Визначення катехінів у листі зеленого чаю методом ВЕРХ у порівнянні з методом спектрофотометрії

Aim. To study the qualitative composition, the quantitative content of catechins in green tea leaves and compare the data obtained with those evaluated by spectrophotometry.Materials and methods. Green tea leaves used for the analysis were collected in Anhui Province, China. The extract for the HPLC analysis was obtained by the maceration method with 60 % ethanol twice in the raw material/extractant ratio of 1 : 20. In the case of the spectrophotometric analysis, green tea leaves were extracted with 70 % ethanol twice by the maceration method in the raw material/extractant ratio of 1 : 20. The analysis of the extract from green tea leaves was performed by high performance liquid chromatography using a Prominence LC-20 Shimadzu chromatographic system (Japan) with a SPD-20AV spectrophotometric detector, an Agilent Technologies Microsorb-MV-150 column (reversed phase, C18 modified silica gel, length – 150 mm, diameter – 4.6 mm, particles size – 5 μm). Substances in the extract were identified by comparing the retention time and the spectral characteristics of the test substances with the same characteristics of the reference standards. Spectrophotometric measurements were carried out using a UV-1000 single beam spectrophotometer (China) with the pair of S90-309Q quartz square cells.Results and discussion. Using high performance liquid chromatography 5 catechins were identified. Among them epigallocatechin-3-O-gallate (10.85 %) predominated, while catechin (0.61 %) had the lowest concentration. The total amount of catechins in green tea leaves was 30.56 and 24.79 % by HPLC and spectrophotometry, respectively. The F- and t-tests showed that there was no significant difference between the results of HPLC and spectrophotometry.Conclusions. The qualitative composition and the quantitative content of catechins have been determined in the extract from green tea leaves by high performance liquid chromatography and spectrophotometry. Both HPLC and spectrophotometric methods can be used to determine the total catechin content in green tea leaves. The high content of catechins makes the extract promising for further study and creation of new herbal medicinal products and dietary supplements. The results obtained will be used for standardization of green tea leaves and for future pharmacological research of its extract.Мета. Методом ВЕРХ вивчити якісний склад і кількісний вміст катехінів листя зеленого чаю та порівняти результати з даними, отриманими методом спектрофотометрії.Матеріали та методи. Для аналізу використовували листя зеленого чаю, зібране в провінції Аньхой, Китай. Для ВЕРХ-аналізу екстракт отримували двічі методом мацерації 60 % спиртом у співвідношенні сировина/екстрагент 1 : 20. У випадку спектрофотометричного аналізу листя зеленого чаю двічі екстрагували 70 % спиртом методом мацерації у співвідношенні сировина/екстрагент 1 : 20. Аналіз витяжки листя зеленого чаю проводили методом високоефективної рідинної хроматографії за допомогою хроматографічної системи Prominence LC-20 Shimadzu (Японія) зі спектрофотометричним детектором SPD-20AV, колонка Agilent Technologies Microsorb-MV-150 (обернено-фазова, C18 модифікований силікагель, довжина 150 мм, діаметр 4,6 мм, розмір зерен сорбенту 5 мкм). Ідентифікацію речовин у витяжці проводили шляхом порівняння часу утримування і спектральних характеристик досліджуваних речовин з аналогічними характеристиками стандартів. Спектрофотометричні вимірювання виконували за допомогою однопроменевого спектрофотометра UV-1000 (Китай) з парою кварцових кювет S90-309Q.Результати та їх обговорення. За допомогою високоефективної рідинної хроматографії у листі зеленого чаю було ідентифіковано 5 катехінів, з-поміж яких переважає епігалокатехін-3-О-галат (10,85 %), а найменший вміст мав катехін (0,61 %). Сумарний вміст катехінів у досліджуваній сировині склав 30,56 % та 24,79 % за методом ВЕРХ та спектрофотометрією відповідно. Розрахунки F- і t- продемонстрували, що немає суттєвої різниці між результатами ВЕРХ та спектрофотометрією.Висновки. Якісний склад та кількісний вміст катехінів в екстракті листя зеленого чаю визначено за допомогою високоефективної рідинної хроматографії та спектрофотометрії. Для визначення загального вмісту катехінів у листі зеленого чаю можна використовувати як ВЕРХ, так і спектрофотометричний метод. Високий вміст катехінів в екстракті робить цю сировину перспективною для подальшого вивчення і ство-рення нових фітопрепаратів та дієтичних добавок. Отримані результати будуть використані для стандартизації листя зеленого чаю та для подальших фармакологічних досліджень його екстракту

Визначення кратності екстракції листя зеленого чаю антиоксидантним методом

Aim. To determine the optimal extraction frequency of green tea leaves with 60 % ethanol by the antioxidant method.Materials and methods. Chun Myn green tea leaves were the object of the study, the raw material was collected in Anhui province (China) from March to April. Dry green tea leaves were standardized according to the European Pharmacopeia 9.0. Spectrophotometry was used to quantify biologically active substances. The antioxidant activity was determined by the potentiometric method. Potentiometric measurements were performed on a HANNA 2550 pH meter (Germany) with a combined platinum EZDO 50 PO electrode (Taiwan). A UV-1000 spectrophotometer (China) was used to measure the optical density.Results and discussion. The total content of phenolic compounds was 9.60 ± 0.17, 1.30 ± 0.03 and 0.12 ± 0.002 %, catechins – 9.20 ± 0.18, 1.20 ± 0.02 and 0.07 ± 0.002 %, flavonoids – 0.27 ± 0.005, 0.04 ± 0.001, 0.005 ± 0.001, hydroxycinnamic acids – 0.49 ± 0.01, 0.07 ± 0.002 and 0.007 ± 0.001 %, dry residue – 10.75 ± 0.11, 1.59 ± 0.02 and 0.15 ± 0.002 %, the antioxidant activity was 474.08 ± 9.48, 67.70 ± 1.35 and 7.01 ± 0.14 mmol-equiv mdry res-1 for the first, second and third extraction, respectively. According to the results obtained, the optimal number of extractions of the raw material with 60 % ethanol was found to be two.Conclusions. The dynamic of extractions of biologically active substances of green tea leaves has been studied by triple extraction of the raw material to find the optimal extraction frequency; for the first time, a method for determining the extraction frequency based on the antioxidant activity of the extracts has been developed and proposed. It has been found that the optimal extraction rate is 2 times. The results obtained will be used in the further production of herbal medicines, dietary supplements, and cosmetic products with a green tea extract.Мета. Визначити оптимальну кратність екстракції листя зеленого чаю 60 % етанолом антиоксидантним методом.Матеріали та методи. Об’єктом дослідження було листя зеленого чаю сорту Чун Мін, зібране в провінції Анхуй (Китай) з березня до квітня. Сухе листя було стандартизовано відповідно до Європейської фармакопеї 9.0. Для кількісного визначення біологічно активних речовин використовували спектрофотометрію. Для визначення антиоксидантної активності використовували потенціометричний метод. Потенціометричні вимірювання виконували на pH-метрі HANNA 2550 (ФРН) із комбінованим платиновим електродом EZDO 50 PO (Тайвань). Для вимірювання оптичної густини використовували спектрофотометр UV-1000 (Китай).Результати та їх обговорення. Сумарний вміст фенольних сполук становив 8,60 ± 0,17, 1,30 ± 0,03 і 0,11 ± 0,002 %, катехінів – 9,20 ± 0,18, 1,20 ± 0,02 і 0,07 ± 0,002 %, флавоноїдів – 0,27, 0,04 і 0,005 %, гідроксикоричних кислот – 0,49 ± 0,01, 0,07 ± 0,002 і 0,007 ± 0,001 %, сухий залишок – 10,75 ± 0,11, 1,59 ± 0,02 і 0,15 ± 0,002 %, антиоксидантна активність становила 474,08 ± 9.48, 67,70 ± 1.35 і 7,01 ± 0.14 ммоль-екв. mсух.зал.-1 для першої, другої і третьої екстракції відповідно. Одержані результати свідчать, що двократна екстракція досліджуваної сировини 60 % етанолом є оптимальною.Висновки. Для визначення оптимальної кратності екстракцій було проведено дослідження динаміки екстракцій біологічних активних речовин листя зеленого чаю шляхом трикратної екстракції сировини, а також уперше розроблено й запропоновано метод визначення кратності екстракції, заснований на визначенні антиоксидантної активності екстрактів. Виявлено, що двократна екстракція є оптимальна. Отримані результати будуть використані для створення фітопрепаратів, дієтичних добавок та косметологічної продукції з екстрактом зеленого чаю

Дослідження якісного складу та кількісного вмісту фенольних сполук у дієтичних добавках з брусницею

Aim. Today, there are a lot of dietary supplements with lingonberry at the pharmaceutical market of Ukraine; therefore, the analysis and quality control of these products are relevant. In this connection, the aim of the research was to study the qualitative composition and determine the quantitative content of phenolic compounds in dietary supplements with lingonberry.Materials and methods. Such dietary supplements as “Extract of lingonberry” (MEDAGROPROM), “Lingonberry” (Danikafarm), “Lingonberry nano” (LSS SYSTEM) were chosen for the study. The qualitative analysis was performed by thin layer chromatography (TLC), spectrophotometry was used for the quantitative determination.Results and discussion. Hydroquinone derivatives, flavonoids and hydroxycinnamic acids were found in the dietary supplements analyzed. The total content of phenolic compounds was 8.70, 0.26, 0.30 %, flavonoids – 6.37, 0.15, 0.12 %, hydroxycinnamic acids – 0.94, 0.06, 0.13 %, and hydroquinone derivatives – 1.01, 0.04, 0.03 % in such dietary supplements as “Extract of lingonberry” (MEDAGROPROM), “Lingonberry” (Danikafarm), “Lingonberry nano” (LSS SYSTEM), respectively. Conclusions. The qualitative and quantitative analysis of the dietary supplements with lingonberry analyzed has been performed. “Extract of lingonberry” (MEDAGROPROM) dietary supplement meets the requirements of the State of Pharmacopoeia of Ukraine 2.0, whereas “Lingonberry” (Danikafarm) and “Lingonberry nano” (LSS SYSTEM) do not. Based on the results of the study it can be concluded that the problem of compliance of dietary supplements is relevant today and requires the introduction of regulatory documentation for the detection and determination of biologically active substances in dietary supplements.Мета. Сьогодні на фармацевтичному ринку України існує велика кількість дієтичних добавок з брусницею, тому аналіз і контроль якості цих продуктів є актуальними. У зв’язку з цим метою роботи було вивчення якісного складу та визначення кількісного вмісту фенольних сполук у дієтичних добавках з брусницею.Матеріали та методи. Для дослідження було обрано дієтичні добавки «Екстракт брусниці» (МЕДАГРОПРОМ), «Брусниця» (Danikafarm), «Брусниця нано» (LSS SYSTEM). Якісний аналіз проводили методом тонкошарової хроматографії (ТШХ), для кількісного визначення використовували спектрофотометрію.Результати та їх обговорення. У досліджуваних дієтичних добавках було виявлено похідні гідрохінону, флавоноїдів та гідроксикоричних кислот. Сумарний вміст фенольних сполук становив 8,70, 0,26, 0,30 %, флавоноїдів 6,37, 0,15, 0,12 %, гідроксикоричних кислот 0,94, 0,06, 0,13 % і похідних гідрохінону 1,01, 0,04, 0,03 % для дієтичних добавок «Екстракт брусниці» (МЕДАГРОПРОМ), «Брусниця» (Danikafarm), «Брусниця нано» (LSS SYSTEM) відповідно. Висновки. Проведений якісний і кількісний аналіз фенольних сполук трьох дієтичних добавок з брусницею дозволив з’ясувати, що дієтична добавка «Екстракт брусниці» (МЕДАГРОПРОМ) відповідає вимогам Державної фармакопеї України 2.0, тоді як «Брусниця» (Danikafarm) і «Брусниця нано» (LSS SYSTEM) не відповідають. Результати дослідження дозволяють констатувати, що проблема відповідності біологічно активних добавок є актуальною, тому необхідним постає введення нормативної документації на виявлення та визначення біологічно активних речовин у дієтичних добавках

Study of total antioxidant capacity of red raspberry (Rubus idaeous L.) shoots

BACKGROUND: Today, cardiovascular, oncological, and neurodegenerative diseases are the main causes of death in the world, according to official World Health Organization (WHO) statistics. Antioxidants are used to treat and prevent these diseases. In order to develop optimal technology for obtaining drugs based on plant extracts with antioxidant action, it is necessary to determine the total antioxidant capacity of raspberry shoots. OBJECTIVES: The study aimed to determine the total antioxidant capacity of red raspberry shoots, study the content of biologically active substances (BAS), and the antioxidant activity of red raspberry shoot extracts obtained during subsequent exhaustive extraction. METHODS: The number of phenolic compounds, catechins, flavonoids, and hydroxycinnamic acids was determined by a spectrophotometric analysis method, whereas organic acids were determined by the alkalimetric method in red raspberry shoot extracts; the antioxidant activity of obtained extracts was evaluated by potentiometric method. RESULTS:  The total antioxidant capacity of red raspberry shoots was 164.12 mmol-equiv./m dry weight, the sum of the total content of phenolic compounds was 24.40 mg gallic acid (GA)/mL, catechins – 21.36 mg epigallocatechin-3-O-gallate (EGCG)/mL, flavonoids – 0.77 mg rutin (R)/mL, hydroxycinnamic acids derivatives – 2.56 mg chlorogenic acid (ChA)/mL and organic acids – 1.88 mg citric acid (CA)/mL in red raspberry shoot extracts obtained during subsequent exhaustive extraction. The analysis showed that there is a very high positive correlation between antioxidant activity and total phenolic compounds, catechin, flavonoid, hydroxycinnamic acids derivatives, and organic acids content in red raspberry shoot extracts. CONCLUSIONS: Total red raspberry shoots' antioxidant capacity has been determined. The study results can be used to develop optimal technology for obtaining drugs based on the extract of red raspberry shoots, which has an antioxidant effect

Metrological Characteristics of the Potentiometric Assay Developed for Determining the Antioxidant Activity of Ascorbic Acid

The potentiometric assay for determining the antioxidant activity of ascorbic acid has been developed and validated according to the following parameters: specificity, linearity, accuracy, repeatability, intermediate precision. The linearity was in the concentration range of 0.002 – 0.02 mol L–1 (r2 = 0.9993). The percentage of recovery was found to be in the range from 95.38 to 105.00 %. The values of %RSD for repeatability and intermediate precision were 1.86 and 1.95 %, respectively. The method is accurate and reliable, with the relative standard deviation of less than 2 %. It has been proven that the method developed is express, rapid, highly sensitive, accurate and sufficiently reliable

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.

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

Phytochemical Research and Anti-inflammatory Activity of the Dry Extracts From Northern Highbush Blueberry Leaves

All over the world, non-steroidal anti-inflammatory drugs (NSAIDs) are taken annually by about three hundred million people and this figure is constantly increasing. At the same time, NSAIDs are also one of the most common causes of side effects of drug therapy. The development and implementation of new anti-inflammatory drugs, including those of plant origin, with minimal side effects is an urgent task of modern pharmaceutical science. Vaccinium corymbosum L. (family Ericaceae), which is gaining more and more popularity among berry crops and is successfully cultivated in Ukraine, is promising in this direction for research. The aim: phytochemical analysis of dry extracts from blueberry leaves to establish the possibility of creating new drugs with anti-inflammatory activity. Materials and methods. The objects of the study were dry extracts of northern highbush blueberry leaves. The content of amino acids and phenolic compounds was determined by HPLC and spectrophotometry. The prototypal activity was studied in vivo and in vitro. Research results. 4 dry extracts were obtained from northern highbush blueberry leaves. In the extracts obtained by HPLC, 7 amino acids were identified, including 3 essential ones: arginine, histidine, and phenylalanine. As a result of the HPLC study, 7 phenolic compounds were identified in extracts from the leaves of northern highbush blueberry: 5 flavonoids - rutin, quercetin-3-O-glucoside, kaempferol-3-O-glucoside, quercetin and kaempferol and 2 hydroxycinnamic acids, chlorogenic and caffeic acid. For the first time, the anti-inflammatory effect of extracts from blueberry leaves was investigated. It was revealed that extract 1 at a dose of 50 mg/kg and extract 4 modified with arginine at a dose of 25 mg/kg have the highest anti-inflammatory activity. Conclusions. The results of the conducted studies indicate that extracts from the leaves of northern highbush blueberry in terms of the content of biologically active substances are promising sources for the creation of new drugs and dietary supplements with anti-inflammatory activit

Kidney and Cardiovascular Effects of Canagliflozin According to Age and Sex: A Post Hoc Analysis of the CREDENCE Randomized Clinical Trial

Rationale &amp; Objective: It is unclear whether the effect of canagliflozin on adverse kidney and cardiovascular events in those with diabetic kid-ney disease varies by age and sex. We assessed the effects of canagliflozin among age group categories and between sexes in the Canagli-flozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study.Study Design: Secondary analysis of a random-ized controlled trial. Setting &amp; Participants: Participants in the CREDENCE trial. Intervention: Participants were randomly assigned to receive canagliflozin 100 mg/d or placebo.Outcomes: Primary composite outcome of kid-ney failure, doubling of serum creatinine con-centration, or death due to kidney or cardiovascular disease. Prespecified secondary and safety outcomes were also analyzed. Out-comes were evaluated by age at baseline (&lt;60, 60-69, and &gt;_70 years) and sex in the intention-to-treat population using Cox regression models.Results: The mean age of the cohort was 63.0 &amp; PLUSMN; 9.2 years, and 34% were female. Older age and female sex were independently associ-ated with a lower risk of the composite of adverse kidney outcomes. There was no evidence that the effect of canagliflozin on the primary outcome (acomposite of kidney failure, a doubling of serum creatinine concentration, or death from kidney or cardiovascular causes) differed between age groups (HRs, 0.67 [95% CI, 0.52-0.87], 0.63 [0.4 8-0.82], and 0.89 [0.61-1.29] for ages &lt;60, 60-69, and &gt;_70 years, respectively; P = 0.3 for interaction) or sexes (HRs, 0.71 [95% CI, 0.5 4-0.95] and 0.69 [0.56-0.8 4] in women and men, respectively; P = 0.8 for interaction). No differences in safety outcomes by age group or sex were observed.Limitations: This was a post hoc analysis with multiple comparisons.Conclusions: Canagliflozin consistently reduced the relative risk of kidney events in people with diabetic kidney disease in both sexes and across age subgroups. As a result of greater background risk, the absolute reduction in adverse kidney outcomes was greater in younger participants.Funding: This post hoc analysis of the CREDENCE trial was not funded. The CREDENCE study was sponsored by Janssen Research and Development and was conducted collaboratively by the sponsor, an academic-led steering committee, and an academic research organization, George Clinical.Trial Registration: The original CREDENCE trial was registered at ClinicalTrials.gov with study number NCT02065791

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 (&lt;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. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02065791