ВЛИЯНИЕ СЕЛЕКТИВНОСТИ И ПЕРИОДА ПОЛУВЫВЕДЕНИЯ НЕСТЕРОИДНЫХ ПРОТИВОВОСПАЛИТЕЛЬНЫХ ПРЕПАРАТОВ НА РАЗВИТИЕ СУБКЛИНИЧЕСКОГО ПОРАЖЕНИЯ ПОЧЕК

Objective: to investigate the impact of the selectivity and half-life of nonsteroidal anti-inflammatory drugs (NSAIDs) on the development of subclinical kidney injury (SKI). A standard physical examination was made.Patients and methods. The study included 80 patients with a verified rheumatoid arthritis (RA) diagnosis. The patients filled in a specially designed questionnaire to explore a history of drug use. As markers of SKI, the investigators determined the concentrations of albumin, α1-microglobulin (α1-MG), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) in urine. A control group consisted of 20 apparently healthy individuals matched for age and gender.Results. 80 patients suffering from RA received drug therapy. Of them, 82.5% and 87.5% took NSAIDs and disease-modifying antirheumatic drugs, respectively. The levels of SKI markers were compared in three groups of the examinees: 1) NSAID-treated patients; 2) NSAID-untreated patients; 3) a control group. There were statistically significant differences between all the groups (p<0.05). Comparison of the levels of SKI markers revealed no statistically significant difference in the groups receiving selective cyclooxygenase-2 (COX-2) inhibitors (n=18.6%), in those taking nonselective ones (n=68.6%), and the control group. Comparison of the levels of SKI markers demonstrated significantly higher >< 0.05). Comparison of the levels of SKI markers revealed no statistically significant difference in the groups receiving selective cyclooxygenase-2 (COX-2) inhibitors (n=18.6%), in those taking nonselective ones (n=68.6%), and the control group. Comparison of the levels of SKI markers demonstrated significantly higher α1-MG levels in the long-acting NSAID groups (n=8.6%) than in the short-acting NSAID group (n=80%). ALT, ALP, and microalbuminuria showed a similar trend that failed to reach statistical significance.Conclusion: NSAIDs remain a group of medications with a certain nephrotoxic effect. At the same time, the design of selective COX-2 inhibitors has failed to solve the problem of nephrotoxicity. NSAIDs with long half-lives are characterized by greater nephrotoxicity. The available data provide preconditions for the more differentiated use of NSAIDs, particularly in patients with RA.Цель исследования – изучение влияния селективности и периода полувыведения нестероидных противовоспалительных препаратов (НПВП) на развитие субклинического поражения почек (СПП).Пациенты и методы. В исследование включено 80 пациентов с верифицированным диагнозом ревматоидного артрита (РА). Пациенты заполняли специально разработанную анкету для изучения лекарственного анамнеза. Проводилось стандартное общеклиническое обследование. В качестве маркеров СПП определяли концентрацию в моче альбумина, α1-микроглобулина (α1-МГ), аланинаминотрансферазы (АЛТ) и щелочной фосфатазы (ЩФ). Контрольную группу составили 20 практически здоровых испытуемых, сопоставимых по возрасту и полу.Результаты. Лекарственную терапию получали 80 пациентов, страдающих РА. Из них базисные противовоспалительные препараты принимали 82,5%, НПВП – 87,5%. Сравнивали уровень маркеров СПП в трех группах обследованных: в группе получавших НПВП, в группе не получавших НПВП и в группе контроля. Установлены статистически достоверные различия для всех групп (p<0,05). В результате сравнения уровня маркеров СПП в группах, получавших селективные (n=18,6%) и неселективные (n=68,6%) ингибиторы циклооксигеназы 2 (ЦОГ2), а также в группе контроля статистически достоверной разницы не выявлено. При сравнении уровня маркеров СПП в группах, получавших «длительноживущие» (n=8,6%) и «короткоживущие» (n=80%) НПВП, отмечено достоверное повышение уровня α1-МГ в группе пациентов, получавших «длительноживущие» НПВП, по сравне- нию с группой пациентов, принимавших «короткоживущие» НПВП. При оценке показателей АЛТ, ЩФ и микроальбуминурии вы- явлена похожая тенденция, однако не достигавшая статистической достоверности. Выводы. НПВП характеризуются определенным нефротоксическим эффектом. При этом разработка селективных ингибиторов ЦОГ2 не решила проблемы нефротоксичности. НПВП с длительным периодом полувыведения обладают большей нефротоксично- стью. Имеющиеся данные создают предпосылки для более дифференцированного использование НПВП, особенно у пациентов с РА. Ключевые слова: ревматоидный артрит; нестероидные противовоспалительные препараты; α1-микроглобулин; поражение почек.>< 0,05). В результате сравнения уровня маркеров СПП в группах, получавших селективные (n=18,6%) и неселективные (n=68,6%) ингибиторы циклооксигеназы 2 (ЦОГ2), а также в группе контроля статистически достоверной разницы не выявлено. При сравнении уровня маркеров СПП в группах, получавших «длительноживущие» (n=8,6%) и «короткоживущие» (n=80%) НПВП, отмечено достоверное повышение уровня α1-МГ в группе пациентов, получавших «длительноживущие» НПВП, по сравнению с группой пациентов, принимавших «короткоживущие» НПВП. При оценке показателей АЛТ, ЩФ и микроальбуминурии выявлена похожая тенденция, однако не достигавшая статистической достоверности.Выводы. НПВП характеризуются определенным нефротоксическим эффектом. При этом разработка селективных ингибиторов ЦОГ2 не решила проблемы нефротоксичности. НПВП с длительным периодом полувыведения обладают большей нефротоксичностью. Имеющиеся данные создают предпосылки для более дифференцированного использование НПВП, особенно у пациентов с РА.

Effect of SGLT2 inhibitors on stroke and atrial fibrillation in diabetic kidney disease: Results from the CREDENCE trial and meta-analysis

BACKGROUND AND PURPOSE: Chronic kidney disease with reduced estimated glomerular filtration rate or elevated albuminuria increases risk for ischemic and hemorrhagic stroke. This study assessed the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on stroke and atrial fibrillation/flutter (AF/AFL) from CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) and a meta-Analysis of large cardiovascular outcome trials (CVOTs) of SGLT2i in type 2 diabetes mellitus. METHODS: CREDENCE randomized 4401 participants with type 2 diabetes mellitus and chronic kidney disease to canagliflozin or placebo. Post hoc, we estimated effects on fatal or nonfatal stroke, stroke subtypes, and intermediate markers of stroke risk including AF/AFL. Stroke and AF/AFL data from 3 other completed large CVOTs and CREDENCE were pooled using random-effects meta-Analysis. RESULTS: In CREDENCE, 142 participants experienced a stroke during follow-up (10.9/1000 patient-years with canagliflozin, 14.2/1000 patient-years with placebo; hazard ratio [HR], 0.77 [95% CI, 0.55-1.08]). Effects by stroke subtypes were: ischemic (HR, 0.88 [95% CI, 0.61-1.28]; n=111), hemorrhagic (HR, 0.50 [95% CI, 0.19-1.32]; n=18), and undetermined (HR, 0.54 [95% CI, 0.20-1.46]; n=17). There was no clear effect on AF/AFL (HR, 0.76 [95% CI, 0.53-1.10]; n=115). The overall effects in the 4 CVOTs combined were: Total stroke (HRpooled, 0.96 [95% CI, 0.82-1.12]), ischemic stroke (HRpooled, 1.01 [95% CI, 0.89-1.14]), hemorrhagic stroke (HRpooled, 0.50 [95% CI, 0.30-0.83]), undetermined stroke (HRpooled, 0.86 [95% CI, 0.49-1.51]), and AF/AFL (HRpooled, 0.81 [95% CI, 0.71-0.93]). There was evidence that SGLT2i effects on total stroke varied by baseline estimated glomerular filtration rate (P=0.01), with protection in the lowest estimated glomerular filtration rate (45 mL/min/1.73 m2]) subgroup (HRpooled, 0.50 [95% CI, 0.31-0.79]). CONCLUSIONS: Although we found no clear effect of SGLT2i on total stroke in CREDENCE or across trials combined, there was some evidence of benefit in preventing hemorrhagic stroke and AF/AFL, as well as total stroke for those with lowest estimated glomerular filtration rate. Future research should focus on confirming these data and exploring potential mechanisms

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 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 m 2), 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 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<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

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 m 2 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 m 2 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: AbbVie

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

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

Abstract 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 .)

IMPACT OF THE SELECTIVITY AND HALF-LIFE OF NONSTEROIDAL ANTI-INFLAMMATORY DRUGS ON THE DEVELOPMENT OF SUBCLINICAL KIDNEY INJURY

Objective: to investigate the impact of the selectivity and half-life of nonsteroidal anti-inflammatory drugs (NSAIDs) on the development of subclinical kidney injury (SKI). A standard physical examination was made.Patients and methods. The study included 80 patients with a verified rheumatoid arthritis (RA) diagnosis. The patients filled in a specially designed questionnaire to explore a history of drug use. As markers of SKI, the investigators determined the concentrations of albumin, α1-microglobulin (α1-MG), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) in urine. A control group consisted of 20 apparently healthy individuals matched for age and gender.Results. 80 patients suffering from RA received drug therapy. Of them, 82.5% and 87.5% took NSAIDs and disease-modifying antirheumatic drugs, respectively. The levels of SKI markers were compared in three groups of the examinees: 1) NSAID-treated patients; 2) NSAID-untreated patients; 3) a control group. There were statistically significant differences between all the groups (p&lt;0.05). Comparison of the levels of SKI markers revealed no statistically significant difference in the groups receiving selective cyclooxygenase-2 (COX-2) inhibitors (n=18.6%), in those taking nonselective ones (n=68.6%), and the control group. Comparison of the levels of SKI markers demonstrated significantly higher &gt;&lt; 0.05). Comparison of the levels of SKI markers revealed no statistically significant difference in the groups receiving selective cyclooxygenase-2 (COX-2) inhibitors (n=18.6%), in those taking nonselective ones (n=68.6%), and the control group. Comparison of the levels of SKI markers demonstrated significantly higher α1-MG levels in the long-acting NSAID groups (n=8.6%) than in the short-acting NSAID group (n=80%). ALT, ALP, and microalbuminuria showed a similar trend that failed to reach statistical significance.Conclusion: NSAIDs remain a group of medications with a certain nephrotoxic effect. At the same time, the design of selective COX-2 inhibitors has failed to solve the problem of nephrotoxicity. NSAIDs with long half-lives are characterized by greater nephrotoxicity. The available data provide preconditions for the more differentiated use of NSAIDs, particularly in patients with RA