Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 295
Filtrar
1.
Circulation ; 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31707794

RESUMO

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to improve cardiovascular outcomes including hospitalization for heart failure and mortality in people with and without diabetes.1, 2 The mechanism(s) underlying this benefit remain unclear. While several hypotheses have been suggested (including SGLT2 inhibitor mediated diuresis and natriuresis, reduction in blood pressure and afterload, direct effects on myocardial sodium and calcium handling, alterations in myocardial energetics, reduction in left ventricular mass and improved progenitor cell response),3 a mediation analysis from the EMPA-REG OUTCOME trial suggests that an increase in hematocrit may account for over half of the mortality benefit observed. The consistent observation of an increase in hematocrit, even in those without diabetes, has led to the hypothesis that SGLT2 inhibitors may increase erythropoiesis via enhanced erythropoietin (EPO) secretion by the kidney.4 This SGLT2 inhibitor mediated increase in EPO production (and resultant rise in hematocrit) could lead to systemic organ protection by virtue of its capacity as a circulating pleiotropic cytokine, known to favorably influence cardiomyocyte mitochondrial function, angiogenesis, cell proliferation and inflammation. In addition, an increase in EPO-induced hematocrit may also improve myocardial function by directly enhancing myocardial and systemic tissue oxygen delivery.

2.
JAMA ; 322(18): 1780-1788, 2019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31714986

RESUMO

Importance: Additional treatment options are needed for patients who do not achieve sufficient reduction in low-density lipoprotein cholesterol (LDL-C) level with available lipid-lowering therapies. Objective: To assess the efficacy of bempedoic acid vs placebo in patients at high cardiovascular risk receiving maximally tolerated lipid-lowering therapy. Design, Setting, and Participants: Phase 3, randomized, double-blind, placebo-controlled clinical trial conducted at 91 clinical sites in North America and Europe from November 2016 to September 2018, with a final date of follow-up of September 22, 2018. A total of 779 patients with atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or both met randomization criteria, which included LDL-C level 70 mg/dL (1.8 mmol/L) or greater while receiving maximally tolerated lipid-lowering therapy. Interventions: Patients were randomized 2:1 to treatment with bempedoic acid (180 mg) (n = 522) or placebo (n = 257) once daily for 52 weeks. Main Outcomes and Measures: The primary end point was percent change from baseline in LDL-C level at week 12. Secondary measures included changes in levels of lipids, lipoproteins, and biomarkers. Results: Among 779 randomized patients (mean age, 64.3 years; 283 women [36.3%]), 740 (95.0%) completed the trial. At baseline, mean LDL-C level was 120.4 (SD, 37.9) mg/dL. Bempedoic acid lowered LDL-C levels significantly more than placebo at week 12 (-15.1% vs 2.4%, respectively; difference, -17.4% [95% CI, -21.0% to -13.9%]; P < .001). Significant reductions with bempedoic acid vs placebo were observed at week 12 for non-high-density lipoprotein cholesterol (-10.8% vs 2.3%; difference, -13.0% [95% CI, -16.3% to -9.8%]; P < .001), total cholesterol (-9.9% vs 1.3%; difference, -11.2% [95% CI, -13.6% to -8.8%]; P < .001), apolipoprotein B (-9.3% vs 3.7%; difference, -13.0% [95% CI, -16.1% to -9.9%]; P < .001), and high-sensitivity C-reactive protein (median, -18.7% vs -9.4%; difference, -8.7% [asymptotic confidence limits, -17.2% to -0.4%]; P = .04). Common adverse events included nasopharyngitis (5.2% vs 5.1% with bempedoic acid and placebo, respectively), urinary tract infection (5.0% vs 1.9%), and hyperuricemia (4.2% vs 1.9%). Conclusions and Relevance: Among patients at high risk for cardiovascular disease receiving maximally tolerated statins, the addition of bempedoic acid compared with placebo resulted in a significant lowering of LDL-C level over 12 weeks. Further research is needed to assess the durability and clinical effect as well as long-term safety. Trial Registration: ClinicalTrials.gov Identifier: NCT02991118.


Assuntos
Anticolesterolemiantes/uso terapêutico , Aterosclerose/tratamento farmacológico , Ácidos Dicarboxílicos/uso terapêutico , Ácidos Graxos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipidemia Familiar Combinada/tratamento farmacológico , Idoso , Anticolesterolemiantes/efeitos adversos , Aterosclerose/sangue , Doenças Cardiovasculares/prevenção & controle , LDL-Colesterol/sangue , Ácidos Dicarboxílicos/efeitos adversos , Método Duplo-Cego , Quimioterapia Combinada , Ácidos Graxos/efeitos adversos , Feminino , Humanos , Hiperlipidemia Familiar Combinada/sangue , Masculino , Pessoa de Meia-Idade
3.
Cardiovasc Diabetol ; 18(1): 149, 2019 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-31706300

RESUMO

BACKGROUND: Individuals with diabetes often have high levels of atherogenic lipoproteins and cholesterol reflected by elevated low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), and LDL particle number (LDL-PN). The presence of atherosclerotic cardiovascular disease (ASCVD) increases the risk of future cardiovascular events. We evaluated the efficacy and safety of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, alirocumab, among individuals with type 2 diabetes (T2DM), high LDL-C or non-HDL-C, and established ASCVD receiving maximally tolerated statin in ODYSSEY DM-DYSLIPIDEMIA (NCT02642159) and DM-INSULIN (NCT02585778). METHODS: In DM-DYSLIPIDEMIA, individuals with T2DM and mixed dyslipidemia (non-HDL-C ≥ 100 mg/dL; n = 413) were randomized to open-label alirocumab 75 mg every 2 weeks (Q2W) or usual care (UC) for 24 weeks, with UC options selected before stratified randomization. In DM-INSULIN, insulin-treated individuals with T2DM (LDL-C ≥ 70 mg/dL; n = 441) were randomized in a double-blind fashion to alirocumab 75 mg Q2W or placebo for 24 weeks. Study participants also had a glycated hemoglobin < 9% (DM-DYSLIPIDEMIA) or < 10% (DM-INSULIN). Alirocumab dose was increased to 150 mg Q2W at week 12 if week 8 LDL-C was ≥ 70 mg/dL (DM-INSULIN) or non-HDL-C was ≥ 100 mg/dL (DM-DYSLIPIDEMIA). Lipid reductions and safety were assessed in patients with ASCVD from these studies. RESULTS: This analysis included 142 DM-DYSLIPIDEMIA and 177 DM-INSULIN participants with ASCVD, including 95.1% and 86.4% with coronary heart disease, and 32.4% and 49.7% with microvascular diabetes complications, respectively. At week 24, alirocumab significantly reduced LDL-C, non-HDL-C, ApoB, and LDL-PN from baseline versus control. This translated into a greater proportion of individuals achieving non-HDL-C < 100 mg/dL (64.6% alirocumab/23.8% UC [DM-DYSLIPIDEMIA]; 65.4% alirocumab/14.9% placebo [DM-INSULIN]) and ApoB < 80 mg/dL (75.1% alirocumab/35.4% UC and 76.8% alirocumab/24.8% placebo, respectively) versus control at week 24 (all P < 0.0001). In pooling these studies, 66.4% (alirocumab) and 67.0% (control) of individuals reported treatment-emergent adverse events. The adverse event pattern was similar with alirocumab versus controls. CONCLUSIONS: Among individuals with T2DM and ASCVD who had high non-HDL-C/LDL-C levels despite maximally tolerated statin, alirocumab significantly reduced atherogenic cholesterol and LDL-PN versus control. Alirocumab was generally well tolerated. Trial registration Clinicaltrials.gov. NCT02642159. Registered 30 December 2015 and Clinicaltrials.gov. NCT02585778. Registered 23 October 2015.

4.
Mayo Clin Proc ; 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31630870

RESUMO

OBJECTIVE: To investigate the pharmacodynamic properties of inclisiran, a small interfering RNA targeting proprotein convertase subtilisin-kexin type 9 (PCSK9), in individuals with normal renal function and renal impairment (RI). PATIENTS AND METHODS: The analysis included participants with normal renal function and mild, moderate, and severe RI from the phase 1 ORION-7 renal study (n=31) and the phase 2 ORION-1 study (n=247) who received 300 mg of inclisiran sodium or placebo. RESULTS: In ORION-7, PCSK9 values were reduced at day 60 in the normal renal function group (68.1%±12.4%), mild RI group (74.2%±12.3%), moderate RI group (79.8%±4.9%), and severe RI group (67.9%±16.4%) (P<.001 vs placebo in all groups). Low-density lipoprotein cholesterol levels were significantly reduced versus placebo: normal renal function, 57.6%±10.7%; mild RI, 35.1%±13.5%; moderate RI, 53.1%±21.3%; severe RI, 49.2%±26.6% (P<.001 for all). In ORION-1, PCSK9 level reductions at day 180 were 48.3% to 58.6% in the 300-mg single-dose groups and 67.3% to 73.0% in the 300-mg 2-dose groups (P<.001 vs placebo in all groups). The corresponding low-density lipoprotein cholesterol level reductions were 35.7% to 40.2% in the 300-mg single-dose groups and 50.9% to 58.0% in the 300 mg 2-dose groups (P<.001 vs placebo in all groups). In ORION-7, exposure to inclisiran was proportionally greater in individuals with increasing RI; inclisiran was undetectable in plasma 48 hours after administration in any group. CONCLUSION: The pharmacodynamic effects and safety profile of inclisiran were similar in study participants with normal and impaired renal function. Dose adjustments of inclisiran are not required in these patients. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: NCT02597127 and NCT03159416.

5.
Lancet ; 394(10204): 1169-1180, 2019 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-31484629

RESUMO

BACKGROUND: Patients with stable coronary artery disease and diabetes with previous percutaneous coronary intervention (PCI), particularly those with previous stenting, are at high risk of ischaemic events. These patients are generally treated with aspirin. In this trial, we aimed to investigate if these patients would benefit from treatment with aspirin plus ticagrelor. METHODS: The Effect of Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study (THEMIS) was a phase 3 randomised, double-blinded, placebo-controlled trial, done in 1315 sites in 42 countries. Patients were eligible if 50 years or older, with type 2 diabetes, receiving anti-hyperglycaemic drugs for at least 6 months, with stable coronary artery disease, and one of three other mutually non-exclusive criteria: a history of previous PCI or of coronary artery bypass grafting, or documentation of angiographic stenosis of 50% or more in at least one coronary artery. Eligible patients were randomly assigned (1:1) to either ticagrelor or placebo, by use of an interactive voice-response or web-response system. The THEMIS-PCI trial comprised a prespecified subgroup of patients with previous PCI. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, or stroke (measured in the intention-to-treat population). FINDINGS: Between Feb 17, 2014, and May 24, 2016, 11 154 patients (58% of the overall THEMIS trial) with a history of previous PCI were enrolled in the THEMIS-PCI trial. Median follow-up was 3·3 years (IQR 2·8-3·8). In the previous PCI group, fewer patients receiving ticagrelor had a primary efficacy outcome event than in the placebo group (404 [7·3%] of 5558 vs 480 [8·6%] of 5596; HR 0·85 [95% CI 0·74-0·97], p=0·013). The same effect was not observed in patients without PCI (p=0·76, pinteraction=0·16). The proportion of patients with cardiovascular death was similar in both treatment groups (174 [3·1%] with ticagrelor vs 183 (3·3%) with placebo; HR 0·96 [95% CI 0·78-1·18], p=0·68), as well as all-cause death (282 [5·1%] vs 323 [5·8%]; 0·88 [0·75-1·03], p=0·11). TIMI major bleeding occurred in 111 (2·0%) of 5536 patients receiving ticagrelor and 62 (1·1%) of 5564 patients receiving placebo (HR 2·03 [95% CI 1·48-2·76], p<0·0001), and fatal bleeding in 6 (0·1%) of 5536 patients with ticagrelor and 6 (0·1%) of 5564 with placebo (1·13 [0·36-3·50], p=0·83). Intracranial haemorrhage occurred in 33 (0·6%) and 31 (0·6%) patients (1·21 [0·74-1·97], p=0·45). Ticagrelor improved net clinical benefit: 519/5558 (9·3%) versus 617/5596 (11·0%), HR=0·85, 95% CI 0·75-0·95, p=0·005, in contrast to patients without PCI where it did not, pinteraction=0·012. Benefit was present irrespective of time from most recent PCI. INTERPRETATION: In patients with diabetes, stable coronary artery disease, and previous PCI, ticagrelor added to aspirin reduced cardiovascular death, myocardial infarction, and stroke, although with increased major bleeding. In that large, easily identified population, ticagrelor provided a favourable net clinical benefit (more than in patients without history of PCI). This effect shows that long-term therapy with ticagrelor in addition to aspirin should be considered in patients with diabetes and a history of PCI who have tolerated antiplatelet therapy, have high ischaemic risk, and low bleeding risk. FUNDING: AstraZeneca.


Assuntos
Doença da Artéria Coronariana/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Agregação de Plaquetas/uso terapêutico , Ticagrelor/uso terapêutico , Idoso , Aspirina/uso terapêutico , Doenças Cardiovasculares/mortalidade , Angiografia Coronária , Ponte de Artéria Coronária , Doença da Artéria Coronariana/complicações , Estenose Coronária/diagnóstico por imagem , Diabetes Mellitus Tipo 2/complicações , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Hemorragia/induzido quimicamente , Humanos , Hipoglicemiantes/uso terapêutico , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Intervenção Coronária Percutânea , Prevenção Secundária , Acidente Vascular Cerebral/epidemiologia
6.
JAMA Cardiol ; 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31553410

RESUMO

Importance: Sustained reductions in low-density lipoprotein cholesterol (LDL-C) with lipid-lowering therapies that require frequent dosing are reliant on patient adherence, and poor adherence is associated with worse clinical outcomes. Objective: To determine whether inclisiran, a small interfering RNA, reduces mean LDL-C exposure with an infrequent dosing regimen. Design, Setting, and Participants: Prespecified analysis of a randomized, double-blind, placebo-controlled multicenter phase 2 clinical trial. Participants were followed up monthly for LDL-C levels and proprotein convertase subtilisin-kexin type 9 (PCSK9) measurements as well as safety until their LDL-C levels had returned to within 20% of their change from baseline (maximum 360 days). The study included patients with elevated LDL-C despite maximally tolerated statin therapy. Data were analyzed between January 11, 2016, and June 7, 2017. Interventions: One dose (200, 300, or 500 mg on day 1) or 2 doses (100, 200, or 300 mg on days 1 and 90) of inclisiran sodium or placebo. Main Outcomes and Measures: Duration of time to return to within 20% of change from baseline for LDL-C levels and time-averaged LDL-C reductions over 1 year. Results: At baseline, among the 501 participants, 65% were men (n = 326 of 501), mean age was 63 years, 6% had familial hypercholesterolemia (n = 28 of 501), and 69% had established ASCVD (n = 347 of 501). Baseline LDL-C was 128 mg/dL among 501 randomized participants. The percentage of participants who were followed up to day 360 because their LDL-C levels had not returned to within 20% of their change from baseline ranged from 48.3% to 65.0% for those receiving a single dose and between 55.9% and 83.1% of those receiving 2 doses, with similar effects observed for PCSK9. Time-averaged reduction in LDL-C levels over 1 year after a single dose ranged from 29.5% to 38.7% (P < .001 between groups) and from 29.9% to 46.4% (P < .001 between groups) for those who received 2 doses. The 2-dose 300-mg regimen produced the highest proportion of responders at day 360 and the greatest mean reduction in LDL-C over 1 year. Incidence of adverse events was similar through to 1 year. Conclusions and Relevance: Treatment with inclisiran resulted in durable reductions in LDL-C over 1 year. Inclisiran may offer a novel approach to LDL-C reduction with the convenience of infrequent dosing. Trial Registration: ClinicalTrials.gov identifier: NCT02597127.

7.
N Engl J Med ; 381(14): 1309-1320, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31475798

RESUMO

BACKGROUND: Patients with stable coronary artery disease and diabetes mellitus who have not had a myocardial infarction or stroke are at high risk for cardiovascular events. Whether adding ticagrelor to aspirin improves outcomes in this population is unclear. METHODS: In this randomized, double-blind trial, we assigned patients who were 50 years of age or older and who had stable coronary artery disease and type 2 diabetes mellitus to receive either ticagrelor plus aspirin or placebo plus aspirin. Patients with previous myocardial infarction or stroke were excluded. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, or stroke. The primary safety outcome was major bleeding as defined by the Thrombolysis in Myocardial Infarction (TIMI) criteria. RESULTS: A total of 19,220 patients underwent randomization. The median follow-up was 39.9 months. Permanent treatment discontinuation was more frequent with ticagrelor than placebo (34.5% vs. 25.4%). The incidence of ischemic cardiovascular events (the primary efficacy outcome) was lower in the ticagrelor group than in the placebo group (7.7% vs. 8.5%; hazard ratio, 0.90; 95% confidence interval [CI], 0.81 to 0.99; P = 0.04), whereas the incidence of TIMI major bleeding was higher (2.2% vs. 1.0%; hazard ratio, 2.32; 95% CI, 1.82 to 2.94; P<0.001), as was the incidence of intracranial hemorrhage (0.7% vs. 0.5%; hazard ratio, 1.71; 95% CI, 1.18 to 2.48; P = 0.005). There was no significant difference in the incidence of fatal bleeding (0.2% vs. 0.1%; hazard ratio, 1.90; 95% CI, 0.87 to 4.15; P = 0.11). The incidence of an exploratory composite outcome of irreversible harm (death from any cause, myocardial infarction, stroke, fatal bleeding, or intracranial hemorrhage) was similar in the ticagrelor group and the placebo group (10.1% vs. 10.8%; hazard ratio, 0.93; 95% CI, 0.86 to 1.02). CONCLUSIONS: In patients with stable coronary artery disease and diabetes without a history of myocardial infarction or stroke, those who received ticagrelor plus aspirin had a lower incidence of ischemic cardiovascular events but a higher incidence of major bleeding than those who received placebo plus aspirin. (Funded by AstraZeneca; THEMIS ClinicalTrials.gov number, NCT01991795.).


Assuntos
Aspirina/uso terapêutico , Doença da Artéria Coronariana/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Agregação de Plaquetas/uso terapêutico , Ticagrelor/uso terapêutico , Idoso , Aspirina/efeitos adversos , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/mortalidade , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/mortalidade , Método Duplo-Cego , Quimioterapia Combinada/efeitos adversos , Feminino , Seguimentos , Hemorragia/induzido quimicamente , Hemorragia/epidemiologia , Hemorragia/mortalidade , Humanos , Incidência , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/prevenção & controle , Inibidores da Agregação de Plaquetas/efeitos adversos , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/prevenção & controle , Ticagrelor/efeitos adversos , Resultado do Tratamento
8.
Circulation ; 140(19): 1569-1577, 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31474116

RESUMO

BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) are at increased risk of developing heart failure. Sodium-glucose cotransporter-2 inhibitors reduce the risk of hospitalization for heart failure (HHF) in patients with T2DM. We aimed to develop and validate a practical clinical risk score for HHF in patients with T2DM and assess whether this score can identify high-risk patients with T2DM who have the greatest reduction in risk for HHF with a sodium-glucose cotransporter-2 inhibitor. METHODS: We developed a clinical risk score for HHF in 8212 patients with T2DM in the placebo arm of SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53). Candidate variables were assessed using multivariable Cox regression, and independent clinical risk indicators achieving statistical significance of P<0.001 were included in the risk score. We externally validated the score in 8578 patients with T2DM in the placebo arm of DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58). The relative and absolute risk reductions in HHF with the sodium-glucose cotransporter-2 inhibitor dapagliflozin were assessed by baseline HHF risk. RESULTS: Five clinical variables were independent risk predictors of HHF: prior heart failure, history of atrial fibrillation, coronary artery disease, estimated glomerular filtration rate, and urine albumin-to-creatinine ratio. A simple integer-based score (0-7 points) using these predictors identified a >20-fold gradient of HHF risk (P for trend <0.001) in both the derivation and validation cohorts, with C indices of 0.81 and 0.78, respectively. Although relative risk reductions with dapagliflozin were similar for patients across the risk scores (25%-34%), absolute risk reductions were greater in those at higher baseline risk (1-sided P for trend=0.04), with high-risk (2 points) and very-high-risk (≥3 points) patients having 1.5% and 2.7% absolute reductions in Kaplan-Meier estimates of HHF risk at 4 years, respectively. CONCLUSIONS: Risk stratification using a novel clinical risk score for HHF in patients with T2DM identifies patients at higher risk for HHF who derive greater absolute benefit from sodium-glucose cotransporter-2 inhibition. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01107886 and NCT01730534.

9.
Cell Metab ; 30(4): 609-613, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31477497

RESUMO

Hess et al. quantified circulating aldehyde dehydrogenase-expressing (ALDHhi) cell subsets in people with T2DM given either empagliflozin (EMPA) or placebo. EMPA treatment increased circulating pro-angiogenic CD133+ progenitor cells, decreased pro-inflammatory ALDHhi granulocyte precursors, and increased ALDHhi monocytes with M2 polarization. EMPA treatment improved T2DM-associated "regenerative cell depletion" contributing to enhanced vascular health.

10.
Circulation ; 140(21): 1693-1702, 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31434508

RESUMO

BACKGROUND: SGLT2 (sodium-glucose cotransporter 2) inhibitors lower cardiovascular events in type 2 diabetes mellitus but whether they promote direct cardiac effects remains unknown. We sought to determine if empagliflozin causes a decrease in left ventricular (LV) mass in people with type 2 diabetes mellitus and coronary artery disease. METHODS: Between November 2016 and April 2018, we recruited 97 individuals ≥40 and ≤80 years old with glycated hemoglobin 6.5% to 10.0%, known coronary artery disease, and estimated glomerular filtration rate ≥60mL/min/1.73m2. The participants were randomized to empagliflozin (10 mg/day, n=49) or placebo (n=48) for 6 months, in addition to standard of care. The primary outcome was the 6-month change in LV mass indexed to body surface area from baseline as measured by cardiac magnetic resonance imaging. Other measures included 6-month changes in LV end-diastolic and -systolic volumes indexed to body surface area, ejection fraction, 24-hour ambulatory blood pressure, hematocrit, and NT-proBNP (N-terminal pro b-type natriuretic peptide). RESULTS: Among the 97 participants (90 men [93%], mean [standard deviation] age 62.8 [9.0] years, type 2 diabetes mellitus duration 11.0 [8.2] years, estimated glomerular filtration rate 88.4 [16.9] mL/min/1.73m2, LV mass indexed to body surface area 60.7 [11.9] g/m2), 90 had evaluable imaging at follow-up. Mean LV mass indexed to body surface area regression over 6 months was 2.6 g/m2 and 0.01 g/m2 for those assigned empagliflozin and placebo, respectively (adjusted difference -3.35 g/m2; 95% CI, -5.9 to -0.81g/m2, P=0.01). In the empagliflozin-allocated group, there was significant lowering of overall ambulatory systolic blood pressure (adjusted difference -6.8mmHg, 95% CI -11.2 to -2.3mmHg, P=0.003), diastolic blood pressure (adjusted difference -3.2mmHg; 95% CI, -5.8 to -0.6mmHg, P=0.02) and elevation of hematocrit (P=0.0003). CONCLUSIONS: Among people with type 2 diabetes mellitus and coronary artery disease, SGLT2 inhibition with empagliflozin was associated with significant reduction in LV mass indexed to body surface area after 6 months, which may account in part for the beneficial cardiovascular outcomes observed in the EMPA-REG OUTCOME (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02998970.

11.
Eur J Prev Cardiol ; : 2047487319864671, 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31357887

RESUMO

AIMS: The aim of this study was to evaluate the low-density lipoprotein cholesterol lowering efficacy and safety of a bempedoic acid 180 mg and ezetimibe 10 mg fixed-dose combination in patients with hypercholesterolemia and a high risk of cardiovascular disease receiving maximally tolerated statin therapy. METHODS: This phase 3, double-blind clinical trial enrolled adult patients at high risk of cardiovascular disease due to atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or multiple cardiovascular disease risk factors. Patients were randomly assigned (2:2:2:1) to treatment with the fixed-dose combination, bempedoic acid 180 mg, ezetimibe 10 mg or placebo added to stable background statin therapy for 12 weeks. The primary efficacy endpoint was the percentage change from baseline to week 12 in low-density lipoprotein cholesterol. RESULTS: Among the 301 patients included in the primary analysis, the mean baseline low-density lipoprotein cholesterol level was 3.87 mmol/L (149.8 mg/dL). At week 12, the fixed-dose combination lowered low-density lipoprotein cholesterol (-36.2%) significantly more than placebo (1.8% (placebo-corrected difference -38.0%); P < 0.001), ezetimibe alone (-23.2%; P < 0.001) or bempedoic acid alone (-17.2%; P < 0.001). The fixed-dose combination lowered low-density lipoprotein cholesterol levels similarly across subgroups, including patients receiving high-intensity, other-intensity or no statin therapy. Improvements with the fixed-dose combination were also observed in secondary efficacy endpoints, including high-sensitivity C-reactive protein. In this trial, fixed-dose combination treatment had a generally similar safety profile compared with bempedoic acid, ezetimibe or placebo. CONCLUSION: The bempedoic acid and ezetimibe fixed-dose combination significantly lowered low-density lipoprotein cholesterol versus placebo or other oral monotherapies and had a favourable safety profile when added to maximally tolerated statin therapy in patients with hypercholesterolemia and high cardiovascular disease risk. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03337308.

13.
Lancet Diabetes Endocrinol ; 7(8): 606-617, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31196815

RESUMO

BACKGROUND: Sodium-glucose co-transporter-2 (SGLT2) inhibitors have shown beneficial effects on renal outcomes mainly in patients with established atherosclerotic cardiovascular disease. Here we report analyses of renal outcomes with the SGLT2 inhibitor dapagliflozin in the DECLARE-TIMI 58 cardiovascular outcomes trial, which included patients with type 2 diabetes both with and without established atherosclerotic cardiovascular disease and mostly with preserved renal function. METHODS: In DECLARE-TIMI 58, patients with type 2 diabetes, HbA1c 6·5-12·0% (47·5-113·1 mmol/mol), with either established atherosclerotic cardiovascular disease or multiple risk factors, and creatinine clearance of at least 60 mL/min were randomly assigned (1:1) to 10 mg dapagliflozin or placebo once daily. A prespecified secondary cardiorenal composite outcome was defined as a sustained decline of at least 40% in estimated glomerular filtration rate [eGFR] to less than 60 mL/min per 1·73m2, end-stage renal disease (defined as dialysis for at least 90 days, kidney transplantation, or confirmed sustained eGFR <15mL/min per 1·73 m2), or death from renal or cardiovascular causes; a prespecified renal-specific composite outcome was the same but excluding death from cardiovascular causes. In this renal analysis, we report findings for the components of these composite outcomes, subgroup analysis of these composite outcomes, and changes in eGFR at different timepoints. DECLARE-TIMI 58 is registered with ClinicalTrials.gov, number NCT01730534. FINDINGS: The trial took place between April 25, 2013, and Sept 18, 2018; median follow-up was 4·2 years (IQR 3·9-4·4). Of the 17 160 participants who were randomly assigned, 8162 (47·6%) had an eGFR of at least 90 mL/min per 1·73 m2, 7732 (45·1%) had an eGFR of 60 to less than 90 mL/min per 1·73 m2, and 1265 (7·4%) had an eGFR of less than 60 mL/min per 1·73 m2 at baseline (one participant had missing data for eGFR); 6974 (40·6%) had established atherosclerotic cardiovascular disease and 10 186 (59·4%) had multiple risk factors. As previously reported, the cardiorenal secondary composite outcome was significantly reduced with dapagliflozin versus placebo (hazard ratio [HR] 0·76, 95% CI 0·67-0.87; p<0·0001); excluding death from cardiovascular causes, the HR for the renal-specific outcome was 0·53 (0·43-0·66; p<0·0001). We identified a 46% reduction in sustained decline in eGFR by at least 40% to less than 60 mL/min per 1·73 m2 (120 [1·4% vs 221 [2·6%]; HR 0·54 [95% CI 0·43-0·67]; p<0·0001). The risk of end-stage renal disease or renal death was lower in the dapagliflozin group than in the placebo group (11 [0·1%] vs 27 [0·3%]; HR 0·41 [95% CI 0·20-0·82]; p=0·012). Both the cardiorenal and renal-specific composite outcomes were improved with dapagliflozin versus placebo across various prespecified subgroups, including those defined by baseline eGFR (cardiorenal outcome pinteraction=0·97; renal-specific outcome pinteraction=0·87) and the presence or absence of established atherosclerotic cardiovascular disease (cardiorenal outcome pinteraction=0·67; renal-specific outcome pinteraction=0·72). 6 months after randomisation, the mean decrease in eGFR was larger in the dapagliflozin group than in the placebo group. The mean change equalised by 2 years, and at 3 and 4 years the mean decrease in eGFR was less with dapagliflozin than with placebo. INTERPRETATION: Dapagliflozin seemed to prevent and reduce progression of kidney disease compared with placebo in this large and diverse population of patients with type 2 diabetes with and without established atherosclerotic cardiovascular disease, most of whom had preserved renal function. FUNDING: AstraZeneca.

14.
Lancet ; 394(10193): 131-138, 2019 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-31189509

RESUMO

BACKGROUND: Two glucagon-like peptide-1 (GLP-1) receptor agonists reduced renal outcomes in people with type 2 diabetes at risk for cardiovascular disease. We assessed the long-term effect of the GLP-1 receptor agonist dulaglutide on renal outcomes in an exploratory analysis of the REWIND trial of the effect of dulaglutide on cardiovascular disease. METHODS: REWIND was a multicentre, randomised, double-blind, placebo-controlled trial at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo and followed up at least every 6 months for outcomes. Urinary albumin-to-creatinine ratios (UACRs) and estimated glomerular filtration rates (eGFRs) were estimated from urine and serum values measured in local laboratories every 12 months. The primary outcome (first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes), secondary outcomes (including a composite microvascular outcome), and safety outcomes of this trial have been reported elsewhere. In this exploratory analysis, we investigate the renal component of the composite microvascular outcome, defined as the first occurrence of new macroalbuminuria (UACR >33·9 mg/mmol), a sustained decline in eGFR of 30% or more from baseline, or chronic renal replacement therapy. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01394952. FINDINGS: Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). At baseline, 791 (7·9%) had macroalbuminuria and mean eGFR was 76·9 mL/min per 1·73 m2 (SD 22·7). During a median follow-up of 5·4 years (IQR 5·1-5·9) comprising 51 820 person-years, the renal outcome developed in 848 (17·1%) participants at an incidence rate of 3·5 per 100 person-years in the dulaglutide group and in 970 (19·6%) participants at an incidence rate of 4·1 per 100 person-years in the placebo group (hazard ratio [HR] 0·85, 95% CI 0·77-0·93; p=0·0004). The clearest effect was for new macroalbuminuria (HR 0·77, 95% CI 0·68-0·87; p<0·0001), with HRs of 0·89 (0·78-1·01; p=0·066) for sustained decline in eGFR of 30% or more and 0·75 (0·39-1·44; p=0·39) for chronic renal replacement therapy. INTERPRETATION: Long-term use of dulaglutide was associated with reduced composite renal outcomes in people with type 2 diabetes. FUNDING: Eli Lilly and Company.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Hipoglicemiantes/uso terapêutico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Idoso , Albuminúria/prevenção & controle , Creatinina/urina , Método Duplo-Cego , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade
15.
Lancet ; 394(10193): 121-130, 2019 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-31189511

RESUMO

BACKGROUND: Three different glucagon-like peptide-1 (GLP-1) receptor agonists reduce cardiovascular outcomes in people with type 2 diabetes at high cardiovascular risk with high glycated haemoglobin A1c (HbA1c) concentrations. We assessed the effect of the GLP-1 receptor agonist dulaglutide on major adverse cardiovascular events when added to the existing antihyperglycaemic regimens of individuals with type 2 diabetes with and without previous cardiovascular disease and a wide range of glycaemic control. METHODS: This multicentre, randomised, double-blind, placebo-controlled trial was done at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo. Randomisation was done by a computer-generated random code with stratification by site. All investigators and participants were masked to treatment assignment. Participants were followed up at least every 6 months for incident cardiovascular and other serious clinical outcomes. The primary outcome was the first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes (including unknown causes), which was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01394952. FINDINGS: Between Aug 18, 2011, and Aug 14, 2013, 9901 participants (mean age 66·2 years [SD 6·5], median HbA1c 7·2% [IQR 6·6-8·1], 4589 [46·3%] women) were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). During a median follow-up of 5·4 years (IQR 5·1-5·9), the primary composite outcome occurred in 594 (12·0%) participants at an incidence rate of 2·4 per 100 person-years in the dulaglutide group and in 663 (13·4%) participants at an incidence rate of 2·7 per 100 person-years in the placebo group (hazard ratio [HR] 0·88, 95% CI 0·79-0·99; p=0·026). All-cause mortality did not differ between groups (536 [10·8%] in the dulaglutide group vs 592 [12·0%] in the placebo group; HR 0·90, 95% CI 0·80-1·01; p=0·067). 2347 (47·4%) participants assigned to dulaglutide reported a gastrointestinal adverse event during follow-up compared with 1687 (34·1%) participants assigned to placebo (p<0·0001). INTERPRETATION: Dulaglutide could be considered for the management of glycaemic control in middle-aged and older people with type 2 diabetes with either previous cardiovascular disease or cardiovascular risk factors. FUNDING: Eli Lilly and Company.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Hipoglicemiantes/uso terapêutico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Idoso , Doenças Cardiovasculares/mortalidade , Diabetes Mellitus Tipo 2/complicações , Método Duplo-Cego , Feminino , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/prevenção & controle , Acidente Vascular Cerebral/prevenção & controle
16.
Cardiovasc Diabetol ; 18(1): 73, 2019 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-31167654

RESUMO

BACKGROUND: The SUSTAIN 6 trial demonstrated that once-weekly semaglutide (0.5 and 1.0 mg) significantly reduced major adverse cardiovascular (CV) events (MACE) vs placebo in subjects with type 2 diabetes (T2D) and high CV risk. The effects of gender, age and baseline CV risk on outcomes are important considerations for further study. METHODS: Subjects were grouped according to gender, age (50-65 years and > 65 years), and CV risk profile at baseline (prior myocardial infarction [MI] or stroke vs no prior MI or stroke, and established CV disease [CVD] vs CV risk factors alone, including subjects with chronic kidney disease). Time to MACE and its individual components (CV death, nonfatal MI, nonfatal stroke), hospitalization for unstable angina or heart failure, and revascularization (coronary and peripheral) were analyzed for all subgroups. Additional analyses were performed for gender and age to investigate change from baseline in HbA1c and body weight, as well as tolerability. RESULTS: A total of 3297 subjects were included. The majority of subjects (60.7%) were male; 43% were > 65 years of age; 41.5% had a history of MI or stroke; and 76.8% had established CVD. Compared with placebo, semaglutide reduced the risk of the first occurrence of MACE and each MACE component consistently across all subgroups (gender, age, and baseline CV risk profile). Revascularizations, HbA1c and body weight were also reduced consistently across all subgroups compared with placebo. Gastrointestinal adverse events in all treatment groups were more common among women than men, but rates of premature treatment discontinuation were similar for both genders. CONCLUSIONS: In this post hoc analysis of SUSTAIN 6, once-weekly semaglutide vs placebo reduced the risk of MACE in all subjects included in the trial, regardless of gender, age, or baseline CV risk profile. Trial registry Clinicaltrials.gov, Identifying number: NCT01720446, Date of registration: October 29, 2012.

17.
18.
BMJ Open ; 9(5): e024171, 2019 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-31061018

RESUMO

OBJECTIVE: Sugar-sweetened beverages (SSBs) are associated with hyperuricaemia and gout. Whether other important food sources of fructose-containing sugars share this association is unclear. DESIGN: To assess the relation of important food sources of fructose-containing sugars with incident gout and hyperuricaemia, we conducted a systematic review and meta-analysis of prospective cohort studies. METHODS: We searched MEDLINE, Embase and the Cochrane Library (through 13 September 2017). We included prospective cohort studies that investigated the relationship between food sources of sugar and incident gout or hyperuricaemia. Two independent reviewers extracted relevant data and assessed the risk of bias. We pooled natural-log transformed risk ratios (RRs) using the generic inverse variance method with random effects model and expressed as RR with 95% confidence intervals (CIs). The overall certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation system. RESULTS: We identified three studies (1 54 289 participants, 1761 cases of gout), comparing the highest with the lowest level of exposure for SSBs, fruit juices and fruits. No reports were found reporting incident hyperuricaemia. Fruit juice and SSB intake showed an adverse association (fruit juice: RR=1.77, 95% CI 1.20 to 2.61; SSB: RR=2.08, 95% CI 1.40 to 3.08), when comparing the highest to lowest intake of the most adjusted models. There was no significant association between fruit intake and gout (RR 0.85, 95% CI 0.63 to 1.14). The strongest evidence was for the adverse association with SSB intake (moderate certainty), and the weakest evidence was for the adverse association with fruit juice intake (very low certainty) and lack of association with fruit intake (very low certainty). CONCLUSION: There is an adverse association of SSB and fruit juice intake with incident gout, which does not appear to extend to fruit intake. Further research is needed to improve our estimates. TRIAL REGISTRATION NUMBER: NCT02702375; Results.

19.
Clin Chem ; 65(6): 781-790, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30988169

RESUMO

BACKGROUND: Cardiac and renal diseases commonly occur with bidirectional interactions. We hypothesized that cardiac and inflammatory biomarkers may assist in identification of patients with type 2 diabetes mellitus (T2DM) at high risk of worsening renal function. METHODS: In this exploratory analysis from SAVOR-TIMI 53, concentrations of high-sensitivity cardiac troponin T (hs-TnT), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and high-sensitivity C-reactive protein (hs-CRP) were measured in baseline serum samples of 12310 patients. The primary end point for this analysis was a ≥40% decrease in estimated glomerular filtration rate (eGFR) at end of treatment (EOT) at a median of 2.1 years. The relationships between biomarkers and the end point were modeled using adjusted logistic and Cox regression. RESULTS: After multivariable adjustment including baseline renal function, each biomarker was independently associated with an increased risk of ≥40% decrease in eGFR at EOT [Quartile (Q) Q4 vs Q1: hs-TnT adjusted odds ratio (OR), 5.63 (3.49-9.10); NT-proBNP adjusted OR, 3.53 (2.29-5.45); hs-CRP adjusted OR, 1.84 (95% CI, 1.27-2.68); all P values ≤0.001]. Furthermore, each biomarker was independently associated with higher risk of worsening of urinary albumin-to-creatinine ratio (UACR) category (all P values ≤0.002). Sensitivity analyses in patients without heart failure and eGFR >60 mL/min provided similar results. In an adjusted multimarker model, hs-TnT and NT-proBNP remained significantly associated with both renal outcomes (all P values <0.01). CONCLUSIONS: hs-TnT, NT-proBNP, and hs-CRP were each associated with worsening of renal function [reduction in eGFR (≥40%) and deterioration in UACR class] in high-risk patients with T2DM. Patients with high cardiac or inflammatory biomarkers should be treated not only for their risk of cardiovascular outcomes but also followed for renal deterioration.

20.
J Diabetes Sci Technol ; 13(3): 498-506, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30974986

RESUMO

BACKGROUND: A head-to-head trial (NCT03078478) between insulin degludec and insulin glargine U300 with the primary objective of comparing the risk of hypoglycemia is being conducted. During trial conduct, safety concerns related to the glycemic data collection system led to a postinitiation protocol amendment, described here. METHODS: This randomized (1:1), open-label, treat-to-target, multinational trial was initiated in March 2017 with a planned treatment period of 52 weeks (16 weeks titration + 36 weeks maintenance). Overall, ~1600 insulin-experienced patients at risk of developing hypoglycemia based on predefined risk factors were included. The protocol amendment implemented in February 2018 resulted in assuring patient safety and an extension of the total treatment period up to 88 weeks (16 weeks titration + variable maintenance 1 + 36 weeks maintenance 2). The original glycemic data collection system (MyGlucoHealth blood glucose meter + electronic diary) was discontinued because of safety concerns and replaced with an Abbott blood glucose meter and paper diary to collect self-measured blood glucose and hypoglycemic episodes. The primary endpoint of number of severe or blood-glucose confirmed symptomatic hypoglycemic episodes will be evaluated with the same analysis duration and statistical methods as the original protocol. Only relevant changes were implemented to maintain patient safety while permitting evaluation of the scientific objectives of the trial. CONCLUSIONS: These observations highlight the importance of safety surveillance during trial conduct despite the use of currently marketed glucose monitoring devices. The prompt protocol amendment and ensuing actions ensured that the scientific integrity of the trial was not compromised.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA