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OBJECTIVE The principle of replacing prandial insulin lispro with a once-weekly glucagon-like peptide 1 receptor agonist (GLP-1RA) for type 2 diabetes inadequately controlled on a multiple daily insulin injections regimen was tested with albiglutide. RESEARCH DESIGN AND METHODS In this treat-to-target study, basal plus prandial insulin was optimized over 4 weeks before participants were randomized (1:1) to albiglutide plus optimized basal insulin glargine and lispro (dose reduced by 50% at randomization; subsequently, lispro injections were fully discontinued 4 weeks later) (n = 402) or to continued optimized lispro plus optimized glargine (n = 412). RESULTS Mean ± SD HbA1c at baseline, 7.8 ± 0.6% (61 ± 7 mmol/mol) in the albiglutide + glargine group and 7.7 ± 0.6% (60 ± 7 mmol/mol) in the lispro + glargine group, was reduced at week 26 to 6.7 ± 0.8% (49 ± 8 mmol/mol) and 6.6 ± 0.8% (48 ± 8 mmol/mol), respectively (least squares [LS] difference 0.06% [95% CI −0.05 to 0.17]; noninferiority P < 0.0001). In the albiglutide + glargine group, 218 participants (54%) replaced all prandial insulin without reintroducing lispro up to week 26. Total daily prandial insulin dose was similar at baseline but was lower by 62 units/day (95% CI −65.9 to −57.8; P < 0.0001) at week 26 in the albiglutide + glargine group, and the total number of weekly injections was also reduced from 29 to 13 per week. Less severe/documented symptomatic hypoglycemia (57.2% vs. 75.0%) occurred in the albiglutide + glargine group with meaningful weight differences (LS mean ± SE −2.0 ± 0.2 vs. +2.4 ± 0.2 kg; P < 0.0001) vs. lispro + glargine. Gastrointestinal adverse events were higher with albiglutide + glargine (26% vs. 13%). CONCLUSIONS A once-weekly GLP-1RA was able to substitute for prandial insulin in 54% of people, substantially reducing the number of prandial insulin injections; glycemic control improved, with the added benefits of weight loss and less hypoglycemia in the GLP-1RA arm. Replacing prandial insulin with a weekly GLP-1RA can simplify basal plus prandial insulin treatments and achieve better outcomes in type 2 diabetes.

ObjectivesThis ongoing Phase-2, randomised, placebo-controlled, double-blind study evaluated the efficacy, safety and pharmacokinetics of intravenous belimumab in childhood-onset systemic lupus erythematosus (cSLE).MethodsPatients (5 to 17 years) were randomised to belimumab 10 mg/kg intravenous or placebo every 4 weeks, plus standard SLE therapy. Primary endpoint: SLE Responder Index (SRI4) response rate (Week 52). Key major secondary endpoints: proportion of patients achieving the Paediatric Rheumatology International Trials Organisation/American College of Rheumatology (PRINTO/ACR) response using 50 and ‘30 alternative’ definitions (Week 52), and sustained response (Weeks 44 to 52) by SRI4 and Parent Global Assessment of well-being (Parent-global). Safety and pharmacokinetics were assessed. Study not powered for statistical testing.ResultsNinety-three patients were randomised (belimumab, n=53; placebo, n=40). At Week 52, there were numerically more SRI4 responders with belimumab versus placebo (52.8% vs 43.6%; OR 1.49 (95% CI 0.64 to 3.46)). PRINTO/ACR 30 alternative (52.8% vs 27.5%; OR 2.92 (95% CI 1.19 to 7.17)) and PRINTO/ACR 50 (60.4% vs 35.0%; OR 2.74 (95% CI 1.15 to 6.54)) responses were more frequent with belimumab than placebo, as were sustained responses for SRI4 (belimumab, 43.4%; placebo, 41.0%; OR 1.08 (95% CI 0.46 to 2.52)) and Parent-global (belimumab, 59.1%; placebo, 33.3%; OR 3.49 (95% CI 1.23 to 9.91)). Serious adverse events were reported in 17.0% of belimumab patients and 35.0% of placebo patients; one death occurred (placebo). Week-52, geometric mean (95% CI) belimumab trough concentration was 56.2 (45.2 to 69.8) µg/mL.ConclusionThe belimumab intravenous pharmacokinetics and benefit–risk profile in cSLE are consistent with adult belimumab studies and the 10 mg/kg every 4 weeks dose is appropriate.Trial registration numberNCT01649765.

Objective: The principle of replacing prandial insulin lispro with a once-weekly GLP-1 receptor agonist (GLP-1RA) in type 2 diabetes inadequately controlled on a multiple daily insulin injections regimen was tested with albiglutide. Research Design and Methods: In this treat-to-target study, basal+prandial insulin was optimized over 4 weeks before participants were randomized (1:1) to albiglutide plus optimized basal insulin glargine and lispro (dose reduced by 50% at randomization; subsequently lispro injections were fully discontinued 4 weeks later) (n=402), or to continued optimized lispro plus optimized glargine (n=412). Results: Mean±SD HbA1c at baseline, 7.8±0.6% (61±7 mmol/mol) in the albiglutide+glargine group and 7.7±0.6% (60±7 mmol/mol) in the lispro+glargine group, were reduced at week 26 to 6.7±0.8% (49±8 mmol/mol) and 6.6±0.8% (48±8 mmol/mol); respectively (LS difference 0.06% [95% CI, −0.05 to 0.17]; noninferiority P. In the albiglutide+glargine group, 218 participants (54%) replaced all prandial insulin without reintroducing lispro up to week 26. Total daily prandial insulin dose was similar at baseline but was lower by 62U/day (95% CI −65.9 to −57.8; P and the total number of weekly injections was also reduced from 29 to 13 per week. Less severe/documented symptomatic hypoglycemia (57.2% vs. 75.0%) occurred in the albiglutide+glargine group with meaningful weight differences (LS mean±SE: −2.0±0.2 vs. +2.4±0.2 kg; P Conclusions: A once-weekly GLP-1RA was able to substitute for prandial insulin in 54% of people, substantially reducing the number of prandial insulin injections; glycemic control improved, with the added benefits of weight loss and less hypoglycemia in the GLP1RA arm. Replacing prandial insulin with a weekly GLP-1RA can simplify basal+prandial insulin treatments and achieve better outcomes in type 2 diabetes.

Albiglutide, developed for treatment of type 2 diabetes mellitus, is provided in a dual-chamber cartridge (DCC) single-dose pen-injector containing lyophilized drug that must be reconstituted with diluent prior to use. A liquid formulation of albiglutide has been developed that does not require mixing. In this 2-period, randomized, crossover, double-blind, phase I study (NCT02660736) in 59 healthy volunteers, pharmacokinetic parameters were determined and the bioequivalence of the 2 formulations was assessed. Participants received injections from each type of pen-injector, one containing albiglutide 50 mg and one containing placebo, followed by an 8-week washout period between regimens: albiglutide 50-mg liquid formulation from an auto-injector and lyophilized placebo from a DCC pen-injector (Regimen A), or placebo liquid from an auto-injector and lyophilized albiglutide 50 mg from a DCC pen-injector (Regimen B). Geometric mean total exposures (area under the drug concentration-time curve [AUC](0-t) [1345.4 vs 1426.9 (μg · h/mL)], AUC(0-∞) [1376.2 vs 1454.6 (μg · h/mL)], and maximum concentration of drug in blood plasma [4968.5 vs 5314.7 ng/mL]) were comparable between Regimens A and B. Ratios of geometric least square means (90% confidence interval) were 95.3% (89.49-101.52) for AUC(0-∞) , 95.1% (89.12-101.49) for AUC(0-t) , and 93.2% (86.76-100.17) for maximum concentration of drug in blood plasma, falling within the 90% confidence interval of 0.80 to 1.25 for bioequivalence. No new safety concerns were observed.

Aims/Introduction The present phase 3, randomized, double-blind 24-week study with extension to 1 year assessed the efficacy and safety of albiglutide compared with placebo in Japanese patients with type 2 diabetes mellitus inadequately controlled by diet and exercise with or without a single oral antidiabetic drug. Materials and Methods Patients received weekly albiglutide 30 mg (n = 160), albiglutide 50 mg (n = 150) or a placebo switched to albiglutide 30 mg after 24 weeks (n = 77). Open-label daily liraglutide 0.9 mg (n = 103) was included as a reference. Oral antidiabetic drug use was discontinued before baseline. The primary end-point was 24-week change from baseline in glycated hemoglobin (HbA1c). Secondary end-points included fasting plasma glucose, bodyweight and adverse events. Results At 24 weeks, mean HbA1c changes from baseline were −1.10, −1.30, and 0.25% for albiglutide 30, 50 mg and placebo, respectively (P vs placebo

The glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) exenatide and lixisenatide reduce cholecystokinin (CCK)-induced gallbladder emptying in healthy subjects. It is unknown if all GLP-1 RAs share this effect; therefore, the effect of the GLP-1 RA albiglutide on gallbladder function was assessed. In this randomized, double-blind, 2-way crossover study, a single dose of subcutaneous albiglutide 50 mg or placebo was administered to 17 healthy subjects, and CCK-induced gallbladder contractility was measured by ultrasonography. CCK (0.003 μg/kg) was infused intravenously over 50 minutes on study day 4 (3 days after dosing, to coincide with albiglutide's expected time to maximum concentration). Gallbladder volume, ejection fraction, and the main pancreatic and common bile-duct diameters were measured before, during, and following CCK infusion. Gallbladder volume was significantly greater in the albiglutide vs placebo groups before, during, and after CCK infusion, and the mean difference from placebo increased numerically during CCK infusion. The area under the volume-effect curve was significantly greater with albiglutide (P = .029). Starting at the 30-minute CCK infusion time point, the gallbladder ejection fraction was significantly lower with albiglutide than placebo. Changes in pancreatic duct diameter and common bile-duct diameter were not significantly different between albiglutide and placebo. Similar incidences of adverse events were observed between the albiglutide and placebo treatment periods. No new albiglutide safety signals were detected, and no serious adverse events were reported. In conclusion, similar to other GLP-1 RAs, albiglutide decreased CCK-induced gallbladder emptying compared with placebo in healthy individuals. Clinical implications of the gallbladder effects are unclear at this time.

Background: Belimumab (BEL), a monoclonal antibody targeting the B-lymphocyte stimulator, is approved in adults with active systemic lupus erythematosus (SLE). This is the first clinical trial of belimumab in pediatric patients with childhood-onset SLE (cSLE). Objectives: PLUTO, a Phase 2, randomised, double-blind trial (BEL114055; NCT01649765), evaluated the efficacy, safety and pharmacokinetics (PK) of intravenous (IV) BEL vs placebo (PBO), plus standard of care (SoC), in cSLE. Methods: Patients with cSLE 5–17 years of age were randomised to BEL 10 mg/kg IV or PBO every 4 weeks, plus SoC. Primary endpoint: SRI4 at Week 52. Major secondary endpoints: PRINTO/ACR 30 and 50 cSLE evaluation criteria for improvement at Week 52; cSLE core response variables at Week 52; and sustained SRI4 and ParentGA (patient well-being) responses (Weeks 44–52). Other endpoints: components of SRI4 at Week 52; and frequency of severe flares using the modified SELENA-SLEDAI Flare Index. Safety and PK were assessed. Analyses were performed on the intent-to-treat population. The study was not powered to test for differences between groups; p-values were not calculated. Results: 93 patients were included (BEL, n=53; PBO, n=40). Groups (BEL vs PBO) were balanced at baseline for age (mean [standard deviation] 13.5 [2.59] vs 14.8 [2.17] years, respectively) and SELENA-SLEDAI score (10.3 [3.34] vs 10.4 [3.63], respectively). Compared with PBO, there were more SRI4 responders (including all 3 components of SRI4), and PRINTO/ACR 30 and 50 responders in the BEL group (Figure). Likewise, more BEL than PBO recipients had sustained improvement of SRI and patient well-being (ParentGA) (Figure). Changes in cSLE core response variables are shown in the Table. Severe flares were 62% less frequent with BEL vs PBO (hazard ratio 0.38 [95% CI 0.18, 0.82]). PK: BEL exposures in cSLE were similar to adult SLE studies. 9/53 (17%) BEL patients had ≥1 serious adverse event vs 14/40 (35%) PBO patients. One PBO patient died of acute pancreatitis. Conclusion: The benefit:risk profile of BEL IV plus SoC in cSLE is generally consistent with BEL in adult SLE. The 10 mg/kg IV dose used in adults may be an appropriate dose in cSLE. Acknowledgement: The authors would like to acknowledge all investigators (PRINTO, PRCSG and otherwise affiliated) for the PLUTO study. Study funded by GSK. Gosia Carless, PhD, Fishawack Indicia Ltd, UK, provided editorial assistance funded by GSK. Disclosure of Interests: Nicolino Ruperto Grant/research support from: The Gaslini Hospital, where NR works as full-time public employee, has received contributions (> 10.000 USD each) from the following industries in the last 3 years: BMS, Eli-Lilly, GlaxoSmithKline, F Hoffmann-La Roche, Janssen, Novartis, Pfizer, Sobi. This funding has been reinvested for the research activities of the hospital in a fully independent manner, without any commitment with third parties., Consultant for: Received honoraria for consultancies or speaker bureaus ( I perform consultancy activities on behalf of the Gaslini Institute for the companies listed below: AbbVie, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, EMD Serono, Janssen, Novartis, Pfizer, R-Pharm. The money received for these activities are directly transferred to the Gaslini Institute’s bank account. Before March 2016, I was the head of the Pediatric Rheumatology Department at the G. Gaslini Hospital, where the PRINTO Coordinating Centre is located. For the coordination activity of the PRINTO network, the Gaslini Hospital received contributions from the industries listed in this section. This money has been reinvested for the research activities of the hospital in fully independent manners besides any commitment with third parties., Daniel J Lovell Consultant for: Consulting fees and/or honoraria from Astra Zeneca, Wyeth Pharma, Amgen, Abbott, Pfizer, F. Hoffmann-La Roche, Novartis, UBC, Takeda, GSK, Boehringer, and Celgene, Hermine Brunner Grant/research support from: Bristol-Myers Squibb, Pfizer, Consultant for: Pfizer, Bristol-Myers Squibb, Janssen, Novartis, Lilly, Roche, GlaxoSmithKline, Sanofi, Speakers bureau: Novartis, Roche

To evaluate the safety and efficacy of once weekly albiglutide added to a single oral antidiabetic drug (OAD) in Japanese patients with inadequately controlled type 2 diabetes mellitus (T2DM).In this phase 3, 1 year study (NCT01777282), patients (N = 374) received albiglutide 30 mg plus a single OAD (sulfonylurea [n = 120], biguanide [n = 67)], glinide [n = 65], thiazolidinedione [n = 61], or α-glucosidase inhibitor [n = 61]). Albiglutide could be increased to 50 mg after Week 4, based on glycemic criteria. Primary endpoints were the incidence of adverse events (AEs) and hypoglycemia; secondary endpoints were changes from baseline at Week 52 in HbAOn-therapy AEs occurred in 78.6% of patients and serious AEs in 2.1%. Common AEs were nasopharyngitis (32.6%), constipation (7.2%), and diabetic retinopathy (5.3%). No serious AEs occurred more than once or were reported in1 patient. Hypoglycemia occurred in 6.4% of patients, mostly in the albiglutide + sulfonylurea (14.2%) and the albiglutide + glinide (6.2%) groups. Albiglutide was uptitrated in 53.2% of patients. Mean baseline HbAWhen combined with a single OAD in Japanese patients with inadequately controlled T2DM, albiglutide led to favorable changes in all glycemic parameters, with minor changes in body weight depending on the background OAD. No new safety concerns were noted.

Quantitative computed tomography (QCT) measurements have been used extensively to ascertain information about bone quality and density due to the 3-dimensional information provided and the ability to segment out trabecular and cortical bones. QCT imaging helps to improve our understanding of the role that each bone compartment plays in the pathogenesis and prognosis of fracture. This study was conducted to explore longitudinal changes in femoral neck (FN) cortical bone structure using both volumetric bone mineral density (vBMD) and cortical shell thickness assessments via QCT in a double-blind, randomized, multicenter clinical trial in postmenopausal women with type 2 diabetes mellitus. This study also examined whether treatment-associated changes in the cortical bone vBMD and thickness in femoral neck quadrants could be evaluated. Subjects were randomized to rosiglitazone (RSG) or metformin (MET) for 52 wk followed by 24 wk of open-label MET. A subset of 87 subjects underwent QCT scans of the hip at baseline, after 52 wk of double-blind treatment, and after 24 wk of treatment with MET using standard full-body computed tomography scanners. All scans were evaluated and analyzed centrally. Cortical vBMD at the FN was precisely segmented from trabecular bone and used to assess a possible therapeutic effect on this bone compartment. QCT analysis showed reductions in adjusted mean percentage change in vBMD and in absolute cortical thickness occurred with RSG treatment from baseline to week 52, whereas changes with MET were generally minimal. The reductions observed during RSG treatment for 1 yr appeared to partially reverse during the open-label MET phase from weeks 52 to 76. The femoral neck quadrant may provide utility as a potential endpoint in clinical trials for the understanding of the therapeutic effect of new entities on cortical bone vs trabecular bone; however, further clinical validation is needed. Trial registration: The protocol (GSK study number AVD111179) was registered on ClinicalTrials.gov as NCT00679939.

The glycemic efficacy of weekly Albi 50 mg to replace prandial insulin lispro (Lis) was evaluated in T2DM inadequately controlled on a multiple daily insulin regimen (≥3 injections/day). Basal/bolus insulin was optimized during a 4 week run-in phase before randomization to: 1) Albi + optimized insulin glargine (Gla), with prandial Lis subsequently discontinued by week 4 (n = 402) or 2) optimized Lis + optimized Gla (n = 412). At 26 week, the LS mean ± SE change from baseline in HbA1c was −1.04 ± 0.04 vs. −1.10 ± 0.04% (treatment difference 0.[95% CI, −0.05, 0.17]%; non-inferiority p In conclusion, Albi meaningfully improved glucose control; prandial insulin was stopped in 54% of participants, allowing substantial reductions in insulin dose and number of injections, less hypoglycemia, and body weight loss. Disclosure J. Rosenstock: Advisory Panel; Self; Eli Lilly and Company. Consultant; Self; Eli Lilly and Company. Research Support; Self; Novo Nordisk Inc.. Consultant; Self; Novo Nordisk Inc.. Advisory Panel; Self; Sanofi. Consultant; Self; Sanofi. Advisory Panel; Self; Janssen Pharmaceuticals, Inc.. Consultant; Self; Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Advisory Panel; Self; Intarcia Therapeutics, Inc.. Consultant; Self; Intarcia Therapeutics, Inc.. Research Support; Self; Merck & Co., Inc., Pfizer Inc., Sanofi, Novo Nordisk Inc., Bristol-Myers Squibb Company, Eli Lilly and Company, Intarcia Therapeutics, Inc., Genentech, Inc. A.J. Nino: Employee; Self; GlaxoSmithKline plc.. Stock/Shareholder; Self; GlaxoSmithKline plc. J. Soffer: Employee; Self; GlaxoSmithKline plc.. Other Relationship; Self; GlaxoSmithKline plc.. J.M. Mallory: None. L.M. Erskine: Employee; Self; GlaxoSmithKline plc.. Stock/Shareholder; Self; GlaxoSmithKline plc. A. Acusta: Employee; Self; GlaxoSmithKline plc. J.F. Dole: Employee; Self; GlaxoSmithKline plc. M. Carr: Employee; Self; GlaxoSmithKline plc. P. Home: Consultant; Self; AstraZeneca. Other Relationship; Self; Biocon, Boehringer Ingelheim GmbH. Research Support; Self; GlaxoSmithKline plc.. Consultant; Self; Hanmi Pharmaceutical. Other Relationship; Self; Janssen Research & Development. Consultant; Self; Janssen Research & Development, Merck & Co., Inc.. Other Relationship; Self; Merck & Co., Inc.. Research Support; Self; Merck & Co., Inc.. Other Relationship; Self; Novo Nordisk A/S. Consultant; Self; AntriaBio, Inc., Earlysign, Roche Diabetes Care Health and Digital Solutions. Research Support; Self; Sanofi. Consultant; Self; Sanofi.

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 -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 D 3 ≥ 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.

Thiazolidinediones are associated with increased fractures in type 2 diabetes mellitus (T2D). One explanation is that activation of peroxisome proliferator-activated receptor-γ expression alters bone remodeling cells.To investigate whether osteoclast and osteogenic precursor cells are altered by rosiglitazone (RSG) treatment in T2D as compared to metformin (MET) treatment.A randomized controlled trial of RSG or MET for 52 weeks, followed by 24 weeks of MET.Data were generated at a tertiary care center.Seventy-three T2D postmenopausal women participated.Peripheral blood mononuclear cells were isolated and cultured with receptor activator of nuclear factor κB ligand and stained for tartrate-resistant acid phosphatase to measure circulating osteoclast precursors. Peripheral blood mononuclear cells were also characterized for osteogenic, endothelial, and calcification markers by flow cytometry with the ligands osteocalcin (OCN), CD34, and CD 146.Tartrate-resistant acid phosphatase-positive cells increased between weeks 0 and 52 (RSG, 2.9 ± 2 to 14.0 ± 3 U/L, P = .001; MET, 3.3 ± 2 to 16.7 ± 2 U/L, P = .001), increasing further in the RSG group after changing to MET (to 26.5 ± 5 U/L, P = .05 vs wk 52). With RSG, OCN+ cells with CD34 but without CD146 fell from weeks 0 to 52 (20.1 ± 1% to 15.5 ± 2%; P = .03), remaining stable through week 76. The OCN+ cells lacking both CD34 and CD146 increased from weeks 0 to 52 (67.3 ± 2 to 74.4 ± 2%; P = .02), but returned to baseline after switching to MET.In postmenopausal women with T2D, circulating osteoclast precursor cells increase with both RSG and MET, and increase further when switching from RSG to MET. Subpopulations of cells that may be involved in the osteogenic lineage pathway are also altered with RSG. Further work is necessary to elucidate how these changes may relate to fracture risk.

The glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) exenatide and lixisenatide reduce cholecystokinin (CCK)-induced gallbladder emptying in healthy subjects. It is unknown if all GLP-1 RAs share this effect; therefore, the effect of the GLP-1 RA albiglutide on gallbladder function was assessed. In this randomized, double-blind, 2-way crossover study, a single dose of subcutaneous albiglutide 50 mg or placebo was administered to 17 healthy subjects, and CCK-induced gallbladder contractility was measured by ultrasonography. CCK (0.003 μg/kg) was infused intravenously over 50 minutes on study day 4 (3 days after dosing, to coincide with albiglutide's expected time to maximum concentration). Gallbladder volume, ejection fraction, and the main pancreatic and common bile-duct diameters were measured before, during, and following CCK infusion. Gallbladder volume was significantly greater in the albiglutide vs placebo groups before, during, and after CCK infusion, and the mean difference from placebo increased numerically during CCK infusion. The area under the volume-effect curve was significantly greater with albiglutide (P = .029). Starting at the 30-minute CCK infusion time point, the gallbladder ejection fraction was significantly lower with albiglutide than placebo. Changes in pancreatic duct diameter and common bile-duct diameter were not significantly different between albiglutide and placebo. Similar incidences of adverse events were observed between the albiglutide and placebo treatment periods. No new albiglutide safety signals were detected, and no serious adverse events were reported. In conclusion, similar to other GLP-1 RAs, albiglutide decreased CCK-induced gallbladder emptying compared with placebo in healthy individuals. Clinical implications of the gallbladder effects are unclear at this time.

OBJECTIVE to evaluate the efficacy and safety of albiglutide compared with placebo and active comparators from an integrated trial subpopulation of Latino/Hispanic patients whose type 2 diabetes mellitus (T2DM) was inadequately controlled on their current regimen of diet and exercise, with or without oral antidiabetic drugs (OADs) and/or insulin. METHODS Latino/Hispanic patient subpopulations (N = 1204) across 7 phase III albiglutide studies (N = 4400) were evaluated post-hoc for efficacy and safety. Comparators were placebo, sulfonylureas, insulin, thiazolidinediones, and dipeptidyl peptidase-4 inhibitors. Glycatedhemoglobin (HbA1c) change from baseline to the time of the primary endpoint assessment (from 26 to 104 weeks) was evaluated in patients on diet and exercise and/or OADs, with or without insulin. Patients were allowed to continue in the study if hyperglycemic rescue was required, according to a prespecified algorithm and at the discretion of the investigator. RESULTS At baseline in the Latino/Hispanic subpopulation, the mean HbA1c was 8.3%, mean age was 53 years, mean body mass index was 32 kg/m2, and mean duration of T2DM was 8.0 years. The primary endpoint of mean HbA1c difference (albiglutide - placebo) was -0.94% for the Latino/Hispanic subpopulation and -0.86% (p

Aim: The purpose of this study was to evaluate if superior glycaemic control could be achieved with Avandamet® (rosiglitazone/metformin/AVM) compared with metformin (MET) monotherapy, and if glycaemic effects attained with AVM are durable over 18 months of treatment. Bone mineral density (BMD) and bone biomarkers were evaluated in a subgroup of patients. Methods: This was a phase IV, randomized, double-blind, multi-centre study in 688, drug naIve, male and female patients who had an established clinical diagnosis of type 2 diabetes mellitus (T2DM). Patients were randomized in a 1 : 1 ratio either to AVM or MET. Results: As initial therapy in patients with T2DM, AVM was superior to MET in achieving statistically significant reductions in glycated haemoglobin (HbA1c) (p < 0.0001) and fasting plasma glucose (FPG) (p < 0.001), with more patients reaching recommended HbA1c and FPG targets for intensive glycaemic control. The glycaemic effects attained with AVM compared to MET monotherapy were durable over 18 months of treatment. In the bone substudy, AVM was associated with a significantly lower BMD in comparison with MET at week 80 in the lumbar spine and total hip (p < 0.0012 and p = 0.0005, respectively). Between-treatment differences were not statistically significant for distal one-third of radius BMD, femoral neck BMD or total BMD. Conclusion: Superior glycaemic control was achieved with AVM compared with MET monotherapy. The superior glycaemic effects were shown to be durable over 18 months of treatment. AVM was associated with a significantly reduced BMD in comparison with MET at week 80 in the lumbar spine and total hip.

The combination of dutasteride and tamsulosin may be more effective for the treatment of symptomatic benign prostatic hyperplasia than either treatment alone. We report the results of three pharmacokinetics and tolerability studies, which used a dutasteride/tamsulosin HCl (0.5 mg/0.2 mg) fixed-dose combination (FDC) capsules containing a small dutasteride soft gelatin capsule (smaller than commercial Avodart™) and modified-release tamsulosin pellets that have different amounts of enteric coating. These studies compared the test products to commercial Avodart™ (dutasteride 0.5 mg) and two different commercial tamsulosin HCl 0.2 mg products, Harnal™ Capsules or Harnal-D™ Tablets, which are reportedly bioequivalent to each other. All three studies were randomized single-dose studies in healthy male adults. Study 1 [N = 86 (NCT01254071)] was a two-period crossover study of a dutasteride/tamsulosin HCl FDC versus coadministered Avodart™ and Harnal-D™ Tablets. The pharmacokinetics of both dutasteride and tamsulosin were studied. Study 2 [N = 27 (NCT01471678)] was a four-period crossover study of dutasteride/tamsulosin HCl FDC formulations versus Avodart™ and Harnal™ Capsules or Harnal-D™ Tablets. Only the pharmacokinetics of tamsulosin were studied. Study 3 [N = 40 (NCT01495026)] was a two-period study of dutasteride/tamsulosin HCl FDC formulations versus coadministered Avodart™ and Harnal-D™ Tablets. In this study, only the pharmacokinetics of tamsulosin were studied. Study 2 assessed fed-state pharmacokinetics. Studies 1 and 3 assessed fed- and fasted-state pharmacokinetics. All dutasteride/tamsulosin HCl FDC formulations and coadministered treatments were well-tolerated. In Study 1, the FDC dutasteride was bioequivalent to Avodart™ coadministered with tamsulosin under fed and fasted conditions. In Study 1, the FDC tamsulosin had a slower release than commercial Harnal-D™ Tablets coadministered with dutasteride (fed and fasted state). In Study 2, the FDC tamsulosin containing 15 % by weight enteric-coated tamsulosin pellets was bioequivalent to Harnal™ Capsules coadministered with dutasteride in the fed state. In Study 3, the FDC containing 15 % by weight enteric-coated tamsulosin pellets combined with uncoated tamsulosin pellets (coated:uncoated = 10:90) were bioequivalent to Harnal-D™ Tablets coadministered with dutasteride in the fasted state but not the fed state. The FDC formulations were well-tolerated and some FDC formulations were comparable with concomitant administration of commercially available dutasteride and tamsulosin.

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.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.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.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.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.

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/m2; 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. ClinicalTrials.gov number NCT00679939

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

Purpose Up to 71% of South Korean postmenopausal women have vitamin D deficiency {serum 25-hydroxyvitamin D [25(OH) D] level

The number of women who decide to have a child after organ transplantation has increased. We determined the outcomes of 67 pregnancies of women who had undergone kidney, liver or heart transplantation. All recipients had been maintained on immunosuppressive therapy before and during pregnancy. Pregnancy complications at term were observed in 17 out of 67 women (25%), hypertension being the most frequent complication (16.17%). Two transplant rejections were reported. Sixty-eight infants were delivered (including one pair of twins); five women had two pregnancies at term. Twenty-eight miscarriages (29.2%) were recorded. Of these 68 babies (including the pair of twins), 40 (58.8%) were born at term and 28 (41.2%) before term. The babies were followed-up for 2 months to 13 years. According to our previous experience, our study shows that patients who have undergone organ transplantation can give birth to healthy infants as long as they are monitored accurately during pregnancy.