RESUMO
BACKGROUND: Reducing the levels of triglycerides and triglyceride-rich lipoproteins remains an unmet clinical need. Olezarsen is an antisense oligonucleotide targeting messenger RNA for apolipoprotein C-III (APOC3), a genetically validated target for triglyceride lowering. METHODS: In this phase 2b, randomized, controlled trial, we assigned adults either with moderate hypertriglyceridemia (triglyceride level, 150 to 499 mg per deciliter) and elevated cardiovascular risk or with severe hypertriglyceridemia (triglyceride level, ≥500 mg per deciliter) in a 1:1 ratio to either a 50-mg or 80-mg cohort. Patients were then assigned in a 3:1 ratio to receive monthly subcutaneous olezarsen or matching placebo within each cohort. The primary outcome was the percent change in the triglyceride level from baseline to 6 months, reported as the difference between each olezarsen group and placebo. Key secondary outcomes were changes in levels of APOC3, apolipoprotein B, non-high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol. RESULTS: A total of 154 patients underwent randomization at 24 sites in North America. The median age of the patients was 62 years, and the median triglyceride level was 241.5 mg per deciliter. The 50-mg and 80-mg doses of olezarsen reduced triglyceride levels by 49.3 percentage points and 53.1 percentage points, respectively, as compared with placebo (P<0.001 for both comparisons). As compared with placebo, each dose of olezarsen also significantly reduced the levels of APOC3, apolipoprotein B, and non-HDL cholesterol, with no significant change in the LDL cholesterol level. The risks of adverse events and serious adverse events were similar in the three groups. Clinically meaningful hepatic, renal, or platelet abnormalities were uncommon, with similar risks in the three groups. CONCLUSIONS: In patients with predominantly moderate hypertriglyceridemia at elevated cardiovascular risk, olezarsen significantly reduced levels of triglycerides, apolipoprotein B, and non-HDL cholesterol, with no major safety concerns identified. (Funded by Ionis Pharmaceuticals; Bridge-TIMI 73a ClinicalTrials.gov number, NCT05355402.).
Assuntos
Apolipoproteína C-III , Doenças Cardiovasculares , Hipertrigliceridemia , Oligonucleotídeos , Triglicerídeos , Humanos , Hipertrigliceridemia/tratamento farmacológico , Hipertrigliceridemia/complicações , Hipertrigliceridemia/sangue , Pessoa de Meia-Idade , Masculino , Feminino , Apolipoproteína C-III/sangue , Triglicerídeos/sangue , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/etiologia , Oligonucleotídeos/uso terapêutico , Oligonucleotídeos/efeitos adversos , Idoso , Adulto , Método Duplo-Cego , Oligonucleotídeos Antissenso/uso terapêutico , Oligonucleotídeos Antissenso/efeitos adversos , Fatores de Risco de Doenças Cardíacas , LDL-Colesterol/sangue , Hipolipemiantes/uso terapêutico , Hipolipemiantes/efeitos adversos , Apolipoproteínas B/sangueRESUMO
Importance: Dapagliflozin reduces the risk of hospitalizations for heart failure and the progression of chronic kidney disease in patients with and without type 2 diabetes (T2D), whereas the effects on reducing atherosclerotic events appear less clear. Objective: To explore whether N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hsTnT) levels can identify a subset of patients with T2D at higher risk and who might benefit more from dapagliflozin with regard to atherosclerotic events. Design, Setting, and Participants: This was a secondary analysis of the DECLARE-TIMI 58 trial, a randomized clinical trial of dapagliflozin in patients with T2D and either multiple risk factors for atherosclerotic cardiovascular disease (ASCVD; approximately 60%) or established ASCVD (approximately 40%). All patients with available blood samples at randomization were included in these analyses. Data were collected from May 2013 to September 2018, and data were analyzed from May 2019 to June 2022. Interventions: Dapagliflozin vs placebo. Main Outcomes and Measures: Major adverse cardiovascular events (MACE), the composite of myocardial infarction, ischemic stroke, or cardiovascular death, which was one of dual primary outcomes of the main trial. Results: Of 14â¯565 included patients, 9143 (62.8%) were male, and the mean (SD) age was 63.9 (6.8) years. When tested individually in a multivariable model for MACE risk, NT-proBNP and hsTnT were each significantly associated with the risk of MACE (adjusted hazard ratio [aHR] per 1 SD in log-transformed biomarker: NT-proBNP, 1.62; 95% CI, 1.49-1.76; hsTnT: 1.59; 95% CI, 1.46-1.74). The magnitude of the association was similar in patients with ASCVD (NT-proBNP: aHR, 1.60; 95% CI, 1.45-1.77; hsTnT: aHR, 1.62; 95% CI, 1.45-1.81) and multiple risk factors for ASCVD (NT-proBNP: aHR, 1.62; 95% CI, 1.40-1.88; hsTnT: aHR, 1.51; 95% CI, 1.29-1.77). Moreover, both biomarkers remained independently associated with MACE when both were included in the multivariable model (NT-proBNP: aHR, 1.46; 95% CI, 1.34-1.60; hsTnT: aHR, 1.39; 95% CI, 1.26-1.53). Modeled as a continuous variable, baseline biomarker levels did not modify the relative treatment effect of dapagliflozin vs placebo with MACE. However, the relative risk reduction numerically grew with higher biomarker levels, as did the baseline risk. Thus, MACE event rates were nominally lower in dapagliflozin-treated vs placebo-treated patients with biomarker concentrations in the top quartile (NT-proBNP: HR, 0.83; 95% CI, 0.71-0.97; absolute risk reduction [ARR], 2.4%; hsTnT: HR, 0.85; 95% CI, 0.72-0.99; ARR, 2.7%), whereas there was no significant treatment effect in patients with biomarkers levels in quartiles 1 to 3 (NT-proBNP: HR, 1.02; 95% CI, 0.88-1.18; ARR, 0%; hsTnT: HR, 0.97; 95% CI, 0.84-1.13; ARR, 0.2%). Conclusions and Relevance: In this study, NT-proBNP and hsTnT levels were associated with the risk for future cardiovascular events in both primary and secondary prevention patients with T2D. Both cardiac biomarkers were helpful to identify patients at very high risk for atherosclerotic events that may derive reduction in risk of MACE with dapagliflozin. Trial Registration: ClinicalTrials.gov Identifier: NCT01730534.
Assuntos
Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Fatores de Risco , Biomarcadores , Insuficiência Cardíaca/complicaçõesRESUMO
BACKGROUND: In people with type 2 diabetes at high risk of cardiovascular or kidney disease, sodium-glucose co-transporter 2 (SGLT2) inhibitors consistently reduce the risk of hospitalisations for heart failure. Less is known about their effects on hospitalisation from any cause, especially in people with type 2 diabetes without atherosclerotic cardiovascular disease, which includes most of the global population of people with type 2 diabetes. We aimed to assess the effect of the SGLT2 inhibitor, dapagliflozin, on the risks of hospitalisations for any cause and for specific causes in people with type 2 diabetes with and without atherosclerotic cardiovascular disease. METHODS: The DECLARE-TIMI 58 trial was a double-blind, multicentre, randomised, placebo-controlled study. People with type 2 diabetes and either risk factors for or established atherosclerotic cardiovascular disease were randomly assigned (1:1) to receive oral dapagliflozin 10 mg or placebo once daily. In these post-hoc analyses, the effects of dapagliflozin on risks of first non-elective any-cause and cause-specific hospitalisation were assessed with Cox proportional hazards regression models overall and in the subset of participants without prevalent atherosclerotic cardiovascular disease. The risk of total (first plus subsequent) non-elective hospitalisations was assessed with Lin-Wei-Ying-Yang model. Investigator-reported System Organ Class terms were used to classify cause-specific hospitalisations. The trial is registered with ClinicalTrials.gov, NCT01730534. FINDINGS: Between April 25, 2013, and Sept 18, 2018, 17 160 people (6422 [37·4%] women, 10 738 [62·6%] men; mean age 63·9 years [SD 6·8]) were enrolled in the original trial, of whom 10186 (59·4%) had multiple risk factors for but did not have established atherosclerotic cardiovascular disease, and 6835 (39·8%) had both no evidence of atherosclerotic cardiovascular disease and low KDIGO risk. Over a median follow-up of 4·2 years (IQR 3·9-4·4), dapagliflozin was associated with a lower risk of first non-elective hospitalisation for any cause (2779 [32·4%] of 8582 people in the dapagliflozin group vs 3036 [35·4%] of 8578 people in the placebo group; hazard ratio [HR] 0·89 [95% CI 0·85-0·94]) and total (first plus subsequent) non-elective hospitalisations for any cause (risk ratio 0·92 [95% CI 0·86-0·97]). The association between dapagliflozin use and the risk of first non-elective hospitalisation for any cause was consistent in subgroups of participants with (HR 0·92 [95% CI 0·85-0·99] and without (0·87 [0·81-0·94]) atherosclerotic cardiovascular disease at baseline (p interaction=0·31). Compared with the placebo group, the dapagliflozin group had lower risk of first hospitalisations due to cardiac disorders (HR 0·91 [95% CI 0·84-1·00]), metabolism and nutrition disorders (0·73 [0·60-0·89]), renal and urinary disorders (0·61 [0·49-0·77]), and due to any other cause excluding these three causes (0·90 [0·85-0·96]). Treatment with dapagliflozin was also associated with a lower risk of hospitalisations due to musculoskeletal and connective tissue disorders (HR 0·81 [0·67-0·99]) and infections and infastations (HR 0·86 [0·78-0·96]). INTERPRETATION: Dapagliflozin reduced the risk of first and total non-elective hospitalisations for any cause in people with type 2 diabetes, regardless of the presence of atherosclerotic cardiovascular disease, including hospitalisations not directly attributed to cardiac, kidney, or metabolic causes. These findings might have implications on health-related quality of life for people with type 2 diabetes and on health-care costs attributable this condition. FUNDING: AstraZeneca.
Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Inibidores do Transportador 2 de Sódio-Glicose , Masculino , Humanos , Feminino , Pessoa de Meia-Idade , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/induzido quimicamente , Qualidade de Vida , Compostos Benzidrílicos/uso terapêutico , Hospitalização , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêuticoRESUMO
BACKGROUND: The pathobiology of inflammation, thrombosis, and myocardial injury associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) may be assessed by circulating biomarkers. However, their relative prognostic importance has been incompletely described. METHODS: We analyzed data from patients hospitalized with COVID-19 from January 2020, to April 2021, at 122 US hospitals in the American Heart Association (AHA) COVID-19 cardiovascular (CV) disease registry. Patients with data for D-dimer, C-reactive protein (CRP), ferritin, natriuretic peptides [NP], or cardiac troponin (cTn) at admission were included. cTn quintiles were indexed to the assay-specific 99th percentile reference limits. Using multivariable logistic regression, we assessed the association between each biomarker by quintile [Q] and odds of in-hospital death and a cardiovascular and thrombotic composite outcome. RESULTS: Of 32,636 registry patients, 26,424 (81%) had admission values for ≥1 of the key biomarkers, of which 4,527 (17%) had admission values for all 5 biomarkers. Each biomarker revealed a significant gradient for in-hospital mortality from Q1 to Q5: D-dimer 14% to 35%, CRP 11%-32%, ferritin 11% to 30%, cTn 13% to 43%, and NPs 7% to 35% (Ptrend for each <.001). After adjustment for other biomarkers and clinical variables, Q5 for NPs (OR:4.67, 95% CI: 3.05-7.14) retained the greatest relative odds for death; cTn (OR:2.68, 95% CI: 2.00-3.59) and NPs (OR:7.14, 95% CI: 4.92-10.37) were associated with the greatest odds of the CV composite. Q5 for D-dimer was associated with the highest risk of thrombotic events (OR: 9.02, 95% CI: 5.36-15.18). CONCLUSIONS: Among patients hospitalized with COVID-19, cTn and NPs identified patients at high risk for an in-hospital adverse cardiovascular outcome, while elevations in D-dimer identified patients at risk for thrombotic complications.
Assuntos
COVID-19 , Doenças Cardiovasculares , Humanos , COVID-19/complicações , Doenças Cardiovasculares/epidemiologia , SARS-CoV-2 , Mortalidade Hospitalar , American Heart Association , RNA Viral , Biomarcadores , Proteína C-Reativa , Medição de Risco , Sistema de Registros , FerritinasRESUMO
OBJECTIVE: The cardiorenal benefits of adding sodium-glucose cotransporter 2 (SGLT2) inhibitor therapy for patients on insulin, particularly those on intensive regimens that include short-acting (SA) insulin, have not been explored. RESEARCH DESIGN AND METHODS: In Dapagliflozin Effect on Cardiovascular Events trial (DECLARE-TIMI 58), 17,160 patients with type 2 diabetes were randomized to dapagliflozin or placebo for a median follow-up of 4.2 years. Cardiovascular (CV), renal, metabolic, and safety outcomes with dapagliflozin versus placebo by insulin dose and regimen were studied with Cox regression models. RESULTS: The study included 7,013 insulin users at baseline, with 4,650 (66.3%) patients on regimens including SA insulin. Insulin doses varied, with 2,443 (34.8%) patients receiving <0.5 IU/kg, 2,795 (39.9%) 0.5 to ≤1 IU/kg, and 1,339 (19.1%) >1 IU/kg. Dapagliflozin reduced CV death/hospitalization for heart failure among overall insulin users (hazard ratio [HR] 0.82 [95% CI 0.69-0.97]) and consistently in patients on insulin regimens with or without SA insulin (0.83 [0.67-1.03] and 0.78 [0.57-1.07], respectively, Pinteraction = 0.75). No heterogeneity was observed by insulin dose (Pinteraction = 0.43). The HR for major adverse CV events with dapagliflozin among insulin users (0.84 [0.74-0.97]) was similar irrespective of regimen or dose (Pinteraction = 0.75 and 0.07). Dapagliflozin reduced the rate of adverse renal outcomes overall and consistently across subgroups of insulin users. Decreases in HbA1c, weight, and systolic blood pressure with dapagliflozin were seen regardless of insulin dose or regimen. The known safety profile of dapagliflozin was unchanged in patients on intensive insulin regimens. CONCLUSIONS: The benefits and safety of dapagliflozin were maintained in high-risk patients receiving high-dose or intensive insulin regimens including SA insulin.
Assuntos
Diabetes Mellitus Tipo 2 , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Insulina/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Glucosídeos/efeitos adversos , Compostos Benzidrílicos/efeitos adversos , Insulina Regular Humana/uso terapêuticoRESUMO
OBJECTIVE: In patients with moderate to severe albuminuric kidney disease, sodium-glucose cotransporter 2 inhibitors reduce the risk of kidney disease progression. These post hoc analyses assess the effects of dapagliflozin on kidney function decline in patients with type 2 diabetes (T2D), focusing on populations with low kidney risk. RESEARCH DESIGN AND METHODS: In the Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial, patients with T2D at high cardiovascular risk were randomly assigned to dapagliflozin versus placebo. Outcomes were analyzed by treatment arms, overall, and by Kidney Disease: Improving Global Outcomes (KDIGO) risk categories. The prespecified kidney-specific composite outcome was a sustained decline ≥40% in the estimated glomerular filtration rate (eGFR) to <60 mL/min/1.73 m2, end-stage kidney disease, and kidney-related death. Other outcomes included incidence of categorical eGFR decline of different thresholds and chronic (6 month to 4 year) or total (baseline to 4 year) eGFR slopes. RESULTS: Most participants were in the low-moderate KDIGO risk categories (n = 15,201 [90.3%]). The hazard for the kidney-specific composite outcome was lower with dapagliflozin across all KDIGO risk categories (P-interaction = 0.97), including those at low risk (hazard ratio [HR] 0.54, 95% CI 0.38-0.77). Risks for categorical eGFR reductions (≥57% [in those with baseline eGFR ≥60 mL/min/1.73 m2], ≥50%, ≥40%, and ≥30%) were lower with dapagliflozin (HRs 0.52, 0.57, 0.55, and 0.70, respectively; P < 0.05). Slopes of eGFR decline favored dapagliflozin across KDIGO risk categories, including the low KDIGO risk (between-arm differences of 0.87 [chronic] and 0.55 [total] mL/min/1.73 m2/year; P < 0.0001). CONCLUSIONS: Dapagliflozin mitigated kidney function decline in patients with T2D at high cardiovascular risk, including those with low KDIGO risk, suggesting a role of dapagliflozin in the early prevention of diabetic kidney disease.
Assuntos
Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Infarto do Miocárdio , Inibidores do Transportador 2 de Sódio-Glicose , Compostos Benzidrílicos/farmacologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/etiologia , Taxa de Filtração Glomerular , Glucose/farmacologia , Glucosídeos , Humanos , Infarto do Miocárdio/complicações , Sódio , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversosRESUMO
BACKGROUND: Heart failure (HF) is a growing public health problem and ischemic heart disease is an important risk factor. Understanding the epidemiology of HF in patients with atherosclerosis may help identify subgroups at greater risk who have the potential to derive greater benefit from preventive strategies. METHODS AND RESULTS: The TRA 2°P-TIMI 50 trial randomized 26,449 patients with stable atherosclerosis to the antiplatelet agent vorapaxar versus placebo. Hospitalization for HF (HHF) endpoints were adjudicated from serious adverse events by blinded structured review using established definitions. HHF incidence was estimated using Kaplan-Meier analysis. Independent predictors of HHF risk were identified using multivariable logistic regression. The effect of vorapaxar on HHF risk was explored using Cox regression. The estimated incidence of HHF at 3 years was 1.6%. Independent predictors of HHF included prior HF (adjusted odds ratio [adj-OR]: 8.31; 95% confidence interval [CI]: 6.56-10.54), age (adj-OR [per 10 years]: 1.67; 95% CI: 1.47-1.89), type 2 diabetes mellitus (T2DM; adj-OR: 2.55; 95% CI: 2.01-3.24), polyvascular disease (two-territory disease, adj-OR: 1.89; 95% CI: 1.46-2.44; three-territory disease, adj-OR: 2.68; 95% CI: 1.94-3.70), chronic kidney disease (CKD; adj-OR: 1.65; 95% CI: 1.30-2.11), body mass index (BMI; adj-OR [per 5 kg/m2 ]: 1.15; 95% CI: 1.03-1.27), prior myocardial infarction (MI) (adj-OR: 1.35; 95% CI: 1.03-1.78), and hypertension (adj-OR: 1.44; 95% CI: 1.02-2.04). Patients who experienced HHF during follow-up had higher rates of subsequent rehospitalization and death. Vorapaxar did not modify the risk of HHF. CONCLUSIONS: In patients with stable atherosclerosis, prior HF, age, T2DM, polyvascular disease, CKD, BMI, prior MI, and hypertension are important predictors of HHF risk.
Assuntos
Aterosclerose , Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Hipertensão , Infarto do Miocárdio , Insuficiência Renal Crônica , Aterosclerose/epidemiologia , Criança , Pré-Escolar , Diabetes Mellitus Tipo 2/tratamento farmacológico , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/epidemiologia , Hospitalização , Humanos , Infarto do Miocárdio/epidemiologia , Fatores de Risco , Resultado do TratamentoRESUMO
Importance: Dapagliflozin was shown to reduce the cardiovascular (CV) and kidney outcomes in patients with type 2 diabetes. However, data are limited on the relationship of the effect and safety with the concurrent use of CV medications in patients with type 2 diabetes. Objective: To assess whether the cardiorenal efficacy and safety of dapagliflozin were consistent with and without background use of CV medications commonly used for heart failure (HF) and kidney disease in patients with type 2 diabetes. Design, Setting, and Participants: This study is a prespecified secondary analysis of DECLARE-TIMI 58, which was a randomized trial of dapagliflozin vs placebo in 17â¯160 patients with type 2 diabetes and either atherosclerotic disease or multiple risk factors for CV disease. Patients were stratified by baseline use of the following CV medications: angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers (ACEI/ARBs), ß-blockers, diuretics, and mineralocorticoid receptor antagonists (MRAs). The study was conducted from May 2013 to September 2018, and data were evaluated for this analysis from February 2021 to May 2022. Interventions: Dapagliflozin or placebo. Main Outcomes and Measures: The outcomes of interest were the composite of CV death or hospitalization for HF (HHF), HHF alone, and a kidney-specific composite outcome (persistent ≥40% decrease in estimated glomerular filtration rate [eGFR], end-stage kidney disease, or kidney-related death). Results: Among 17â¯160 patients, 13â¯950 (81%) used ACEI/ARBs, 9030 (53%) used ß-blockers, 6205 (36%) used diuretics, and 762 (4%) used MRAs at baseline. Changes in blood pressure and eGFR at 48 months with dapagliflozin compared with placebo did not differ regardless of concurrent therapy (placebo-corrected change, -1.6 mm Hg [95% CI, -4.2 to 1.0] to -2.6 mm Hg [95% CI, -3.3 to -2.9]; P > .05 for each interaction). Dapagliflozin consistently reduced the risk of CV death/HHF, HHF alone, and the kidney-specific composite outcome regardless of background use of selected medications (hazard ratio [HR] range: HR, 0.50; 95% CI, 0.39-0.63; to HR, 0.82; 95% CI, 0.72-0.95; P > .05 for each interaction). In patients receiving ACEI/ARBs + ß-blockers + diuretics (n = 4243), dapagliflozin reduced the risk of CV death/HHF and of the kidney-specific outcome by 24% (HR, 0.76; 95% CI, 0.62-0.93) and 38% (HR, 0.62; 95% CI, 0.44-0.87), respectively. There were no significant treatment interactions with the concomitant CV medications for adverse events of volume depletion, acute kidney injury, or hyperkalemia (range: HR, 0.12; 95% CI, 0.02-0.99; to HR, 1.04; 95% CI, 0.83-1.32; P > .05 for each interaction). Conclusions and Relevance: Dapagliflozin consistently reduced the risk of CV and kidney outcomes irrespective of background use of various CV medications without any treatment interaction for key safety events. These data show the clinical benefit and safety of dapagliflozin in a broad range of patients with type 2 diabetes regardless of background therapy. Trial Registration: ClinicalTrials.gov Identifier: NCT01730534.
Assuntos
Fármacos Cardiovasculares , Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Compostos Benzidrílicos , Fármacos Cardiovasculares/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diuréticos/uso terapêutico , Glucosídeos , Insuficiência Cardíaca/tratamento farmacológico , HumanosRESUMO
BACKGROUND: Dapagliflozin improved heart failure and kidney outcomes in patients with type 2 diabetes (T2DM) with or at high risk for atherosclerotic cardiovascular disease in the DECLARE-TIMI 58 trial (Dapagliflozin Effect on Cardiovascular Events - Thrombolysis in Myocardial Infarction 58). Here, the aim was to analyze the efficacy and safety of dapagliflozin stratified according to baseline systolic blood pressure (SBP). METHODS: The DECLARE-TIMI 58 trial randomly assigned patients with T2DM and either previous atherosclerotic cardiovascular disease or atherosclerotic cardiovascular disease risk factors to dapagliflozin or placebo. Patients were categorized by baseline SBP levels: <120, 120 to 129, 130 to 139, 140 to 159, and ≥160 mm Hg (normal, elevated, stage 1, stage 2, and severe hypertension, respectively). Efficacy outcomes of interest were hospitalization for heart failure and a renal-specific composite outcome (sustained decrease in estimated glomerular filtration rate by 40%, progression to end-stage renal disease, or renal death). Safety outcomes included symptoms of volume depletion, lower extremity amputations, and acute kidney injury. RESULTS: The trial comprised 17 160 patients; mean age, 64.0±6.8 years; 37.4% women; median duration of T2DM, 11 years; 40.6% with prevalent cardiovascular disease. Overall, dapagliflozin reduced SBP by 2.4 mm Hg (95% CI, 1.9-2.9; P<0.0001) compared with placebo at 48 months. The beneficial effects of dapagliflozin on hospitalization for heart failure and renal outcomes were consistent across all baseline SBP categories, with no evidence of modification of treatment effect (Pinteractions=0.28 and 0.52, respectively). Among normotensive patients, the hazard ratios were 0.66 (95% CI, 0.42-1.05) and 0.39 (95% CI, 0.19-0.78), respectively, for hospitalization for heart failure and the renal-specific outcome. Events of volume depletion, amputation, and acute kidney injury did not differ with dapagliflozin overall or within any baseline SBP group. CONCLUSIONS: In patients with T2DM with or at high atherosclerotic cardiovascular disease risk, dapagliflozin reduced risk for hospitalization for heart failure and renal outcomes regardless of baseline SBP, with no difference in adverse events of interest at any level of baseline SBP. These results indicate that dapagliflozin provides cardiorenal benefits in patients with T2DM at high atherosclerotic cardiovascular disease risk independent of baseline blood pressure. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01730534.
Assuntos
Injúria Renal Aguda , Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Infarto do Miocárdio , Inibidores do Transportador 2 de Sódio-Glicose , Injúria Renal Aguda/induzido quimicamente , Idoso , Compostos Benzidrílicos/efeitos adversos , Pressão Sanguínea , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Glucosídeos , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêuticoRESUMO
Background Early reports from the COVID-19 pandemic identified coronary thrombosis leading to ST-segment-elevation myocardial infarction (STEMI) as a complication of COVID-19 infection. However, the epidemiology of STEMI in patients with COVID-19 is not well characterized. We sought to determine the incidence, diagnostic and therapeutic approaches, and outcomes in STEMI patients hospitalized for COVID-19. Methods and Results Patients with data on presentation ECG and in-hospital myocardial infarction were identified from January 14, 2020 to November 30, 2020, from 105 sites participating in the American Heart Association COVID-19 Cardiovascular Disease Registry. Patient characteristics, resource use, and clinical outcomes were summarized and compared based on the presence or absence of STEMI. Among 15 621 COVID-19 hospitalizations, 54 (0.35%) patients experienced in-hospital STEMI. Among patients with STEMI, the majority (n=40, 74%) underwent transthoracic echocardiography, but only half (n=27, 50%) underwent coronary angiography. Half of all patients with COVID-19 and STEMI (n=27, 50%) did not undergo any form of primary reperfusion therapy. Rates of all-cause shock (47% versus 14%), cardiac arrest (22% versus 4.8%), new heart failure (17% versus 1.4%), and need for new renal replacement therapy (11% versus 4.3%) were multifold higher in patients with STEMI compared with those without STEMI (P<0.050 for all). Rates of in-hospital death were 41% in patients with STEMI, compared with 16% in those without STEMI (P<0.001). Conclusions STEMI in hospitalized patients with COVID-19 is rare but associated with poor in-hospital outcomes. Rates of coronary angiography and primary reperfusion were low in this population of patients with STEMI and COVID-19. Adaptations of systems of care to ensure timely contemporary treatment for this population are needed.
Assuntos
COVID-19 , Doenças Cardiovasculares , Infarto do Miocárdio , Infarto do Miocárdio com Supradesnível do Segmento ST , American Heart Association , COVID-19/epidemiologia , COVID-19/terapia , Doenças Cardiovasculares/epidemiologia , Mortalidade Hospitalar , Humanos , Infarto do Miocárdio/epidemiologia , Pandemias , Sistema de Registros , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/epidemiologia , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Estados Unidos/epidemiologiaRESUMO
OBJECTIVE: Current guidelines recommend prescribing SGLT2 inhibitors to patients with type 2 diabetes and established or at high risk for atherosclerotic cardiovascular disease (ASCVD), irrespective of HbA1c levels. We studied the association of HbA1c with cardiovascular and renal outcomes and whether the benefit of dapagliflozin varies by baseline HbA1c. RESEARCH DESIGN AND METHODS: In the Dapagliflozin Effect on Cardiovascular Events trial (DECLARE-TIMI 58), 17,160 patients with type 2 diabetes were randomly assigned to dapagliflozin or placebo for a median follow-up of 4.2 years. Cardiovascular and renal outcomes by baseline HbA1c in the overall population and with dapagliflozin versus placebo in HbA1c subgroups were studied by Cox regression models. RESULTS: In the overall population, higher baseline HbA1c was associated with a higher risk of cardiovascular death or hospitalization for heart failure (HHF); major adverse cardiovascular events (MACE), including cardiovascular death, myocardial infarction, and ischemic stroke; and cardiorenal outcomes (adjusted hazard ratios 1.12 [95% CI 1.06-1.19], 1.08 [1.04-1.13], and 1.17 [1.11-1.24] per 1% higher level, respectively). Elevated HbA1c was associated with a greater increased risk for MACE and cardiorenal outcomes in patients with multiple risk factors (MRF) than in established ASCVD (P-interaction = 0.0064 and 0.0093, respectively). Compared with placebo, dapagliflozin decreased the risk of cardiovascular death/HHF, HHF, and cardiorenal outcomes, with no heterogeneity by baseline HbA1c (P-interaction > 0.05). CONCLUSIONS: Higher HbA1c levels were associated with greater cardiovascular and renal risk, particularly in the MRF population, yet the benefits of dapagliflozin were observed in all subgroups irrespective of baseline HbA1c, including patients with HbA1c <7%.
Assuntos
Doenças Cardiovasculares , Sistema Cardiovascular , Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Inibidores do Transportador 2 de Sódio-Glicose , Compostos Benzidrílicos , Doenças Cardiovasculares/complicações , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hemoglobinas Glicadas , Insuficiência Cardíaca/complicações , Humanos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêuticoRESUMO
AIMS: Ceramide (Cer) and phosphatidylcholine (PC) lipids are associated with pathophysiological processes in cardiovascular (CV) diseases. A previously derived and validated plasma Cer-PC risk score (CERT2) was associated with CV death risk in patients with stable disease, but its prognostic value has not been evaluated in patients early post-acute coronary syndrome (ACS). METHODS AND RESULTS: Prespecified plasma Cer and PC species in the CERT2 risk score were measured in 4871 subjects from SOLID-TIMI 52, which enrolled patients ≤30 days after ACS (median follow-up 2.5 years). The CERT2 score (scale 0-12 points) was calculated as previously defined. The primary outcome was CV death; Coronary heart disease death, all-cause death, hospitalization for heart failure (HF), myocardial infarction (MI) and stroke were also analyzed. Poisson models included baseline characteristics and established biomarkers. Patients with higher CERT2 risk scores were more likely to be older, female, current smokers, presenting with STEMI, and to have impaired renal function and higher LDL-C. After multivariable adjustment, patients in the highest risk score category remained at a nearly two-fold higher risk of CV death (adj relative risk [RR] 1.92, 95% CI 1.01-3.66, P = 0.047). Patients in the highest risk score category were also at higher risk of all-cause death (adj RR 2.01, 95% CI 1.21-3.35, P = 0.007), whereas the relationships with HF, MI, and stroke were attenuated with multivariable adjustment. CONCLUSIONS: A plasma ceramide and phospholipid-based risk score is associated with the risk of CV death independent of established clinical risk factors and biomarkers in patients after ACS.
Assuntos
Síndrome Coronariana Aguda , Insuficiência Cardíaca , Infarto do Miocárdio , Acidente Vascular Cerebral , Síndrome Coronariana Aguda/diagnóstico , Biomarcadores , Ceramidas , Feminino , Insuficiência Cardíaca/diagnóstico , Humanos , Fosfolipídeos , Fatores de RiscoAssuntos
COVID-19/complicações , Doenças Cardiovasculares/epidemiologia , Sistema de Registros/estatística & dados numéricos , Choque Cardiogênico/epidemiologia , Idoso , American Heart Association , Doenças Cardiovasculares/complicações , Feminino , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/mortalidade , Mortalidade Hospitalar , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/patogenicidade , Choque Cardiogênico/complicações , Estados UnidosRESUMO
Background Patients with peripheral artery disease are at increased risk of both major adverse cardiovascular events (MACEs) and limb events. The pathobiology of limb events is likely multifactorial. Observational studies suggest a benefit of statin therapy for reducing the risk of limb ischemic events while randomized trials demonstrate a benefit with more potent antithrombotic therapies, particularly those targeting thrombin. Whether the effects of these therapeutic pathways are independent and complementary is not known. Methods and Results The TRA 2°P-TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events-Thrombolysis in Myocardial Infarction 50) trial demonstrated that vorapaxar significantly reduced MACEs and limb events. The purpose of the current analysis was to evaluate the association of statin use and intensity and the occurrence of MACEs and limb events in 5845 patients with symptomatic peripheral artery disease randomized in TRA 2°P-TIMI 50 and then to understand whether statin use modified the benefits of vorapaxar for MACEs or limb ischemic events. We found that statin therapy was associated with significantly lower risk of MACEs (hazard ratio [HR], 0.77; 95% CI, 0.66-0.89; P<0.001) and limb ischemic events (HR, 0.73; 95% CI, 0.60-0.89; P=0.002). The benefit of vorapaxar for reducing MACEs and limb events was consistent regardless of background statin (P-interaction=0.715 and 0.073, respectively). Event rates were lowest in patients receiving the combination of statin therapy and vorapaxar. Conclusions In conclusion, statin use and intensity is associated with significantly lower rates of MACEs and limb ischemic events. Thrombin inhibition with vorapaxar is effective regardless of background statin therapy. These results suggest that targeting both lipid and thrombotic risk in peripheral artery disease is necessary in order to optimize outcomes.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Doença Arterial Periférica , Acidente Vascular Cerebral , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Isquemia , Lactonas/efeitos adversos , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/tratamento farmacológico , Inibidores da Agregação Plaquetária/efeitos adversos , Piridinas , Trombina , Resultado do TratamentoRESUMO
OBJECTIVE: Heart failure (HF) is an impactful complication of type 2 diabetes mellitus (T2DM). We aimed to develop and validate a risk score for hospitalization for HF (HHF) incorporating biomarkers and clinical factor(s) in patients with T2DM. RESEARCH DESIGN AND METHODS: We derived a risk score for HHF using clinical data, high-sensitivity troponin T (hsTnT), and N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) from 6,106 placebo-treated patients with T2DM in SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53). Candidate variables were assessed using Cox regression. The strongest indicators of HHF risk were included in the score using integer weights. The score was externally validated in 7,251 placebo-treated patients in DECLARE-TIMI 58 (Dapagliflozin Effect on CardiovascuLAR Events-Thrombolysis in Myocardial Infarction 58). The effect of dapagliflozin on HHF was assessed by risk category in DECLARE-TIMI 58. RESULTS: The strongest indicators of HHF risk were NT-proBNP, prior HF, and hsTnT (each P < 0.001). A risk score using these three variables identified a gradient of HHF risk (P-trend <0.001) in the derivation and validation cohorts, with C-indices of 0.87 (95% CI, 0.84-0.89) and 0.84 (0.81-0.86), respectively. Whereas there was no significant effect of dapagliflozin versus placebo on HHF in the low-risk group (hazard ratio [HR] 0.98 [95% CI 0.50-1.92]), dapagliflozin significantly reduced HHF in the intermediate-, high-, and very-high-risk groups (HR 0.64 [0.43-0.95], 0.63 [0.43-0.94], and 0.72 [0.54-0.96], respectively). Correspondingly, absolute risk reductions (95% CI) increased across these latter 3 groups: 1.0% (0.0-1.9), 3.0% (0.7-5.3), and 4.4% (-0.2 to 8.9) (P-trend <0.001). CONCLUSIONS: We developed and validated a risk score for HHF in T2DM that incorporated NT-proBNP, prior HF, and hsTnT. The risk score identifies patients at higher risk of HHF who derive greater absolute benefit from dapagliflozin.
Assuntos
Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Hospitalização , Medição de Risco/métodos , Biomarcadores , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Fatores de RiscoRESUMO
OBJECTIVE: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve albuminuria in patients with high cardiorenal risk. We report albuminuria change in the Dapagliflozin Effect on Cardiovascular Events (DECLARE-TIMI 58) cardiovascular outcome trial, which included populations with lower cardiorenal risk. RESEARCH DESIGN AND METHODS: DECLARE-TIMI 58 randomized 17,160 patients with type 2 diabetes, creatinine clearance >60 mL/min, and either atherosclerotic cardiovascular disease (CVD; 40.6%) or risk-factors for CVD (59.4%) to dapagliflozin or placebo. Urinary albumin-to-creatinine ratio (UACR) was tested at baseline, 6 months, 12 months, and yearly thereafter. The change in UACR over time was measured as a continuous and categorical variable (≤15, >15 to <30, ≥30 to ≤300, and >300 mg/g) by treatment arm. The composite cardiorenal outcome was a ≥40% sustained decline in the estimated glomerular filtration rate (eGFR) to <60 mL/min/1.73 m2, end-stage kidney disease, and cardiovascular or renal death; specific renal outcome included all except cardiovascular death. RESULTS: Baseline UACR was available for 16,843 (98.15%) participants: 9,067 (53.83%) with ≤15 mg/g, 2,577 (15.30%) with >15 to <30 mg/g, 4,030 (23.93%) with 30-300 mg/g, and 1,169 (6.94%) with >300 mg/g. Measured as a continuous variable, UACR improved from baseline to 4.0 years with dapagliflozin, compared with placebo, across all UACR and eGFR categories (all P < 0.0001). Sustained confirmed ≥1 category improvement in UACR was more common in dapagliflozin versus placebo (hazard ratio 1.45 [95% CI 1.35-1.56], P < 0.0001). Cardiorenal outcome was reduced with dapagliflozin for subgroups of UACR ≥30 mg/g (P < 0.0125, P interaction = 0.033), and the renal-specific outcome was reduced for all UACR subgroups (P < 0.05, P interaction = 0.480). CONCLUSIONS: In DECLARE-TIMI 58, dapagliflozin demonstrated a favorable effect on UACR and renal-specific outcome across baseline UACR categories, including patients with normal albumin excretion. The results suggest a role for SGLT2i also in the primary prevention of diabetic kidney disease.
Assuntos
Diabetes Mellitus Tipo 2 , Inibidores do Transportador 2 de Sódio-Glicose , Albuminúria/tratamento farmacológico , Compostos Benzidrílicos/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Taxa de Filtração Glomerular , Glucosídeos/uso terapêutico , Humanos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêuticoRESUMO
Background Patients with stable atherothrombotic disease vary in their risk of developing heart failure (HF). Circulating cardiovascular biomarkers may improve HF risk assessment and identify patients who may benefit from emerging HF preventive therapies. Methods and Results We measured high-sensitivity cardiac troponin I and BNP (B-type natriuretic peptide) in 15 833 patients with prior myocardial infarction, ischemic stroke, or peripheral artery disease from the TRA 2°P-TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events-Thrombolysis in Myocardial Infarction 50) trial, excluding patients with recent myocardial infarction (<30 days). Biomarkers were categorized using a priori cut points. Hospitalization for HF (HHF) end points were adjudicated with blinded structured review of serious adverse events. Associations between biomarkers and HHF outcomes were adjusted for sex and independent clinical risk predictors of HHF in our cohort (age ≥75, prior HF, type 2 diabetes mellitus, polyvascular disease, body mass index, anemia, chronic kidney disease, hypertension). Baseline high-sensitivity cardiac troponin I and BNP each identified a significant graded risk of HHF independent of clinical risk predictors, including in the subgroups of patients with and without type 2 diabetes mellitus and with and without prior HF. Patients with both high-sensitivity cardiac troponin I ≥5 ng/L and BNP ≥100 pg/mL had the highest HHF event rates. When added to a multivariable Cox regression model with clinical risk predictors (C-index 0.88; 95% CI, 0.85-0.90), BNP (C -index 0.92; 95% CI, 0.90-0.93), and high-sensitivity cardiac troponin I (C-index 0.90; 95% CI, 0.88-0.92) each significantly improved the prognostic performance of the model (both PLRT<0.001). Conclusions Biomarkers of myocardial injury and hemodynamic stress are independent predictors of HHF risk in patients with stable atherothrombotic disease, with and without prior HF and/or type 2 diabetes mellitus. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT00526474.
Assuntos
Aterosclerose/complicações , Insuficiência Cardíaca/sangue , Infarto do Miocárdio/complicações , Peptídeo Natriurético Encefálico/sangue , Prevenção Secundária/métodos , Trombose/complicações , Troponina I/sangue , Idoso , Aterosclerose/sangue , Biomarcadores/sangue , Feminino , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/prevenção & controle , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Infarto do Miocárdio/terapia , Fatores de Risco , Terapia Trombolítica/métodos , Trombose/sangueRESUMO
Importance: Sodium-glucose cotransporter 2 inhibitors, such as dapagliflozin, promote renal glucose excretion and reduce cardiovascular (CV) deaths and hospitalizations for heart failure (HHF) among patients with type 2 diabetes. The relative CV efficacy and safety of dapagliflozin according to baseline kidney function and albuminuria status are unknown. Objective: To assess the CV efficacy and safety of dapagliflozin according to baseline estimated glomerular filtration rate (eGFR) and urinary albumin to creatinine ratio (UACR). Design, Setting, and Participants: This secondary analysis of the randomized clinical trial Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 compared dapagliflozin vs placebo in 17â¯160 patients with type 2 diabetes and a baseline creatinine clearance of 60 mL/min or higher. Patients were categorized according to prespecified subgroups of baseline eGFR (<60 vs ≥60 mL/min/1.73 m2), urinary albumin to creatinine ratio (UACR; <30 vs ≥30 mg/g), and of chronic kidney disease (CKD) markers using these subgroups (0, 1, or 2). The study was conducted from May 2013 to September 2018. Interventions: Dapagliflozin vs placebo. Main Outcomes and Measures: The dual primary end points were major adverse cardiovascular events (myocardial infarction, stroke, and CV death) and the composite of CV death or HHF. Results: At baseline, 1265 patients (7.4%) had an eGFR below 60 mL/min/1.73 m2, and 5199 patients (30.9%) had albuminuria. Among patients having data for both eGFR and UACR, 10â¯958 patients (65.1%) had an eGFR equal to or higher than 60 mL/min/1.73 m2 and an UACR below 30 mg/g (mean [SD] age, 63.7 [6.7] years; 40.1% women), 5336 patients (31.7%) had either an eGFR below 60 mL/min/1.73 m2 or albuminuria (mean [SD] age, 64.1 [7.1] years; 32.6% women), and 548 patients (3.3%) had both (mean [SD] age, 66.8 [6.9] years; 30.5% women). In the placebo group, patients with more CKD markers had higher event rates at 4 years as assessed using the Kaplan-Meier approach for the composite of CV death or HHF (3.9% for 0 markers, 8.3% for 1 marker, and 17.4% for 2 markers) and major adverse cardiovascular events (7.5% for 0 markers, 11.6% for 1 marker, and 18.9% for 2 markers). Estimates for relative risk reductions for the composite of CV death or HHF and for major adverse cardiovascular events were generally consistent across subgroups (both P > .24 for interaction), although greater absolute risk reductions were observed with more markers of CKD. The absolute risk difference for the composite of CV death or HHF was greater for patients with more markers of CKD (0 markers, -0.5%; 1 marker, -1.0%; and 2 markers, -8.3%; P = .02 for interaction). The numbers of amputations, cases of diabetic ketoacidosis, fractures, and major hypoglycemic events were balanced or numerically lower with dapagliflozin compared with placebo for patients with an eGFR below 60 mL/min/1.73 m2 and an UACR of 30 mg/g or higher. Conclusions and Relevance: The effect of dapagliflozin on the relative risk for CV events was consistent across eGFR and UACR groups, with the greatest absolute benefit for the composite of CV death or HHF observed among patients with both reduced eGFR and albuminuria. Trial Registration: ClinicalTrials.gov Identifier: NCT01730534.
Assuntos
Albuminúria/tratamento farmacológico , Compostos Benzidrílicos/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Creatinina/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Taxa de Filtração Glomerular/efeitos dos fármacos , Glucosídeos/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Idoso , Albuminúria/etiologia , Compostos Benzidrílicos/efeitos adversos , Doenças Cardiovasculares/mortalidade , Diabetes Mellitus Tipo 2/complicações , Feminino , Glucosídeos/efeitos adversos , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/prevenção & controle , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/prevenção & controle , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Resultado do TratamentoRESUMO
OBJECTIVE: International guidelines propose prescribing sodium-glucose cotransporter 2 (SGLT2) inhibitors to patients with type 2 diabetes (T2D) as secondary prevention in patients with established atherosclerotic cardiovascular disease (ASCVD) or for primary prevention of cardiovascular events in high-risk patients with multiple risk factors (MRF) for ASCVD. The current analyses expand on the cardiovascular renal and metabolic effects of SGLT2 inhibitors in MRF patients. RESEARCH DESIGN AND METHODS: In DECLARE-TIMI 58, 17,160 patients with T2D and MRF (59.4%) or established ASCVD (40.6%) were randomized to dapagliflozin versus placebo; patients were followed for a median of 4.2 years. The cardiovascular and renal outcomes in the MRF cohort were studied across clinically relevant subgroups for treatment effect and subgroup-based treatment interaction. RESULTS: Among patients with MRF, the reduction with dapagliflozin in risk of cardiovascular death or hospitalization for heart failure (CVD/HHF) (hazard ratio [HR] 0.84, 95% CI 0.67-1.04) and the renal-specific outcome (HR 0.51, 95% CI 0.37-0.69) did not differ from that for patients with ASCVD (P interaction 0.99 and 0.72, respectively). The effect on CVD/HHF was entirely driven by a reduction in HHF (HR 0.64, 95% CI 0.46-0.88). The benefits of dapagliflozin on HHF and on the renal-specific outcome, among the subset with MRF, were directionally consistent across clinically relevant subgroups. At 48 months, HbA1c, weight, systolic blood pressure, and urinary albumin-to-creatinine ratio were lower with dapagliflozin versus placebo and estimated glomerular filtration rate was higher (P < 0.001). CONCLUSIONS: In patients with T2D and MRF, dapagliflozin reduced the risk of HHF and adverse renal outcomes regardless of baseline characteristics. These analyses support the benefit of dapagliflozin for important outcomes in a broad primary prevention population.