Association of hypogonadism and estradiol levels with bone mineral density in elderly men from the Framingham study.

BACKGROUND: Both hypogonadism and low estrogen levels adversely affect bone health in young men. In elderly men, who are at greatest risk for osteoporotic fracture, the influence of hypogonadism on bone mineral density remains unclear, as does the relative effect of estrogen status compared to hypogonadism. OBJECTIVE: To examine the relation of hypogonadism and estrogen status to bone mineral density in elderly men. DESIGN: Community-based, prospective cohort study. SETTING: Framingham, Massachusetts. PATIENTS: Male participants of the Framingham Study. MEASUREMENTS: Total testosterone, total estradiol, and luteinizing hormone were measured in participants at all four biennial examinations from 1981 to 1989. Values from at least three of four examinations were averaged. Hypogonadism was defined as a mean testosterone level less than 10.4 nmol/L (<3.0 ng/mL) or a mean luteinizing hormone level of 20 IU/L or greater. An alternate definition of hypogonadism based only on a mean testosterone level less than 10.4 nmol/L (<3.0 ng/mL) was also used. In 1988-1989, bone mineral density was measured at the proximal femur (femoral neck, Ward triangle, and trochanter) and lumbar spine by using dual-photon absorptiometry and at the radial shaft by using single-photon absorptiometry. The association of hypogonadism with bone mineral density was examined with adjustment for confounders, including estradiol levels. A similar model that adjusted for hypogonadism was used to examine the association of estradiol level (ranked as quartiles) with bone mineral density. RESULTS: Of 448 men with bone mineral density measurements, 405 had evaluable hormone levels (mean age, 75.7 years [range, 68 to 96 years]); 71 (17.5%) of the 405 men were hypogonadal. Bone mineral density at any site did not significantly differ in hypogonadal men compared with eugonadal men (for example, bone mineral density at the femoral neck was 0.89 g/cm(2) vs. 0.87 g/cm(2), respectively; P > 0.2), even when alternate definitions of hypogonadism were used. In contrast, compared with the lowest estradiol quartile, men with higher estradiol levels had greater mean bone mineral density at all sites (for example, bone mineral density at the femoral neck was 0.84 g/cm(2), 0.88 g/cm(2), 0.86 g/cm(2), and 0.91 g/cm(2) from the lowest to the highest estradiol quartile; P for trend = 0.002). The difference in mean bone mineral density between men in the lowest and those in the highest estradiol quartile levels was similar to the effect of 10 years of aging on bone mineral density. CONCLUSIONS: In elderly men, hypogonadism related to aging has little influence on bone mineral density, but serum estradiol levels have a strong and positive association with bone mineral density.

Effect of intensive glycemic control on microalbuminuria in type 2 diabetes. Veterans Affairs Cooperative Study on Glycemic Control and Complications in Type 2 Diabetes Feasibility Trial Investigators.

OBJECTIVE: Microalbuminuria can reflect the progress of microvascular complications and may be predictive of macrovascular disease in type 2 diabetes. The effect of intensive glycemic control on microalbuminuria in patients in the U.S. who have had type 2 diabetes for several years has not previously been evaluated. RESEARCH DESIGN AND METHODS: We randomly assigned 153 male patients to either intensive treatment (INT) (goal HbA(1c) 7.1%) or to standard treatment (ST) (goal HbA(1c) 9.1%; P = 0.001), and data were obtained during a 2-year period. Mean duration of known diabetes was 8 years, mean age of the patients was 60 years, and patients were well matched at baseline. We obtained 3-h urine samples for each patient at baseline and annually and defined microalbuminuria as an albumin:creatinine ratio of 0.03-0.30. All patients were treated with insulin and received instructions regarding diet and exercise. Hypertension and dyslipidemia were treated with similar goals in each group. RESULTS: A total of 38% of patients had microalbuminuria at entry and were evenly assigned to both treatment groups. INT retarded the progression of microalbuminuria during the 2-year period: the changes in albumin:creatinine ratio from baseline to 2 years of INT versus ST were 0.045 vs. 0.141, respectively (P = 0.046). Retardation of progressive urinary albumin excretion was most pronounced in those patients who entered the study with microalbuminuria and were randomized to INT. Patients entering with microalbuminuria had a deterioration in creatinine clearance at 2 years regardless of the intensity of glycemic control. In the group entering without microalbuminuria, the subgroup receiving ST had a lower percentage of patients with a macrovascular event (17%) than the subgroup receiving INT (36%) (P = 0.03). Use of ACE inhibitors or calcium-channel blockers was similarly distributed among the groups. CONCLUSIONS: Intensive glycemic control retards microalbuminuria in patients who have had type 2 diabetes for several years but may not lessen the progressive deterioration of glomerular function. Increases in macrovascular event rates in the subgroup entering without albuminuria who received INT remain unexplained but could reflect early worsening, as observed with microvascular disease in the Diabetes Control and Complications Trial.

Two years of intensive glycemic control and left ventricular function in the Veterans Affairs Cooperative Study in Type 2 Diabetes Mellitus (VA CSDM).

OBJECTIVE: The Veterans Affairs Cooperative Study in Type 2 Diabetes Mellitus (VA CSDM) was a multicenter randomized prospective study of 153 male type 2 diabetic patients to assess the ability to sustain clinically significant glycemic separation between intensive and standard treatment arms. A trend toward an excess of combined cardiovascular events in the intensive treatment arm of this trial was reported earlier. The present analysis was done to evaluate the effect of 2 years of intensive glycemic control on the left ventricular (LV) function. RESEARCH DESIGN AND METHODS: The patients were randomized to intensive step treatment with insulin alone or with sulfonylurea (intensive treatment arm [INT], n = 75) or to standard once-daily insulin injection (standard treatment arm [STD], n = 78) treatment. A total of 136 patients (standard treatment arm [STD], n = 70; INT, n = 66) had radionuclide ventriculography at entry and at 24 months for the assessment of LV function. RESULTS: There was no difference in the mean LV ejection fraction (at entry: STD 57.1+/-9.51%; INT 58.1+/-8.7%; at 24 months: STD 57.3+/-10.8%, INT 59.5+/-10.7%), peak filling rate (at entry: STD 2.6+/-0.7 end diastolic volume per second, INT 2.4+/-0.8 end diastolic volume per second; at 24 months: STD 2.7+/-1.0 end diastolic volume per second, INT 2.5+/-0.7 end diastolic volume per second), or time to peak filling rate (at entry: STD 195.3+/-69.5 ms, INT 185.6 +/-62.4 ms; at 24 months: STD 182.6+/-64.8 ms, INT 179.2+/-61.2 ms) between the 2 treatment arms. A subgroup analysis of 104 patients (STD, n = 53; INT, n = 51) that omitted individuals with intervening cardiac events/revascularization or a change in cardioactive medications also showed no difference in the LV function at entry and at 24 months between the 2 groups. Abnormal LV ejection fraction at baseline predicted cardiac events (interval between cardiac beats [RR] = 2.5). CONCLUSIONS: Two years of intensive glycemic control does not affect the LV systolic or diastolic function in patients with type 2 diabetes.

The effects of intensive glycemic control on neuropathy in the VA cooperative study on type II diabetes mellitus (VA CSDM).

To determine whether a difference in HbA(1c) could be safely sustained between a standard therapy (STD) arm and an intensive therapy (INT) arm, while maintaining HbA(1c) levels in both arms within a range acceptable in community practice. The effects of intensive treatment on various parameters were studied in this feasibility trial. We report here the results of 24 months of INT on peripheral and autonomic neuropathy.A prospective trial was conducted in five medical centers in 153 men of 60 +/- 6 years of age who had a known diagnosis of diabetes for 7.8 +/- 4 years. They were randomly assigned to a standard insulin treatment group (one morning injection per day) or to an intensive therapy group designed to attain near-normal glycemia and a clinically significant separation of glycohemoglobin from the standard arm. A four-step plan was used in the intensive therapy group along with daily self-monitoring of glucose: (1) an evening insulin injection, (2) the same injection adding daytime glipizide, (3) two injections of insulin alone, and (4) multiple daily injections. Peripheral neuropathy was diagnosed clinically by a history and physical examination, and by abnormal autonomic neuropathy Valsalva ratio (VR < 1.2) and RR variation (RRV < 10). An average HbA(1c) separation of 2.07% was achieved with INT, having HbA(1c) at or below 7.3% (p = 0. 001 versus STD). Baseline prevalence of peripheral neuropathy was 53% in STD, and 48% in INT. By 24 months, the prevalence increased to 69% in STD (p = 0.005 versus baseline), and to 64% in INT (p = 0. 008 versus baseline, but no different than STD). Though INT did not reverse all elements of peripheral neuropathy, there was a decreased prevalence of cranial neuropathy (p = 0.053 versus STD) and more frequent preservation of touch sensation in the upper extremities (p = 0.03 versus STD) in INT. At baseline, an abnormal Valsalva ratio and/or RR variation was seen in 38% of STD and 31% of INT. By 24 months in STD, the prevalence rose to 55% (p = 0.0067 versus baseline), and in INT, to 48% (p = 0.012 versus baseline and no different from STD). The prevalence of erectile dysfunction increased from 53% at baseline to 73% at 2 years, p = 0.002 in STD, and from 51% to 73% at 2 years (p = 0.003 versus baseline) and no different from STD. There was no change in the frequency of abnormal gastrointestinal or sweating symptoms. Our conclusion was that 2 years of meticulous glycemic control did not decrease overall prevalence of peripheral or autonomic neuropathy. In fact, the prevalence rose equivalently and significantly in both treatment arms. There was some benefit, however, in decreased frequency of cranial neuropathy and better preservation of touch sensation in INT.

Ethnic differences in the glycemic response to exogenous insulin treatment in the Veterans Affairs Cooperative Study in Type 2 Diabetes Mellitus (VA CSDM).

OBJECTIVE: The Veterans Affairs Cooperative Study in Type 2 Diabetes Mellitus was conducted in NIDDM patients to determine if a significant difference in HbA1c could be achieved between groups receiving standard and intensive treatment. We observed differences in the response to exogenous insulin between African-Americans and other intensively treated patients. Therefore, we assessed the variations of response and correlated factors that might explain such differences. RESEARCH DESIGN AND METHODS: One hundred fifty-three men aged 40-69 years with NIDDM for < or = 15 years were randomized to either the standard therapy (n = 78) or the intensive therapy (n = 75) arm. Of the 75 patients in the intensive therapy group, 57 completed the study on insulin therapy alone. Of these, 18 were African-Americans and 39 were non-African-Americans. We conducted an analysis of the data collected to determine differences in baseline characteristics, glycemic response, insulin requirement, body weight, exercise, and basal C-peptide level, factors that may explain a difference in response to insulin therapy. RESULTS: Glycemic control improved in all patients with intensive insulin therapy. African-Americans achieved a greater improvement in HbA1c compared with non-African-Americans with a similar increment in insulin. This difference could not be explained by differences in body weight, activity, concomitant use of other medicines, or insulin-secretory capacity of the pancreas. CONCLUSIONS: We conclude that ethnic differences may exist in the response to insulin therapy. A knowledge of such differences may aid in achieving good glycemic control, especially since minorities have a greater prevalence of and burden from the microvascular complications of diabetes.

Response to intensive therapy steps and to glipizide dose in combination with insulin in type 2 diabetes. VA feasibility study on glycemic control and complications (VA CSDM).

OBJECTIVE: The feasibility study for the VA Cooperative Study on Glycemic Control and Complications in Type 2 Diabetes (VA CSDM) prospectively studied 153 insulin-requiring type 2 diabetes patients, randomized between an intensively treated arm and a standard treatment arm during a mean follow-up of 27 months. The glycemic response to each of the progressive, sequential phases of insulin treatment was assessed, along with the incidence of hypoglycemic reactions and the relative efficacy of different doses of glipizide in combination with fixed doses of insulin. RESEARCH DESIGN AND METHODS: Five medical centers participated; half of the patients were assigned to the intensive treatment arm aiming for normal HbA1c levels. Age of patients was 60 +/- 6 years, duration of diabetes 8 +/- 3 years, and BMI 30.7 +/- 4 kg/m2. A four-step management technique was used, with patients moving to the next step if the operational goals were not met: Phase I, evening intermediate or long-acting insulin; phase II, added day-time glipizide; phase III, two injections of insulin alone; and phase IV, multiple daily insulin injections. Home glucose monitoring measurements were done twice daily and at 3:00 A.M. once a week. Hypoglycemic reactions and home glucose monitoring results were recorded and counted in each of the treatment phases. RESULTS: Baseline HbA1c was 9.3 +/- 1.8%, and fasting plus serum glucose was 11.4 +/- 3.3 mmol/1. Fasting serum glucose fell to near normal in phase I, and remained so in the other treatment phases. An HbA1c separation of 2.1% between the arms was maintained during the course of the study, while the intensive arm kept HbA1c levels below 7.3% (P = 0.001). Most of the decrease in HbA1c occurred with one injection of insulin alone (phase I, -1.4%) or adding day-time glipizide (phase II, -1.9% compared with baseline). HbA1c did not decrease further after substituting two injections of insulin alone, with twice the insulin dose. Multiple daily injections resulted in an additional HbA1c fall (-2.4% compared with baseline). However, two-thirds of the patients were still on one or two injections a day at the end of the study. Changes in home glucose monitoring levels paralleled those of the HbA1c, as did the increments in number of reported hypoglycemic reactions, virtually all either "mild" or "moderate" in character. For the combination of glipizide and insulin (phase II), the only significant effect was obtained with daily doses up to 10 mg a day; there were no significant additional benefits with up to fourfold higher daily doses, and HbA1c levels had an upward trend with doses > 20 mg/day. CONCLUSIONS: A simple regime of a single injection of insulin, alone or with glipizide, seemed sufficient to obtain clinically acceptable levels of HbA1c for most obese, insulin-requiring type 2 diabetes patients. Further decrease of HbA1c demanded multiple daily injections at the expense of doubling the insulin dose and the rate of hypoglycemic events. In combination therapy, doses of glipizide > 20 mg/day offered no additional benefit.

Theories of causation of Graves' disease. A historical perspective.

There have been many theories regarding the origin or etiology of the peculiar disorder Robert James Graves first described in 1834. This article is a chronological discussion of the main ideas and the eras in which they were prominent, including the cardiac, neural, thyroid, pituitary, and modern eras.

Radioiodine and the treatment of hyperthyroidism: the early history.

Little was known about iodine metabolism in the mid-1930s, but when Saul Hertz and his chief, J. Howard Means, at the Massachusetts General Hospital (MGH) realized in 1936 that radioiodine could be made and used as a tracer, they arranged with physicists Robley Evans and Arthur Roberts at the Massachusetts Institute of Technology (MIT) to make the short-lived 128I and study its physiology in rabbits. By 1938, they showed that the rabbit's thyroid gland rapidly took up 128I, especially when there was only a little non-radioactive iodine present. There was, however, no hope of using 128I as a treatment because of its brief half-life (25 minutes). In 1939, Joseph Hamilton and Mayo Soley, working with Ernest Lawrence's cyclotron in Berkeley, California, were able to make several radioiodines; one was 130I (12-hour half-life) and another 131I (8-day half-life). They were the first to give these radioiodines to humans to study iodine physiology. The MGH-MIT group also built a cyclotron and by 1940 had generated these two new radioiodines. One of the goals of both groups was the treatment of hyperthyroidism. Hertz and Roberts were the first to do so on March 31, 1941; Hamilton and John Lawrence, Ernest's brother, began on October 12, 1941. By 1942, the United States was actively fighting in World War II. That year both Boston and Berkeley groups have preliminary data on the treatment of hyperthyroidism in Atlantic City; both showed that it was effective and went on to treat more patients. In Berkeley the therapy was viewed cautiously, and, in many case, the physicists were mainly occupied with work for the Manhattan District. In Boston Hertz used the therapy as often as he could, emphasizing the use of 130I, until he joined the U.S. Navy in 1943. Earle Chapman, a clinician on the voluntary staff of the MGH, took over Hertz's practice in 1943; their later differences over the precise treatment and who was in charge led to their falling out. After Hertz's release from the Navy he was not permitted to return to the MGH and became quite bitter; Chapman stayed on at the MGH. After the war was over, both had acquired a sufficient number of patients--there was then no such thing as a controlled trial--and wrote up the results for publication. Each wrote a different physicist, Hertz with Roberts and Chapman with Evans. When Hertz learned that Chapman's paper was being considered by the Journal of the American Medical Associations, he quickly sent his manuscript to JAMA as well. Although the editor of JAMA was puzzled by two papers on the same topic from the same institution, both papers appeared in the same issue of JAMA on May 11, 1964, and announced the new therapy was effective treatment for hyperthyroidism.

Cardiovascular events and correlates in the Veterans Affairs Diabetes Feasibility Trial. Veterans Affairs Cooperative Study on Glycemic Control and Complications in Type II Diabetes.

BACKGROUND: The risks and benefits of intensive therapy in non-insulin-dependent diabetes mellitus (NIDDM) need to be defined. In preparation for a long-term trial, a feasibility study of 153 men in 5 medical centers compared standard vs intensive insulin therapy. OBJECTIVE: To assess the rate of development of new cardiovascular events and their correlates. METHODS: Patients with a mean +/- SD age of 60 +/- 6 years and diagnosis of NIDDM for 7.8 +/- 4.0 years were randomly assigned to a standard (1 insulin injection every morning) or to an intensive treatment arm (stepped plan from 1 evening injection of insulin, alone or with glipizide, to multiple daily injections) designed to attain near-normal glycemia levels. A 2.07% separation of glycosylated hemoglobin (HbA1c) was sustained for a mean follow-up of 27 months (P < .001). Predefined cardiovascular events were assessed by a committee unaware of treatment assignment. RESULTS: Mild and moderate hypoglycemic events were more frequent in the intensive than in the standard treatment arm (16.5 vs 1.5 per patient per year, respectively). Mean insulin dose was 23% lower in the standard treatment arm (P < .001). There were 61 new cardiovascular events in 24 patients (32%) in the intensive treatment arm and in 16 patients (20%) in the standard treatment arm (P = .10). There was no difference in total and cardiovascular mortality (n = 5 and n = 3 in the intensive and standard treatment arms, respectively) or in new events in patients with cardiovascular history (n = 10 in each arm). In Cox regression analysis, the only significant correlate for new cardiovascular events was previous cardiovascular disease (P = .04). Entering in the analysis any baseline cardiovascular abnormality, the regression model indicated a lower HbA1c level prior to the event as the only correlate for new cardiovascular events (P = .05). CONCLUSION: A long-term prospective trial is needed to assess the risk-benefit ratio of intensive insulin therapy for NIDDM in patients who require it.

Radioiodine and thyroid disease: the beginning.

In 1936, Karl Compton, then president of the Massachusetts Institute of Technology (MIT) and the thyroid group of the Massachusetts General Hospital (MGH), undertook a joint study that led to the production of small amounts of short-lived radioiodine (iodine 128, half-life, 25 min). The original intent was to use it for diagnosis and treatment of thyroid disease, but in order to explore the underlying physiology, their first work was performed in rabbits and published in 1938. It clearly showed that the radioiodine was selectively and avidly taken up by the thyroid gland. It was immediately apparent to the MGH-MIT group and another team working at the Berkeley, CA cyclotron that longer-lasting iodine isotopes were needed, and soon both developed procedures for cyclotron-produced 130 (half-life, 12.5 hr) and 131I (half-life, 8 d). In 1939, the Berkeley group, using 131I, was the first to show that the normal human thyroid gland accumulated radioiodine. By 1941, the MGH-MIT team, using mainly 130I, was able to successfully treat a few patients with hyperthyroidism, and so achieved their original goal. The Berkeley group did the same a few months later, using mainly 131I. Both presented results at the same meeting of the American Society for Clinical Investigation in Atlantic City, NJ in the spring of 1942. This was in the midst of World War II and it was not easy to get much 130I or 131I, so experience was limited. Although effective, radioiodine treatment of hyperthyroidism had not been widely adopted by the end of the war in 1945, partly because radioiodine remained in short supply and partly because another medical therapy for hyperthyroidism, antithyroid drugs, had been invented. However, by 1946, fission-derived radioiodine became readily available as a by-product of the Manhattan project in Oak Ridge, TN; hundreds of patients were treated within a few years, both for hyperthyroidism and for thyroid cancer. A new treatment, based on the physiological application of a radioisotope of iodine, was then a reality.

Screening for mild thyroid failure at the periodic health examination: a decision and cost-effectiveness analysis.

OBJECTIVE: To estimate the cost-effectiveness of periodic screening for mild thyroid failure by measurement of serum thyroid stimulating hormone (TSH) concentration. DESIGN: Cost-utility analysis using a state-transition computer decision model that accounted for case finding, medical consequences of mild thyroid failure, and costs of care during 40 years of simulated follow-up. SETTING: Periodic health examinations in offices of primary care physicians. PATIENTS: Hypothetical cohorts of women and men screened every 5 years during the recommended periodic examination, beginning at age 35 years. INTERVENTIONS: Adding the serum TSH assay to total serum cholesterol screening was compared to cholesterol screening alone. MAIN OUTCOME MEASURES: Discounted quality-adjusted life years (QALYs) and direct medical costs from a societal perspective. RESULTS: The cost-effectiveness of screening 35-year-old patients with a serum TSH assay every 5 years was $9223 per QALY for women and $22595 per QALY for men. The cost-effectiveness became more favorable when age at first screening was increased for both sexes and was always more favorable for women than men. Reduced progression to overt hypothyroidism and relief of symptoms increased QALYs, but did not substantially reduce direct medical costs. Finding hypercholesterolemia induced by mild thyroid failure reduced direct medical costs, but did not substantially increase QALYs. The cost of a TSH assay and the importance to patients of symptoms associated with thyroid failure were the most influential factors in sensitivity analyses. CONCLUSIONS: The cost-effectiveness of screening for mild thyroid failure compares favorably with other generally accepted preventive medical practices. Physicians should consider measuring serum TSH concentration in patients aged 35 years and older undergoing routine periodic health examinations. The cost-effectiveness of screening is most favorable in elderly women.

Lack of association between thyroid status and chondrocalcinosis or osteoarthritis: the Framingham Osteoarthritis Study.

OBJECTIVE: To assess whether current thyroid status is associated with chondrocalcinosis or osteoarthritis (OA), we examined the cross sectional association of serum thyrotropin (thyroid stimulating hormone, TSH) with chondrocalcinosis and with knee OA in members of the Framingham OA study. METHODS: Knee radiographs were taken at the 18th biennial examination (1983-85) and measurement of serum TSH at either the 15th (1977-79) or the 18th biennial examination. Chondrocalcinosis was dichotomized as absent or present and knee OA was based on a Kellgren and Lawrence score of grade 2 or greater in either knee. Thyroid status was determined by serum TSH concentration classed into clinically relevant categories: < or = 0.1 mU/l(low); > 0.1 < 0.4 mU/l (slightly low); 0.4 to 5.0 mU/l (normal); > 5 < or = 10 mU/l (slightly high); and > 10 mU/l (high). RESULTS: Data were collected on 577 men and 798 women. We found no association between elevated serum TSH concentration and chondrocalcinosis. Our results, though not statistically significant, suggest an inverse relation, with an odds ratio (OR) of 0.41 (95% CI 0.10, 1.73) for those subjects. in the highest TSH group and 1.79 (95% CI 0.39, 8.24) for those in the lowest TSH group, compared to subjects in the normal range. We found no association between serum TSH concentration and radiographic knee OA, with an OR of 0.85 (95% CI 0.47, 1.51) for those in the highest serum TSH group and 1.51 (95 CI 0.54, 4.22) for those in the lowest TSH group, compared to the normal group. Exclusion of subjects taking thyroid hormone confirmed these null results. CONCLUSION: There was no evidence, in a large unselected population of older persons, of a significant association between current thyroid status and either chondrocalcinosis or OA.

Veterans Affairs Cooperative Study on glycemic control and complications in type II diabetes (VA CSDM). Results of the feasibility trial. Veterans Affairs Cooperative Study in Type II Diabetes.

OBJECTIVE: It is not clear whether intensive pharmacological therapy can be effectively sustained in non-insulin-dependent diabetes mellitus (NIDDM). The relative risks and benefits of intensive insulin therapy in NIDDM are not well defined. Accordingly, we designed a feasibility study that compared standard therapy and intensive therapy in a group of NIDDM men who required insulin due to sustained hyperglycemia. RESEARCH DESIGN AND METHODS: A prospective trial was conducted in five medical centers in 153 men of 60 +/- 6 years of age who had a known diagnosis of diabetes for 7.8 +/- 4 years. They were randomly assigned to a standard insulin treatment group (one morning injection per day) or to an intensive therapy group designed to attain near-normal glycemia and a clinically significant separation of glycohemoglobin from the standard arm. A four-step plan was used in the intensive therapy group along with daily self-monitoring of glucose: 1) an evening insulin injection, 2) the same injection adding daytime glipizide, 3) two injections of insulin alone, and 4) multiple daily injections. Patient accrual and adherence, glycohemoglobin (HbA1c), side effects, and measurements of endpoints for a prospective long-term trial were assessed. RESULTS: Accrual goals were met, mean follow-up time was 27 months (range 18-35 months), and patients kept 98.6% of scheduled visits. After 6 months, the mean HbA1c in the intensive therapy group was at or below 7.3% and remained 2% lower than the standard group for the duration of the trial. Most of the decrease in the mean HbA1c in the intensive group was obtained by a single injection of evening intermediate insulin, alone or with daytime glipizide. By the end of the trial, 64% of the patients had advanced to two or more injections of insulin a day, aiming for normal HbA1c. However, only a small additional fall in HbA1c was attained. Severe hypoglycemia was rare (two events per 100 patients per year) and not significantly different between the groups, nor were changes in weight, blood pressure, or plasma lipids. There were 61 new cardiovascular events in 40 patients and 10 deaths (6 due to cardiovascular causes). CONCLUSIONS: Intense stepped insulin therapy in NIDDM patients who have failed glycemic control on pharmacological therapy is effective in maintaining near-normal glycemic control for > 2 years without excessive severe hypoglycemia, weight gain, hypertension, or dyslipidemia. Cardiovascular event rates are high at this stage of NIDDM. A long-term prospective trial is needed to assess the risk-benefit ratio of intensified treatment of hyperglycemia in NIDDM patients requiring insulin.

Subclinical hypothyroidism in older persons.

Because subclinical hypothyroidism is common (4%-8% of people older than 60 years of age), has some clinical consequences, and is easily and safely treated, screening of older persons is justified. Diagnosis depends on showing a raised serum TSH (less than 10 mU/L), a test that will cost less in the near future. There are, however, still some uncertainties about this condition, and supportive data are not perfect. Better studies are essential to help define clinical practice.

Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons.

BACKGROUND: Low serum thyrotropin concentrations are a sensitive indicator of hyperthyroidism but can also occur in persons who have no clinical manifestations of the disorder. We studied whether low serum thyrotropin concentrations in clinically euthyroid older persons are a risk factor for subsequent atrial fibrillation. METHODS: We studied 2007 persons (814 men and 1193 women) 60 years of age or older who did not have atrial fibrillation in order to determine the frequency of this arrhythmia during a 10-year follow-up period. The subjects were classified according to their serum thyrotropin concentrations: those with low values (< or = 0.1 mU per liter; 61 subjects); those with slightly low values (> 0.1 to 0.4 mU per liter; 187 subjects); those with normal values (> 0.4 to 5.0 mU per liter; 1576 subjects); and those with high values (> 5.0 mU per liter; 183 subjects). RESULTS: During the 10-year follow-up period, atrial fibrillation occurred in 13 persons with low initial values for serum thyrotropin, 23 with slightly low values, 133 with normal values, and 23 with high values. The cumulative incidence of atrial fibrillation at 10 years was 28 percent among the subjects with low serum thyrotropin values (< or = 0.1 mU per liter), as compared with 11 percent among those with normal values; the age-adjusted incidence of atrial fibrillation was 28 per 1000 person-years among those with low values and 10 per 1000 person-years among those with normal values (P = 0.005). After adjustment for other known risk factors, the relative risk of atrial fibrillation in elderly subjects with low serum thyrotropin concentrations, as compared with those with normal concentrations, was 3.1 (95 percent confidence interval, 1.7 to 5.5; P < 0.001). The 10-year incidence of atrial fibrillation in the groups with slightly low and high serum thyrotropin values was not significantly different from that in the group with normal values. CONCLUSIONS: Among people 60 years of age or older, a low serum thyrotropin concentration is associated with a threefold higher risk that atrial fibrillation will develop in the subsequent decade.