Mechanism of action study to evaluate the effect of rosiglitazone on bone in postmenopausal women with type 2 diabetes mellitus: rationale, study design and baseline characteristics.

OBJECTIVES: Post-hoc analyses have shown an increase incidence of fractures among type 2 diabetes (T2DM) patients treated with thiazolidinediones (TZDs). The mechanisms by which TZDs may be associated with increased fracture risk is not well understood. This article describes the study design and baseline characteristics for a prospective, randomized, double-blind, active-controlled trial to evaluate the effects of rosiglitazone on changes in measures of skeletal structure, surrogates of bone strength and metabolism. METHODS: Postmenopausal women without osteoporosis and diagnosed with T2DM were randomized in a double-blind design to either rosiglitazone or metformin for 52 weeks, then all subjects received open-label metformin for 24 weeks. Study endpoints included changes in bone mineral density (BMD), quantitative computed tomography (QCT), digitized hip radiography (HXR) and high resolution magnetic resonance imaging (hrMRI). Serum markers of bone metabolism and indices of glycemic control were assessed within and between treatment groups. RESULTS: A total of 226 subjects were randomized. Baseline characteristics included: age 63.8 ± 6.5 years; years postmenopausal 16.9 ± 8.4; duration of diabetes 3.5 (1.8-7.8) years; body mass index (BMI) 31.4 ± 5.9 kg/m(2); and glycated hemoglobin (HbA1c) 6.4 ± 0.65%. At baseline, mean T-scores were -0.95 ± 0.91 at the femoral neck, -0.02 ± 0.97 at the total hip and -0.55 ± 1.25 at the total spine. Since there are no well recognized techniques to determine bone mass and structure at the distal limbs (cortical bone sites where fractures were reported in RSG subjects), using the femoral neck as a surrogate for these areas may be a potential limitation of the study. CONCLUSION: This is the first randomized trial utilizing multiple techniques to evaluate bone mass, structure, serum markers of bone remodeling, and potential reversibility of changes after discontinuation of rosiglitazone. This study will provide information about RSG bone effects in a population of postmenopausal women at risk for bone loss and subsequent fracture. CLINICALTRIALSGOV NUMBER: NCT00679939.

Evaluation of in-stent restenosis in the APPROACH trial (Assessment on the Prevention of Progression by Rosiglitazone On Atherosclerosis in diabetes patients with Cardiovascular History).

To determine (1) the medium-term effect of rosiglitazone and glipizide on intra-stent neointima hyperplasia, (2) restenosis pattern as assessed by intra-vascular ultrasound (IVUS) and quantitative coronary angiography (QCA) in patients with T2DM and coronary artery disease. A total of 462 patients with T2DM were randomized to rosiglitazone or glipizide for up to 18 months in the APPROACH trial, and had evaluable baseline and follow-up IVUS examinations. There was no significant difference in the size of plaque behind stent between the rosiglitazone and glipizide groups at 18 months among those treated with a bare metal stent (-5.6 mm(3) vs. 1.9 mm(3); P = 0.61) or with a drug-eluting stent (12.1 mm(3) vs. 5.5 mm(3); P = 0.09). Similarly, there was no significant difference in percentage intimal hyperplasia volume between the rosiglitazone and glipizide groups at 18 months among those treated with a bare metal stent (24.1% vs. 19.8%; P = 0.38) or with a drug-eluting stent (9.8% vs. 8.3%; P = 0.57). QCA data (intra-stent late loss, intra-stent diameter stenosis or binary restenosis) were not different between the rosiglitazone and glipizide groups. This study suggests that both rosiglitazone and glipizide have a similar effect on neointimal growth at medium term follow-up, a finding that warrants investigation in dedicated randomized trials.

The Fok1 vitamin D receptor gene polymorphism is associated with plasma renin activity in Caucasians.

OBJECTIVES: 25-Hydroxyvitamin D (25(OH)D) deficiency and excess activity of the renin-angiotensin system (RAS) are both associated with cardiovascular disease. Vitamin D interacts with the vitamin D receptor (VDR) to negatively regulate renin expression in mice; however, human studies linking genetic variation in the VDR with renin are lacking. We evaluated (i) whether genetic variation in the VDR at the Fok1 polymorphism was associated with plasma renin activity (PRA) in a population of hypertensives and a separate population of normotensives and (ii) whether the association between Fok1 genotype and PRA was independent of 25(OH)D levels. DESIGN/PATIENTS/MEASUREMENTS: Genetic association study, assuming an additive model of inheritance, of 375 hypertensive and 146 normotensive individuals from the HyperPATH cohort, who had PRA assessments after 1 week of high dietary sodium balance (HS) and l week of low dietary sodium balance (LS). RESULTS: The minor allele (T) at the Fok1 polymorphism was significantly associated with lower PRA in hypertensives (LS: ß = -0·22, P < 0·01; HS: ß = -0·19, P < 0·01); when repeated in normotensives, a similar relationship was observed (LS: ß = -0·17, P < 0·05; HS: ß = -0·18, P = 0·14). In multivariable analyses, both higher 25(OH)D levels and the T allele at Fok1 were independently associated with lower PRA in hypertensives; however, 25(OH)D was not associated with PRA in normotensives. CONCLUSIONS: Genetic variation at the Fok1 polymorphism of the VDR gene, in combination with 25(OH)D levels, was associated with PRA in hypertension. These findings support the vitamin D-VDR complex as a potential regulator of renin activity in humans.

Beta2-adrenergic receptor genotype affects the renin-angiotensin-aldosterone system response to the Dietary Approaches to Stop Hypertension (DASH) dietary pattern.

BACKGROUND: Beta(2)-adrenergic receptor (beta2-AR) is a susceptibility locus for hypertension, and polymorphisms at this site relate to salt sensitivity and low plasma renin activity (PRA). The Dietary Approaches to Stop Hypertension (DASH) dietary pattern lowers blood pressure and appears to interact with the renin-angiotensin-aldosterone system (RAAS). OBJECTIVE: We hypothesized that the DASH diet associates with increased RAAS activity, and genotype status at beta2-AR G46A modifies this response. DESIGN: We genotyped participants in the DASH-Sodium study (n = 372) at beta2-AR G46A to determine the association with blood pressure, RAAS components, and consumption of the DASH diet. We used 2-way mixed linear regression and an additive model for all primary analyses. RESULTS: Mean (+/-SEM) PRA was significantly higher in participants in the DASH group than in participants in the control group (0.68 +/- 0.03 compared with 0.54 +/- 0.03 ng x mL(-1) x h(-1), P = 0.002). Serum aldosterone, urinary aldosterone, and urinary potassium concentrations were also significantly higher in the DASH group (P < 0.01 for all). We observed significant gene-diet interactions for changes in systolic blood pressure (SBP) and concentrations of aldosterone and urinary potassium (P for interaction = 0.048, 0.017, and 0.001 for SBP and aldosterone and urinary potassium concentrations, respectively). There was an association between the A allele of beta2-AR G46A and greater blood pressure reduction and blunted aldosterone and PRA responses to the DASH diet. CONCLUSIONS: Our results indicate that the DASH diet lowers blood pressure and increases PRA and aldosterone concentrations. There is an association between the G46A polymorphism of beta2-AR and blood pressure and RAAS responses to the DASH diet, which suggests that beta2-AR may be a genetic modifier of DASH-diet responsiveness. This trial was registered at clinicaltrials.gov as NCT00000608.

Effect of rosiglitazone on progression of coronary atherosclerosis in patients with type 2 diabetes mellitus and coronary artery disease: the assessment on the prevention of progression by rosiglitazone on atherosclerosis in diabetes patients with cardiovascular history trial.

BACKGROUND: Rosiglitazone has several properties that may affect progression of atherosclerosis. The Assessment on the Prevention of Progression by Rosiglitazone on Atherosclerosis in Diabetes Patients With Cardiovascular History (APPROACH) study was undertaken to determine the effect of the thiazolidinedione rosiglitazone on coronary atherosclerosis as assessed by intravascular ultrasound compared with the sulfonylurea glipizide. METHODS AND RESULTS: This was a randomized, double-blind, controlled 18-month study in 672 patients aged 30 to 80 years with established type 2 diabetes mellitus treated by lifestyle, 1 oral agent, or submaximal doses of 2 oral agents who had at least 1 atherosclerotic plaque with 10% to 50% luminal narrowing in a coronary artery that had not undergone intervention during a clinically indicated coronary angiography or percutaneous coronary intervention. The primary outcome was change in percent atheroma volume in the longest and least angulated epicardial coronary artery that had not undergone intervention. Secondary outcomes included change in normalized total atheroma volume and change in total atheroma volume in the most diseased baseline 10-mm segment. Rosiglitazone did not significantly reduce the primary outcome of percent atheroma volume compared with glipizide (-0.64%; 95% confidence interval, -1.46 to 0.17; P=0.12). The secondary outcome of normalized total atheroma volume was significantly reduced by rosiglitazone compared with glipizide (-5.1 mm(3); 95% confidence interval, -10.0 to -0.3; P=0.04); however, no significant difference between groups was observed for the change in total atheroma volume within the most diseased baseline 10-mm segment (-1.7 mm(3); 95% confidence interval, -3.9 to 0.5; P=0.13). CONCLUSIONS: Rosiglitazone did not significantly decrease the primary end point of progression of coronary atherosclerosis more than glipizide in patients with type 2 diabetes mellitus and coronary atherosclerosis. Clinical Trial Registration- http://www.clinicaltrials.gov. Unique Identifier: NCT00116831.

Brigham fracture intervention team initiatives for hospital patients with hip fractures: a paradigm shift.

We designed, implemented, and revised the Brigham Fracture Intervention Team (B-FIT) initiatives to improve in-hospital care of fracture (Fx) patients. Effectiveness was evaluated for 181 medical records of 4 cohorts in four successive years of consecutive patients who were admitted with a fragility hip Fx. The Discharge Initiative (DI) (computer-based) includes 1200 mg calcium and 1000 IU vitamin D(3) daily. The Admission Initiative (AI) was introduced one year later with reminders for serum 25OHD measurement, initiation of daily calcium (1200 mg) and vitamin D (800 IU), and an order for Endocrinology consultation, with an amendment for a computer-assisted reminder and a dose of D(2) (50 000 IU). Initially, the computer-based DI was more effective (67%) than the surgeon-driven AI (33%, P < .001). After introduction of a computer-assisted reminder, AI effectiveness increased to 68%. The marked prevalence of vitamin D insufficiency reaffirms the importance of incorporating vitamin D recommendations in Fx care pathways.

The incidence of heart failure among nondiabetic patients with and without impaired fasting glucose.

OBJECTIVE: The purpose of this study was to elucidate the relationship between fasting plasma glucose (FPG), development of diabetes, and incident heart failure (HF) in a large, community sample of nondiabetic subjects. RESEARCH DESIGN AND METHODS: From Kaiser Permanente Northwest medical records, we identified 10,113 subjects with an FPG level of 100-125 mg/dl in 1997 or 1998 who were free of diabetes and HF and matched them to an equal number of subjects with an FPG level of <100 mg/dl on sex and 5-year age groups. Subjects were followed until a new diagnosis of HF was entered into the medical record, death, termination of health plan membership, or December 31, 2005, whichever came first. RESULTS: After controlling for known HF risk factors, each 10 mg/dl increase in FPG was independently associated with an 8% increase in the risk of HF over a mean follow-up of 79 months [hazard ratio (HR)=1.08, 95% confidence interval (CI) 1.03-1.13, P=.003]. However, in a subsequent analysis that included only those HF cases that occurred prior to diabetes onset and censored follow-up at the time of diabetes development, FPG was not a significant predictor of HF risk (HR=1.01, 95% CI 0.96-1.07, P=.621). Age, male sex, body mass index, smoking, and cardiovascular disease were highly predictive of HF incidence. CONCLUSIONS: Although the risk of HF is increased among subjects with higher FPG, the increased risk is explained by greater likelihood of developing diabetes. Risk factors other than FPG are much stronger independent predictors of incident HF.

Assessment on the Prevention of Progression by Rosiglitazone on Atherosclerosis in diabetes patients with Cardiovascular History (APPROACH): study design and baseline characteristics.

BACKGROUND: Rosiglitazone, a thiazolidinedione, has effects on insulin sensitivity and cardiovascular risk factors that may favorably impact the progression of coronary atherosclerosis. METHODS: APPROACH is a double-blind randomized clinical trial comparing the effects of the insulin sensitizer rosiglitazone with the insulin secretagogue glipizide on the progression of coronary atherosclerosis. Patients with type 2 diabetes and coronary artery disease undergoing clinically indicated coronary angiography or percutaneous coronary intervention are randomized to receive rosiglitazone or glipizide for 18 months using a titration algorithm designed to provide comparable glycemic control between treatment groups. The primary end point is change in percent atheroma volume from baseline to study completion in a nonintervened coronary artery, as measured by intravascular ultrasound. Cardiovascular events are adjudicated by an end point committee. RESULTS: A total of 672 patients were randomized. The mean age was 61 years, hemoglobin A(1c) (HbA(1c)) 7.2%, body mass index 29.5 kg/m(2), and median duration of diabetes 4.8 years. At baseline, approximately half of the participants were receiving oral antidiabetic monotherapy (53.9%) with 27.5% receiving dual combination therapy and 17.9% treated with diet and exercise alone. Approximately two thirds of the participants (68%) had dyslipidemia, 79.9% hypertension, and 24% prior myocardial infarction. CONCLUSIONS: APPROACH has fully enrolled a high-risk patient population and will compare the glucose-independent effects of rosiglitazone and glipizide on the progression of coronary atherosclerosis, as well as provide additional data on the cardiovascular safety of rosiglitazone in patients with type 2 diabetes and coronary artery disease.

Computational analysis of non-adherence and non-attendance using the text of narrative physician notes in the electronic medical record.

Non-adherence to physician recommendations is common and is thought to lead to poor clinical outcomes. However, no techniques exist for a large-scale assessment of this phenomenon. We evaluated a computational approach that quantifies patient non-adherence from an analysis of the text of physician notes. Index of non-adherence (INA) was computed based on the number of non-adherence word tags detected in physician notes. INA was evaluated by comparing the results to a manual patient record review at the individual sentence and patient level. The relationship between INA and frequency of Emergency Department visits was determined. The positive predictive value of identification of individual non-adherence word tags was 93.3%. The Pearson correlation coefficient between the INA and the number of documented instances of non-adherence identified by manual review was 0.62. The frequency of ED visits was more than twice as high for patients with INA in the highest quartile (least adherent) than for patients with INA in the lowest (most adherent) quartile (p < 0.0001). We have described the design and evaluation of a novel approach that allows quantification of patient non-adherence with physician recommendations through an analysis of physician notes. This approach has been validated at several levels and demonstrated to correlate with clinical outcomes.

Urinary free cortisol: an intermediate phenotype and a potential genetic marker for a salt-resistant subset of essential hypertension.

CONTEXT: Emerging evidence suggests a role for cortisol in essential hypertension, and preliminary reports indicate that urinary free cortisol (UFC) may be an intermediate phenotype. OBJECTIVES: The objectives of this study were: 1) confirm bimodality of UFC, 2) assess whether UFC variations aggregate in hypertensive families, and 3) compare low-mode and high-mode UFC groups for distinguishing features. SUBJECTS/SETTING: Subjects included 390 hypertensives and 166 normotensives from the general community. DESIGN/INTERVENTIONS: Subjects had blood pressure and laboratory measurements on high- and low-salt diets. Familial aggregation was evaluated in 250 hypertensive siblings from 117 families. RESULTS: Hypertensives had higher UFC than normotensives (P<0.001) and bimodal distribution of UFC (P<0.0001). Analyses were controlled for gender and dietary sodium, which are confounding determinants of UFC. Mean low-mode UFC (33.8+/-10.6 microg per 24 h) was similar to that of normotensives. The high mode, comprising 31.3% of hypertensives, had less change in mean arterial pressure between diets than the low mode (P=0.01) without any other significant differences. Observed proportions of concordance and discordance for UFC mode differed significantly from that expected (P<0.001). Observed concordance for the high mode was twice that expected, whereas for the low mode, it was similar to that expected by chance. Family membership explained a significant proportion of variance in UFC classification (P=0.027). UFC mode of one sibling was a significant predictor of the UFC mode of the other sibling [odds ratio 6.6, 95% confidence interval (2.4-18.0), P<0.001]. CONCLUSION: High-mode UFC is an intermediate phenotype of hypertension associated with salt resistance and a strong familial component supporting heritability.

Drug insight: Existing and emerging therapies for osteoporosis.

Osteoporosis is a major public health problem that is characterized by microarchitectural deterioration, low bone mass, and increased risk of fractures. Currently, many women and men affected with this disease are not diagnosed or treated. As osteoporosis is often clinically silent, risk-factor assessment and measurement of BMD are needed to identify those who may benefit from osteoporosis therapy. Although adequate daily intake of calcium and vitamin D, and regular weight-bearing exercise are important for skeletal health, they are not adequate treatments for individuals with osteoporosis. Therapies approved for treatment and/or prevention of osteoporosis in the United States include oral bisphosphonates (alendronate, ibandronate and risedronate), calcitonin, estrogens, teriparatide (parathyroid hormone fragment [1-34]), and raloxifene. For most patients, oral bisphosphonates are the treatment of choice, given the large-scale randomized-trial data demonstrating efficacy in fracture reduction, although bisphosphonates that reduce spine and nonspine fractures (e.g. alendronate and risedronate) are preferred. For high-risk patients (those with very low bone density, or with fractures), teriparatide therapy for 2 years should be considered. The treatment paradigm for osteoporosis will evolve further as promising new treatments progress through clinical development.

Beta-2 adrenergic receptor diplotype defines a subset of salt-sensitive hypertension.

Two genetic variants of the beta-2 adrenergic receptor, 46G>A and 79C>G, affect agonist-mediated receptor downregulation and vascular reactivity. We determined whether these variants were associated with hypertension, per se, blood pressure response to dietary sodium, 2 forms of salt-sensitive hypertension (low renin and nonmodulation), and the activity of the renin-angiotensin-aldosterone system. Included are 280 hypertensive and 65 normotensive white subjects who had the 2 beta-2 adrenergic receptor genotypes available. Of all subjects, 171 hypertensive and 48 normotensive subjects had complete data for intermediate phenotyping and blood pressure evaluation on high- and low-sodium balance. The beta-2 adrenergic receptor variants were not associated with hypertension per se. However, among hypertensive subjects, the change (from low to high sodium balance) in mean arterial pressure differed significantly by genotype and by diplotype. Compared with all of the other diplotypes combined, 46AA/79CC was associated with a greater change in blood pressure. Furthermore, this diplotype was associated with low-renin (LR) hypertension (identifying 32% of the LR hypertensives), higher plasma aldosterone, and lower plasma renin and serum potassium levels. In conclusion, the 46AA/79CC diplotype is associated with greater blood pressure response to dietary sodium and higher odds of LR hypertension. We propose that the mechanism for the observed association is inadequate suppression of aldosterone with salt intake, implicating the beta-2 adrenergic receptor in the regulation of aldosterone secretion. This hypothesis was confirmed in isolated glomerulosa cells, where beta-2 adrenergic receptor stimulation increased aldosterone secretion, whereas blockade reduced the stimulated aldosterone response. Importantly, this association could only be detected with an intermediate and not a distant phenotype.

Using regular expressions to abstract blood pressure and treatment intensification information from the text of physician notes.

This case study examined the utility of regular expressions to identify clinical data relevant to the epidemiology of treatment of hypertension. We designed a software tool that employed regular expressions to identify and extract instances of documented blood pressure values and anti-hypertensive treatment intensification from the text of physician notes. We determined sensitivity, specificity and precision of identification of blood pressure values and anti-hypertensive treatment intensification using a gold standard of manual abstraction of 600 notes by two independent reviewers. The software processed 370 Mb of text per hour, and identified elevated blood pressure documented in free text physician notes with sensitivity and specificity of 98%, and precision of 93.2%. Anti-hypertensive treatment intensification was identified with sensitivity 83.8%, specificity of 95.0%, and precision of 85.9%. Regular expressions can be an effective method for focused information extraction tasks related to high-priority disease areas such as hypertension.