In pituitary adenoma surgery, no vs. perioperative hydrocortisone was noninferior for new-onset adrenal insufficiency.

SOURCE CITATION: Guo X, Zhang D, Pang H, et al. Safety of withholding perioperative hydrocortisone for patients with pituitary adenomas with an intact hypothalamus-pituitary-adrenal axis: a randomized clinical trial. JAMA Netw Open. 2022;5:e2242221. 36383383.

In uncontrolled T2DM treated with a basal-bolus insulin regimen, weekly icodec was noninferior to daily glargine for HbA1c at 26 wk.

SOURCE CITATION: Mathieu C, Ásbjörnsdóttir B, Bajaj HS, et al. Switching to once-weekly insulin icodec versus once-daily insulin glargine U100 in individuals with basal-bolus insulin-treated type 2 diabetes (ONWARDS 4): a phase 3a, randomised, open-label, multicentre, treat-to-target, non-inferiority trial. Lancet. 2023;401:1929-1940. 37156252.

In T2DM uncontrolled with noninsulin glucose-lowering agents, weekly icodec reduced HbA1c vs. daily degludec at 26 wk.

SOURCE CITATION: Lingvay I, Asong M, Desouza C, et al. Once-weekly insulin icodec vs once-daily insulin degludec in adults with insulin-naive type 2 diabetes: the ONWARDS 3 randomized clinical trial. JAMA. 2023;330:228-237. 37354562.

In T2DM uncontrolled with noninsulin glucose-lowering agents, weekly icodec reduced HbA1c vs. daily glargine at 52 wk.

SOURCE CITATION: Rosenstock J, Bain SC, Gowda A, et al; ONWARDS 1 Trial Investigators. Weekly icodec versus daily glargine U100 in type 2 diabetes without previous insulin. N Engl J Med. 2023;389:297-308. 37356066.

In type 2 diabetes, tirzepatide reduced HbA1c vs. semaglutide.

SOURCE CITATION: Frias JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med. 2021;385:503-15. 34170647.

In type 2 diabetes, some glucose-lowering drugs reduce HbA1c more than others; drugs do not differ for mortality.

SOURCE CITATION: Tsapas A, Avgerinos I, Karagiannis T, et al. Comparative effectiveness of glucose-lowering drugs for type 2 diabetes: a systematic review and network meta-analysis. Ann Intern Med. 2020;173:278-86. 32598218.

A Case of Metastatic Choriocarcinoma-Related Paraneoplastic Thyroid Storm.

Thyroid storm due to gestational trophoblastic disease (GTD) with metastatic choriocarcinoma is a rare but potentially life-threatening endocrine emergency. We report on a woman with molar pregnancy and metastatic choriocarcinoma who presented with thyroid storm (Burch-Wartofsky point scale of 45) a few weeks after the evacuation of GTD. She was initially managed with intravenous hydrocortisone, oral propylthiouracil (PTU), and esmolol infusion. After stabilization in the intensive care unit, 10 cycles of chemotherapy with etoposide, methotrexate, leucovorin, dactinomycin, and cyclophosphamide (EMA-CO) were initiated for stage 4 choriocarcinoma with brain and lung metastases. She underwent a hysterectomy soon after completing chemotherapy and received an additional 3 cycles of chemotherapy after the hysterectomy. As human chorionic gonadotropin (hCG) levels normalized, thyroid function reverted to normal as well. At the last follow-up, the patient was asymptomatic, euthyroid (without antithyroid medication), had a normal hCG titer of 1.7 mIU/mL (normal nonpregnant reference is < 5 mIU/mL), and the lung and brain lesions had resolved entirely. Management of thyroid storm in the presence of untreated metastatic choriocarcinoma requires a high index of suspicion and a multidisciplinary team approach to prevent complications and improve survival.

Clinical Considerations for Insulin Therapy in Older Adults with Type 1 Diabetes.

Type 1 diabetes represents an autoimmune condition with a strong inherited background, and its incidence is increasing worldwide. About 25% of such cases are diagnosed in adulthood, some even as late as the ninth decade of life. The number of older adults with type 1 diabetes is increasing due to improvements in care and decreased mortality rate. However, there is a lack of clinical trials in people older than 70 years of age with type 1 diabetes complicated with comorbidities, frailty, and dependency. The management of type 1 diabetes and the goals of therapy should be individualized based on the patient's health status and life expectancy. In healthier older adults, insulin treatment regimens (multiple daily insulin injections or insulin pump therapy) that approximate the normal physiology of insulin secretion should be used to achieve lower glycemic goals, while reducing the risk of hypoglycemia with frequent glucose monitoring (preferably using continuous glucose monitoring systems). For frail individuals with poor health, simpler insulin regimens and less stringent glycemic targets would be more appropriate. Poor cognition, vision and hearing, impaired mobility, depression, and chronic pain can interfere with complex insulin regimens. In these individuals, the principal goals of therapy are to reduce the acute effects of hyperglycemia, minimize hypoglycemia risk, and optimize quality of life. The newer insulin preparations and technological advances in insulin delivery and blood glucose monitoring have enhanced the management of type 1 diabetes in all age groups.

Management of Hyperglycemia in Older Adults with Type 2 Diabetes.

The increasing incidence of type 2 diabetes in the general population as well as enhanced life expectancy has resulted in a rapid rise in the prevalence of diabetes in the older population. Diabetes causes significant morbidity and impairs quality of life. Managing diabetes in older adults is a daunting task due to unique health and psychosocial challenges. Medical management is complicated by polypharmacy, cognitive impairment, urinary incontinence, injurious falls, and persistent pain. Health care providers now have several traditional and contemporary pharmacologic agents to manage diabetes. Avoidance of hypoglycemia is critical; however, evidence-based guidelines are lacking due to the paucity of clinical trials in older adults. For many in this population, maintaining independence is more important than adherence to published guidelines to prevent diabetes complications. The goal of diabetes care in older adults is to enhance the quality of life without subjecting these patients to intrusive and complicated interventions. Recent technological advancements such as continuous glucose monitoring systems can have crucial supplementary benefits in the geriatric population.

Clavicular Metastasis as an Initial Presentation of Papillary Thyroid Cancer.

OBJECTIVE: We present the case of a 44-year-old man with a large neck mass to highlight the unique presentation of papillary thyroid carcinoma (PTC) metastatic to the clavicle. METHODS: We reviewed the medical record for a detailed history and physical examination findings. Our radiology colleagues examined the diagnostic imaging studies performed. The pathology team reviewed the neck mass biopsy and the confirmatory surgical pathology after total resection of the mass. RESULTS: A 44-year-old man presented with an enlarging neck mass. Initial X-rays revealed a large soft tissue density mass that extended to the midline of the right clavicle. A neck ultrasound established a 5.4 × 3.6 cm mass with increased vascularity and calcification extending from the thyroid. A CT scan noted the extension of the mass into the adjacent sternoclavicular junction with osteolysis of the middle third of the clavicle and the superior aspect of the sternal body. Fine-needle aspiration revealed a thyroid neoplasm with follicular features and positive immunostaining consistent with thyroid carcinoma. The patient underwent a composite resection of the tumor, including a segmental osteotomy of approximately two-thirds of the medial clavicle. The pathology report confirmed PTC with extrathyroidal extension and clavicle involvement (staged pT4a pN0), with further genomic findings showing positive KRAS mutation. CONCLUSION: Clavicular metastasis from differentiated thyroid cancer is rare. While the prognosis is generally favorable, various factors, including age greater than 45 years, poor differentiation, follicular thyroid carcinoma, Hurthle cell variant, and extrapulmonary metastasis, have typically been associated with poorer cancer-specific survival.

Symptomatic Pituitary Metastasis as Initial Manifestation of Renal Cell Carcinoma: Case Report and Review of Literature.

Metastasis to the pituitary gland is extremely rare (∼2% of sellar masses). Clinical, biochemical, and radiologic characteristics of pituitary metastasis are poorly defined and can be difficult to diagnose before surgery. We present an unusual case with pituitary metastasis as the first manifestation of renal cell carcinoma (RCC). A 70-year-old male presented with acute onset of weakness, dizziness, diplopia, and progressively worsening headache. The initial CT head revealed a heterogeneous sellar mass measuring 2.8 × 1.9 × 1.7 cm. A follow-up MRI showed the sellar mass invading the right cavernous sinus. The presumptive diagnosis was a pituitary macroadenoma. Physical examination revealed bilateral 6th cranial nerve palsy and episodes of intermittent binocular horizontal diplopia. Hormonal testing noted possible secondary adrenal insufficiency (AM serum cortisol: 3.3 mcg/dL, ACTH: 8 pg/mL), secondary hypothyroidism (TSH: <0.01 mIU/L, FT4: 0.7 ng/dL), secondary hypogonadism (testosterone: 47 ng/dL, LH: 1.3 mIU/mL, and FSH: 2.3 mIU/mL), and elevated serum prolactin (prolactin: 56.8 ng/ml, normal: 4.0-15.2 ng/ml). IGF-1 level was normal at 110 ng/mL (47-192 ng/mL). The patient was discharged on levothyroxine and hydrocortisone therapy with plans for close surveillance. However, his condition worsened over the next three months, and he was subsequently readmitted with nausea, vomiting, and hypernatremia secondary to diabetes insipidus. Repeat MRI pituitary showed an interval increase in the size of the sellar mass with suprasellar extension and a new mass effect on the optic chiasm. The sellar mass was urgently resected via a trans-sphenoidal approach. The tumor was negative for neuroendocrine markers and pituitary hormone panel, ruling out the diagnosis of pituitary adenoma and triggered workup for metastatic renal cell carcinoma, clear cell type. The diagnosis of renal cell carcinoma was confirmed by the diffuse and strong staining for renal cell carcinoma markers (Pax-8, RCC-1, and CD10). A follow-up CT scan noted large right renal mass measuring 11 × 10 × 11 cm. The patient underwent a cytoreductive robotic right radical nephrectomy for WHO/ISUP histologic grade II clear cell RCC, stage pT2b pNX pM1. He subsequently received fractionated stereotactic radiotherapy to the pituitary gland. He is presently stable with no radiological evidence of progression or new intracranial disease on subsequent imaging. Pituitary metastasis most commonly occurs from breast, lung, or gastrointestinal tumors but also rarely from renal cell carcinoma. Biochemical findings such as panhypopituitarism, acute clinical signs such as headache, visual symptoms, and diabetes insipidus and interval increase in sellar mass in a short time interval should raise suspicion for sellar metastasis.

Incretins in the ICU: is insulin on its way out?

Incretins such as glucagon-like peptide-1 (GLP-1) are gut-derived hormones that stimulate insulin secretion and suppress glucagon secretion, thus playing a key role in glucose homeostasis. While incretin mimetics and enhancers are approved for treatment of outpatients with diabetes, evidence is only starting to accumulate regarding the therapeutic potential of incretins in hospitalized patients. Small exploratory studies suggest that GLP-1 safely reduces hyperglycemia without causing hypoglycemia, a key advantage over insulin if efficacy is established in larger studies. Potential limitations include the need for a continuous infusion for delivery, attenuation but not normalization of glucose levels, increased deceleration of gastric emptying and nausea. The exact mechanism of action, dosing, adverse effects, patient subgroups that would be most suitable and safety of combination treatment with insulin remain to be studied. While promising, additional research is required studying effects on hard clinical endpoints.

Effect of perioperative insulin infusion on surgical morbidity and mortality: systematic review and meta-analysis of randomized trials.7.

OBJECTIVE: To conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the effect of perioperative insulin infusion on outcomes important to patients. PATIENTS AND METHODS: We used 6 search strategies including an electronic database search of MEDLINE, EMBASE, and Cochrane CENTRAL, from their inception up to May 1, 2006, and included RCTs of perioperative insulin infusion (with or without glucose targets) measuring outcomes in patients undergoing any surgery. Pairs of reviewers working independently assessed the methodological quality and characteristics of included trials and abstracted data on perioperative outcomes (ie, outcomes that occurred during hospitalization or within 30 days of surgery). RESULTS: We identified 34 eligible trials. In the 14 trials that assessed mortality, there were 68 deaths among 2192 patients randomized to insulin infusion compared with 98 deaths among 2163 patients randomized to control therapy (random-effects pooled relative risk, 0.69; 95% confidence interval [CI], 0.51-0.94; 99% CI, 0.46-1.04; I2, 0%; 95% CI, 0.0%-47.4%). Hypoglycemia increased in the intensively treated group (20 trials, 119/1470 patients in insulin infusion vs 48/1476 patients in control group; relative risk, 2.07; 95% CI, 1.29-3.32; 99% CI, 1.09-3.88; I2, 31.5%; 95% CI, 0.0%-59.0%). No significant effect was seen in any other outcomes. The available mortality data represent only 40% of the optimal information size required to reliably detect a plausible treatment effect; potential methodological and reporting biases weaken inferences. CONCLUSION: Perioperative insulin infusion may reduce mortality but increases hypoglycemia in patients who are undergoing surgery; however, mortality results require confirmation in large and rigorous RCTs.

Immunotherapeutic agents in type 1 diabetes: a systematic review and meta-analysis of randomized trials.

OBJECTIVE: Although recent trial results of anti-CD3 therapy are promising, there have been conflicting results of various immunotherapeutic agents used in patients with type 1 diabetes. We conducted a systematic review and meta-analysis to determine the efficacy of nonantigen-based immunotherapeutic approaches for preservation of beta-cell function in patients with type 1 diabetes. METHODS: We searched MEDLINE, EMBASE, Cochrane CENTRAL, reference lists, and content expert files up to September 2006. Eligible studies were randomized controlled trials (RCTs) of antiproliferative agents (methotrexate, azathioprine), monoclonal antibodies (CD3, CD4), T-cell inhibitors (cyclosporin) and other immunotherapeutic agents (photopheresis, linomide, fusidin, buffy coat, intravenous immunoglobulin, BCG, nicotinamide) in patients with newly diagnosed type 1 diabetes followed for > or = 6 months. Pairs of reviewers working independently and with adequate reliability assessed the trials' methodological quality, collected data, and conducted random-effects meta-analyses on measures of preservation of beta-cell function (e.g. C-peptide secretion, insulin independence). RESULTS: Of the 299 potentially relevant articles identified after an initial search, 20 trials met selection criteria. Meta-analysis of 20 trials (n = 1187 patients) found a small to moderate improvement in beta-cell function with immunotherapy [vs. placebo, effect size 0.37, 95% confidence interval (CI) 0.14-0.6] but there was moderate inconsistency in results across trials (I(2) 65%, 95% CI 39-77%). Subgroup analysis suggested a greater effect of cyclosporin and antiproliferative agents on beta-cell function when used for > or = 6 months (pooled effect size 0.77 vs. -0.11, respectively; P(interaction) = 0.002). CONCLUSIONS: Long-term immunotherapy may preserve beta-cell function in newly diagnosed patients with type 1 diabetes. Patients and clinicians must await the conduct of rigorous trials reporting on diabetes resolution, adverse events, and other patient-important outcomes.

Intensive intraoperative insulin therapy versus conventional glucose management during cardiac surgery: a randomized trial.

BACKGROUND: It is not known whether rigorous intraoperative glycemic control reduces death and morbidity in cardiac surgery patients. OBJECTIVE: To compare outcomes of intensive insulin therapy during cardiac surgery with those of conventional intraoperative glucose management. DESIGN: A randomized, open-label, controlled trial with blinded end point assessment. SETTING: Tertiary care center. PATIENTS: Adults with and without diabetes who were undergoing on-pump cardiac surgery. MEASUREMENTS: The primary outcome was a composite of death, sternal infections, prolonged ventilation, cardiac arrhythmias, stroke, and renal failure within 30 days after surgery. Secondary outcome measures were length of stay in the intensive care unit and hospital. INTERVENTION: Patients were randomly assigned to receive continuous insulin infusion to maintain intraoperative glucose levels between 4.4 (80 mg/dL) and 5.6 mmol/L (100 mg/dL) (n = 199) or conventional treatment (n = 201). Patients in the conventional treatment group were not given insulin during surgery unless glucose levels were greater than 11.1 mmol/L (>200 mg/dL). Both groups were treated with insulin infusion to maintain normoglycemia after surgery. RESULTS: Mean glucose concentrations were statistically significantly lower in the intensive treatment group at the end of surgery (6.3 mmol/L [SD, 1.6] [114 mg/dL {SD, 29}] in the intensive treatment group vs. 8.7 mmol/L [SD, 2.3] [157 mg/dL {SD, 42}] in the conventional treatment group; difference, -2.4 mmol/L [95% CI, -2.8 to -1.9 mmol/L] [-43 mg/dL {CI, -50 to -35 mg/dL}]). Eighty two of 185 patients (44%) in the intensive treatment group and 86 of 186 patients (46%) in the conventional treatment group had an event (risk ratio, 1.0 [CI, 0.8 to 1.2]). More deaths (4 deaths vs. 0 deaths; P = 0.061) and strokes (8 strokes vs. 1 strokes; P = 0.020) occurred in the intensive treatment group. Length of stay in the intensive care unit (mean, 2 days [SD, 2] vs. 2 days [SD, 3]; difference, 0 days [CI, -1 to 1 days]) and in the hospital (mean, 8 days [SD, 4] vs. 8 days [SD, 5]; difference, 0 days [CI, -1 to 0 days]) was similar for both groups. LIMITATIONS: This single-center study used a composite end point and could not examine whether outcomes differed by diabetes status. CONCLUSIONS: Intensive insulin therapy during cardiac surgery does not reduce perioperative death or morbidity. The increased incidence of death and stroke in the intensive treatment group raises concern about routine implementation of this intervention.

Patient-important outcomes in registered diabetes trials.

CONTEXT: Concerns about the safety and efficacy of diabetes interventions persist, in part because randomized clinical trials (RCTs) have not measured their effect on patient-important outcomes, ie, death and quality of life (morbidity, pain, function). OBJECTIVE: To systematically determine the extent to which ongoing and future RCTs in diabetes will ascertain patient-important outcomes. DATA SOURCES: On November 10, 2007, we searched primary RCT registries ClinicalTrials.gov (http://www.clinicaltrials.gov), International Standard Randomized Controlled Trial Number Register (http://isrctn.org), and Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au). STUDY SELECTION: We identified phase 2 through 4 RCTs enrolling patients with diabetes. Of 2019 RCTs, 1054 proved eligible. We randomly sampled 50% of the eligible RCTs (527 of 1054) and selected 436 registered since registration became mandatory (2004). DATA EXTRACTION: Pairs of reviewers working independently collected study characteristics and determined the outcomes measured and their type (physiological outcomes, surrogate outcomes thought to reflect an increased risk for patient-important outcomes, and patient-important outcomes). RESULTS: Of the 436 registered RCTs included in this analysis, 24 (6%) had not started enrollment, 109 (25%) were actively enrolling, and 303 (69%) had completed enrollment. Primary outcomes were patient-important outcomes in only 78 of 436 RCTs (18%; 95% confidence interval [CI], 14%-22%), physiological and laboratory outcomes in 69 of 436 (16%; 95% CI, 13%-20%), and surrogate outcomes in 268 of 436 (61%; 95% CI, 57%-66%). Patient-important outcomes were reported as primary or secondary outcomes in 201 of 436 (46%; 95% CI, 41%-51%). In multivariate analysis, large trials (odds ratio [OR], 1.10; 95% CI, 1.02-1.19 for every additional 100 patients) and trials of longer duration (OR, 1.03; 95% CI, 1.01-1.06 for every additional 30 days) were more likely while parallel design RCTs (OR, 0.15; 95% CI, 0.05-0.44) and type 2 diabetes trials (OR, 0.23; 95% CI, 0.09-0.61) were less likely to assess patient-important outcomes as a primary outcome. CONCLUSION: In this sample of registered ongoing RCTs in diabetes, only 18% included patient-important outcomes as primary outcomes.

Endocrinopathy in POEMS syndrome: the Mayo Clinic experience.

OBJECTIVE: To determine the prevalence and characteristics of endocrinopathies at diagnosis of POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) syndrome. PATIENTS AND METHODS: From January 1, 1960, through June 30, 2006, we identified 170 patients with POEMS syndrome in the Mayo Clinic dysproteinemia database. We abstracted information about endocrine abnormalities from their medical records. RESULTS: Of the 170 patients with POEMS syndrome during the entire study period, the 64 patients seen after 2000 had more complete endocrine evaluations; of these 64 patients, 54 (84%) had a recognized endocrinopathy (38 men; median age, 50 years; interquartile range, 43-59 years). Hypogonadism was the most common endocrine abnormality; 26 (79%) of 33 men had subnormal total testosterone levels, and 10 men had gynecomastia. Among the 35 patients with measured prolactin levels, 7 men and 3 women had elevated levels. Hypothyroidism was noted in 17 men and 11 women. Abnormalities in glucose metabolism were present in 24 (48%) of 50 patients; 16 patients had impaired fasting glucose levels, and 8 were diagnosed as having diabetes. Adrenal insufficiency (defined by an abnormal response of cortisol to stimulation with standard high-dose [250 microg] synthetic adrenocorticotropic hormone) was noted in 6 of 9 patients tested. Fourteen (27%) of 51 patients tested had hypocalcemia. Twenty-nine (54%) of 54 patients had evidence of multiple endocrinopathies in the 4 major endocrine axes (gonadal, thyroid, glucose, and adrenal). CONCLUSION: The high prevalence of endocrinopathy in our study, to our knowledge the largest published series of POEMS cases, calls for a thorough endocrine investigation in patients presenting with this syndrome.