Gilbert H. Daniels

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

BACKGROUND The cardiovascular effect of liraglutide, a glucagon-like peptide 1 analogue, when added to standard care in patients with type 2 diabetes, remains unknown. METHODS In this double-blind trial, we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo. The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome, with a margin of 1.30 for the upper boundary of the 95% confidence interval of the hazard ratio. No adjustments for multiplicity were performed for the prespecified exploratory outcomes. RESULTS A total of 9340 patients underwent randomization. The median follow-up was 3.8 years. The primary outcome occurred in significantly fewer patients in the liraglutide group (608 of 4668 patients [13.0%]) than in the placebo group (694 of 4672 [14.9%]) (hazard ratio, 0.87; 95% confidence interval [CI], 0.78 to 0.97; P<0.001 for noninferiority; P=0.01 for superiority). Fewer patients died from cardiovascular causes in the liraglutide group (219 patients [4.7%]) than in the placebo group (278 [6.0%]) (hazard ratio, 0.78; 95% CI, 0.66 to 0.93; P=0.007). The rate of death from any cause was lower in the liraglutide group (381 patients [8.2%]) than in the placebo group (447 [9.6%]) (hazard ratio, 0.85; 95% CI, 0.74 to 0.97; P=0.02). The rates of nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure were nonsignificantly lower in the liraglutide group than in the placebo group. The most common adverse events leading to the discontinuation of liraglutide were gastrointestinal events. The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group. CONCLUSIONS In the time-to-event analysis, the rate of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo. (Funded by Novo Nordisk and the National Institutes of Health; LEADER ClinicalTrials.gov number, NCT01179048.).

Comparison of administration of recombinant human thyrotropin with withdrawal of thyroid hormone for radioactive iodine scanning in patients with thyroid carcinoma.

BACKGROUND To detect recurrent disease in patients who have had differentiated thyroid cancer, periodic withdrawal of thyroid hormone therapy may be required to raise serum thyrotropin concentrations to stimulate thyroid tissue so that radioiodine (iodine-131) scanning can be performed. However, withdrawal of thyroid hormone therapy causes hypothyroidism. Administration of recombinant human thyrotropin stimulates thyroid tissue without requiring the discontinuation of thyroid hormone therapy. METHODS One hundred twenty-seven patients with thyroid cancer underwent whole-body radioiodine scanning by two techniques: first after receiving two doses of thyrotropin while thyroid hormone therapy was continued, and second after the withdrawal of thyroid hormone therapy. The scans were evaluated by reviewers unaware of the conditions of scanning. The serum thyroglobulin concentrations and the prevalence of symptoms of hypothyroidism and mood disorders were also determined. RESULTS Sixty-two of the 127 patients had positive whole-body radioiodine scans by one or both techniques. The scans obtained after stimulation with thyrotropin were equivalent to the scans obtained after withdrawal of thyroid hormone in 41 of these patients (66 percent), superior in 3 (5 percent), and inferior in 18 (29 percent). When the 65 patients with concordant negative scans were included, the two scans were equivalent in 106 patients (83 percent). Eight patients (13 percent of those with at least one positive scan) were treated with radioiodine on the basis of superior scans done after withdrawal of thyroid hormone. Serum thyroglobulin concentrations increased in 15 of 35 tested patients: 14 after withdrawal of thyroid hormone and 13 after administration of thyrotropin. Patients had more symptoms of hypothyroidism (P<0.001) and dysphoric mood states (P<0.001) after withdrawal of thyroid hormone than after administration of thyrotropin. CONCLUSIONS Thyrotropin stimulates radioiodine uptake for scanning in patients with thyroid cancer, but the sensitivity of scanning after the administration of thyrotropin is less than that after the withdrawal of thyroid hormone. Thyrotropin scanning is associated with fewer symptoms and dysphoric mood states.

Extra-Adrenal Pheochromocytoma

Extra-adrenal pheochromocytomas may arise in any portion of the paraganglion system, although they most commonly occur below the diaphragm. The most common site of occurrence of extra-adrenal pheochromocytoma is the superior para-aortic region between the diaphragm and lower renal poles. Although the traditional teaching has been that 10% of all pheochromocytomas are at extra-adrenal sites, this may be an underestimation. Extra-adrenal pheochromocytomas probably represent at least 15% of adult and 30% of childhood pheochromocytomas. They may be malignant in up to 40% of the cases, although conflicting data add to the uncertainty of this point. Patients with tumors arising at extra-adrenal sites commonly present with headache, palpitations, sweating and hypertension. The diagnosis is most often confirmed by demonstrating increased catecholamine production, usually by measurement of urinary catecholamines and/or their metabolites. CT scanning is presently the imaging procedure of choice for localization. The roles of MRI and 131I-MIBG scintigraphy in the localization process are still being determined. Thorough preoperative pharmacological preparation, attentive intraoperative monitoring and aggressive surgical therapy all have an important role in achieving the safest and most successful outcome. Complete surgical excision is the treatment of choice for primary extra-adrenal pheochromocytoma as well as recurrent or metastatic disease. When residual tumor cannot be resected, medical therapy for symptomatic relief is preferred, since radiotherapy and chemotherapy have limited effectiveness. Extra-adrenal pheochromocytomas are more likely to recur and to metastasize than their adrenal counterparts, making lifelong followup with annual determinations of catecholamine production essential.

Subclinical Hyperthyroidism and reduced bone density as a possible result of prolonged suppression of the pituitary-thyroid axis with L-Thyroxine

Spontaneous hyperthyroidism and that due to excessive administration of thyroid hormone result in osteopenia. Bone density was measured in 28 white premenopausal female patients who were taking commonly prescribed suppressive doses of L-thyroxine (mean dose 0.171 +/- 0.035 g) for five or more years. The thyroxine level was 13.5 +/- 2.6 micrograms/dl (normal 8.0 +/- 2.4 micrograms/dl), the free thyroxine index was 4.4 +/- 1.0 (normal 2.4 +/- 0.8), and the triiodothyronine value was 154 +/- 26 ng/dl (normal 132 +/- 32 ng/dl). Basal thyrotropin was undetectable (less than 0.08 microIU/ml) in 23 patients, and thyrotropin measured 20 minutes after thyrotropin-releasing hormone administration was not demonstrable in 13 patients and subnormal in 10 patients. Women who had taken L-thyroxine for 10 or more years (n = 12, age 37 +/- 4 years) had a 9 percent reduction in bone density (0.667 +/- 0.044 g/cm2, p less than 0.01) compared with normal premenopausal age-matched control subjects (n = 56, age 35 +/- 6 years, bone density 0.733 +/- 0.055 g/cm2). It is concluded that prolonged suppressive L-thyroxine treatment may result in mild subclinical hyperthyroidism with adverse effects on bone. Patients requiring suppression of the pituitary-thyroid axis should be given the smallest dose of L-thyroxine necessary to achieve a satisfactory clinical response.

Noninvasive evaluation of cardiac function in hypothyroidism. Response to gradual thyroxine replacement.

Left ventricular performance was studied in 15 patients with severe, primary hypothyroidism (mean serum total thyroxine of 0.8 mug per 100 ml and serum thyrotropin of 160 muU per milliliter). Pretreatment systolic-time intervals were characterized by prolongation of the pre-ejection period (delta PEP = +30) and reduction of the left ventricular ejection period (delta LVET = -23) with a resultant increase in the PEP/LVET ratio (0.47). Nine of 14 patients demonstrated pericardial effusions. These abnormalities were reversed with physiologic thyroxine replacement. Further reductions of the delta PEP and PEP/LVET ratio occurred with supraphysiologic doses (200 to 300 mug per day). During therapy, delta PEP was inversely correlated with serum thyroxine (P less than 0.001) and directly correlated with serum thyrotropin (P less than 0.001). Thus physiologic thyroid hormone replacement, appropriately adjusted to need, appears necessary in hypothyroidism for optimal left ventricular function.

Agranulocytosis associated with antithyroid drugs. Effects of patient age and drug dose

The records of all patients with antithyroid drug-related agranulocytosis at two Boston hospitals (Group 1, 14 patients), as well as the published case reports of 36 patients with this syndrome (Group 2) were reviewed. The clinical characteristics of these patients were then compared with those of 50 hyperthyroid patients who had taken antithyroid medication without untoward hematologic reactions (Group 3). The mean ages of patients in Group 1 and Group 2 were significantly greater than that of Group 3 (50.6 +/- 16 years versus 35.7 +/- 13.7 years, p less than 0.001; 46.3 +/- 18.7 years versus 35.7 +/-- 13.7 years, p less than 0.02). By chi-square analysis, the relative risk of developing agranulocytosis in patients over age 40 was 6.4 times that among younger patients (p less than 0.001). The mean doses of methimazole in Group 1 and Group 2 were significantly higher than that in Group 3 (43.8 +/- 9.9 mg/d versus 29.5 +/- 10.4 mg/d, p less than 0.001; 40.7 +/- 15.7 mg/d versus 29.5 +/- 10.4 mg/d, p less than 0.02), with and 8.6-fold increased risk of agranulocytosis with doses greater than 40 mg/d (p less than 0.01). In contrast, the mean doses of propylthiouracil did not differ among the three groups. These data suggest that antithyroid drugs should be administered cautiously to patients over age 40. Because no cases of agranulocytosis were seen with methimazole doses less than 30 mg/d, low-dose methimazole therapy may be safer than high-dose therapy or treatment with conventional doses of propylthiouracil.

GLP-1 and Calcitonin Concentration in Humans: Lack of Evidence of Calcitonin Release from Sequential Screening in over 5000 Subjects with Type 2 Diabetes or Nondiabetic Obese Subjects Treated with the Human GLP-1 Analog, Liraglutide

BACKGROUND Serum calcitonin (CT) is a well-accepted marker of C-cell proliferation, particularly in medullary thyroid carcinoma. Chronic glucagon-like peptide-1 (GLP-1) receptor agonist administration in rodents has been associated with increased serum CT levels and C-cell tumor formation. There are no longitudinal studies measuring CT in humans without medullary thyroid carcinoma or a family history of medullary thyroid carcinoma and no published studies on the effect of GLP-1 receptor agonists on human serum CT concentrations. AIM The aim of the study was to determine serum CT response over time to the GLP-1 receptor agonist liraglutide in subjects with type 2 diabetes mellitus or nondiabetic obese subjects. METHODS Unstimulated serum CT concentrations were measured at 3-month intervals for no more than 2 yr in a series of trials in over 5000 subjects receiving liraglutide or control therapy. RESULTS Basal mean CT concentrations were at the low end of normal range in all treatment groups and remained low throughout the trials. At 2 yr, estimated geometric mean values were no greater than 1.0 ng/liter, well below upper normal ranges for males and females. Proportions of subjects whose CT levels increased above a clinically relevant cutoff of 20 ng/liter were very low in all groups. There was no consistent dose or time-dependent relationship and no consistent difference between treatment groups. CONCLUSIONS These data do not support an effect of GLP-1 receptor activation on serum CT levels in humans and suggest that findings previously reported in rodents may not apply to humans. However, the long-term consequences of GLP-1 receptor agonist treatment are a subject of further studies.

Complications of surgery in hypothyroid patients

Hypothyroidism has generally been considered a contraindication to surgery. To determine the actual risks of perioperative complications in hypothyroid patients, the clinical courses of 40 hypothyroid surgical patients (serum thyroxine concentration 1.9 +/- 1.0 micrograms/dl) were retrospectively compared with those of 80 control patients matched for age, sex, and operative procedure. The two study groups were comparable in preoperative anesthetic physical class, prevalence of other medical conditions, and year of operation. During noncardiac surgery, intraoperative hypotension was encountered more frequently in the hypothyroid patients than in the control patients (61 versus 30 percent, p less than 0.05). Cardiac surgery was complicated by heart failure more often in the hypothyroid patients (29 versus 6 percent, p less than 0.05). Postoperatively, the hypothyroid patients more commonly had gastrointestinal (19 versus 1 percent, p less than 0.02) and neuropsychiatric (38 versus 18 percent, p less than 0.02) complications than control patients. Despite comparable rates of perioperative infection (38 versus 33 percent, p = NS), the hypothyroid patients less frequently manifested fever (35 versus 79 percent, p less than 0.001). There were no differences in perioperative blood loss, duration of hospitalization, or the prevalences of perioperative arrhythmia, hypothermia, hyponatremia, delayed anesthetic recovery, abnormal tissue integrity, impaired wound healing, pulmonary complications, or death. Preoperative clinical and chemical features of hypothyroidism were not useful in defining a subgroup of patients at special risk. Thus, surgery in hypothyroid patients is associated with an increased risk of several minor perioperative complications, which should be anticipated and preemptively managed in the course of their anesthetic and surgical care.

Design of the liraglutide effect and action in diabetes: Evaluation of cardiovascular outcome results (LEADER) trial

BACKGROUND Diabetes is a multisystem disorder associated with a nearly twofold excess risk for a broad range of adverse cardiovascular outcomes including coronary heart disease, stroke, and cardiovascular death. Liraglutide is a human glucagon-like peptide receptor analog approved for use in patients with type 2 diabetes mellitus (T2DM). STUDY DESIGN To formally assess the cardiovascular safety of liraglutide, the Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial was commenced in 2010. LEADER is a phase 3B, multicenter, international, randomized, double-blind, placebo-controlled clinical trial with long-term follow-up. Patients with T2DM at high risk for cardiovascular disease (CVD) who were either drug naive or treated with oral antihyperglycemic agents or selected insulin regimens (human NPH, long-acting analog, or premixed) alone or in combination with oral antihyperglycemics were eligible for inclusion. Randomized patients are being followed for up to 5 years. The primary end point is the time from randomization to a composite outcome consisting of the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. CONCLUSIONS LEADER commenced in September 2010, and enrollment concluded in April 2012. There were 9,340 patients enrolled at 410 sites in 32 countries. The mean age of patients was 64.3 ± 7.2 years, 64.3% were men, and mean body mass index was 32.5 ± 6.3 kg/m2. There were 7,592 (81.3%) patients with prior CVD and 1,748 (18.7%) who were high risk but without prior CVD. It is expected that LEADER will provide conclusive data regarding the cardiovascular safety of liraglutide relative to the current standard of usual care for a global population of patients with T2DM.

Redifferentiation of Iodine-Refractory BRAF V600E-Mutant Metastatic Papillary Thyroid Cancer with Dabrafenib

Purpose: To determine whether the selective BRAF inhibitor, dabrafenib, can stimulate radioiodine uptake in BRAF V600E-mutated unresectable or metastatic iodine-refractory papillary thyroid cancer (PTC). Experimental Design: Ten patients with BRAF V600E-mutant iodine-refractory PTC were enrolled. Absence of radioiodine uptake on iodine-131 whole body scan obtained within 14 months of study entry was required. Each patient received dabrafenib (150 mg twice daily) for 25 days before thyrotropin α-stimulated iodine-131 whole body scan (4 mCi/148 MBq). Patients whose scan showed new sites of radioiodine uptake remained on dabrafenib for 17 more days, and then were treated with 150 mCi (5.5 GBq) iodine-131. The primary endpoint of the study was the percentage of patients with new radioiodine uptake after treatment with dabrafenib. Results: Six of 10 patients (60%) demonstrated new radioiodine uptake on whole body scan after treatment with dabrafenib. All 6 were treated with 5.5 GBq iodine-131. Two patients had partial responses and 4 patients had stable disease on standard radiographic restaging at 3 months. Thyroglobulin decreased in 4 of 6 treated patients. One patient developed squamous cell carcinoma of the skin. There were no other significant adverse events attributed to dabrafenib. Conclusions: Dabrafenib can stimulate radioiodine uptake in patients with metastatic BRAF V600E-mutant iodine-refractory PTC, representing a potential new therapeutic approach for these patients. Clin Cancer Res; 21(5); 1028–35. ©2014 AACR.