Background Odanacatib, a cathepsin K inhibitor, reduces bone resorption while maintaining bone formation. Previous work has shown that odanacatib increases bone mineral density in postmenopausal... Show moreBackground Odanacatib, a cathepsin K inhibitor, reduces bone resorption while maintaining bone formation. Previous work has shown that odanacatib increases bone mineral density in postmenopausal women with low bone mass. We aimed to investigate the efficacy and safety of odanacatib to reduce fracture risk in postmenopausal women with osteoporosis.Methods The Long-term Odanacatib Fracture Trial (LOFT) was a multicentre, randomised, double-blind, placebo-controlled, event-driven study at 388 outpatient clinics in 40 countries. Eligible participants were women aged at least 65 years who were postmenopausal for 5 years or more, with a femoral neck or total hip bone mineral density T-score between -2.5 and -4.0 if no previous radiographic vertebral fracture, or between -1.5 and -4.0 with a previous vertebral fracture. Women with a previous hip fracture, more than one vertebral fracture, or a T-score of less than -4.0 at the total hip or femoral neck were not eligible unless they were unable or unwilling to use approved osteoporosis treatment. Participants were randomly assigned (1:1) to either oral odanacatib (50 mg once per week) or matching placebo. Randomisation was done using an interactive voice recognition system after stratification for previous radiographic vertebral fracture, and treatment was masked to study participants, investigators and their staff, and sponsor personnel. If the study completed before 5 years of double-blind treatment, consenting participants could enrol in a double-blind extension study (LOFT Extension), continuing their original treatment assignment for up to 5 years from randomisation. Primary endpoints were incidence of vertebral fractures as assessed using radiographs collected at baseline, 6 and 12 months, yearly, and at final study visit in participants for whom evaluable radiograph images were available at baseline and at least one other timepoint, and hip and non-vertebral fractures adjudicated as being a result of osteoporosis as assessed by clinical history and radiograph. Safety was assessed in participants who received at least one dose of study drug. The adjudicated cardiovascular safety endpoints were a composite of cardiovascular death, myocardial infarction, or stroke, and new-onset atrial fibrillation or flutter. Individual cardiovascular endpoints and death were also assessed. LOFT and LOFT Extension are registered with ClinicalTrials.gov (number NCT00529373) and the European Clinical Trials Database (EudraCT number 2007-002693-66).Findings Between Sept 14, 2007, and Nov 17, 2009, we randomly assigned 16 071 evaluable patients to treatment: 8043 to odanacatib and 8028 to placebo. After a median follow-up of 36.5 months (IQR 34.43-40.15) 4297 women assigned to odanacatib and 3960 assigned to placebo enrolled in LOFT Extension (total median follow-up 47.6 months, IQR 35.45-60.06). In LOFT, cumulative incidence of primary outcomes for odanacatib versus placebo were: radiographic vertebral fractures 3.7% (251/6770) versus 7.8% (542/6910), hazard ratio (HR) 0.46, 95% CI 0.40-0.53; hip fractures 0.8% (65/8043) versus 1.6% (125/8028), 0.53, 0.39-0.71; non-vertebral fractures 5.1% (412/8043) versus 6.7% (541/8028), 0.77, 0.68-0.87; all p<0.0001. Combined results from LOFT plus LOFT Extension for cumulative incidence of primary outcomes for odanacatib versus placebo were: radiographic vertebral fractures 4.9% (341/6909) versus 9.6% (675/7011), HR 0.48, 95% CI 0.42-0.55; hip fractures 1.1% (86/8043) versus 2.0% (162/8028), 0.52, 0.40-0.67; non-vertebral fractures 6.4% (512/8043) versus 8.4% (675/8028), 0.74, 0.66-0.83; all p<0.0001. In LOFT, the composite cardiovascular endpoint of cardiovascular death, myocardial infarction, or stroke occurred in 273 (3.4%) of 8043 patients in the odanacatib group versus 245 (3.1%) of 8028 in the placebo group (HR 1.12, 95% CI 0.95-1.34; p=0.18). New-onset atrial fibrillation or flutter occurred in 112 (1.4%) of 8043 patients in the odanacatib group versus 96 (1.2%) of 8028 in the placebo group (HR 1.18, 0.90-1.55; p=0.24). Odanacatib was associated with an increased risk of stroke (1.7% [136/8043] vs 1.3% [104/8028], HR 1.32, 1.02-1.70; p=0.034), but not myocardial infarction (0.7% [60/8043] vs 0.9% [74/8028], HR 0.82, 0.58-1.15; p=0.26). The HR for all-cause mortality was 1.13 (5.0% [401/8043] vs 4.4% [356/8028], 0.98-1.30; p=0.10). When data from LOFT Extension were included, the composite of cardiovascular death, myocardial infarction, or stroke occurred in significantly more patients in the odanacatib group than in the placebo group (401 [5.0%] of 8043 vs 343 [4.3%] of 8028, HR 1.17, 1.02-1.36; p=0.029, as did stroke (2.3% [187/8043] vs 1.7% [137/8028], HR 1.37, 1.10-1.71; p=0.0051).Interpretation Odanacatib reduced the risk of fracture, but was associated with an increased risk of cardiovascular events, specifically stroke, in postmenopausal women with osteoporosis. Based on the overall balance between benefit and risk, the study's sponsor decided that they would no longer pursue development of odanacatib for treatment of osteoporosis. Copyright (C) 2019 Elsevier Ltd. All rights reserved. Show less
Griffin, S.J.; Rutten, G.E.H.M.; Khunti, K.; Witte, D.R.; Lauritzen, T.; Sharp, S.J.; ... ; Sandbaek, A. 2019
Background The multicentre, international ADDITION-Europe study investigated the effect of promoting intensive treatment of multiple risk factors among people with screen-detected type 2 diabetes... Show moreBackground The multicentre, international ADDITION-Europe study investigated the effect of promoting intensive treatment of multiple risk factors among people with screen-detected type 2 diabetes over 5 years. Here we report the results of a post-hoc 10-year follow-up analysis of ADDITION-Europe to establish whether differences in treatment and cardiovascular risk factors have been maintained and to assess effects on cardiovascular outcomes.Methods As previously described, general practices from four centres (Denmark, Cambridge [UK], Leicester [UK], and the Netherlands) were randomly assigned by computer-generated list to provide screening followed by routine care of diabetes, or screening followed by intensive multifactorial treatment. Population-based stepwise screening programmes among people aged 40-69 years (50-69 years in the Netherlands), between April, 2001, and December, 2006, identified patients with type 2 diabetes. Allocation was concealed from patients. Following the 5-year follow-up, no attempts were made to maintain differences in treatment between study groups. In this report, we did a post-hoc analysis of cardiovascular and renal outcomes over 10 years following randomisation, including a 5 years post-intervention follow-up. As in the original trial, the primary endpoint was a composite of first cardiovascular event, including cardiovascular mortality, cardiovascular morbidity (non-fatal myocardial infarction and non-fatal stroke), revascularisation, and non-traumatic amputation, up to Dec 31, 2014. Analyses were based on the intention-to-treat principle. ADDITION-Europe is registered with ClinicalTrials.gov, NCT00237549.Findings 343 general practices were randomly assigned to routine diabetes care (n=176) or intensive multifactorial treatment (n=167). 317 of these general practices (157 in the routine care group, 161 in the intensive treatment group) included eligible patients between April, 2001, and December, 2006. Of the 3233 individuals with screen-detected diabetes, 3057 agreed to participate (1379 in the routine care group, 1678 in the intensive treatment group), but at the 10-year follow-up 14 were lost to follow-up and 12 withdrew, leaving 3031 to enter 10-year follow-up analysis. Mean duration of follow-up was 9.61 years (SD 2.99). Sustained reductions over 10 years following diagnosis were apparent for bodyweight, HbA1c, blood pressure, and cholesterol in both study groups, but between-group differences identified at 1 and 5 years were attenuated at the 10-year follow-up. By 10 years, 443 participants had a first cardiovascular event and 465 died. There was no significant difference between groups in the incidence of the primary composite outcome (16.1 per 1000 person-years in the routine care group vs 14.3 per 1000 person-years in the intensive treatment group; hazard ratio [HR] 0.87, 95% CI 0.73-1.04; p=0.14) or all-cause mortality (15.6 vs 14.3 per 1000 person-years; HR 0.90, 0.76-1.07).Interpretation Sustained reductions in glycaemia and related cardiovascular risk factors over 10 years among people with screen-detected diabetes managed in primary care are achievable. The differences in prescribed treatment and cardiovascular risk factors in the 5 years following diagnosis were not maintained at 10 years, and the difference in cardiovascular events and mortality remained non-significant. Copyright (C) 2019 Elsevier Ltd. All rights reserved. Show less
Ray, K.K.; Colhoun, H.M.; Szarek, M.; Baccara-Dinet, M.; Bhatt, D.L.; Bittner, V.A.; ... ; Vidotti 2019
Background After acute coronary syndrome, diabetes conveys an excess risk of ischaemic cardiovascular events. A reduction in mean LDL cholesterol to 1.4-1.8 mmol/L with ezetimibe or statins reduces... Show moreBackground After acute coronary syndrome, diabetes conveys an excess risk of ischaemic cardiovascular events. A reduction in mean LDL cholesterol to 1.4-1.8 mmol/L with ezetimibe or statins reduces cardiovascular events in patients with an acute coronary syndrome and diabetes. However, the efficacy and safety of further reduction in LDL cholesterol with an inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9) after acute coronary syndrome is unknown. We aimed to explore this issue in a prespecified analysis of the ODYSSEY OUTCOMES trial of the PCSK9 inhibitor alirocumab, assessing its effects on cardiovascular outcomes by baseline glycaemic status, while also assessing its effects on glycaemic measures including risk of new-onset diabetes.Methods ODYSSEY OUTCOMES was a randomised, double-blind, placebo-controlled trial, done at 1315 sites in 57 countries, that compared alirocumab with placebo in patients who had been admitted to hospital with an acute coronary syndrome (myocardial infarction or unstable angina) 1-12 months before randomisation and who had raised concentrations of atherogenic lipoproteins despite use of high-intensity statins. Patients were randomly assigned (1: 1) to receive alirocumab or placebo every 2 weeks; randomisation was stratified by country and was done centrally with an interactive voice-response or web-response system. Alirocumab was titrated to target LDL cholesterol concentrations of 0.65-1.30 mmol/L. In this prespecified analysis, we investigated the effect of alirocumab on cardiovascular events by glycaemic status at baseline (diabetes, prediabetes, or normoglycaemia)-defined on the basis of patient history, review of medical records, or baseline HbA(1c) or fasting serum glucose-and risk of new-onset diabetes among those without diabetes at baseline. The primary endpoint was a composite of death from coronary heart disease, non-fatal myocardial infarction, fatal or non-fatal ischaemic stroke, or unstable angina requiring hospital admission. ODYSSEY OUTCOMES is registered with ClinicalTrials. gov, number NCT01663402.Findings At study baseline, 5444 patients (28.8%) had diabetes, 8246 (43.6%) had prediabetes, and 5234 (27.7%) had normoglycaemia. There were no significant differences across glycaemic categories in median LDL cholesterol at baseline (2.20-2.28 mmol/L), after 4 months' treatment with alirocumab (0.80 mmol/L), or after 4 months' treatment with placebo (2.25-2.28 mmol/L). In the placebo group, the incidence of the primary endpoint over a median of 2.8 years was greater in patients with diabetes (16.4%) than in those with prediabetes (9.2%) or normoglycaemia (8.5%); hazard ratio (HR) for diabetes versus normoglycaemia 2.09 (95% CI 1.78-2.46, p<0.0001) and for diabetes versus prediabetes 1.90 (1.65-2.17, p<0.0001). Alirocumab resulted in similar relative reductions in the incidence of the primary endpoint in each glycaemic category, but a greater absolute reduction in the incidence of the primary endpoint in patients with diabetes (2.3%, 95% CI 0.4 to 4.2) than in those with prediabetes (1.2%, 0.0 to 2.4) or normoglycaemia (1.2%, -0.3 to 2.7; absolute risk reduction p(interaction) = 0.0019). Among patients without diabetes at baseline, 676 (10.1%) developed diabetes in the placebo group, compared with 648 (9.6%) in the alirocumab group; alirocumab did not increase the risk of new-onset diabetes (HR 1.00, 95% CI 0.89-1.11). HRs were 0.97 (95% CI 0.87-1.09) for patients with prediabetes and 1.30 (95% CI 0.93-1.81) for those with normoglycaemia (p(interaction) = 0.11).Interpretation After a recent acute coronary syndrome, alirocumab treatment targeting an LDL cholesterol concentration of 0.65-1.30 mmol/L produced about twice the absolute reduction in cardiovascular events among patients with diabetes as in those without diabetes. Alirocumab treatment did not increase the risk of new-onset diabetes. Copyright (C) 2019 Elsevier Ltd. All rights reserved. Show less
Interpretation Patients with Cushing's disease who have been in remission for more than 10 years are at increased risk of overall mortality compared with the general population, particularly from... Show moreInterpretation Patients with Cushing's disease who have been in remission for more than 10 years are at increased risk of overall mortality compared with the general population, particularly from circulatory disease. However, median survival from cure is excellent at about 40 years of remission. Treatment complexity and an increased number of treatments, reflecting disease that is more difficult to control, appears to negatively affect survival. Pituitary surgery alone is the preferred treatment to secure an optimum outcome, and should be done in a centre of surgical excellence. Show less
