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Purpose: Up to 71% of South Korean postmenopausal women have vitamin D deficiency {serum 25-hydroxyvitamin D [25(OH) D] level <50 nmol/L}. Data on vitamin D supplementation was collected during the screening phase of an efficacy/safety study of denosumab in Korean postmenopausal women with osteoporosis. This report describes the effect of vitamin D supplementation on repletion to 25(OH)D levels =50 nmol/L in Korean postmenopausal women with osteoporosis. Materials and Methods: Vitamin D levels of Korean postmenopausal women (60-90 years old) were measured by extracting 25(OH)D2 and 25(OH)D3 from serum samples via protein precipitation and using liquid chromatography with tandem mass spectrometry detection. Calibration curves were constructed from the mass chromatograms to obtain total vitamin D levels. Subjects with serum 25(OH)D levels <50 nmol/L were supplemented with 1000 IU of vitamin D tablets during the 2.5-month-long screening period. Dose, frequency, and duration were determined by the investigator. If repletion was achieved (=50 nmol/L) on retest, subjects were eligible to be rescreened for study entry. Results: Of 371 subjects screened, 191 (52%) required vitamin D supplementation, and 88% (168 of 191) were successfully repleted. More than half of the subjects (58%) who were successfully repleted received doses of 2000 IU daily. The mean time to successful repletion was 31 days (standard deviation 8.4 days; range 11-48 days). Conclusion: Supplementation with daily median doses of 2000 IU vitamin D successfully repleted 88% of Korean postmenopausal women with osteoporosis within 48 days to a serum vitamin D level of 50 nmol/L. [ABSTRACT FROM AUTHOR]

Purpose: The efficacy and safety of denosumab was compared with placebo in Korean postmenopausal women with osteoporosis in this phase III study. Materials and Methods: Women aged 60 to 90 years with a T-score of <-2.5 and =-4.0 at the lumbar spine or total hip were randomized to a single 60 mg subcutaneous dose of denosumab or placebo for the 6-month double-blind phase. Eligible subjects entered the 6-month open-label extension phase and received a single dose of denosumab 60 mg. Results: Baseline demographics were similar in the 62 denosumab- and 64 placebo-treated subjects who completed the doubleblind phase. Treatment favored denosumab over placebo for the primary endpoint {mean percent change from baseline in lumbar spine bone mineral density (BMD) at Month 6 [3.2% (95% confidence interval 2.1%, 4.4%; p<0.0001)]}; and secondary endpoints (mean percent change from baseline in lumbar spine BMD at Month 1, total hip, femoral neck, and trochanter BMD at Months 1 and 6, and median percent change from baseline in bone turnover markers at Months 1, 3, and 6). Endpoint improvements were sustained over 12 months in the open-label extension (n=119). There were no new or unexpected safety signals. Conclusion: Denosumab was well tolerated and effective in increasing BMD and decreasing bone turnover markers over a 12-month period in Korean postmenopausal women. The findings of this study demonstrate that denosumab has beneficial effects on the measures of osteoporosis in Korean postmenopausal women. [ABSTRACT FROM AUTHOR]

Introduction: Osteoporosis is a serious condition affecting up to 50% of Indian postmenopausal women. Denosumab reduces bone resorption by targeting the receptor activator of nuclear factor-κB ligand. This study assessed the efficacy and safety of denosumab in Indian postmenopausal women with osteoporosis. Materials and Methods: In this double-blind, multicenter, phase 3 study, 250 Indian postmenopausal women aged 55 to 75 years (T-score <-2.5 and >-4.0 at the lumbar spine or total hip; serum 25(OH) D levels ≥20 ng/mL) were randomized to receive one subcutaneous dose of denosumab 60 mg or placebo. All subjects received oral calcium ≥1000 mg and vitamin D3 ≥ 400 IU daily. The primary end point was mean percent change in bone mineral density (BMD) at the lumbar spine from baseline to Month 6. Secondary end points included mean percent change from baseline in BMD at total hip, femoral neck, and trochanter at Month 6 and median percent change from baseline in bone turnover markers at Months 1, 3, and 6. Results: Total 225 subjects (denosumab = 111, placebo = 114) completed the six-month study. Baseline demographics were similar between groups. A 3.1% (95% confidence interval, 1.9%, 4.2%) increase favoring denosumab versus placebo was seen for the primary end point (P < 0.0001). Denosumab demonstrated a significant treatment benefit over placebo for the secondary end points. There were no fractures or withdrawals due to adverse events. Conclusions: Consistent with results from studies conducted in other parts of the world, denosumab was well tolerated and effective in increasing BMD and decreasing bone turnover markers over a six-month period in Indian postmenopausal women. [ABSTRACT FROM AUTHOR]

Purpose: To determine effects of denosumab (DMAb) in postmenopausal osteoporotic women from India. Materials and Methods: Double-blind, multicenter study. Two hundred and fifty Indian postmenopausal women from 55 to 75 years of age, with osteoporosis (dual-energy X-ray absorptiometry bone mineral density (DXA BMD)) equivalent to a T score of <-0.5 and >- 4.0 at either lumbar spine (LS) or total hip (TH) and serum levels of 25-(OH) vitamin D³20 ng/mLwere randomized to DMAb 60 mg subcutaneous (SC) injection or placebo. BMD, serum bone turnover markers (serum C-terminal telopeptide of type I collagen (s-CTx) and serum procollagen type I N propeptide (s-PINP)), and safety were evaluated. All subjects received daily calcium (≥1,000 mg) and vitamin D (³400 IU). All sites obtained Ethics Committee approval and all subjects signed informed consent. Results: Baseline age and years since menopause were similar with mean 62.6 years (standard deviation (SD) 4.96) and median 15 years since menopause. At month 6, compared with placebo, the DMAb group showed a statistically significant increase in percentage change in BMD from baseline at the LS (primary endpoint) (3.1%; 95% CI: 1.9%, 4.2%; P < 0.0001), TH (1.7%; 95% confidence interval (CI): 0.9%, 2.5%; P< 0.0001), femoral neck (FN) (2.3%; 95% CI: 1.1%, 3.4%; P = 0.0001), and trochanter (1.8%; 95% CI: 0.8%, 2.8%; P = 0.0006]. A decrease in percentage change from baseline was observed for s-CTx (median: -33.4%; 95% CI: -40.8%; -26.0%; P< 0.0001 ] and s-PINP (median: -37.6%; 95% CI: -44.2%, -31.2%; P < 0.0001). 31 % DMAb and 37% placebo subjects experienced adverse events (AEs). The most common DMAb AE was upper respiratory infection (6%) vs 2% in the placebo group. One subject (DMAb) and three (placebo) experienced seriousAEs (SAEs), none attributed to study drug. Conclusions: After 6 months, DMAb statistically significantly increased percentage change from baseline in BMDatthe LS,TH, FN, and trochanter; and significantly decreased percentage change from baseline s-CTx and s-PINP compared to placebo. No new or unexpected safety signals were detected. This study was sponsored by GlaxoSmithKline Pharmaceuticals. [ABSTRACT FROM AUTHOR]

In A Diabetes Outcomes Progression Trial (ADOPT), rosiglitazone (RSG) was shown to decrease progression to monothempy failure relative to glyburide (GLY) and metformin (MET) in recently diagnosed type 2 diabetic patients. We previously reported that obesity at baseline was the main determinant of C-reactive protein (CRP) in these patients. While thiazolidinediones (TZDs) have been shown to reduce inflammation, as measured by high sensitivity CRP, previous studies have been short-term and small and therefore have been unable to assess whether the increased weight gain with TZDs might attenuate their effects on CRP. We examined this issue in 783 patients from the North American Cohort of ADOPT with a median follow-up of 4.0 years. The median body mass index at baseline was 32.8 kg/m² and was similar in each treatment group. The median baseline CRP values were 4.5 mg/L for RSG, 3.7 mg/L for GLY, and 4.2 mg/L for MET. All treatments decreased CRP levels from baseline, but RSG decreased CRP levels by 47.6% (95% CI = 57.8%, 35.0%, p< 0.0001) relative to GLY and 30.5% (43.3 %, 14.9%, p=0.0004) relative to MET in spite of greater weight gain with RSG compared to both GLY by 3.85 kg (95% CI=2.39, 5.31) and MET by 8.56 kg (95% CI=7.16, 9.95). Thus, although the mechanism is unclear, RSG decreases inflammation relative to metformin and glyburide in spite of greater weight gain during four years of follow up. [ABSTRACT FROM AUTHOR]

ADOPT compared initial oral monotherapies in recently diagnosed type 2 diabetic patients and found rosiglitazone to be superior to metformin (Met) and glyburide (Gly) as assessed by time to monotherapy failure (MF), defined as time to the first of two successive fasting plasma glucose (FPG) values >180 mg/dl. Previously, the UKPDS compared Met and sulfonylurea treatment in overweight patients (≥120% ideal body weight, mean BMI 31.4 kg/m²) and found that the A1c responses to therapy were similar. We present here the ADOPT results comparing the efficacy of Met and Gly, which was a prespecified secondary analysis. Eligible patients had type 2 diabetes diagnosed within 3 years, were 30-75 years of age, and had FPG levels between 126-180 mg/dl with lifestyle management alone. Mean BMI was 32.2 kg/m². 1454 patients were randomized to Met and 1441 to Gly. Study medication was titrated to a total daily dose of 2 g Met or 15 mg Gly. Compared to Gly, Met reduced the risk of MF by 46.5% (p<0.01). At 4 years, 36% in the Met group and 26% in the Gly group remained on monotherapy and had A1c <7% (p<0.01). From a longitudinal linear model, mean A1c <7% was maintained until the 45 month visit in the Met group and the 33 month visit in the Gly group. More Met-treated patients experienced gastrointestinal adverse events (38% vs. 22%, p<0.01) but fewer experienced hypoglycemia (12% vs. 39%, p<0.01). There was weight gain at 4 years with Gly but not with Met (1.81 kg vs -2.53 kg, p<0.01). In conclusion, ADOPT demonstrated that in recently diagnosed patients with type 2 diabetes, Met is more effective than Gly, providing more durable glycemic control with less hypoglycemia and no weight gain. [ABSTRACT FROM AUTHOR]

The article highlights a study regarding the phenotypic features that influence monotherapy failure (MTF) in a diabetes outcome progression trial (ADOPT). It was found that increasing age was associated with decreasing risk of MTF and lengthen time to MTF for rosiglitazone (RSG), metformin (MET) and glyburide (GLY) therapies. For MET and GLY, higher HbA1c and FPG levels decrease time to MTF. For RSG, higher HOMA%S levels delay MTF while lower HOMA%B levels and higher HbA1c levels reduce time.

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.

Objective: To assess and compare healthcare utilization and costs over a 2-year period in older patients (> or = 60 years) with type 2 diabetes receiving combination therapy with rosiglitazone plus a sulfonylurea (glipizide) or progressive up-titration of glipizide monotherapy., Study Design: Two-year, randomized, double-blind, parallel-group clinical trial., Patients and Methods: Older type 2 diabetic patients initially receiving submaximal doses of a sulfonylurea were randomized to receive rosiglitazone plus glipizide (n = 115) or up-titrated glipizide monotherapy (n = 110). Information on patient self-reported healthcare utilization (hospitalizations, emergency department [ED] visits, physician office visits) was collected prospectively for the duration of the trial. National average healthcare costs per unit were applied to calculate direct medical costs., Results: Demographic characteristics of the 2 groups were similar. At the study's end, glycemic values were better in the rosiglitazone-plus-glipizide group. Compared with the glipizide group, patients receiving rosiglitazone plus glipizide had significantly fewer ED visits (P = .0006) and hospitalizations (P = .0263). Although the glipizide group had more unscheduled physician office visits, the difference was not statistically significant. Estimated treatment costs per patient per month were significantly lower for the rosiglitazone-plus-glipizide group than for the glipizide group (480 dollars vs 645 dollars; P < .05)., Conclusion: Addition of rosiglitazone to sulfonylurea therapy was associated with decreased use of medical resources, in particular hospitalizations and ED visits, compared with progressive sulfonylurea up-titration. Although causality could not be established, this therapeutic approach could improve clinical outcomes in patients with type 2 diabetes and reduce healthcare utilization and costs.