriate to pregnancy, in contrast to other commercially available systems in the United States. Additional study is needed to confirm these findings, evaluate the effects on obstetric and neonatal outcomes, and identify optimal candidates. (See "Pregestational (preexisting) diabetes mellitus: Antenatal glycemic control", section on 'Continuous subcutaneous insulin infusion (insulin pump)'.)

Glucagon-like peptide 1 (GLP-1) receptor agonists may increase risk of aspiration during anesthesia (July 2023)

Patients who take glucagon-like peptide 1 (GLP-1) receptor agonists (eg, semaglutide, liraglutide) for weight loss or diabetes may be at increased risk of aspiration during anesthesia due to delayed gastric emptying. In 2023, the American Society of Anesthesiologists suggested holding the day-of-surgery or weekly dose of GLP-1 agonists prior to elective surgery because of case reports of aspiration [7]. For patients who have not held their GLP-1 (ie, no drug on day of procedure/surgery for daily dosing, no drug in the week prior to procedure/surgery for weekly dosing), gastric ultrasound can be used to assess for gastric contents or a rapid sequence induction and intubation should be considered. (See "Rapid sequence induction and intubation (RSII) for anesthesia", section on 'Patients taking GLP-1 receptor agonists'.)

MENOPAUSE

Fezolinetant, a neurokinin 3 receptor antagonist for hot flashes (August 2023)

Hormone therapy remains the most effective treatment for hot flashes. However, a new class of nonhormonal drugs, neurokinin 3 receptor (NK3R) antagonists, appears to be a reasonable alternative for those who cannot take hormone therapy. The first NK3R antagonist to be approved and available for clinical use is fezolinetant. In one trial of over 500 postmenopausal women with moderate-to-severe hot flashes, fezolinetant significantly reduced hot flash frequency and severity when compared with placebo [8,9]. After 12 weeks of therapy, the mean reductions in hot flash frequency for fezolinetant 45 mg, 30 mg, or placebo were 64, 59, and 45 percent, respectively. Women receiving fezolinetant 45 mg also had significant improvements in sleep disturbances when compared with placebo. (See "Menopausal hot flashes", section on 'Neurokinin 3 receptor antagonist'.)

Nonhormonal therapies for menopausal hot flashes (August 2023)

The 2023 nonhormonal therapy position statement from the Menopause Society suggests a number of treatment options for hot flashes in women who cannot take hormone therapy [10]. These include cognitive behavioral therapy, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, oxybutynin, gabapentin, and fezolinetant. Nonhormonal therapies that NAMS does not recommend for vasomotor symptoms include paced respiration, supplements/herbal remedies, cooling techniques, avoiding triggers, exercise, yoga, mindfulness-based intervention, relaxation, soy, cannabinoids, acupuncture, and clonidine. (See "Menopausal hot flashes", section on 'NAMS 2023 recommendations'.)

OSTEOPOROSIS

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) 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) [11]. 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 has been added for brand name denosumab (Prolia) [12], underscoring the need for greater caution and increased monitoring during treatment. (See "Denosumab for osteoporosis", section on 'Hypocalcemia'.)

Investigational transdermal formulation of abaloparatide for the treatment of osteoporosis (November 2023)

In individuals with osteoporosis, the bone anabolic agent abaloparatide increases bone mineral density (BMD) and reduces fracture risk but requires daily subcutaneous injections. Noninjectable formulations may facilitate use of anabolic therapy for the treatment of osteoporosis. In a 12-month trial in 511 postmenopausal women with osteoporosis, participants were randomly assigned to daily treatment with an investigational, transdermal formulation of abaloparatide or subcutaneous abaloparatide. Transdermal abaloparatide increased BMD at the lumbar spine, although not as robustly as subcutaneous abaloparatide (mean increase of 7.14 versus 10.86 percent, respectively) [13]. Transdermal abaloparatide similarly led to a smaller increase in BMD at the total hip (mean increase of 1.97 versus 3.7 percent with subcutaneous abaloparatide). Further studies are needed to determine whether transdermal abaloparatide reduces fracture risk. (See "Parathyroid hormone/parathyroid hormone-related protein analog therapy for osteoporosis", section on 'Dosing'.)

THYROID DISORDERS

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 [14]. 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'.)

Updated Bethesda system for reporting thyroid cytopathology (November 2023)

The National Cancer Institute Thyroid Fine-Needle Aspiration (FNA) State of the Science Conference ("Bethesda Conference") updated the six FNA cytologic findings and associated risks of thyroid cancer based on surgically resected thyroid nodules (table 1) [15]. To avoid confusion with reporting terminology, the term "follicular lesion of undetermined significance" is no longer used. Atypia of undetermined significance is subdivided into nuclear atypia and other atypia. Other atypia includes architectural atypia (previously referred to as follicular lesion of undetermined significance), oncocytic atypia, and lymphocytic atypia. (See "Atlas of thyroid cytopathology", section on 'FNA cytology classification scheme'.)

Selpercatinib for RET-mutated medullary thyroid cancer (November 2023)

In an open-label, randomized trial comparing selpercatinib (a selective RET inhibitor) with either cabozantinib or vandetanib (less selective antiangiogenic kinase inhibitors with some RET inhibition) in 291 patients with progressive, locally advanced or metastatic RET-mutated medullary thyroid cancer, median progression-free survival was not reached in the selpercatinib group and was 16.8 months in the active comparator group [16]. The 12-month progression-free survival was better with selpercatinib (87 versus 66 percent with cabozantinib or vandetanib); complete response occurred in 12 and 4 percent, respectively. There were fewer grade ≥3 adverse events in the selpercatinib group, and fewer patients discontinued treatment due to adverse events. These finding support our recommendation for selpercatinib as initial therapy in patients with RET-mutated tumors who meet criteria for systemic treatment. (See "Medullary thyroid cancer: Systemic therapy and immunotherapy", section on 'Selpercatinib'.)

Preoperative treatment of hyperthyroidism (September 2023)

In patients with untreated or poorly controlled hyperthyroidism, an acute event such as surgery can precipitate thyroid storm, a potentially life-threatening condition. Preoperative treatment with a thionamide until the free T4 and T3 are normal reduces this risk. A recent retrospective study suggests thyroid surgery in patients with uncontrolled hyperthyroidism may be performed safely [17]. However, the study used a more stringent definition for the diagnosis of thyroid storm, potentially underestimating its occurrence. We continue to suggest preoperative thionamide and beta blocker treatment for patients with hyperthyroidism. There may be some patients in whom euthyroidism cannot be achieved prior to thyroidectomy (eg, poor compliance, severe hyperthyroidism), and the risk of thyroid storm may be higher if thyroidectomy is deferred. In this setting, surgery in a thyrotoxic patient ideally should be performed at a center with experienced anesthesiologists. (See "Surgical management of hyperthyroidism", section on 'Management of hyperthyroidism'.)

Treatment of symptomatic benign thyroid nodules (September 2023)

In a systematic review and network meta-analysis of 16 studies (3 randomized trials and 13 comparative case series) using thermal ablation techniques (eg, radiofrequency ablation, laser ablation, microwave ablation, high-intensity focused ultrasound) or conventional surgery to treat benign thyroid nodules, thyroidectomy was associated with the largest reduction in thyroid volume compared with thermal ablation techniques but a higher risk of postoperative complications (eg, laryngeal nerve damage) and hypothyroidism [18]. There was no difference among the thermal ablation techniques in volume reduction, symptom score, or cosmetic score. There were no trials comparing thyroid lobectomy with any thermal ablation technique. Surgical complications are generally lower when the extent of resection is limited (lobectomy versus total thyroidectomy). We continue to suggest surgery (typically lobectomy) for the treatment of symptomatic benign thyroid nodules. Ultrasound-directed thermal ablation techniques are alternatives when clinical expertise is available. (See "Diagnostic approach to and treatment of thyroid nodules", section on 'Symptomatic benign nodules'.)

OTHER ENDOCRINOLOGY

No benefit to tight glucose control in critically ill patients (December 2023)

In earlier studies that showed benefit from tight glucose control in critically ill patients, early parenteral nutrition was a potential variable that influenced the outcome. In a recent study of over 9000 patients in whom parenteral nutrition was withheld for a week, 90-day mortality, duration of intensive care unit care, and several other outcomes (eg, infections) were similar when liberal glucose control was compared with tight glucose control [19]. These results are consistent with more recent studies that support the use of liberal rather than tight targets for glucose control in critically ill patients. (See "Glycemic control in critically ill adult and pediatric patients", section on 'Adults'.)

  1. Pelsma ICM, Fassnacht M, Tsagarakis S, et al. Comorbidities in mild autonomous cortisol secretion and the effect of treatment: systematic review and meta-analysis. Eur J Endocrinol 2023; 189:S88.
  2. Zuraikat FM, Laferrère B, Cheng B, et al. Chronic Insufficient Sleep in Women Impairs Insulin Sensitivity Independent of Adiposity Changes: Results of a Randomized Trial. Diabetes Care 2024; 47:117.
  3. Waibel M, Wentworth JM, So M, et al. Baricitinib and β-Cell Function in Patients with New-Onset Type 1 Diabetes. N Engl J Med 2023; 389:2140.
  4. Hughes AE, Houghton JAL, Bunce B, et al. Bringing precision medicine to the management of pregnancy in women with glucokinase-MODY: a study of diagnostic accuracy and feasibility of non-invasive prenatal testing. Diabetologia 2023; 66:1997.
  5. Russell-Jones D, Babazono T, Cailleteau R, et al. Once-weekly insulin icodec versus once-daily insulin degludec as part of a basal-bolus regimen in individuals with type 1 diabetes (ONWARDS 6): a phase 3a, randomised, open-label, treat-to-target trial. Lancet 2023; 402:1636.
  6. Lee TTM, Collett C, Bergford S, et al. Automated Insulin Delivery in Women with Pregnancy Complicated by Type 1 Diabetes. N Engl J Med 2023; 389:1566.
  7. https://www.asahq.org/about-asa/newsroom/news-releases/2023/06/american-society-of-anesthesiologists-consensus-based-guidance-on-preoperative.
  8. Lederman S, Ottery FD, Cano A, et al. Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): a phase 3 randomised controlled study. Lancet 2023; 401:1091.
  9. Johnson KA, Martin N, Nappi RE, et al. Efficacy and Safety of Fezolinetant in Moderate to Severe Vasomotor Symptoms Associated With Menopause: A Phase 3 RCT. J Clin Endocrinol Metab 2023; 108:1981.
  10. “The 2023 Nonhormone Therapy Position Statement of The North American Menopause Society” Advisory Panel. The 2023 nonhormone therapy position statement of The North American Menopause Society. Menopause 2023; 30:573.
  11. Bird ST, Smith ER, Gelperin K, et al. Severe Hypocalcemia With Denosumab Among Older Female Dialysis-Dependent Patients. JAMA 2024.
  12. FDA drug safety communication for Prolia. Available at: https://www.fda.gov/media/175509/download?attachment (Accessed on January 22, 2024).
  13. Lewiecki EM, Czerwinski E, Recknor C, et al. Efficacy and Safety of Transdermal Abaloparatide in Postmenopausal Women with Osteoporosis: A Randomized Study. J Bone Miner Res 2023; 38:1404.
  14. Douglas RS, Parunakian E, Tolentino J, et al. A Prospective Study Examining Audiometry Outcomes Following Teprotumumab Treatment for Thyroid Eye Disease. Thyroid 2023.
  15. Ali SZ, Baloch ZW, Cochand-Priollet B, et al. The 2023 Bethesda System for Reporting Thyroid Cytopathology. Thyroid 2023; 33:1039.
  16. Hadoux J, Elisei R, Brose MS, et al. Phase 3 Trial of Selpercatinib in Advanced RET-Mutant Medullary Thyroid Cancer. N Engl J Med 2023; 389:1851.
  17. Fazendin J, Zmijewski P, Allahwasaya A, et al. Surgical Treatment of Hyperthyroidism Can Be Performed Safely Before a Euthyroid State is Achieved. Thyroid 2023; 33:691.
  18. Chorti A, Bontinis V, Tzikos G, et al. Minimally Invasive Treatments of Benign Thyroid Nodules: A Network Meta-Analysis of Short-Term Outcomes. Thyroid 2023; 33:950.
  19. Gunst J, Debaveye Y, Güiza F, et al. Tight Blood-Glucose Control without Early Parenteral Nutrition in the ICU. N Engl J Med 2023; 389:1180.
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