Вплив імунологічних маркерів кардіоваскулярного ризику на ранній розвиток атеросклерозу у хворих на ревматоїдний артрит

Aim of the study. To investigate the peculiarities of immunological markers of systemic inflammation in patients with rheumatoid arthritis (RA) depending on the clinical-immunological variant of the course of RA and on the duration of the disease.Materials and methods. We examined 82 patients with RA, aged (37.6±5,1) years. The history of the disease was less than 3 years in 47.5 % of patients (n=39) and in 52.5 % of patients (n=43) – it was more than 3 years. In 48 (58.5 %) patients a seropositive variant of RA was observed and 34 (41.5 %) patients were with seronegative variant of the disease. All patients underwent a complex clinical, laboratory and immunological examination. RA activity was assessed using the DAS 28 index; immune-enzyme assay method was used to assess the level of rheumatoid factor (RF), antibodies to cyclic citrulinated peptide (ACCP), C-reactive protein (CRP), proinflammatory cytokines (tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and IL-6).Results. The levels of pro-inflammatory cytokines in RA showed a statistically significant increase in their concentration in all groups of examined patients compared with the control one. The highest levels of TNF-α (p=0.046) and IL-1β (p=0.025) were in the group of patients with the seronegative variant of RA lasting less than 3 years; the highest concentration of IL-6 (p=0.018) was determined in patients with a long course of seropositive RA. Correlation analysis allowed determining the association of hyperproduction of TNF-α, IL-1β and IL-6 with the duration of RA and disease activity. In all groups of patients with RA an increase in the serum CRP concentration was detected. It was more expressed in patients with a seropositive variant of RA with a disease duration of more than 3 years. In addition, correlation links between CRP and IL-6, IL-1β, TNF-α have been established. The direct correlation between the level of CRP and the DAS28 index (p<0.0001), RF concentration, ACCP (p=0.05) was also revealed.Conclusions. A study in the serum of mediators of immune inflammation in patients with different clinical and immunological variants and duration of RA revealed differences in their content. In patients with anamnesis of RA less than 3 years, a predominant increase in TNF-α and IL-1β was detected in case of a seronegative disease type. In patients with a disease duration of seropositive RA for more than 3 years, the content of IL-6 was increased largely, compared with rates in patients with a similar duration of the seronegative disease. In patients with a RA seropositive duration of more than 3 years, the CRP content was 1.3 times (p=0.05) higher than in the group of patients with a history of the disease less than 3 years and 1,6 times (p=0.001) higher than in patients with similar duration of seronegative RA Цель исследования. Изучить особенности содержания иммунологических маркеров системного воспаления у больных с ревматоидным артритом (РА) в зависимости от клинико-иммунологического варианта течения и длительности заболевания.Материалы и методы. Обследовано 82 пациента с РА, в возрасте (37,6±5,1) лет. У 47,5 % больных (n=39) длительность анамнеза болезни менее 3-х лет, у 52,5 % больных (n=43) – более 3-х лет. У 48 (58,5 %) пациентов отмечался серопозитивный вариант РА, у 34 (41,5 %) – серонегативный вариант. Всем пациентам проводилось комплексное клиническое, лабораторное и иммуннологическое исследование. Активность РА оценивали с использованием индекса DAS28, иммуноферментным методом оценивали уровень ревматоидного фактора (РФ), антител к циклическому цитрулинированному пептиду (АЦЦП), С-реактивного белка (СРБ), провоспалительных цитокинов (фактора некроза опухолей-α (ФНО-α), интерлейкина-1β (ИЛ-1β) и ИЛ-6).Результаты. Содержание провоспалительных цитокинов при РА было статистически значимо повышено во всех группах больных по сравнению с контролем. Наибольший уровень ФНО-α (р=0,046) и ИЛ-1β (р=0,025) выявлен в группе больных с серонегативным вариантом РА длительностью менее 3-х лет; а максимально высокая концентрация ИЛ-6 (р=0,018) отмечалась у больных с длительным течением серопозитивного РА. Определение корреляционных связей показало наличие ассоциации гиперпродукции ФНО-α, ИЛ-1β и ИЛ-6 с длительностью РА и активностью заболевания. Во всех группах больных РА выявлено повышение сывороточной концентрации СРБ, в большей степени выраженное при серопозитивном варианте РА с длительностью болезни более 3-х лет. Установлены прямые корреляционные связи между СРБ и ИЛ-6, ИЛ-1β, ФНО-α и уровнем СРБ и индексом DAS28 (p<0,0001), концентрацией РФ, АЦЦП (p=0,05).Выводы. Проведенное исследование в сыворотке крови медиаторов иммунного воспаления у больных с различными клинико-иммунологическими вариантами и длительностью РА установило различия в их содержании. У больных с анамнезом РА менее 3-х лет выявлено преимущественное повышение ФНО-α и ИЛ-1β при серонегативном варианте заболевания. При длительности серопозитивного РА более 3-х лет в большей степени увеличено содержание ИЛ-6, в сравнении с показателями у больных с аналогичной длительностью серонегативного варианта. При длительности серопозитивного варианта РА более 3-х лет содержание СРБ было в 1,3 раза (р=0,05) выше показателя в группе пациентов с анамнезом болезни менее 3-х лет и в 1,6 раза (р=0,001) выше, чем у больных с аналогичной длительностью серонегативного варианта РА.Мета дослідження. Вивчити особливості вмісту імунологічних маркерів системного запалення у хворих на ревматоїдний артрит (РА) залежно від клініко-імунологічного варіанту перебігу та тривалості захворювання.Матеріали та методи. Обстежено 82 пацієнта з РА, у віці (37,6±5,1) років. У 47,5 % хворих (n=39) тривалість анамнезу хвороби менше 3-х років, у 52,5 % хворих (n=43) – більше 3-х років. У 48 (58,5 %) пацієнтів визначався серопозитивний варіант РА, у 34 (41,5 %) пацієнтів – серонегативний варіант. Всім пацієнтам проводили комплексне клінічне, лабораторне та імунологічне дослідження. Активність РА оцінювали з використанням індексу DAS28, імуноферментним методом оцінювали рівень ревматоїдного фактору (РФ), антитіл до циклічного цитрулінованого пептиду (АЦЦП), С-реактивного білку (СРБ), прозапальних цитокінів (фактору некрозу пухлин-α (ФНП-α), інтерлейкіну-1β (ІЛ-1β) та ІЛ-6).Результати. Рівні прозапальних цитокінів при РА показали статистично достовірне підвищення їх концентрації у всіх групах хворих порівняно з контролем. Найбільший рівень ФНО-α (р=0,046) і ІЛ-1β (р=0,025) мав місце в групі хворих з серонегативним варіантом РА тривалістю менше 3-х років; а максимально висока концентрація ІЛ-6 (р=0,018) визначалася у хворих з тривалим перебігом серопозитивного РА. Визначення кореляційних зв'язків показало наявність асоціації гіперпродукції ФНП-α, ІЛ-1β і ІЛ-6 з тривалістю і активністю захворювання. У всіх групах хворих на РА виявлено підвищення сироваткової концентрації СРБ, більшою мірою при серопозитивному варіанті РА з тривалістю хвороби більше 3-х років. Встановлені прямі кореляційні зв'язки між СРБ та ІЛ-6, ІЛ-1β, ФНП-α, між рівнем СРБ та індексом DAS28 (p<0,0001), концентрацією РФ, АЦЦП (p=0,05).Висновки. Проведене дослідження в сироватці крові медіаторів імунного запалення у хворих з різними клініко-імунологічними варіантами і тривалістю РА встановило відмінності в їх вмісті. У хворих з анамнезом РА менше 3-х років виявлено переважне підвищення ФНП-α і ІЛ-1β при серонегативному варіанті захворювання. При тривалості серопозитивного РА більше 3-х років в більшій мірі збільшений вміст ІЛ-6, у порівнянні з показниками у хворих з аналогічною тривалістю серонегативного варіанту захворювання. При тривалості серопозитивного варіанту РА більше 3-х років вміст СРБ був в 1,3 рази (р=0,05) вище показника в групі пацієнтів з анамнезом хвороби менше 3-х років і в 1,6 рази (р=0,001) вище, ніж у хворих з аналогічною тривалістю серонегативного варіанту РА

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR) 25–75 mL/min per 1·73 m² of body surface area, and a urine albumin-to-creatinine ratio (UACR) of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders) were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days) or end-stage kidney disease (eGFR <15 mL/min per 1·73 m² sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure) in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325) or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%) of 1325 patients in the atrasentan group and 105 (7·9%) of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR] 0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%) of 1325 patients in the atrasentan group and 34 (2·6%) of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%) patients in the atrasentan group and 52 (3·9%) in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding AbbVi

Ertugliflozin and Slope of Chronic eGFR: Prespecified Analyses from the Randomized VERTIS CV Trial

Background and objectives A reduction in the rate of eGFR decline, with preservation of $0.75 ml/min per 1.73 m2 per year, has been proposed as a surrogate for kidney disease progression. We report results from prespecified analyses assessing effects of ertugliflozin versus placebo on eGFR slope from the eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes (VERTIS CV) trial (NCT01986881). Design, setting, participants, & measurements Patients with type 2 diabetes mellitus and established atherosclerotic cardiovascular disease were randomized to placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg (1:1:1). The analyses compared the effect of ertugliflozin (pooled doses, n55499) versus placebo (n52747) on eGFR slope per week and per year by random coefficient models. Study periods (weeks 0–6 and weeks 6–52) and total and chronic slopes (week 0 or week 6 to weeks 104, 156, 208, and 260) were modeled separately and by baseline kidney status. Results In the overall population, for weeks 0–6, the least squares mean eGFR slopes (ml/min per 1.73 m2 per week [95% confidence interval (95% CI)]) were 20.07 (20.16 to 0.03) and 20.54 (20.61 to 20.48) for the placebo and ertugliflozin groups, respectively; the difference was 20.47 (20.59 to 20.36). During weeks 6–52, least squares mean eGFR slopes (ml/min per 1.73 m2 per year [95% CI]) were 20.12 (20.70 to 0.46) and 1.62 (1.21 to 2.02) for the placebo and ertugliflozin groups, respectively; the difference was 1.74 (1.03 to 2.45). For weeks 6–156, least squares mean eGFR slopes (ml/min per 1.73 m2 per year [95% CI]) were 21.51 (21.70 to 21.32) and 20.32 (20.45 to 20.19) for the placebo and ertugliflozin groups, respectively; the difference was 1.19 (0.95 to 1.42). During weeks 0–156, the placebo-adjusted difference in least squares mean slope was 1.06 (0.85 to 1.27). These findings were consistent by baseline kidney status. Conclusions Ertugliflozin has a favorable placebo-adjusted eGFR slope .0.75 ml/min per 1.73 m2 per year, documenting the kidney function preservation underlying the clinical benefits of ertugliflozin on kidney disease progression in patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease. Clinical Trial registry name and registration number: US National Library of Medicine, ClinicalTrials.gov NCT01986881. Date of trial registration: November 13, 2013

Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of bodysurface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2 ), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of endstage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years. (Funded by Janssen Research and Development; CREDENCE ClinicalTrials.gov number, NCT02065791.

Effects of ertugliflozin on kidney composite outcomes, renal function and albuminuria in patients with type 2 diabetes mellitus: an analysis from the randomised VERTIS CV trial

Aims/hypothesis In previous work, we reported the HR for the risk (95% CI) of the secondary kidney composite endpoint (time to first event of doubling of serum creatinine from baseline, renal dialysis/transplant or renal death) with ertugliflozin compared with placebo as 0.81 (0.63, 1.04). The effect of ertugliflozin on exploratory kidney-related outcomes was evaluated using data from the eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes (VERTIS CV) trial (NCT01986881). Methods Individuals with type 2 diabetes mellitus and established atherosclerotic CVD were randomised to receive ertugliflozin 5 mg or 15 mg (observations from both doses were pooled), or matching placebo, added on to existing treatment. The kidney composite outcome in VERTIS CV (reported previously) was time to first event of doubling of serum creatinine from baseline, renal dialysis/transplant or renal death. The pre-specified exploratory composite outcome replaced doubling of serum creatinine with sustained 40% decrease from baseline in eGFR. In addition, the impact of ertugliflozin on urinary albumin/creatinine ratio (UACR) and eGFR over time was assessed. Results A total of 8246 individuals were randomised and followed for a mean of 3.5 years. The exploratory kidney composite outcome of sustained 40% reduction from baseline in eGFR, chronic kidney dialysis/transplant or renal death occurred at a lower event rate (events per 1000 person-years) in the ertugliflozin group than with the placebo group (6.0 vs 9.0); the HR (95% CI) was 0.66 (0.50, 0.88). At 60 months, in the ertugliflozin group, placebo-corrected changes from baseline (95% CIs) in UACR and eGFR were −16.2% (−23.9, −7.6) and 2.6 ml min−1 [1.73 m]−2 (1.5, 3.6), respectively. Ertugliflozin was associated with a consistent decrease in UACR and attenuation of eGFR decline across subgroups, with a suggested larger effect observed in the macroalbuminuria and Kidney Disease: Improving Global Outcomes in Chronic Kidney Disease (KDIGO CKD) high/very high-risk subgroups. Conclusions/interpretation Among individuals with type 2 diabetes and atherosclerotic CVD, ertugliflozin reduced the risk for the pre-specified exploratory composite renal endpoint and was associated with preservation of eGFR and reduced UACR. Trial registration ClinicalTrials.gov NCT0198688

Cardiovascular Outcomes with Ertugliflozin in Type 2 Diabetes

BACKGROUND The cardiovascular effects of ertugliflozin, an inhibitor of sodium–glucose cotransporter 2, have not been established. METHODS In a multicenter, double-blind trial, we randomly assigned patients with type 2 diabetes and atherosclerotic cardiovascular disease to receive 5 mg or 15 mg of ertugliflozin or placebo once daily. With the data from the two ertugliflozin dose groups pooled for analysis, the primary objective was to show the noninferiority of ertugliflozin to placebo with respect to the primary outcome, major adverse cardiovascular events (a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). The noninferiority margin was 1.3 (upper boundary of a 95.6% confidence interval for the hazard ratio [ertugliflozin vs. placebo] for major adverse cardiovascular events). The first key secondary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure. RESULTS A total of 8246 patients underwent randomization and were followed for a mean of 3.5 years. Among 8238 patients who received at least one dose of ertugliflozin or placebo, a major adverse cardiovascular event occurred in 653 of 5493 patients (11.9%) in the ertugliflozin group and in 327 of 2745 patients (11.9%) in the placebo group (hazard ratio, 0.97; 95.6% confidence interval [CI], 0.85 to 1.11; P<0.001 for noninferiority). Death from cardiovascular causes or hospitalization for heart failure occurred in 444 of 5499 patients (8.1%) in the ertugliflozin group and in 250 of 2747 patients (9.1%) in the placebo group (hazard ratio, 0.88; 95.8% CI, 0.75 to 1.03; P=0.11 for superiority). The hazard ratio for death from cardiovascular causes was 0.92 (95.8% CI, 0.77 to 1.11), and the hazard ratio for death from renal causes, renal replacement therapy, or doubling of the serum creatinine level was 0.81 (95.8% CI, 0.63 to 1.04). Amputations were performed in 54 patients (2.0%) who received the 5-mg dose of ertugliflozin and in 57 patients (2.1%) who received the 15-mg dose, as compared with 45 patients (1.6%) who received placebo. CONCLUSIONS Among patients with type 2 diabetes and atherosclerotic cardiovascular disease, ertugliflozin was noninferior to placebo with respect to major adverse cardiovascular events. (Funded by Merck Sharp & Dohme and Pfizer; VERTIS CV ClinicalTrials.gov number, NCT01986881.)

Design and baseline characteristics of the eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes trial (VERTIS-CV)

Background Ertugliflozin is an inhibitor of sodium-glucose co-transporter-2 (SGLT2), approved in the United States and European Union to improve glycemic control in adults with type 2 diabetes mellitus (T2DM). The VERTIS cardiovascular (CV) outcomes trial (NCT01986881) has a primary objective to demonstrate non-inferiority of ertugliflozin versus placebo on major adverse CV events: time to the first event of CV death, nonfatal myocardial infarction, or nonfatal stroke. Secondary objectives are to demonstrate superiority of ertugliflozin versus placebo on time to: 1) the composite outcome of CV death or hospitalization for heart failure (HF); 2) CV death; and 3) the composite outcome of renal death, dialysis/transplant, or doubling of serum creatinine from baseline. Methods Patients ≥40 years old with T2DM (HbA1c 7.0–10.5%) and established atherosclerotic cardiovascular disease (ASCVD) of the coronary, cerebral, and/or peripheral arterial systems, were randomized 1:1:1 to once daily double-blind placebo, ertugliflozin 5 mg or 15 mg added to existing therapy. Results 8246 patients were randomized and 8238 received at least 1 dose of investigational product. Mean age was 64.4 years, 11.0% were ≥75 years old, and mean diabetes duration was 12.9 years with screening HbA1c of 8.3%. At entry, coronary artery disease, cerebrovascular disease, and peripheral arterial disease were present in 76.3%, 23.1%, and 18.8% of patients, respectively. HF was present in 23.1%, and Stage 3 kidney disease in 21.6% of patients. Conclusion The results from the VERTIS-CV trial will define the CV and renal safety and efficacy of ertugliflozin in patients with T2DM and ASCVD. (Am Heart J 2018;206:11-23.

Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes

BACKGROUND The cardiovascular effects of adding once-weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown. METHODS We randomly assigned patients with type 2 diabetes, with or without previous cardiovascular disease, to receive subcutaneous injections of extended-release exenatide at a dose of 2 mg or matching placebo once weekly. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The coprimary hypotheses were that exenatide, administered once weekly, would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy. RESULTS In all, 14,752 patients (of whom 10,782 [73.1%] had previous cardiovascular disease) were followed for a median of 3.2 years (interquartile range, 2.2 to 4.4). A primary composite outcome event occurred in 839 of 7356 patients (11.4%; 3.7 events per 100 person-years) in the exenatide group and in 905 of 7396 patients (12.2%; 4.0 events per 100 person-years) in the placebo group (hazard ratio, 0.91; 95% confidence interval [CI], 0.83 to 1.00), with the intention-to-treat analysis indicating that exenatide, administered once weekly, was noninferior to placebo with respect to safety (P<0.001 for noninferiority) but was not superior to placebo with respect to efficacy (P=0.06 for superiority). The rates of death from cardiovascular causes, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, hospitalization for heart failure, and hospitalization for acute coronary syndrome, and the incidence of acute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and serious adverse events did not differ significantly between the two groups. CONCLUSIONS Among patients with type 2 diabetes with or without previous cardiovascular disease, the incidence of major adverse cardiovascular events did not differ significantly between patients who received exenatide and those who received placebo. (Funded by Amylin Pharmaceuticals; EXSCEL ClinicalTrials.gov number, NCT01144338.

Tiotropium versus Salmeterol for the Prevention of Exacerbations of COPD

BACKGROUND Treatment guidelines recommend the use of inhaled long-acting bronchodilators to alleviate symptoms and reduce the risk of exacerbations in patients with moderate-tovery-severe chronic obstructive pulmonary disease (COPD) but do not specify whether a long-acting anticholinergic drug or a β2-agonist is the preferred agent. We investigated whether the anticholinergic drug tiotropium is superior to the β2-agonist salmeterol in preventing exacerbations of COPD. METHODS In a 1-year, randomized, double-blind, double-dummy, parallel-group trial, we compared the effect of treatment with 18 μg of tiotropium once daily with that of 50 μg of salmeterol twice daily on the incidence of moderate or severe exacerbations in patients with moderate-to-very-severe COPD and a history of exacerbations in the preceding year. RESULTS A total of 7376 patients were randomly assigned to and treated with tiotropium (3707 patients) or salmeterol (3669 patients). Tiotropium, as compared with salmeterol, increased the time to the first exacerbation (187 days vs. 145 days), with a 17% reduction in risk (hazard ratio, 0.83; 95% confidence interval [CI], 0.77 to 0.90; P<0.001). Tiotropium also increased the time to the first severe exacerbation (hazard ratio, 0.72; 95% CI, 0.61 to 0.85; P<0.001), reduced the annual number of moderate or severe exacerbations (0.64 vs. 0.72; rate ratio, 0.89; 95% CI, 0.83 to 0.96; P=0.002), and reduced the annual number of severe exacerbations (0.09 vs. 0.13; rate ratio, 0.73; 95% CI, 0.66 to 0.82; P<0.001). Overall, the incidence of serious adverse events and of adverse events leading to the discontinuation of treatment was similar in the two study groups. There were 64 deaths (1.7%) in the tiotropium group and 78 (2.1%) in the salmeterol group. CONCLUSIONS These results show that, in patients with moderate-to-very-severe COPD, tiotropium is more effective than salmeterol in preventing exacerbations. (Funded by Boehringer Ingelheim and Pfizer; ClinicalTrials.gov number, NCT00563381.

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to &lt;90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], &gt;300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of &lt;15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P&lt;0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P&lt;0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years