Features of blood pressure variability and arterial stiffness in hypertensive men with androgen deficiency

Male sex has long been argued as a strong risk factor for arterial hypertension. Noteworthy is that available data support the negative impact of low testosterone on male cardiovascular health. Objective. This study was designed to assess characteristics of circadian blood pressure and arterial stiffness in hypertensive men with and without testosterone deficiency. Materials and methods. A total of 60 male hypertensive patients aged above 45 years were screened on androgen deficiency symptoms via Male andropause symptoms self-assessment questionnaire (MASSQ). 42 subjects with suspected low testosterone level were recruited into the study for subsequent total testosterone (TT) measurement. 24 h BP monitoring was carried out for all participants. Aortic stiffness was assessed using BPLab Vasotens System (cuff-based oscillometry method). Results. 43 % of patients had biochemically confirmed low testosterone level. The total score of MASSQ in this group was significantly higher compared to patients with normal testosterone. The decreasing of TT concentration with age was detected. The low TT group was characterized by significantly higher values of 24 h systolic blood pressure (SBP) and pulse pressure (PP) values. The lower testosterone appears to be associated with prevalence of “non-dipper” pattern. The results of the multiple regression analysis revealed the relationship between plasma testosterone levels and SBP values in both study groups, while the relationship between testosterone and DBP values was not significant. A significant relationship was also found in each group between TT and PWV. Conclusion. The study revealed the high prevalence of androgen deficiency among hypertensive middle-aged men. These patients are characterized by higher BP values compared to those with normal TT levels in the same age range. Low TT concentration may be considered also as the contributor of increased arterial stiffness in hypertensive males

ОЦІНКА СЕРЦЕВО-СУДИННОГО РИЗИКУ У ЧОЛОВІКІВ ІЗ ГІПЕРТОНІЧНОЮ ХВОРОБОЮ НА ТЛІ АНДРОГЕННОГО ДЕФІЦИТУ

Data from numerous studies show the correlation of low testosterone in men with certain CVD risk factors such as obesity, type 2 diabetes, metabolic syndrome. Statistical approaches include the calculation of cardiovascular risk for general population, and their use for risk assessment in men with testosterone deficiency is still not well-described in the literature.The aim of the study – to determine the most valid approach for assessment of cardiovascular risk in hypertensive men with androgen deficiency using the comparative analysis of Framingham, SCORE and PROCAM scales.Material and Methods. The study included 50 male patients with a diagnosis of stage II hypertension and 11 healthy subjects who were included into the control group. All participants were subjected to the general clinical examination, evaluation of lipid profile and total serum testosterone (TT), cardiovascular risk assessment using Framingham scale (FS), SCORE and PROCAM scales. Depending on the level of TT, the patients were divided into 2 groups: 1 group (n = 27) – with testosterone deficiency, 2 group (n = 23) with normal TT level.Results. Analysis of cardiovascular risk of the study participants showed that 55.6 % of men in group 1 and 43.5 % of group 2 had high cardiovascular risk according to FS, while PROCAM risk of over 20 % had 66.7 % and 39.1 % of patients respectively. 51.8 % of men in group 1 and 39.1 % of group 2 were in high risk cohort due to SCORE scale. There was no significant difference between the risk by FS and by SCORE between groups 1 and 2, while the difference between these groups was statistically significant when PROCAM scale was used. Negative correlation was found between cardiovascular risk and TT level, with a statistically significant correlation between TT and PROCAM (p <0.05).Conclusions. The use of the PROCAM scale is the most reasonable for categorizing of cardiovascular risk in cohort of hypertensive men associated with androgen deficiency. Введение. Данные многочисленных исследований указывают на связь низкого уровня тестосте- рона у мужчин с отдельными факторами риска ССЗ (ожирение, сахарный диабет 2 типа, метаболический синдром и т.п.). Статистические подходы предусматривают расчет кардиоваскулярного риска для общей популяции, а ис- пользование их для оценки риска у мужчин с дефицитом тестостерона в литературе не описано.Цель исследования – на основании сравнительного анализа ряда шкал (Фремингемской, SCORE и PROCAM) определить наиболее валидную для оценки сердечно-сосудистого риска у мужчин с гипертонической болезнью на фоне андрогенного дефицита.Материал и методы. Исследование включало 50 пациентов мужского пола с установленным диагнозом гипертонической болезни II стадии и 11 практически здоровых лиц, вошедших в контрольную группу. У всех участников исследования, наряду с общеклиническим обследованием, определяли параметры липидного профиля и общий тестостерон (ОТ) сыворотки крови, оценивали сердечно-сосудистый риск по Фремингемской шкале (ФШ), шкалам SCORE и PROCAM. В зависимости от уровня ОТ обследованные были поделены на 2 группы: 1 группа (n=27) – с дефицитом ОТ, 2 группа (n=23) с нормальным уровнем ОТ.Результаты. При анализе сердечно-сосудистого риска участников исследования установлено, что по ФШ к группе высокого риска принадлежали 55,6 % мужчин 1 группы и 43,5 % лиц 2 группы, по шкале PROCAM риск выше 20 % имели 66,7 % и 39,1 % пациентов соответственно. Доля обследованных, имевших высокий риск по шкале SCORE, составила 51,8 % среди мужчин 1 группы и 39,1 % – 2 группы. Значимых различий между риском по ФШ и SCORE между группами 1 и 2 обнаружено не было, в то время как разница между указанными группами быластатистическидостовернойпошкале PROCAM. Корреляционныйанализпоказалтенденциюкотрицательной обратной связи между сердечно-сосудистым риском и уровнем ОТ, при этом статистически значимой корреляция была только между ОТ и риском по шкале PROCAM (р<0,05).Выводы. Использование шкалы PROCAM является наиболее обоснованным для категоризации риска в когорте мужчин с гипертонической болезнью, ассоциированной с андрогенным дефицитом.Вступ. Дані численних досліджень вказують на зв’язок низького рівня тестостерону у чоловіків із окремими факторами ризику ССЗ (ожиріння, цукровий діабет 2 типу, метаболічний синдром тощо). Статистичні підходи передбачають розрахунок кардіоваскулярного ризику для загальної популяції, а використання їх для оцінки ризику у чоловіків із дефіцитом тестостерону в літературі не описане.Мета дослідження. На підставі порівняльного аналізу ряду шкал (Фремінгемська, SCORE та PROCAM ) визначити найбільш валідну для оцінки серцево-судинного ризику у чоловіків із гіпертонічною хворобою на тлі андрогенного дефіциту.Матеріал і методи дослідження. Дослідження включало 50 пацієнтів чоловічої статі із встановленим діагнозом гіпертонічної хвороби ІІ стадії та 11 практично здорових осіб, що увійшли до контрольної групи. Всім учасникам дослідження поряд із загальноклінічним обстеженням визначалися параметри ліпідного профілю та загальний тестостерон (ЗТ) сироватки крові, оцінювався серцево-судинний ризик за Фремінгемською шкалою (ФШ), шкалами SCORE та PROCAM. В залежності від рівня ЗТ обстежені були розподілені на 2 групи: 1 група (n=27) – з дефіцитом ЗТ, 2 група (n=23) з нормальним рівнем ЗТ.Результати досліджень. При аналізі серцево-судинного ризику учасників дослідження встановлено, що за ФШ до групи високого ризику  належали 55,6% чоловіків 1 групи та 43,5% осіб 2 групи, за шкалою PROCAM  ризик вище 20% мали 66,7% та 39,1% пацієнтів відповідно. Частка обстежених, що мали високий ризик за шкалою SCORE, склала 51,8% серед чоловіків 1 групи та 39,1% - 2 групи. Значущих відмінностей між  ризиком за ФШ та SCORE між групою 1 та 2 виявлено не було, в той час як різниця між вказаними групами була статистично вірогідною за шкалою PROCAM. Кореляційний аналіз продемонстрував тенденцію до негативного зворотного зв’язку між серцево-судинним ризиком та рівнем ЗТ, при цьому статистично значущою кореляція була лише між ЗТ та ризиком за шкалою PROCAM (р<0.05).Висновки. Використання шкали PROCAM є найбільш обґрунтованим для категоризації ризику у когорті чоловіків із гіпертонічною хворобою, асоційованою з андрогенним дефіцитом

EFFECT OF CANDESARTAN ON PARAMETERS OFDAILYBLOOD PRESSURE IN PATIENTS WITH CHRONIC KIDNEYDISEASE ON HEMODIALYSIS

Introduce.Advances of normal blood pressure in patients on program hemodialysis presented a serious problem related disciplines. For verification hypertension used routine blood pressure measurement and ambulatory monitoring to control the pressure in interdialytic time, which is an important predictor of cardiovascular events among these patients. The aim of research was to investigate features ofparameters the ambulatory monitoring of blood pressure in the dynamics after treatment of candesartan in patients receiving renal replacement therapy. Materials and methods: 53patients ongoing chronic hemodialysis were makethe ambulatory monitoring of blood pressure before and after 12–weeks treatment of candesartan (4–32 mg). Results. It was established that the prevalence of hypertension in a population of patients on hemodialysis influenced by candesartan treatment decreased from 53.6 % to 32.1 %. Patients on hemodialysis in 75 % of cases have incresedpulse pressure (> 60 mm Hg), the percentage of which after therapy decreased to 51.8. Prevailing type of daily blood pressure as the treatment and after treatment is «non–dipper». Established that candesartan showed a positive effect in relation to a statistically significant reduction in the average time indices and blood pressure Conclusion: results of the study allowtorecommend candesartan for treatment of hypertension in hemodialysis patients

Advancing Translational Space Research Through Biospecimen Sharing: Amplifying the Impact of Ground-Based Studies

Biospecimen Sharing Programs (BSPs) have been organized by NASA Ames Research Center since the 1960s with the goal of maximizing utilization and scientific return from rare, complex and costly spaceflight experiments. BSPs involve acquiring otherwise unused biological specimens from primary space research experiments for distribution to secondary experiments. Here we describe a collaboration leveraging Ames expertise in biospecimen sharing to magnify the scientific impact of research informing astronaut health funded by the NASA Human Research Program (HRP) Human Health Countermeasures (HHC) Element. The concept expands biospecimen sharing to one-off ground-based studies utilizing analogue space platforms (e.g., Hind limb Unloading (HLU), Artificial Gravity) for rodent experiments, thereby significantly broadening the range of research opportunities with translational relevance for protecting human health in space and on Earth. In this presentation, we will report on biospecimens currently being acquired from HHC Award Head-Down Tilt as a Model for Intracranial and Intraocular Pressures, and Retinal Changes during Spaceflight, and their availability. The BSP add-on to the project described herein has already yielded for HHC-funded investigators more than 4,700 additional tissues that would otherwise have been discarded as waste, with additional tissues available for analysis. Young (3-mo old) male and female rats and Older (9-mo old) male rats are being exposed to HLU for either 7, 14, 28, or 90 days. Additional groups are exposed to 90 days of unloading followed by either 7, 14, 28 days or 90 days of recovery (normal loading). Comparisons are made with non-suspended controls. Unused tissues are: Skin, Lungs, Thymus, Adrenals, Kidneys, Spleen, Hindlimb Muscles (Soleus, Extensor Digitorum Longus, Tibialis Anterior, Plantaris Gastrocnemius), Fat Pads, Reproductive Organs, and Intestines. Tissues are harvested, weighed, preserved then archived (with metadata) using a sample tracking system (CryoTrack). Preservation techniques include snap-freezing and RNALatersnap-freezing. Specimens were weighed at the time of dissection, and organ mass: body mass ratios analyzed to determine unloading effects across conditions and durations. The results corroborate previously reported effects of short-term exposure to microgravity or unloading exposure on various organs, and provide new insights into adaptation to long-duration unloading relevant to sustained spaceflight exposures on ISS. Supported by the Human Research Program (HRP) Human Health Countermeasures (HHC) Element and NASA Grant NNX13AD94G (CAF)

Advancing Translational Space Research Through Biospecimen Sharing: Amplified Impact of Studies Utilizing Analogue Space Platforms

Biospecimen Sharing Programs (BSPs) have been organized by NASA Ames Research Center since the 1960s with the goal of maximizing utilization and scientific return from rare, complex and costly spaceflight experiments. BSPs involve acquiring otherwise unused biological specimens from primary space research experiments for distribution to secondary experiments. Here we describe a collaboration leveraging Ames expertise in biospecimen sharing to magnify the scientific impact of research informing astronaut health funded by the NASA Human Research Program (HRP) Human Health Countermeasures (HHC) Element. The concept expands biospecimen sharing to one-off ground-based studies utilizing analogue space platforms (e.g., Hindlimb Unloading (HLU), Artificial Gravity) for rodent experiments, thereby significantly broadening the range of research opportunities with translational relevance for protecting human health in space and on Earth. In this presentation, we will report on biospecimens currently being acquired from HHC Award Head-Down Tilt as a Model for Intracranial and Intraocular Pressures, and Retinal Changes during Spaceflight, and their availability. The BSP add-on to the project described herein has already yielded for HHC-funded investigators more than 4,700 additional tissues that would otherwise have been discarded as waste, with additional tissues available for analysis. Young (3-mo old) male and female rats and Older (9-mo old) male rats are being exposed to HLU for either 7, 14, 28, or 90 days. Additional groups are exposed to 90 days of unloading followed by either 7, 14, 28 days or 90 days of recovery (normal loading). Comparisons are made with non-suspended controls. Unused tissues are: Skin, Lungs, Thymus, Adrenals, Kidneys, Spleen, Hindlimb Muscles (Soleus, Extensor Digitorum Longus, Tibialis Anterior, Plantaris Gastrocnemius), Fat Pads, Reproductive Organs, and Intestines. Tissues are harvested, weighed, preserved then archived (with metadata) using a sample tracking system (CryoTrack). Preservation techniques include snap-freezing and RNALatersnap-freezing. Specimens were weighed at the time of dissection, and organ mass:body mass ratios analyzed to determine unloading effects across conditions and durations. The results corroborate previously reported effects of short-term exposure to microgravity or unloading exposure on various organs, and provide new insights into adaptation to long-duration unloading relevant to sustained spaceflight exposures on ISS

Efficacy and safety of canagliflozin when used in conjunction with incretin-mimetic therapy in patients with type 2 diabetes

Aims: To assess the efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes enrolled in the CANagliflozin cardioVascular Assessment Study (CANVAS) who were on an incretin mimetic [dipeptidyl peptidase-4 (DPP-4) inhibitor or glucagon-like peptide-1 (GLP-1) receptor agonist]. Methods: CANVAS is a double-blind, placebo-controlled study that randomized participants to canagliflozin 100 or 300 mg or placebo added to routine therapy. The present post hoc analysis assessed the efficacy and safety of canagliflozin 100 and 300 mg compared with placebo in subsets of patients from CANVAS who were taking background DPP-4 inhibitors or GLP-1 receptor agonists with or without other antihyperglycaemic agents at week 18. Results: Of the 4330 patients in CANVAS, 316 were taking DPP-4 inhibitors and 95 were taking GLP-1 receptor agonists. At 18 weeks, canagliflozin 100 and 300 mg provided larger placebo-subtracted reductions in glycated haemoglobin (HbA1c) in patients taking DPP-4 inhibitors [-0.56% (95% confidence interval [CI]: -0.77, -0.35), and -0.75% (95% CI: -0.95, -0.54), respectively] and GLP-1 receptor agonists [-1.00% (95% CI: -1.35, -0.65), and -1.06% (95% CI: -1.43, -0.69), respectively]. Body weight and blood pressure (BP) reductions were seen with canagliflozin versus placebo in both subsets. Higher incidences of genital mycotic infections and osmotic diuresis-related adverse events (AEs) were seen with canagliflozin compared with placebo. The incidence of hypoglycaemia was numerically higher with canagliflozin versus placebo; nearly all events occurred in patients on background insulin or insulin secretagogues. Conclusions: In patients on background incretin mimetics, canagliflozin improved HbA1c, body weight and BP, with an increased incidence of AEs related to SGLT2 inhibition

Dapagliflozin and cardiovascular outcomes in type 2 diabetes

BACKGROUND The cardiovascular safety profile of dapagliflozin, a selective inhibitor of sodium– glucose cotransporter 2 that promotes glucosuria in patients with type 2 diabetes, is undefined. METHODS We randomly assigned patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease to receive either dapagliflozin or placebo. The primary safety outcome was a composite of major adverse cardiovascular events (MACE), defined as cardiovascular death, myocardial infarction, or ischemic stroke. The primary efficacy outcomes were MACE and a composite of cardiovascular death or hospitalization for heart failure. Secondary efficacy outcomes were a renal composite (≥40% decrease in estimated glomerular filtration rate to <60 ml per minute per 1.73 m2 of body-surface area, new end-stage renal disease, or death from renal or cardiovascular causes) and death from any cause. RESULTS We evaluated 17,160 patients, including 10,186 without atherosclerotic cardiovascular disease, who were followed for a median of 4.2 years. In the primary safety outcome analysis, dapagliflozin met the prespecified criterion for noninferiority to placebo with respect to MACE (upper boundary of the 95% confidence interval [CI], <1.3; P<0.001 for noninferiority). In the two primary efficacy analyses, dapagliflozin did not result in a lower rate of MACE (8.8% in the dapagliflozin group and 9.4% in the placebo group; hazard ratio, 0.93; 95% CI, 0.84 to 1.03; P=0.17) but did result in a lower rate of cardiovascular death or hospitalization for heart failure (4.9% vs. 5.8%; hazard ratio, 0.83; 95% CI, 0.73 to 0.95; P=0.005), which reflected a lower rate of hospitalization for heart failure (hazard ratio, 0.73; 95% CI, 0.61 to 0.88); there was no between-group difference in cardiovascular death (hazard ratio, 0.98; 95% CI, 0.82 to 1.17). A renal event occurred in 4.3% in the dapagliflozin group and in 5.6% in the placebo group (hazard ratio, 0.76; 95% CI, 0.67 to 0.87), and death from any cause occurred in 6.2% and 6.6%, respectively (hazard ratio, 0.93; 95% CI, 0.82 to 1.04). Diabetic ketoacidosis was more common with dapagliflozin than with placebo (0.3% vs. 0.1%, P=0.02), as was the rate of genital infections that led to discontinuation of the regimen or that were considered to be serious adverse events (0.9% vs. 0.1%, P<0.001). CONCLUSIONS In patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease, treatment with dapagliflozin did not result in a higher or lower rate of MACE than placebo but did result in a lower rate of cardiovascular death or hospitalization for heart failure, a finding that reflects a lower rate of hospitalization for heart failure. (Funded by AstraZeneca; DECLARE–TIMI 58 ClinicalTrials.gov number, NCT01730534.

Blood pressure-lowering effects of nifedipine/candesartan combinations in high-risk individuals: Subgroup analysis of the DISTINCT randomised trial

The DISTINCT study (reDefining Intervention with Studies Testing Innovative Nifedipine GITS - Candesartan Therapy) investigated the efficacy and safety of nifedipine GITS/candesartan cilexetil combinations vs respective monotherapies and placebo in patients with hypertension. This descriptive sub-analysis examined blood pressure (BP)-lowering effects in high-risk participants, including those with renal impairment (estimated glomerular filtration rate<90 ml min-1, n=422), type 2 diabetes mellitus (n=202), hypercholesterolaemia (n=206) and cardiovascular (CV) risk factors (n=971), as well as the impact of gender, age and body mass index (BMI). Participants with grade I/II hypertension were randomised to treatment with nifedipine GITS (N) 20, 30, 60 mg and/or candesartan cilexetil (C) 4, 8, 16, 32 mg or placebo for 8 weeks. Mean systolic BP and diastolic BP reductions after treatment in high-risk participants were greater, overall, with N/C combinations vs respective monotherapies or placebo, with indicators of a dose-response effect. Highest rates of BP control (ESH/ESC 2013 guideline criteria) were also achieved with highest doses of N/C combinations in each high-risk subgroup. The benefits of combination therapy vs monotherapy were additionally observed in patient subgroups categorised by gender, age or BMI. All high-risk participants reported fewer vasodilatory adverse events in the pooled N/C combination therapy than the N monotherapy group. In conclusion, consistent with the DISTINCT main study outcomes, high-risk participants showed greater reductions in BP and higher control rates with N/C combinations compared with respective monotherapies and lesser vasodilatory side-effects compared with N monotherapy

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