Assessment of Denosumab in Korean Postmenopausal Women with Osteoporosis: Randomized, Double-Blind, Placebo-Controlled Trial with Open-Label Extension.

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 double-blind 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.

Vitamin D Repletion in Korean Postmenopausal Women with Osteoporosis.

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.

A randomized placebo-controlled trial of the efficacy of denosumab in Indian postmenopausal women with osteoporosis.

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.

Rosiglitazone decreases bone mineral density and increases bone turnover in postmenopausal women with type 2 diabetes mellitus.

CONTEXT: Postmenopausal status and type 2 diabetes mellitus (T2DM) are independent risk factors for fractures. An increased fracture risk has been observed with rosiglitazone (RSG), a thiazolidinedione, in patients with T2DM. DESIGN AND SETTING: This was a randomized, double-blind study in postmenopausal women with T2DM. A 52-week double-blind phase (RSG or metformin [MET]) was followed by a 24-week open-label phase, during which time all patients received MET. MAIN OUTCOME MEASURES: The primary endpoint was to assess the mean percentage change in bone mineral density (BMD) at the femoral neck (FN) by dual-energy x-ray absorptiometry from baseline to week 52 in the RSG treatment group. Key secondary objectives included assessment of changes in BMD at the total hip, trochanter, and lumbar spine and to evaluate RSG effects on bone turnover markers. RESULTS: From baseline to week 52, RSG was associated with a reduction in FN BMD by dual-energy x-ray absorptiometry (-1.47%). During the open-label phase (weeks 52-76), no further loss in FN BMD was observed. A decrease in BMD occurred at the total hip during RSG or MET treatment at 52 weeks (-1.62 and -0.72%, respectively). Total hip BMD loss by RSG was attenuated after switching to MET and was similar between treatment groups at the end of the open-label phase. From baseline to week 52, bone turnover markers significantly increased with RSG compared with MET, but decreased significantly during the open-label phase. CONCLUSIONS: RSG for 52 weeks in postmenopausal women with T2DM was associated with small reductions in FN, total hip, and lumbar spine BMD and increased bone turnover markers. These effects are attenuated after cessation of RSG treatment.

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.

Renal function in type 2 diabetes with rosiglitazone, metformin, and glyburide monotherapy.

BACKGROUND AND OBJECTIVES: In ADOPT (A Diabetes Outcomes Prevention Trial), initial monotherapy with rosiglitazone provided more durable glycemic control than metformin or glyburide in patients with recently diagnosed type 2 diabetes. Herein, we examine differences in albumin excretion, renal function (estimated GFR), and BP over 5 years between treatment groups. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A total of 4351 recently diagnosed, drug-naïve patients with type 2 diabetes were treated and followed for up to 5 years with rosiglitazone, metformin, or glyburide and were examined with periodic assessments of albumin/creatinine ratio (ACR), modification of diet in renal disease (MDRD)-estimated GFR, and BP. RESULTS: The ACR rose slowly with metformin. It fell with rosiglitazone and less so with glyburide over the first 2 years, and then rose slowly over time. Estimated GFR (eGFR) with all therapies rose into the high normal range over the first 3 to 4 years, more so with rosiglitazone, and then declined, more so with glyburide. Systolic BP was stable over time, values with rosiglitazone being lower, and diastolic BP declined over time, more so with rosiglitazone than with metformin or glyburide. There was no difference among groups in the incidence of emergent albuminuria (ACR ≥30 mg/g), hypertension, or impaired eGFR (<60 ml/min per 1.73 m(2)). CONCLUSIONS: Over a 5-year period, initial monotherapy with rosiglitazone retards the rise of ACR compared with metformin, preserves eGFR compared with glyburide, and lowers BP relative to both comparators.

Effects of rosiglitazone, glyburide, and metformin on ß-cell function and insulin sensitivity in ADOPT.

OBJECTIVE: ADOPT (A Diabetes Outcome Progression Trial) demonstrated that initial monotherapy with rosiglitazone provided superior durability of glycemic control compared with metformin and glyburide in patients with recently diagnosed type 2 diabetes. Herein, we examine measures of ß-cell function and insulin sensitivity from an oral glucose tolerance test (OGTT) over a 4-year period among the three treatments. RESEARCH DESIGN AND METHODS: Recently diagnosed, drug-naïve patients with type 2 diabetes (4,360 total) were treated for a median of 4.0 years with rosiglitazone, metformin, or glyburide and were examined with periodic metabolic testing using an OGTT. RESULTS: Measures of ß-cell function and insulin sensitivity from an OGTT showed more favorable changes over time with rosiglitazone versus metformin or glyburide. Persistent improvements were seen in those who completed 4 years of monotherapy and marked deterioration of ß-cell function in those who failed to maintain adequate glucose control with initial monotherapy. CONCLUSIONS: The favorable combined changes in ß-cell function and insulin sensitivity over time with rosiglitazone appear to be responsible for its superior glycemic durability over metformin and glyburide as initial monotherapy in type 2 diabetes.

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.

Rosiglitazone decreases C-reactive protein to a greater extent relative to glyburide and metformin over 4 years despite greater weight gain: observations from a Diabetes Outcome Progression Trial (ADOPT).

OBJECTIVE: C-reactive protein (CRP) is closely associated with obesity and cardiovascular disease in both diabetic and nondiabetic populations. In the short term, commonly prescribed antidiabetic agents have different effects on CRP; however, the long-term effects of those agents are unknown. RESEARCH DESIGN AND METHODS: In A Diabetes Outcome Progression Trial (ADOPT), we examined the long-term effects of rosiglitazone, glyburide, and metformin on CRP and the relationship among CRP, weight, and glycemic variables in 904 subjects over 4 years. RESULTS: Baseline CRP was significantly correlated with homeostasis model assessment of insulin resistance (HOMA-IR), A1C, BMI, waist circumference, and waist-to-hip ratio. CRP reduction was greater in the rosiglitazone group by -47.6% relative to glyburide and by -30.5% relative to metformin at 48 months. Mean weight gain from baseline (at 48 months) was 5.6 kg with rosiglitazone, 1.8 kg with glyburide, and -2.8 kg with metformin. The change in CRP from baseline to 12 months was correlated positively with change in BMI in glyburide (r = 0.18) and metformin (r = 0.20) groups but not in the rosiglitazone (r = -0.05, NS) group. However, there was no longer a significant correlation between change in CRP and change in HOMA-IR, A1C, or waist-to-hip ratio in any of the three treatment groups. CONCLUSIONS: Rosiglitazone treatment was associated with durable reductions in CRP independent of changes in insulin sensitivity, A1C, and weight gain. CRP in the glyburide and metformin groups was positively associated with changes in weight, but this was not the case with rosiglitazone.

Effect of rosiglitazone, metformin, and glyburide on bone biomarkers in patients with type 2 diabetes.

CONTEXT: An increase in bone fractures has been observed in women taking thiazolidinediones. OBJECTIVE: The objective of the study was to examine whether changes in circulating bone biomarkers provide insight into the underlying mechanisms responsible for the increase in bone fractures in female participants randomized to rosiglitazone in A Diabetes Outcome Progression Trial (ADOPT). RESEARCH DESIGN AND METHODS: Paired stored baseline and 12-month serum samples were available from 1605 participants (689 women, 916 men) in ADOPT, a long-term clinical trial comparing the effects of rosiglitazone, glyburide, and metformin on glycemic control in patients with type 2 diabetes. RESULTS: This subset was well matched to the total ADOPT study population. In women a marker of osteoclast activity, C-terminal telopeptide (for type 1 collagen), increased by 6.1% with rosiglitazone compared with reductions of 1.3% (P = 0.03 vs. rosiglitazone) and 3.3% (P = 0.002 vs. rosiglitazone) with metformin and glyburide, respectively. In men, C-terminal telopeptide was unchanged on rosiglitazone (-1.0%) and fell on metformin (-12.7%; P < 0.001) and glyburide (-4.3%, P = NS). Markers of osteoblast activity, procollagen type 1 N-propeptide (P1NP) and bone alkaline phosphatase, were reduced for women and men in almost all treatment groups, with the greatest changes in the metformin group (P1NP in females, -14.4%; P1NP in males, -19.3%), intermediate for rosiglitazone (P1NP in females, -4.4%; P1NP in males, -14.4%), and smallest for glyburide (P1NP in males, +0.2%; bone alkaline phosphatase in females, -11.6%). CONCLUSIONS: Commonly measured bone biomarkers suggest that changes in bone resorption may be partly responsible for the increased risk of fracture in women taking thiazolidinediones.

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.

Rosiglitazone-associated fractures in type 2 diabetes: an Analysis from A Diabetes Outcome Progression Trial (ADOPT).

OBJECTIVE: The purpose of this study was to examine possible factors associated with the increased risk of fractures observed with rosiglitazone in A Diabetes Outcome Progression Trial (ADOPT). RESEARCH DESIGN AND METHODS: Data from the 1,840 women and 2,511 men randomly assigned in ADOPT to rosiglitazone, metformin, or glyburide for a median of 4.0 years were examined with respect to time to first fracture, rates of occurrence, and sites of fractures. RESULTS: In men, fracture rates did not differ between treatment groups. In women, at least one fracture was reported with rosiglitazone in 60 patients (9.3% of patients, 2.74 per 100 patient-years), metformin in 30 patients (5.1%, 1.54 per 100 patient-years), and glyburide in 21 patients (3.5%, 1.29 per 100 patient-years). The cumulative incidence (95% CI) of fractures in women at 5 years was 15.1% (11.2-19.1) with rosiglitazone, 7.3% (4.4-10.1) with metformin, and 7.7% (3.7-11.7) with glyburide, representing hazard ratios (95% CI) of 1.81 (1.17-2.80) and 2.13 (1.30-3.51) for rosiglitazone compared with metformin and glyburide, respectively. The increase in fractures with rosiglitazone occurred in pre- and postmenopausal women, and fractures were seen predominantly in the lower and upper limbs. No particular risk factor underlying the increased fractures in female patients who received rosiglitazone therapy was identified. CONCLUSIONS: Further investigation into the risk factors and underlying pathophysiology for the increased fracture rate in women taking rosiglitazone is required to relate them to preclinical data and better understand the clinical implications of and possible interventions for these findings.

Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy.

BACKGROUND: The efficacy of thiazolidinediones, as compared with other oral glucose-lowering medications, in maintaining long-term glycemic control in type 2 diabetes is not known. METHODS: We evaluated rosiglitazone, metformin, and glyburide as initial treatment for recently diagnosed type 2 diabetes in a double-blind, randomized, controlled clinical trial involving 4360 patients. The patients were treated for a median of 4.0 years. The primary outcome was the time to monotherapy failure, which was defined as a confirmed level of fasting plasma glucose of more than 180 mg per deciliter (10.0 mmol per liter), for rosiglitazone, as compared with metformin or glyburide. Prespecified secondary outcomes were levels of fasting plasma glucose and glycated hemoglobin, insulin sensitivity, and beta-cell function. RESULTS: Kaplan-Meier analysis showed a cumulative incidence of monotherapy failure at 5 years of 15% with rosiglitazone, 21% with metformin, and 34% with glyburide. This represents a risk reduction of 32% for rosiglitazone, as compared with metformin, and 63%, as compared with glyburide (P<0.001 for both comparisons). The difference in the durability of the treatment effect was greater between rosiglitazone and glyburide than between rosiglitazone and metformin. Glyburide was associated with a lower risk of cardiovascular events (including congestive heart failure) than was rosiglitazone (P<0.05), and the risk associated with metformin was similar to that with rosiglitazone. Rosiglitazone was associated with more weight gain and edema than either metformin or glyburide but with fewer gastrointestinal events than metformin and with less hypoglycemia than glyburide (P<0.001 for all comparisons). CONCLUSIONS: The potential risks and benefits, the profile of adverse events, and the costs of these three drugs should all be considered to help inform the choice of pharmacotherapy for patients with type 2 diabetes. (ClinicalTrials.gov number, NCT00279045 [ClinicalTrials.gov].).

Obesity is a major determinant of the association of C-reactive protein levels and the metabolic syndrome in type 2 diabetes.

The inflammatory factor C-reactive protein (CRP) and the fibrinolytic variables fibrinogen and plasminogen activator-1 (PAI-1) are associated with long-term cardiovascular morbidity. To determine the contribution of body adiposity (BMI), insulin sensitivity (homeostasis model assessment of insulin resistance [HOMA-IR], and glycemia (HbA(1c) [A1C]) to the levels of these inflammatory and fibrinolytic variables in recently diagnosed (

Reduction in use of healthcare services with combination sulfonylurea and rosiglitazone: findings from the Rosiglitazone Early vs SULfonylurea Titration (RESULT) study.

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.