ABSTRACT
BACKGROUND: Several SGLT2i (sodium-glucose transport protein 2 inhibitors) and GLP1-RA (glucagon-like peptide-1 receptor agonists) reduce cardiovascular events and improve kidney outcomes in patients with type 2 diabetes; however, utilization remains low despite guideline recommendations. METHODS: A randomized, remote implementation trial in the Mass General Brigham network enrolled patients with type 2 diabetes with increased cardiovascular or kidney risk. Patients eligible for, but not prescribed, SGLT2i or GLP1-RA were randomly assigned to simultaneous virtual patient education with concurrent prescription of SGLT2i or GLP1-RA (ie, Simultaneous) or 2 months of virtual education followed by medication prescription (ie, Education-First) delivered by a multidisciplinary team driven by nonlicensed navigators and clinical pharmacists who prescribed SGLT2i or GLP1-RA using a standardized treatment algorithm. The primary outcome was the proportion of patients with prescriptions for either SGLT2i or GLP1-RA by 6 months. RESULTS: Between March 2021 and December 2022, 200 patients were randomized. The mean age was 66.5 years; 36.5% were female, and 22.0% were non-White. Overall, 30.0% had cardiovascular disease, 5.0% had cerebrovascular disease, and 1.5% had both. Mean estimated glomerular filtration rate was 77.9 mL/(minâ§1.73 m2), and mean urine/albumin creatinine ratio was 88.6 mg/g. After 2 months, 69 of 200 (34.5%) patients received a new prescription for either SGLT2i or GLP1-RA: 53.4% of patients in the Simultaneous arm and 8.3% of patients in the Education-First arm (P<0.001). After 6 months, 128 of 200 (64.0%) received a new prescription: 69.8% of patients in the Simultaneous arm and 56.0% of patients in Education-First (P<0.001). Patient self-report of taking SGLT2i or GLP1-RA within 6 months of trial entry was similarly greater in the Simultaneous versus Education-First arm (69 of 116 [59.5%] versus 37 of 84 [44.0%]; P<0.001) Median time to first prescription was 24 (interquartile range [IQR], 13-50) versus 85 days (IQR, 65-106), respectively (P<0.001). CONCLUSIONS: In this randomized trial, a remote, team-based program identifies patients with type 2 diabetes and high cardiovascular or kidney risk, provides virtual education, prescribes SGLT2i or GLP1-RA, and improves guideline-directed medical therapy. These findings support greater utilization of virtual team-based approaches to optimize chronic disease management. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT06046560.
Subject(s)
Diabetes Mellitus, Type 2 , Sodium-Glucose Transporter 2 Inhibitors , Humans , Female , Male , Aged , Diabetes Mellitus, Type 2/drug therapy , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Middle Aged , Patient Education as Topic , Glucagon-Like Peptide-1 Receptor/agonists , Hypoglycemic Agents/therapeutic use , Practice Guidelines as Topic , Cardiovascular Diseases , Telemedicine , Guideline Adherence , Treatment OutcomeABSTRACT
BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure or death from cardiovascular causes among patients with stable heart failure. However, the safety and efficacy of SGLT2 inhibitors when initiated soon after an episode of decompensated heart failure are unknown. METHODS: We performed a multicenter, double-blind trial in which patients with type 2 diabetes mellitus who were recently hospitalized for worsening heart failure were randomly assigned to receive sotagliflozin or placebo. The primary end point was the total number of deaths from cardiovascular causes and hospitalizations and urgent visits for heart failure (first and subsequent events). The trial ended early because of loss of funding from the sponsor. RESULTS: A total of 1222 patients underwent randomization (608 to the sotagliflozin group and 614 to the placebo group) and were followed for a median of 9.0 months; the first dose of sotagliflozin or placebo was administered before discharge in 48.8% and a median of 2 days after discharge in 51.2%. Among these patients, 600 primary end-point events occurred (245 in the sotagliflozin group and 355 in the placebo group). The rate (the number of events per 100 patient-years) of primary end-point events was lower in the sotagliflozin group than in the placebo group (51.0 vs. 76.3; hazard ratio, 0.67; 95% confidence interval [CI], 0.52 to 0.85; P<0.001). The rate of death from cardiovascular causes was 10.6 in the sotagliflozin group and 12.5 in the placebo group (hazard ratio, 0.84; 95% CI, 0.58 to 1.22); the rate of death from any cause was 13.5 in the sotagliflozin group and 16.3 in the placebo group (hazard ratio, 0.82; 95% CI, 0.59 to 1.14). Diarrhea was more common with sotagliflozin than with placebo (6.1% vs. 3.4%), as was severe hypoglycemia (1.5% vs. 0.3%). The percentage of patients with hypotension was similar in the sotagliflozin group and the placebo group (6.0% and 4.6%, respectively), as was the percentage with acute kidney injury (4.1% and 4.4%, respectively). The benefits of sotagliflozin were consistent in the prespecified subgroups of patients stratified according to the timing of the first dose. CONCLUSIONS: In patients with diabetes and recent worsening heart failure, sotagliflozin therapy, initiated before or shortly after discharge, resulted in a significantly lower total number of deaths from cardiovascular causes and hospitalizations and urgent visits for heart failure than placebo. (Funded by Sanofi and Lexicon Pharmaceuticals; SOLOIST-WHF ClinicalTrials.gov number, NCT03521934.).
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Glycosides/therapeutic use , Heart Failure/drug therapy , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Acute Kidney Injury/chemically induced , Aged , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/mortality , Diabetes Mellitus, Type 2/complications , Double-Blind Method , Female , Glycosides/adverse effects , Heart Failure/complications , Hospitalization/statistics & numerical data , Humans , Hypotension/chemically induced , Male , Middle Aged , Sodium-Glucose Transporter 1/antagonists & inhibitors , Sodium-Glucose Transporter 2 Inhibitors/adverse effectsABSTRACT
BACKGROUND: The efficacy and safety of sodium-glucose cotransporter 2 inhibitors such as sotagliflozin in preventing cardiovascular events in patients with diabetes with chronic kidney disease with or without albuminuria have not been well studied. METHODS: We conducted a multicenter, double-blind trial in which patients with type 2 diabetes mellitus (glycated hemoglobin level, ≥7%), chronic kidney disease (estimated glomerular filtration rate, 25 to 60 ml per minute per 1.73 m2 of body-surface area), and risks for cardiovascular disease were randomly assigned in a 1:1 ratio to receive sotagliflozin or placebo. The primary end point was changed during the trial to the composite of the total number of deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure. The trial ended early owing to loss of funding. RESULTS: Of 19,188 patients screened, 10,584 were enrolled, with 5292 assigned to the sotagliflozin group and 5292 assigned to the placebo group, and followed for a median of 16 months. The rate of primary end-point events was 5.6 events per 100 patient-years in the sotagliflozin group and 7.5 events per 100 patient-years in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.63 to 0.88; P<0.001). The rate of deaths from cardiovascular causes per 100 patient-years was 2.2 with sotagliflozin and 2.4 with placebo (hazard ratio, 0.90; 95% CI, 0.73 to 1.12; P = 0.35). For the original coprimary end point of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, the hazard ratio was 0.84 (95% CI, 0.72 to 0.99); for the original coprimary end point of the first occurrence of death from cardiovascular causes or hospitalization for heart failure, the hazard ratio was 0.77 (95% CI, 0.66 to 0.91). Diarrhea, genital mycotic infections, volume depletion, and diabetic ketoacidosis were more common with sotagliflozin than with placebo. CONCLUSIONS: In patients with diabetes and chronic kidney disease, with or without albuminuria, sotagliflozin resulted in a lower risk of the composite of deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure than placebo but was associated with adverse events. (Funded by Sanofi and Lexicon Pharmaceuticals; SCORED ClinicalTrials.gov number, NCT03315143.).
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Glycosides/therapeutic use , Renal Insufficiency, Chronic/drug therapy , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Aged , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/mortality , Diabetes Mellitus, Type 2/complications , Diabetic Ketoacidosis/chemically induced , Diarrhea/chemically induced , Double-Blind Method , Female , Glycosides/adverse effects , Hospitalization/statistics & numerical data , Humans , Male , Middle Aged , Mycoses/etiology , Renal Insufficiency, Chronic/complications , Sodium-Glucose Transporter 1/antagonists & inhibitors , Sodium-Glucose Transporter 2 Inhibitors/adverse effectsABSTRACT
BACKGROUND: Diabetes mellitus (DM) and Lp(a) are well-established predictors of coronary artery disease (CAD) outcomes. However, their combined association remains poorly understood. OBJECTIVE: To investigate the relationship between elevated Lp(a) and DM with CAD outcomes. METHODS: Retrospective analysis of the MGB Lp(a) Registry involving patients ≥ 18 years who underwent Lp(a) measurements between 2000 and 2019. Exclusion criteria were severe kidney dysfunction, malignant neoplasms, and prior atherosclerotic cardiovascular disease (ASCVD). The primary outcome was a combination of cardiovascular death or myocardial infarction (MI). Elevated Lp(a) was defined as > 90th percentile (≥ 216 nmol/L). RESULTS: Among 6,238 patients who met the eligibility criteria, the median age was 54, 45% were women, and 12% had DM. Patients with DM were older, more frequently male, and had a higher prevalence of additional cardiovascular risk factors. Over a median follow-up of 12.9 years, patients with either DM or elevated Lp(a) experienced higher rates of the primary outcome. Notably, those with elevated Lp(a) had a higher incidence of the primary outcome regardless of their DM status. The annual event rates were as follows: No-DM and Lp(a) < 90th% - 0.6%; No-DM and Lp(a) > 90th% - 1.3%; DM and Lp(a) < 90th% - 1.9%; DM and Lp(a) > 90th% - 4.7% (p < 0.001). After adjusting for confounders, elevated Lp(a) remained independently associated with the primary outcome among both patients with DM (HR = 2.66 [95%CI: 1.55-4.58], p < 0.001) and those without DM (HR = 2.01 [95%CI: 1.48-2.74], p < 0.001). CONCLUSIONS: Elevated Lp(a) constitutes an independent and incremental risk factor for CAD outcomes in patients with and without DM.
Subject(s)
Biomarkers , Coronary Artery Disease , Diabetes Mellitus , Heart Disease Risk Factors , Lipoprotein(a) , Registries , Humans , Male , Female , Lipoprotein(a)/blood , Middle Aged , Retrospective Studies , Risk Assessment , Diabetes Mellitus/epidemiology , Diabetes Mellitus/diagnosis , Diabetes Mellitus/blood , Aged , Biomarkers/blood , Coronary Artery Disease/blood , Coronary Artery Disease/epidemiology , Coronary Artery Disease/diagnosis , Coronary Artery Disease/mortality , Adult , Time Factors , Prognosis , Incidence , Up-Regulation , Prevalence , Myocardial Infarction/epidemiology , Myocardial Infarction/blood , Myocardial Infarction/diagnosis , Myocardial Infarction/mortalityABSTRACT
AIM: To explore the effect of canagliflozin on kidney and cardiovascular events and safety outcomes in individuals with type 2 diabetes and chronic kidney disease across geographic regions and racial groups. MATERIALS AND METHODS: A stratified Cox proportional hazards model was used to assess efficacy and safety outcomes by geographic region and racial group. The primary composite outcome was a composite of end-stage kidney disease (ESKD), doubling of the serum creatinine (SCr) level, or death from kidney or cardiovascular causes. Secondary outcomes included: (i) cardiovascular death or heart failure (HF) hospitalization; (ii) cardiovascular death, myocardial infarction (MI) or stroke; (iii) HF hospitalization; (iv) doubling of the SCr level, ESKD or kidney death; (v) cardiovascular death; (vi) all-cause death; and (vii) cardiovascular death, MI, stroke, or hospitalization for HF or for unstable angina. RESULTS: The 4401 patients were divided into six geographic region subgroups: North America (n = 1182, 27%), Central and South America (n = 941, 21%), Eastern Europe (n = 947, 21%), Western Europe (n = 421, 10%), Asia (n = 749, 17%) and Other (n = 161, 4%). The analyses included four racial groups: White (n = 2931, 67%), Black or African American (n = 224, 5%), Asian (n = 877, 20%) and Other (n = 369, 8%). Canagliflozin reduced the relative risk of the primary composite outcome in the overall trial by 30% (hazard ratio 0.70, 95% confidence interval 0.59-0.82; P = 0.00001). Across geographic regions and racial groups, canagliflozin consistently reduced the primary composite endpoint without evidence of heterogeneity (interaction P values of 0.39 and 0.91, respectively) or significant safety outcome differences. CONCLUSIONS: Canagliflozin reduces the risk of kidney and cardiovascular events similarly across geographic regions and racial groups.
Subject(s)
Canagliflozin , Cardiovascular Diseases , Diabetes Mellitus, Type 2 , Sodium-Glucose Transporter 2 Inhibitors , Humans , Canagliflozin/therapeutic use , Canagliflozin/adverse effects , Male , Female , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/ethnology , Middle Aged , Aged , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Sodium-Glucose Transporter 2 Inhibitors/adverse effects , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/mortality , Cardiovascular Diseases/prevention & control , Diabetic Nephropathies , Renal Insufficiency, Chronic/complications , Renal Insufficiency, Chronic/ethnology , Hospitalization/statistics & numerical data , Kidney Failure, Chronic/complications , Kidney Failure, Chronic/ethnology , Europe/epidemiology , Treatment Outcome , North America/epidemiology , Proportional Hazards ModelsABSTRACT
BACKGROUND: Transgender women (TW) experience significant inequities in healthcare access and health disparities compared to cisgender populations. Access to non-transition related healthcare is understudied among TW. We aimed to assess the association between access to care and gender minority stress and resilience factors among TW living with and without HIV in eastern and southern United States. METHODS: This study was a cross-sectional analysis of baseline data drawn from a cohort of 1613 adult TW from the LITE Study. The cohort permitted participation through two modes: a site-based, technology-enhanced mode and an exclusively online (remote) mode. Exploratory and confirmatory factor analyses determined measurement models for gender minority stress, resilience, and healthcare access. Structural equation modeling was used to assess the relationships between these constructs. Models were evaluated within the overall sample and separately by mode and HIV status. RESULTS: Higher levels of gender minority stress, as measured by anticipated discrimination and non-affirmation were associated with decreased access to healthcare. Among TW living with HIV, higher levels of anticipated discrimination, non-affirmation, and social support were associated with decreased healthcare access. Among TW living without HIV in the site-based mode, resilience was positively associated with positive healthcare experiences and inversely associated with barriers to healthcare access. Among TW living without HIV in the online mode, anticipated discrimination was associated with barriers to healthcare access; resilience was positively associated with positive healthcare experiences and inversely associated with barriers to healthcare access. CONCLUSIONS: Gender minority stress was associated with increased barriers to healthcare access among TW in the US, regardless of HIV status. Resilience factors did not mediate this effect. Interventions aiming to increase healthcare access among TW can be aided by efforts to mitigate drivers of gender minority stress and improve patient experiences in healthcare facilities.
Subject(s)
HIV Infections , Resilience, Psychological , Sexual and Gender Minorities , Transgender Persons , Adult , Humans , United States/epidemiology , Female , Cross-Sectional Studies , HIV Infections/epidemiology , Health Services Accessibility , Gender IdentityABSTRACT
AIMS: Interest in targeted screening programmes for atrial fibrillation (AF) has increased, yet the role of genetics in identifying patients at highest risk of developing AF is unclear. METHODS AND RESULTS: A total of 36,662 subjects without prior AF were analyzed from four TIMI trials. Subjects were divided into quintiles using a validated polygenic risk score (PRS) for AF. Clinical risk for AF was calculated using the CHARGE-AF model. Kaplan-Meier event rates, adjusted hazard ratios (HRs), C-indices, and net reclassification improvement were used to determine if the addition of the PRS improved prediction compared with clinical risk and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Over 2.3 years, 1018 new AF cases developed. AF PRS predicted a significant risk gradient for AF with a 40% increased risk per 1-SD increase in PRS [HR: 1.40 (1.32-1.49); P < 0.001]. Those with high AF PRS (top 20%) were more than two-fold more likely to develop AF [HR 2.45 (1.99-3.03), P < 0.001] compared with low PRS (bottom 20%). Furthermore, PRS provided an additional gradient of risk stratification on top of the CHARGE-AF clinical risk score, ranging from a 3-year incidence of 1.3% in patients with low clinical and genetic risk to 8.7% in patients with high clinical and genetic risk. The subgroup of patients with high clinical risk, high PRS, and elevated NT-proBNP had an AF risk of 16.7% over 3 years. The C-index with the CHARGE-AF clinical risk score alone was 0.65, which improved to 0.67 (P < 0.001) with the addition of NT-proBNP, and increased further to 0.70 (P < 0.001) with the addition of the PRS. CONCLUSION: In patients with cardiovascular conditions, AF PRS is a strong independent predictor of incident AF that provides complementary predictive value when added to a validated clinical risk score and NT-proBNP.
Subject(s)
Atrial Fibrillation , Cardiovascular Diseases , Humans , Atrial Fibrillation/complications , Atrial Fibrillation/genetics , Atrial Fibrillation/epidemiology , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/genetics , Prognosis , Biomarkers , Risk Factors , Natriuretic Peptide, Brain , Peptide FragmentsABSTRACT
AIMS: Levels of growth differentiation factor 15 (GDF-15), a cytokine secreted in response to cellular stress and inflammation, have been associated with multiple types of cardiovascular (CV) events. However, its comparative prognostic performance across different presentations of atherosclerotic cardiovascular disease (ASCVD) remains unknown. METHODS AND RESULTS: An individual patient meta-analysis was performed using data pooled from eight trials including 53 486 patients. Baseline GDF-15 concentration was analyzed as a continuous variable and using established cutpoints (<1200 ng/L, 1200-1800 ng/L, > 1800 ng/L) to evaluate its prognostic performance for CV death/hospitalization for heart failure (HHF), major adverse cardiovascular events (MACE), and their components using Cox models adjusted for clinical variables and established CV biomarkers. Analyses were further stratified on ASCVD status: acute coronary syndrome (ACS), stabilized after recent ACS, and stable ASCVD. Overall, higher GDF-15 concentration was significantly and independently associated with an increased rate of CV death/HHF and MACE (P < 0.001 for each). However, while GDF-15 showed a robust and consistent independent association with CV death and HHF across all presentations of ASCVD, its prognostic association with future myocardial infarction (MI) and stroke only remained significant in patients stabilized after recent ACS or with stable ASCVD [hazard ratio (HR): 1.24, 95% confidence interval (CI): 1.17-1.31 and HR: 1.16, 95% CI: 1.05-1.28 for MI and stroke, respectively] and not in ACS (HR: 0.98, 95% CI: 0.90-1.06 and HR: 0.87, 95% CI: 0.39-1.92, respectively). CONCLUSION: Growth differentiation factor 15 consistently adds prognostic information for CV death and HHF across the spectrum of ASCVD. GDF-15 also adds prognostic information for MI and stroke beyond clinical risk factors and cardiac biomarkers but not in the setting of ACS.
Subject(s)
Acute Coronary Syndrome , Atherosclerosis , Cardiovascular Diseases , Heart Failure , Myocardial Infarction , Stroke , Humans , Cardiovascular Diseases/complications , Growth Differentiation Factor 15 , Risk Factors , Myocardial Infarction/etiology , Acute Coronary Syndrome/complications , Biomarkers , Heart Failure/complications , Stroke/complications , Heart Disease Risk Factors , Atherosclerosis/complicationsABSTRACT
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.).
Subject(s)
Atherosclerosis/drug therapy , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Cardiovascular Diseases/epidemiology , Diabetes Mellitus, Type 2/drug therapy , Hospitalization/statistics & numerical data , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Aged , Atherosclerosis/complications , Bridged Bicyclo Compounds, Heterocyclic/administration & dosage , Bridged Bicyclo Compounds, Heterocyclic/adverse effects , Cardiovascular Diseases/mortality , Diabetes Mellitus, Type 2/complications , Diabetic Nephropathies/complications , Double-Blind Method , Female , Humans , Male , Middle Aged , Placebos/therapeutic use , Sodium-Glucose Transporter 2 Inhibitors/administration & dosage , Sodium-Glucose Transporter 2 Inhibitors/adverse effectsABSTRACT
RATIONALE & OBJECTIVE: It is unclear whether the effect of canagliflozin on adverse kidney and cardiovascular events in those with diabetic kidney disease varies by age and sex. We assessed the effects of canagliflozin among age group categories and between sexes in the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study. STUDY DESIGN: Secondary analysis of a randomized controlled trial. SETTING & PARTICIPANTS: Participants in the CREDENCE trial. INTERVENTION: Participants were randomly assigned to receive canagliflozin 100mg/d or placebo. OUTCOMES: Primary composite outcome of kidney failure, doubling of serum creatinine concentration, or death due to kidney or cardiovascular disease. Prespecified secondary and safety outcomes were also analyzed. Outcomes were evaluated by age at baseline (<60, 60-69, and≥70 years) and sex in the intention-to-treat population using Cox regression models. RESULTS: The mean age of the cohort was 63.0±9.2 years, and 34% were female. Older age and female sex were independently associated with a lower risk of the composite of adverse kidney outcomes. There was no evidence that the effect of canagliflozin on the primary outcome (a composite 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 [0.48-0.82], and 0.89 [0.61-1.29] for ages<60, 60-69, and≥70 years, respectively; P=0.3for interaction) or sexes (HRs, 0.71 [95% CI, 0.54-0.95] and 0.69 [0.56-0.84] in women and men, respectively; P=0.8for 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.
Subject(s)
Cardiovascular Diseases , Diabetes Mellitus, Type 2 , Diabetic Nephropathies , Renal Insufficiency , Sodium-Glucose Transporter 2 Inhibitors , Male , Female , Humans , Middle Aged , Aged , Canagliflozin/therapeutic use , Diabetic Nephropathies/drug therapy , Diabetic Nephropathies/epidemiology , Diabetic Nephropathies/complications , Sodium-Glucose Transporter 2 Inhibitors/adverse effects , Creatinine , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/epidemiology , Treatment Outcome , Kidney , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/prevention & control , Cardiovascular Diseases/drug therapyABSTRACT
PURPOSE OF REVIEW: The purpose of this review is to analyze and discuss the most recent data on in hospital prescription of Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) inhibitors in patients with acute coronary syndrome (ACS). RECENT FINDINGS: Recent randomized clinical trials (RTCs) have demonstrated a beneficial effect of monoclonal antibodies (mAb) PCSK9i prescription in patients with ACS on rapid reduction of low-density lipoprotein cholesterol (LDL-C) and on coronary atherosclerosis assessed by intracoronary imaging. Additionally, the safety profile of mAb PCSK9i was confirmed in all RTCs. Available RCTs show the effectiveness and rapid achievement of LDL-C levels according to American College of Cardiology/American Heart Association and European Society of Cardiology guidelines for ACS patients. However, RCTs addressing cardiovascular outcomes of PCSK9i in-hospital initiation in ACS patients are currently ongoing.
Subject(s)
Acute Coronary Syndrome , Anticholesteremic Agents , Hydroxymethylglutaryl-CoA Reductase Inhibitors , United States , Humans , Proprotein Convertase 9 , PCSK9 Inhibitors , Cholesterol, LDL , Subtilisin/therapeutic use , Acute Coronary Syndrome/drug therapy , Proprotein Convertases/therapeutic use , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal/pharmacology , Anticholesteremic Agents/therapeutic use , Anticholesteremic Agents/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic useABSTRACT
AIM: To conduct a post hoc analysis to explore indices of hepatic steatosis/fibrosis and cardiorenal outcomes in the VERTIS CV study. MATERIALS AND METHODS: Patients with type 2 diabetes and atherosclerotic cardiovascular (CV) disease were randomized to ertugliflozin or placebo. Liver steatosis and fibrosis were assessed post hoc using the hepatic steatosis index (HSI) and fibrosis-4 (FIB-4) index to explore associations with cardiorenal outcomes (ertugliflozin and placebo data pooled, intention-to-treat analysis set). Cardiorenal outcomes (major adverse CV events [MACE]; hospitalization for heart failure [HHF]/CV death; CV death; HHF; and a composite kidney outcome) were stratified by baseline HSI and FIB-4 quartiles (Q1-Q4). Change in liver indices and enzymes over time were assessed (for ertugliflozin vs. placebo). RESULTS: Amongst 8246 participants, the mean age was 64.4 years, body mass index 32.0 kg/m2 , HSI 44.0 and FIB-4 score 1.34. The hazard ratios (HRs) for MACE, HHF/CV death, CV death, and HHF by FIB-4 score quartile (Q4 vs. Q1) were 1.48 (95% confidence interval [CI] 1.25, 1.76), 2.0 (95% CI 1.63, 2.51), 1.85 (95% CI 1.45, 2.36), and 2.94 (95% CI 1.98, 4.37), respectively (P < 0.0001 for all). With HSI, the incidence of HHF was higher in Q4 versus Q1 (HR 1.52 [95% CI 1.07, 2.17]; P < 0.05). The kidney composite outcome did not differ across FIB-4 or HSI quartiles. Liver enzymes and HSI decreased over time with ertugliflozin. CONCLUSION: In VERTIS CV, higher FIB-4 score was associated with CV events. HSI correlated with HHF. Neither measure was associated with the composite kidney outcome. Ertugliflozin was associated with a reduction in liver enzymes and HSI.
Subject(s)
Cardiovascular Diseases , Diabetes Mellitus, Type 2 , Fatty Liver , Heart Failure , Sodium-Glucose Transporter 2 Inhibitors , Humans , Middle Aged , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/chemically induced , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/etiology , Cardiovascular Diseases/prevention & control , Sodium-Glucose Transporter 2 Inhibitors/adverse effects , Heart Failure/complications , Fibrosis , Fatty Liver/drug therapy , Glucose/therapeutic use , SodiumABSTRACT
AIM: To examine improvement in the use of optimal medical therapy (OMT) for secondary prevention in patients with atherosclerotic cardiovascular disease (ASCVD) and diabetes. MATERIALS AND METHODS: Patients with ASCVD (coronary, cerebrovascular, peripheral) and low-density lipoprotein-cholesterol of 70 mg/dl or higher were enrolled from December 2016 to July 2018 from 107 US sites/physicians (47% cardiology, 41% primary care, 12% other) and prospectively followed for 2 years (current analysis restricted to subgroup with diabetes). OMT was defined as high-intensity lipid-lowering (high-intensity statin, any statin + ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitor), antithrombotic (antiplatelet or anticoagulant), angiotensin-converting enzyme-inhibitor/angiotensin II receptor blocker/angiotensin receptor neprilysin inhibitor (ACE-I/ARB/ARNI) (excluding glomerular filtration rate [GFR] < 30 ml/min/1.73m2 ) and sodium-glucose co-transporter-2 inhibitor (SGLT2i)/glucagon-like peptide-1 receptor agonist (GLP-1 RA) (excluding GFR < 30 ml/min/1.73m2 and type 1 diabetes). RESULTS: Among 1590 patients with ASCVD and diabetes (96% type 2 diabetes), 58% were on high-intensity lipid-lowering therapy at the end of follow-up, 87% antithrombotic, 71% ACE-I/ARB/ARNI and 17% SGLT2i/GLP-1 RA. Overall, 11% of patients received comprehensive OMT, which modestly improved over time (vs. 8% at baseline; P = .002). Patients treated by cardiologists (vs. non-cardiologists) were more likely to be on high-intensity lipid lowering, but less likely to be on an SGLT2i/GLP-1 RA, and thus had lower rates of composite OMT (7.8% vs. 13.7%, P < .001). In a hierarchical multivariable model, older age was associated with lower odds of OMT (OR 0.74 per 10 years, 95% CI 0.60-0.90), whereas private insurance (OR 1.93, 95% CI 1.32-2.84) and coronary disease (OR 1.62, 95% CI 1.01-2.61) were associated with higher odds. The median odds ratio was 1.82 (95% CI 1.03-7.32), indicating a moderate variability in OMT use, independent of patient factors. CONCLUSIONS: We found suboptimal use of secondary prevention in US patients with ASCVD and diabetes, with minimal improvement over time. Further efforts are needed to improve the use of secondary prevention therapies in these patients with high residual risk.
Subject(s)
Atherosclerosis , Cardiovascular Diseases , Diabetes Mellitus, Type 2 , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Humans , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/prevention & control , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/epidemiology , Prospective Studies , Angiotensin Receptor Antagonists/therapeutic use , Fibrinolytic Agents , Longitudinal Studies , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Atherosclerosis/drug therapy , Atherosclerosis/epidemiology , Atherosclerosis/prevention & control , Cholesterol, LDL , Glucagon-Like Peptide 1ABSTRACT
PURPOSE: The sodium-glucose transporter 2 inhibitor (SGLT2i) empagliflozin may reduce the incidence of obstructive sleep apnea (OSA) in patients with type 2 diabetes (T2D) and cardiovascular (CV) disease. This analysis of VERTIS CV, the CV outcome trial for the SGLT2i ertugliflozin conducted in a similar group of patients, explored the effects of ertugliflozin on reported incident OSA. METHODS: In VERTIS CV, patients ≥ 40 years with T2D and atherosclerotic CV disease (ASCVD) were randomized to ertugliflozin 5 or 15 mg or placebo. The primary endpoint was the composite of major adverse CV events. This exploratory analysis evaluated the impact of ertugliflozin (5 and 15 mg pooled) on incident OSA. Patients with prevalent OSA were excluded. Incident OSA events were based on investigator-reported events using the MedDRA SMQ term "sleep apnea syndrome." A multivariable Cox proportional hazards regression model was constructed to assess the association between ertugliflozin and incident OSA. RESULTS: Of 8246 patients enrolled, 7697 (93.3%) were without baseline OSA (placebo, n = 2561; ertugliflozin, n = 5136; mean age 64.4 years; BMI 31.7 kg/m2; HbA1c, 8.2%; 69.2% male; 88.3% White). The OSA incidence rate was 1.44 per 1000 person-years versus 2.61 per 1000 person-years among patients treated with ertugliflozin versus placebo, respectively, corresponding to a 48% relative risk reduction (HR 0.52; 95% CI 0.28-0.96; P = 0.04). CONCLUSIONS: In VERTIS CV, ertugliflozin reduced by nearly half the incidence of OSA in patients with T2D and ASCVD. These data contribute to the literature that SGLT2is may have a significant beneficial impact on OSA. CLINICALTRIALS: gov identifier: NCT01986881.
Subject(s)
Cardiovascular Diseases , Diabetes Mellitus, Type 2 , Sleep Apnea, Obstructive , Sodium-Glucose Transporter 2 Inhibitors , Humans , Male , Middle Aged , Female , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/epidemiology , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Sodium-Glucose Transporter 2 Inhibitors/adverse effects , Bridged Bicyclo Compounds, Heterocyclic/adverse effects , Cardiovascular Diseases/epidemiology , Sleep Apnea, Obstructive/drug therapy , Sleep Apnea, Obstructive/epidemiology , Sleep Apnea, Obstructive/chemically inducedABSTRACT
Accurate assessment of LDL-C levels is important, as they are often used for treatment recommendations. For many years, plasma LDL-C levels were calculated using the Friedewald equation, but there are limitations to this method compared with direct measurement via beta-quantification (BQ). Here, we assessed differences between the Friedewald, Martin-Hopkins, and NIH equation 2 methods of calculating LDL-C and the "gold standard" BQ method using pooled phase 3 data with alirocumab. All randomized patients were included irrespective of the treatment arm (n = 6,122). We compared pairs of LDL-C values (n = 17,077) determined by each equation and BQ. We found that BQ-derived LDL-C values ranged from 1 to 397 mg/dl (mean 90.68 mg/dl). There were strong correlations between Friedewald-calculated, Martin-Hopkins-calculated, and NIH equation 2-calculated LDL-C with BQ-determined LDL-C values (Pearson's correlation coefficient = 0.985, 0.981, and 0.985, respectively). Importantly, for BQ-derived LDL-C values ≥70 mg/dl, only 3.2%, 1.4%, and 1.8% of Friedewald-calculated, Martin-Hopkins-calculated, and NIH equation 2-calculated values were <70 mg/dl, respectively. When triglyceride (TG) levels were <150 mg/dl, differences between calculated and BQ-derived LDL-C values were minimal, regardless of the LDL-C level (<40, <55, or <70 mg/dl). However, when TG levels were >150 mg/dl, NIH equation 2 provided greater accuracy than Friedewald or Martin-Hopkins. When TGs were >250 mg/dl, inaccuracies were seen with all three methods, although NIH equation 2 remained the most accurate. In conclusion, LDL-C calculated by any of the three methods can guide treatment decisions for most patients, including those treated with proprotein convertase subtilisin/kexin type 9 inhibitors.
Subject(s)
Cholesterol, LDLABSTRACT
A growing number of patients undergoing percutaneous coronary intervention (PCI) with stent implantation also have atrial fibrillation. This poses challenges for their optimal antithrombotic management because patients with atrial fibrillation undergoing PCI require oral anticoagulation for the prevention of cardiac thromboembolism and dual antiplatelet therapy for the prevention of coronary thrombotic complications. The combination of oral anticoagulation and dual antiplatelet therapy substantially increases the risk of bleeding. Over the last decade, a series of North American Consensus Statements on the Management of Antithrombotic Therapy in Patients with Atrial Fibrillation Undergoing Percutaneous Coronary Intervention have been reported. Since the last update in 2018, several pivotal clinical trials in the field have been published. This document provides a focused updated of the 2018 recommendations. The group recommends that in patients with atrial fibrillation undergoing PCI, a non-vitamin K antagonist oral anticoagulant is the oral anticoagulation of choice. Dual antiplatelet therapy with aspirin and a P2Y12 inhibitor should be given to all patients during the peri-PCI period (during inpatient stay, until time of discharge, up to 1 week after PCI, at the discretion of the treating physician), after which the default strategy is to stop aspirin and continue treatment with a P2Y12 inhibitor, preferably clopidogrel, in combination with a non-vitamin K antagonist oral anticoagulant (ie, double therapy). In patients at increased thrombotic risk who have an acceptable risk of bleeding, it is reasonable to continue aspirin (ie, triple therapy) for up to 1 month. Double therapy should be given for 6 to 12 months with the actual duration depending on the ischemic and bleeding risk profile of the patient, after which patients should discontinue antiplatelet therapy and receive oral anticoagulation alone.
Subject(s)
Anticoagulants/therapeutic use , Atrial Fibrillation/drug therapy , Fibrinolytic Agents/therapeutic use , Percutaneous Coronary Intervention/methods , Administration, Oral , Anticoagulants/pharmacology , Fibrinolytic Agents/pharmacology , History, 21st Century , HumansABSTRACT
BACKGROUND: Women are underrepresented across cardiovascular clinical trials. Whether women are more likely than men to prematurely discontinue study drug or withdraw consent once enrolled in a clinical trial is unknown. METHODS: Eleven phase 3/4 TIMI (Thrombolysis in Myocardial Infarction) trials were included (135 879 men and 51 812 women [28%]). The association between sex and premature study drug discontinuation and withdrawal of consent were examined by multivariable logistic regression after adjusting for potential confounders in each individual trial and combining the individual point estimates in random effects models. RESULTS: After adjusting for baseline differences, women had 22% higher odds of premature drug discontinuation (adjusted odds ratio [ORadj], 1.22 [95% CI, 1.16-1.28]; P<0.001) compared with men. Qualitatively consistent results were observed for women versus men in the placebo arms (ORadj, 1.20 [95% CI, 1.13-1.27]) and active therapy arms (ORadj, 1.23 [95% CI, 1.17-1.30)]; there was some evidence for regional heterogeneity (P interaction <0.001). Of those who stopped study drug prematurely, a similar proportion of men and women in the active arm stopped because of an adverse event (36% for both; P=0.60). Women were also more likely to withdraw consent compared with men (ORadj, 1.26 [95% CI, 1.17-1.36]; P<0.001). CONCLUSIONS: Women were more likely than men to prematurely discontinue study drug and withdraw consent across cardiovascular outcome trials. Premature study drug discontinuation was not explained by baseline differences by sex or a higher proportion of adverse events. Future trials should better capture reasons for drug discontinuation and withdrawal of consent to understand barriers to continued study drug use and clinical trial participation, particularly among women.
Subject(s)
Drug Therapy/methods , Early Termination of Clinical Trials/methods , Aged , Female , Humans , Male , Middle Aged , Sex FactorsABSTRACT
BACKGROUND: People with type 2 diabetes and chronic kidney disease experience a high burden of hypertension, but the magnitude and consistency of blood pressure (BP) lowering with canagliflozin in this population are uncertain. Whether the effects of canagliflozin on kidney and cardiovascular outcomes vary by baseline BP or BP-lowering therapy is also unknown. METHODS: The CREDENCE trial (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) randomized people with type 2 diabetes and chronic kidney disease to canagliflozin or placebo. In a post hoc analysis, we investigated the effect of canagliflozin on systolic BP across subgroups defined by baseline systolic BP, number of BP-lowering drug classes, and history of apparent treatment-resistant hypertension (BP ≥130/80 mm Hg while receiving ≥3 classes of BP-lowering drugs, including a diuretic). We also assessed whether effects on clinical outcomes differed across these subgroups. RESULTS: The trial included 4401 participants, of whom 3361 (76.4%) had baseline systolic BP ≥130 mm Hg, and 1371 (31.2%) had resistant hypertension. By week 3, canagliflozin reduced systolic BP by 3.50 mm Hg (95% CI, -4.27 to -2.72), an effect maintained over the duration of the trial, with similar reductions across BP and BP-lowering therapy subgroups (all P interaction ≥0.05). Canagliflozin also reduced the need for initiation of additional BP-lowering agents during the trial (hazard ratio, 0.68 [95% CI, 0.61-0.75]). The effect of canagliflozin on kidney failure, doubling of serum creatinine, or death caused by kidney or cardiovascular disease (hazard ratio, 0.70 [95% CI, 0.59-0.82]) was consistent across BP and BP-lowering therapy subgroups (all P interaction ≥0.35), as were effects on other key kidney, cardiovascular, and safety outcomes. CONCLUSIONS: In people with type 2 diabetes and chronic kidney disease, canagliflozin lowers systolic BP across all BP-defined subgroups and reduces the need for additional BP-lowering agents. These findings support use of canagliflozin for end-organ protection and as an adjunct BP-lowering therapy in people with chronic kidney disease. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02065791.
Subject(s)
Canagliflozin/adverse effects , Diabetes Mellitus, Type 2/chemically induced , Renal Insufficiency, Chronic/chemically induced , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Diabetes Mellitus, Type 2/pathology , Female , Humans , Male , Middle Aged , Renal Insufficiency, Chronic/pathology , Sodium-Glucose Transporter 2 Inhibitors/pharmacologyABSTRACT
BACKGROUND: Genome-wide association studies have identified single-nucleotide polymorphisms that are associated with an increased risk of stroke. We sought to determine whether a genetic risk score (GRS) could identify subjects at higher risk for ischemic stroke after accounting for traditional clinical risk factors in 5 trials across the spectrum of cardiometabolic disease. METHODS: Subjects who had consented for genetic testing and who were of European ancestry from the ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation), SOLID-TIMI 52 (Stabilization of Plaques Using Darapladib), SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus), PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin), and FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk) trials were included in this analysis. A set of 32 single-nucleotide polymorphisms associated with ischemic stroke was used to calculate a GRS in each patient and identify tertiles of genetic risk. A Cox model was used to calculate hazard ratios for ischemic stroke across genetic risk groups, adjusted for clinical risk factors. RESULTS: In 51 288 subjects across the 5 trials, a total of 960 subjects had an ischemic stroke over a median follow-up period of 2.5 years. After adjusting for clinical risk factors, a higher GRS was strongly and independently associated with increased risk for ischemic stroke (P trend=0.009). In comparison with individuals in the lowest third of the GRS, individuals in the middle and top tertiles of the GRS had adjusted hazard ratios of 1.15 (95% CI, 0.98-1.36) and 1.24 (95% CI 1.05-1.45) for ischemic stroke, respectively. Stratification into subgroups revealed that the performance of the GRS appeared stronger in the primary prevention cohort with an adjusted hazard ratio for the top versus lowest tertile of 1.27 (95% CI, 1.04-1.53), in comparison with an adjusted hazard ratio of 1.06 (95% CI, 0.81-1.41) in subjects with previous stroke. In an exploratory analysis of patients with atrial fibrillation and CHA2DS2-VASc score of 2, high genetic risk conferred a 4-fold higher risk of stroke and an absolute risk equivalent to those with CHA2DS2-VASc score of 3. CONCLUSIONS: Across a broad spectrum of subjects with cardiometabolic disease, a 32-single-nucleotide polymorphism GRS was a strong, independent predictor of ischemic stroke. In patients with atrial fibrillation but lower CHA2DS2-VASc scores, the GRS identified patients with risk comparable to those with higher CHA2DS2-VASc scores.
Subject(s)
Genome-Wide Association Study/methods , Ischemic Stroke/etiology , Metabolic Syndrome/complications , Aged , Aged, 80 and over , Female , Genotyping Techniques , Humans , Ischemic Stroke/physiopathology , Male , Metabolic Syndrome/genetics , Risk Assessment , Risk FactorsABSTRACT
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 body-surface 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 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. (Funded by Janssen Research and Development; CREDENCE ClinicalTrials.gov number, NCT02065791.).