The Origin of Antithyroid Drugs.

Background: When the antithyroid drugs were discovered in the early 1940s, they were immediately recognized as a revolutionary new treatment for hyperthyroidism. Although much has been learned about their mechanism of action and clinical utility, they continue to be used today in much the same way as they have been since their introduction. Summary: In 1995, Dr. Clark Sawin gave an address on the history of antithyroid drug development at the 11th International Thyroid Congress in Toronto, Ontario, Canada. In his review, Dr. Sawin recounted the original observations by Drs. Julia and Cosmo Mackenzie and Curt Richter at the Johns Hopkins University School of Medicine, and how their work ultimately led to Dr. Edwin (Ted) B. Astwood's seminal 1943 report on the use of thiourea and thiouracil in the Journal of the American Medical Association. He also described the development of propylthiouracil and methimazole as less toxic alternatives. He concluded his remarks by noting the often-serendipitous pathway of drug development and the role of pharmaceutical companies in the process. Conclusions: Antithyroid drugs remain a cornerstone of thyroid therapeutics. It is informative to review the process by which they came into use, as this is a seminal part of the history of thyroid disease in the 20th century. This knowledge may also spark additional research leading to new pharmacotherapies for patients with hyperthyroidism.

Estradiol, testosterone, and the risk for hip fractures in elderly men from the Framingham Study.

BACKGROUND: Low serum estradiol has been more strongly associated with low bone mineral density in elderly men than has testosterone, but its association with incident hip fracture is unknown. We examined whether low estradiol increases the risk for future hip fracture among men and explored whether testosterone levels influence this risk. METHODS: We examined 793 men (mean age = 71 years) evaluated between 1981 and 1983, who had estradiol measures and no history of hip fracture, and followed until the end of 1999. Total estradiol and testosterone were measured between 1981 and 1983. Hip fractures were identified and confirmed through medical records review through the end of 1999. We created 3 groups of men based on estradiol levels and performed a Cox-proportional hazards model to examine the risk for incident hip fracture, adjusted for age, body mass index, height, and smoking status. We performed similar analyses based on testosterone levels, and then based on both estradiol and testosterone levels together. RESULTS: There were 39 men who sustained an atraumatic hip fracture over follow-up. Incidence rates for hip fracture (per 1000 person-years) were 11.0, 3.4, and 3.9 for the low (2.0-18.1 pg/mL [7-67 pmol/L]), middle (18.2-34.2 pg/mL [67-125 pmol/L]), and high (> or =34.3 pg/mL [> or =126 pmol/L]) estradiol groups, respectively. With adjustment for age, body mass index, height, and smoking status, the adjusted hazard ratios for men in the low and middle estradiol groups, relative to the high group, were 3.1 (95% confidence interval [CI], 1.4-6.9) and 0.9 (95% CI, 0.4-2.0), respectively. In similar adjusted analyses evaluating men by their testosterone levels, we found no significant increased risk for hip fracture. However, in analyses in which we grouped men by both estradiol and testosterone levels, we found that men with both low estradiol and low testosterone levels had the greatest risk for hip fracture (adjusted hazard ratio: 6.5, 95% CI, 2.9-14.3). CONCLUSION: Men with low estradiol levels are at an increased risk for future hip fracture. Men with both low estradiol and low testosterone levels seem to be at greatest risk for hip fracture.

Development of evidence-based clinical practice guidelines for diabetes: the Department of Veterans Affairs/Department of Defense guidelines initiative.

OBJECTIVE: To describe the Veterans Affairs (VA)/Department of Defense (DoD) Clinical Practice Guidelines for diabetes and contrast selected recommendations with those of the American Diabetes Association (ADA). RESEARCH DESIGN AND METHODS: We summarize the general structure of the VA/DoD Guidelines and describe the rationale for recommendations issued in 2003 for glycemic control, management of hypertension, and retinopathy screening. We compare the synthesis of evidence and resulting recommendations for these content areas with the 2004 American Diabetes Association Clinical Practice Recommendations. RESULTS: The VA/DoD Guidelines and the ADA Clinical Practice Recommendations reported similar strength of evidence findings by content area, but clinical recommendations varied. The VA/DoD Guidelines and practice recommendations emphasize the use of data on absolute risk reduction from available published randomized clinical trials rather than relative risk reduction from observational analyses. The VA/DoD Guidelines employ an algorithm-based methodology to guide clinicians through a risk-stratified approach to managing individual patients rather than promoting a single standard for most or all patients without explicit consideration of competing comorbidities. CONCLUSIONS: The VA/DoD Guidelines are intended to guide diabetes care by providing Internet-ready, evidence-based annotations in algorithmic form to help clinicians set and revise individual treatment goals for their patients.

Pharmacy costs and glycemic control in the Department of Veterans Affairs.

OBJECTIVE: To determine pharmacy costs for glycemic treatment and its relationship to glycemic control in the Department of Veterans Affairs (VA) between 1994 and 2000. RESEARCH DESIGN AND METHODS: Patients with diabetes in the VA in FY1994, FY1996, FY1998, and FY2000 were identified using an ambulatory care pharmacy-derived database. Total drug acquisition costs, as well as expenditures for insulin, oral glycemic control agents, and self-blood glucose monitoring strips, were determined for these veterans. HbA(1c) levels for the corresponding time periods were also obtained. Pharmacy costs (medications and monitoring) were examined by glycemic control treatment type. RESULTS: In FY2000, 18% (n = 535,016) of all VA pharmacy patients were identified as having diabetes, and they received 30% of all pharmacy prescriptions. Overall, 23% of pharmacy expenditures for these patients were related to glycemic control medications and monitoring supplies. Annual pharmacy costs increased from FY1994 to FY2000. The greatest change was the higher expenditure for monitoring supplies through FY1998, which then decreased in FY2000. Increased pharmacy costs were associated with improved glycemic control. In FY2000, the mean last HbA(1c) level (n = 446,384) fell to 7.6% from 7.8% in FY1998 (n = 204,136) and 8.4% in 1996 (n = 53,348). CONCLUSIONS: Diabetes was associated with high pharmacy costs. Increasing medication expenditures were associated with improved HbA(1c) levels at the aggregated national level. Policies concerning dispensing monitoring supplies and several diabetes quality improvement projects were initiated during this interval. Future challenges include initiatives to further optimize care while controlling costs.

Diabetes process and outcome measures in the Department of Veterans Affairs.

OBJECTIVE: To evaluate performance of process and outcome measures in the care of patients with diabetes seen in Department of Veterans Affairs (VA) facilities. RESEARCH DESIGN AND METHODS: Retrospective audits of records and databases were conducted on randomly selected patients with diabetes over 5 years (1995 [baseline] and 1997-2000) in 22 VA networks. Performance on diabetes-specific and preventive processes was measured. RESULTS: Nationally, significant improvements over time were observed for all measures (P < 0.001). For example, the percentage of patients receiving a dilated retinal examination rose from 44% in 1995 to 67% in 2000. The percentage of patients who received a urinary protein test rose from 23% in 1997 to 54% in 2000. Those who received influenza vaccination rose from 34% in 1995 to 78% in 2000. However, there was significant regional variation among all measures. CONCLUSIONS: Adherence to diabetes-specific and preventive care measures in the VA improved from 1997 to 2000 compared with a 1995 baseline. The improvement occurred in a setting of the provision of guidelines, the contractual setting of specific targets, and the timely feedback of results to medical center and network directors. Future studies are needed to determine whether adherence to these measures will decrease the rates of complications in VA patients with diabetes.

Subclinical thyroid disease: scientific review and guidelines for diagnosis and management.

CONTEXT: Patients with serum thyroid-stimulating hormone (TSH) levels outside the reference range and levels of free thyroxine (FT4) and triiodothyronine (T3) within the reference range are common in clinical practice. The necessity for further evaluation, possible treatment, and the urgency of treatment have not been clearly established. OBJECTIVES: To define subclinical thyroid disease, review its epidemiology, recommend an appropriate evaluation, explore the risks and benefits of treatment and consequences of nontreatment, and determine whether population-based screening is warranted. DATA SOURCES: MEDLINE, EMBASE, Biosis, the Agency for Healthcare Research and Quality, National Guideline Clearing House, the Cochrane Database of Systematic Reviews and Controlled Trials Register, and several National Health Services (UK) databases were searched for articles on subclinical thyroid disease published between 1995 and 2002. Articles published before 1995 were recommended by expert consultants. STUDY SELECTION AND DATA EXTRACTION: A total of 195 English-language or translated papers were reviewed. Editorials, individual case studies, studies enrolling fewer than 10 patients, and nonsystematic reviews were excluded. Information related to authorship, year of publication, number of subjects, study design, and results were extracted and formed the basis for an evidence report, consisting of tables and summaries of each subject area. DATA SYNTHESIS: The strength of the evidence that untreated subclinical thyroid disease is associated with clinical symptoms and adverse clinical outcomes was assessed and recommendations for clinical practice developed. Data relating the progression of subclinical to overt hypothyroidism were rated as good, but data relating treatment to prevention of progression were inadequate to determine a treatment benefit. Data relating a serum TSH level higher than 10 mIU/L to elevations in serum cholesterol were rated as fair but data relating to benefits of treatment were rated as insufficient. All other associations of symptoms and benefit of treatment were rated as insufficient or absent. Data relating a serum TSH concentration lower than 0.1 mIU/L to the presence of atrial fibrillation and progression to overt hyperthyroidism were rated as good, but no data supported treatment to prevent these outcomes. Data relating restoration of the TSH level to within the reference range with improvements in bone mineral density were rated as fair. Data addressing all other associations of subclinical hyperthyroid disease and adverse clinical outcomes or treatment benefits were rated as insufficient or absent. Subclinical hypothyroid disease in pregnancy is a special case and aggressive case finding and treatment in pregnant women can be justified. CONCLUSIONS: Data supporting associations of subclinical thyroid disease with symptoms or adverse clinical outcomes or benefits of treatment are few. The consequences of subclinical thyroid disease (serum TSH 0.1-0.45 mIU/L or 4.5-10.0 mIU/L) are minimal and we recommend against routine treatment of patients with TSH levels in these ranges. There is insufficient evidence to support population-based screening. Aggressive case finding is appropriate in pregnant women, women older than 60 years, and others at high risk for thyroid dysfunction.

Subclinical hyperthyroidism and atrial fibrillation.

Subclinical hyperthyroidism is characterized by a clearly low serum concentration of thyrotropin (TSH) and the absence of obvious symptoms of hyperthyroidism. Whether or not all persons with a low value for serum TSH can be considered subclinically hyperthyroid is uncertain, but the low serum TSH per se is a risk factor for atrial fibrillation and perhaps other cardiovascular disease. Screening all persons, even in the older age groups, for subclinical hyperthyroidism may not be justified in and of itself but such persons would likely be screened for subclinical hypothyroidism and so those with subclinical hyperthyroidism identified. There are no controlled trials that show the benefit of treatment of subclinical hyperthyroidism, thus therapy at present needs to be determined by clinical judgement, aided by monitoring the patient to see if the low serum TSH level persists and assessing the presence or absence of other determinants of therapy such as an elevated serum triiodothyronine (T3) concentration, a multinodular goiter, or the appearance of overt symptoms.