Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 210
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Artigo em Inglês | MEDLINE | ID: mdl-32030422

RESUMO

BACKGROUND: Sodium zirconium cyclosilicate (SZC; formerly ZS-9) is a selective potassium (K+) binder for the treatment of adults with hyperkalaemia. This post hoc analysis of an open-label, single-arm trial (NCT02163499) compared SZC efficacy and safety >12 months among outpatients with hyperkalaemia and Stages 4 and 5 chronic kidney disease (CKD) versus those with Stages 1-3 CKD. METHODS: Adults with serum K+ ≥5.1 mmol/L (measured by point-of-care i-STAT device) received SZC 10 g three times daily for 24-72 h until normokalaemia (i-STAT K+ 3.5-5.0 mmol/L) was achieved [correction phase (CP)], followed by once daily SZC 5 g for ≤12 months [maintenance phase (MP)]. Here, patients were stratified by baseline estimated glomerular filtration rate (eGFR <30 or ≥30 mL/min/1.73 m2). Study endpoints included percent achieving normokalaemia during CP and MP, mean serum K+ and bicarbonate during MP, and adverse events (AEs). RESULTS: Of 751 patients enrolled, 289 (39%), 453 (60%) and 9 (1%) had baseline eGFR values of <30, ≥30 mL/min/1.73 m2 or missing, respectively. During the CP, 82% of patients achieved normokalaemia in both eGFR subgroups within 24 h, and 100 and 95% with baseline eGFR <30 and ≥30 mL/min/1.73 m2, respectively, within 72 h. Corresponding proportions with normokalaemia during the MP were 82 and 90% at Day 365, respectively. Mean serum K+ reduction from baseline during the CP was sustained throughout the MP and serum bicarbonate increased. AEs during the MP were more common in the eGFR <30 ≥30 mL/min/1.73 m2 subgroup. CONCLUSIONS: SZC corrects hyperkalaemia and maintains normokalaemia among outpatients regardless of the CKD stage.

2.
Diabetes Care ; 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32001614

RESUMO

OBJECTIVE: The Diabetes Control and Complications Trial (DCCT) and its observational follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) demonstrated the dominant role of glycemia, second only to age, as a risk factor for a first cardiovascular event in type 1 diabetes (T1D). We now investigate the association between established risk factors and the total cardiovascular disease (CVD) burden, including subsequent (i.e., recurrent) events. RESEARCH DESIGN AND METHODS: CVD events in the 1,441 DCCT/EDIC participants were analyzed separately by type (CVD death, acute myocardial infarction [MI], stroke, silent MI, angina, percutaneous transluminal coronary angioplasty/coronary artery bypass graft [PTCA/CABG], and congestive heart failure [CHF]) or as composite outcomes (CVD or major adverse cardiovascular events [MACE]). Proportional rate models and conditional models assessed associations between risk factors and CVD outcomes. RESULTS: Over a median follow-up of 29 years, 239 participants had 421 CVD events, and 120 individuals had 149 MACE. Age was the strongest risk factor for acute MI, silent MI, stroke, and PTCA/CABG, while glycemia was the strongest risk factor for CVD death, CHF, and angina, second strongest for acute MI and PTCA/CABG, third strongest for stroke, and not associated with silent MI. HbA1c was the strongest modifiable risk factor for a first CVD event (CVD: HR 1.38 [95% CI 1.21, 1.56] per 1% higher HbA1c; MACE: HR 1.54 [1.30, 1.82]) and also for subsequent CVD events (CVD: incidence ratio [IR] 1.28 [95% CI 1.09, 1.51]; MACE: IR 1.89 [1.36, 2.61]). CONCLUSIONS: Intensive glycemic management is recommended to lower the risk of initial CVD events in T1D. After a first event, optimal glycemic control may reduce the risk of recurrent CVD events and should be maintained.

3.
Am J Nephrol ; 51(1): 74-82, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31812955

RESUMO

BACKGROUND: We evaluated the incremental contribution of chronic kidney disease (CKD) to the risk of major adverse cardiovascular (CV) events (MACE), heart failure (HF), and all-cause mortality (ACM) in type 2 diabetes mellitus (T2DM) patients and its importance relative to the presence of other cardio-renal-metabolic (CaReMe) comorbidities. METHODS: Patients (≥40 years) were identified at the time of T2DM diagnosis from US (Humedica/Optum) and UK (Clinical Practice Research Datalink) databases. Patients were monitored post-diagnosis for modified MACE (myocardial infarction, stroke, ACM), HF, and ACM. Adjusted hazard ratios were obtained using Cox proportional-hazards regression to evaluate the relative risk of modified MACE, HF, and ACM due to CKD. Patients were stratified by the presence or absence of atherosclerotic CV disease (ASCVD) and age. RESULTS: Between 2011 and 2015, of 227,224 patients identified with incident T2DM, 40,063 (17.64%) had CKD. Regardless of prior ASCVD, CKD was associated with higher risk of modified MACE, HF, and ACM; this excess hazard was more pronounced in older patients with prior ASCVD. In time-to-event analyses in the overall cohort, patients with T2DM + CKD or T2DM + CKD + hypertension + hyperlipidemia had increased risks for modified MACE, HF, and ACM versus patients with T2DM and no CaReMe comorbidities. Patients with CKD had higher risks for and shorter times to modified MACE, HF, and ACM than those without CKD. CONCLUSION: In T2DM patients, CKD presence was associated with higher risk of modified MACE, HF, and ACM. This may have risk-stratification implications for T2DM patients based on background CKD and highlights the potential importance of novel renoprotective strategies.

4.
Circulation ; 141(2): 100-111, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31736328

RESUMO

BACKGROUND: The DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure) showed that dapagliflozin added to other guideline-recommended therapies reduced the risk of mortality and heart failure hospitalization and improved symptoms in patients with heart failure and reduced ejection fraction. We examined the effects of dapagliflozin according to age, given potential concerns about the efficacy and safety of therapies in the elderly. METHODS: Patients in New York Heart Association functional class II or greater with a left ventricular ejection fraction ≤40% and a modest elevation of NT-proBNP (N-terminal pro-B-type natriuretic peptide) were eligible. Key exclusion criteria included systolic blood pressure <95 mm Hg and estimated glomerular filtration rate <30 mL·min-1·1.73 m-2. The primary outcome was the composite of an episode of worsening heart failure (heart failure hospitalization or urgent heart failure visit) or cardiovascular death, whichever occurred first. RESULTS: A total of 4744 patients 22 to 94 years of age (mean age, 66.3 [SD 10.9] years) were randomized: 636 patients (13.4%) were <55 years of age, 1242 (26.2%) were 55 to 64 years of age, 1717 (36.2%) were 65 to 74 years of age, and 1149 (24.2%) were ≥75 years of age. The rate of the primary outcome (per 100 person-years, placebo arm) in each age group was 13.6 (95% CI, 10.4-17.9), 15.7 (95% CI, 13.2-18.7), 15.1 (95% CI, 13.1-17.5), and 18.0 (95% CI, 15.2-21.4) with corresponding dapagliflozin/placebo hazard ratios of 0.87 (95% CI, 0.60-1.28), 0.71 (95% CI, 0.55-0.93), 0.76 (95% CI, 0.61-0.95), and 0.68 (95% CI, 0.53-0.88; P for interaction=0.76). Consistent benefits were observed for the components of the primary outcome, all-cause mortality, and symptoms. Although adverse events and study drug discontinuation increased with age, neither was significantly more common with dapagliflozin in any age group. CONCLUSIONS: Dapagliflozin reduced the risk of death and worsening heart failure and improved symptoms across the broad spectrum of age studied in DAPA-HF. There was no significant imbalance in tolerability or safety events between dapagliflozin and placebo, even in elderly individuals. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03036124.

5.
Circulation ; 141(2): 90-99, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31736335

RESUMO

BACKGROUND: Goals of management in patients with heart failure and reduced ejection fraction include reducing death and hospitalizations, and improving health status (symptoms, physical function, and quality of life). In the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure), sodium-glucose cotransporter-2 inhibitor, dapagliflozin, reduced death and hospitalizations, and improved symptoms in patients with heart failure and reduced ejection fraction. In this analysis, we examine the effects of dapagliflozin on a broad range of health status outcomes, using the Kansas City Cardiomyopathy Questionnaire (KCCQ). METHODS: KCCQ was evaluated at randomization, 4 and 8 months. Patients were divided by baseline KCCQ total symptom score (TSS); Cox proportional hazards models examined the effects of dapagliflozin on clinical events across these subgroups. We also evaluated the effects of dapagliflozin on KCCQ-TSS, clinical summary score, and overall summary score. Responder analyses were performed to compare proportions of dapagliflozin versus placebo-treated patients with clinically meaningful changes in KCCQ at 8 months. RESULTS: A total of 4443 patients had available KCCQ at baseline (median KCCQ-TSS, 77.1 [interquartile range, 58.3-91.7]). The effects of dapagliflozin vs placebo on reducing cardiovascular death or worsening heart failure were consistent across the range of KCCQ-TSS (lowest to highest tertile: hazard ratio, 0.70 [95% CI, 0.57-0.86]; hazard ratio, 0.77 [95% CI, 0.61-0.98]; hazard ratio, 0.62 [95% CI, 0.46-0.83]; P for heterogeneity=0.52). Patients treated with dapagliflozin had greater improvement in mean KCCQ-TSS, clinical summary score, and overall summary score at 8 months (2.8, 2.5 and 2.3 points higher versus placebo; P<0.0001 for all). Fewer patients treated with dapagliflozin had a deterioration in KCCQ-TSS (odds ratio, 0.84 [95% CI, 0.78-0.90]; P<0.0001); and more patients had at least small, moderate, and large improvements (odds ratio, 1.15 [95% CI, 1.08-1.23]; odds ratio, 1.15 [95% CI, 1.08-1.22]; odds ratio, 1.14 [95% CI, 1.07-1.22]; number needed to treat=14, 15, and 18, respectively; P<0.0001 for all; results consistent for KCCQ clinical summary score and overall summary score). CONCLUSIONS: Dapagliflozin reduced cardiovascular death and worsening heart failure across the range of baseline KCCQ, and improved symptoms, physical function, and quality of life in patients with heart failure and reduced ejection fraction. Furthermore, dapagliflozin increased the proportion of patients experiencing at least small, moderate, and large improvements in health status; these effects were clinically important. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03036124.

6.
Am Heart J ; 219: 70-77, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31726422

RESUMO

BACKGROUND: Guidelines for managing patients with atherosclerotic cardiovascular disease (ASCVD) recommend statin therapy initially. Target levels/goals for low-density lipoprotein-cholesterol (LDL-C) were initially included, subsequently de-emphasized in 2013, and then re-introduced as thresholds, leading to confusion in clinical practice. We designed a multicenter, observational registry of patients with ASCVD, to describe and track LDL-C treatment patterns in the United States over time. METHODS: Patients with ASCVD receiving any pharmacologic lipid-lowering therapy were eligible for enrollment in one of three cohorts: 1) currently receiving a proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i), or not receiving PCSK9i with 2) LDL-C 70-99 mg/dL, or 3) LDL-C ≥100 mg/dL. Patients undergo a 1-year retrospective chart review, followed by chart reviews and phone interviews every 6 months for 2 years. RESULTS: A total of 5006 patients were enrolled at 119 centers. Mean age was 68 years, 40% of patients were female, 86% were white, 80% had coronary artery disease, and 33% had type 2 diabetes mellitus. Among those not on a PCSK9i, high-intensity statins and ezetimibe were utilized in only 44% and 9%, respectively. Among women vs men, only 36.6% vs 48.2% received high-intensity statins (P < .001). Among patients on a PCSK9i, only one-third were receiving a statin, suggesting statin intolerance is a driver of PCSK9i use at present. CONCLUSION: Our data on current practice in the US continue to illustrate that high-intensity statins and ezetimibe are underutilized in at-risk patients outside of clinical trials, particularly women. This study will track temporal changes in treatment patterns and identify opportunities for improvement in lipid management in patients with ASCVD.

7.
Lancet Diabetes Endocrinol ; 8(1): 27-35, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31862149

RESUMO

BACKGROUND: Cardiovascular and kidney outcome trials have shown that sodium-glucose co-transporter-2 (SGLT2) inhibitors slow progression of chronic kidney disease in patients with type 2 diabetes with or without chronic kidney disease. The aim of this study was to assess whether these benefits extend to patients with type 2 diabetes treated in routine clinical practice. METHODS: CVD-REAL 3 was a multinational observational cohort study in which new users of SGLT2 inhibitors and other glucose-lowering drugs with measurements of estimated glomerular filtration rate (eGFR) before and after (within 180 days) initiation were identified via claims, medical records, and national registries in Israel, Italy, Japan, Taiwan, and the UK. Propensity scores for SGLT2 inhibitor initiation were developed in each country, with 1:1 matching with initiators of other glucose-lowering drugs. Propensity score included (in addition to other clinical and demographic variables) baseline eGFR and eGFR slope before SGLT2 inhibitor or other glucose-lowering drug initiation. The main outcome measure was rate of eGFR decline (slope) calculated with a linear mixed regression model. Differences in eGFR slope between SGLT2 inhibitors and other glucose-lowering drugs were calculated and pooled. We also assessed a composite outcome of 50% eGFR decline or end-stage kidney disease. FINDINGS: After propensity matching, there were 35 561 episodes of treatment initiation in each group, from 65 231 individual patients. Dapagliflozin, empagliflozin, canagliflozin, ipragliflozin, tofogliflozin, and luseogliflozin accounted for 57·9%, 34·1%, 5·7%, 1·4%, 0·5%, and 0·4% of SGLT2 inhibitor initiation episodes, respectively. At baseline, 29 363 (41·3%) of 71 122 initiations were in women, mean age was 61·3 years, mean HbA1c was 72 mmol/mol (8·71%), and mean eGFR was 90·7 mL/min per 1·73 m2. During follow-up, SGLT2 inhibitor initiation was associated with reduced eGFR decline (difference in slope for SGLT2 inhibitors vs other glucose-lowering drugs 1·53 mL/min per 1·73 m2 per year, 95% CI 1·34-1·72, p<0·0001). During a mean follow-up of 14·9 months, 351 composite kidney outcomes occurred: 114 (3·0 events per 10 000 patient-years) among initiators of SGLT2 inhibitors and 237 (6·3 events per 10 000 patient-years) among initiators of other glucose-lowering drugs (hazard ratio 0·49, 95% CI 0·35-0·67; p<0·0001). These findings were consistent across countries (pheterogeneity 0·10) and prespecified subgroups. INTERPRETATION: In this large, international, real-world study of patients with type 2 diabetes, initiation of SGLT2 inhibitor therapy was associated with a slower rate of kidney function decline and lower risk of major kidney events compared with initiation of other glucose-lowering drugs. These data suggest that the benefits of SGLT2 inhibitors on kidney function identified in clinical trials seem to be largely generalisable to clinical practice. FUNDING: AstraZeneca.

8.
Diabetes Obes Metab ; 22(1): 66-78, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31468637

RESUMO

AIM: To assess glycaemic control and factors associated with poor glycaemic control at initiation of second-line therapy in the DISCOVER programme. MATERIALS AND METHODS: DISCOVER (NCT02322762 and NCT02226822) comprises two similar prospective observational studies of 15 992 people with type 2 diabetes (T2D) initiating second-line glucose-lowering therapy in 38 countries across six regions (Africa, Americas, South-East Asia, Eastern Mediterranean, Europe and Western Pacific). Data were collected using a standardized case report form. Glycated haemoglobin (HbA1c) levels were measured according to standard clinical practice in each country, and factors associated with poor glycaemic control (HbA1c >8.0%) were evaluated using hierarchical regression models. RESULTS: HbA1c levels were available for 80.9% of patients (across-region range [ARR] 57.5%-97.5%); 92.2% (ARR 59.2%-99.1%) of patients had either HbA1c or fasting plasma glucose levels available. The mean HbA1c was 8.3% (ARR 7.9%-8.7%). In total, 26.7% of patients had an HbA1c level ≥9.0%, with the highest proportions in South-East Asia (35.6%). Factors associated with having HbA1c >8.0% at initiation of second-line therapy included low education level, low country income, and longer time since T2D diagnosis. CONCLUSIONS: The poor levels of glycaemic control at initiation of second-line therapy suggest that intensification of glucose-lowering treatment is delayed in many patients with T2D. In some countries, HbA1c levels are not routinely measured. These findings highlight an urgent need for interventions to improve monitoring and management of glycaemic control worldwide, particularly in lower-middle- and upper-middle-income countries.

9.
Circulation ; 140(25): 2108-2118, 2019 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-31841369

RESUMO

Following regulatory guidance set forth in 2008 by the US Food and Drug Administration for new drugs for type 2 diabetes mellitus, many large randomized, controlled trials have been conducted with the primary goal of assessing the safety of antihyperglycemic medications on the primary end point of major adverse cardiovascular events, defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Heart failure (HF) was not specifically mentioned in the US Food and Drug Administration guidance and therefore it was not a focus of these studies when planned. Several trials subsequently showed the impact of antihyperglycemic drugs on HF outcomes, which were not originally specified as the primary end point of the trials. The most impressive finding has been the substantial and consistent risk reduction in HF hospitalization seen across 4 trials of sodium glucose cotransporter 2 inhibitors. However, to date, these results have not led to regulatory approval of any of these drugs for a HF indication or a recommendation for use by US HF guidelines. It is therefore important to explore to what extent persuasive treatment effects on nonprimary end points can be used to support regulatory claims and guideline recommendations. This topic was discussed by researchers, clinicians, industry sponsors, regulators, and representatives from professional societies, who convened on the US Food and Drug Administration campus on March 6, 2019. This report summarizes these discussions and the key takeaway messages from this meeting.

10.
Am J Cardiol ; 124 Suppl 1: S12-S19, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31741435

RESUMO

Type 2 diabetes mellitus has long been recognized as a major risk factor for adverse atherosclerotic cardiovascular disease events; however, recent data indicate that heart failure is now emerging as the most common and morbid cardiovascular complication of type 2 diabetes mellitus. When heart failure develops in patients with type 2 diabetes, prognosis is ominous, highlighting the need for glucose-lowering therapies that can prevent heart failure, improve outcomes, or both. Prior to 2008, there was a paucity of randomized controlled trials evaluating long-term cardiovascular outcomes with glucose-lowering therapies. This changed after guidance on the assessment of novel glucose-lowering agents was issued by both the US Food and Drug Administration and the European Medicines Agency. Since then, significant progress has been made as a result of large cardiovascular outcomes trials. Though randomized controlled trials on insulin, sulfonylureas, and metformin are still limited, cardiovascular outcomes trials on newer glucose-lowering agents have included hundreds of thousands of patients with multiple years of follow-up. The increased risk of thiazolidinediones on heart failure had been well theorized and is now established; however, the increase in heart failure hospitalization with certain dipeptidyl peptidase-4 inhibitors was unexpected. The reasons for discrepancies with regard to heart failure risk with different dipeptidyl peptidase-4 inhibitors remain unclear, and further mechanistic studies are ongoing. The role of glucagon-like peptide-1 receptor agonists among patients with heart failure also remains unclear, and their effects may differ in patients with and without established heart failure, particularly those with decompensated heart failure with reduced ejection fraction.

11.
Am J Nephrol ; 50(6): 473-480, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31658466

RESUMO

BACKGROUND: Sodium zirconium cyclosilicate (SZC; formerly ZS-9) is a selective potassium (K+) binder for treatment of hyperkalemia. An open-label extension (OLE) of the -HARMONIZE study evaluated efficacy and safety of SZC for ≤11 months. METHODS: Patients from HARMONIZE with point-of-care device i-STAT K+ 3.5-6.2 mmol/L received once-daily SZC 5-10 g for ≤337 days. End points included achievement of mean serum K+ ≤5.1 mmol/L (primary) or ≤5.5 mmol/L (secondary). RESULTS: Of 123 patients who entered the extension (mean serum K+ 4.8 mmol/L), 79 (64.2%) completed the study. The median daily dose of SZC was 10 g (range 2.5-15 g). The primary end point was achieved by 88.3% of patients, and 100% achieved the secondary end point. SZC was well tolerated with no new safety concerns. CONCLUSION: In the HARMONIZE OLE, most patients maintained mean serum K+ within the normokalemic range for ≤11 months during ongoing SZC treatment.

12.
J Am Coll Cardiol ; 74(15): 1926-1942, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31601373

RESUMO

Although significant progress has been made to reduce the global burden of cardiovascular disease, efforts have focused primarily on treatment of manifest disease rather than on prevention of events. An enormous opportunity exists to transition focus from intervention to providing equal attention to prevention of cardiovascular disease. The nascent specialty of "preventive cardiology" is emerging from the background of long-established services such as lipid, diabetes, hypertension, and general cardiology clinics. It is incumbent on the cardiology community to invest in cardiovascular prevention because past gains are threatened with the rising tide of obesity and diabetes. Now is the time to establish a dedicated preventive cardiology subspecialty to train the clinicians of the future. This American College of Cardiology Council Perspective aims to define the need for preventive cardiology as a unique subspecialty, broaches controversies, provides a structure for future training and education, and identifies possible paths forward to professional certification.

13.
N Engl J Med ; 381(21): 1995-2008, 2019 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-31535829

RESUMO

BACKGROUND: In patients with type 2 diabetes, inhibitors of sodium-glucose cotransporter 2 (SGLT2) reduce the risk of a first hospitalization for heart failure, possibly through glucose-independent mechanisms. More data are needed regarding the effects of SGLT2 inhibitors in patients with established heart failure and a reduced ejection fraction, regardless of the presence or absence of type 2 diabetes. METHODS: In this phase 3, placebo-controlled trial, we randomly assigned 4744 patients with New York Heart Association class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either dapagliflozin (at a dose of 10 mg once daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of worsening heart failure (hospitalization or an urgent visit resulting in intravenous therapy for heart failure) or cardiovascular death. RESULTS: Over a median of 18.2 months, the primary outcome occurred in 386 of 2373 patients (16.3%) in the dapagliflozin group and in 502 of 2371 patients (21.2%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P<0.001). A first worsening heart failure event occurred in 237 patients (10.0%) in the dapagliflozin group and in 326 patients (13.7%) in the placebo group (hazard ratio, 0.70; 95% CI, 0.59 to 0.83). Death from cardiovascular causes occurred in 227 patients (9.6%) in the dapagliflozin group and in 273 patients (11.5%) in the placebo group (hazard ratio, 0.82; 95% CI, 0.69 to 0.98); 276 patients (11.6%) and 329 patients (13.9%), respectively, died from any cause (hazard ratio, 0.83; 95% CI, 0.71 to 0.97). Findings in patients with diabetes were similar to those in patients without diabetes. The frequency of adverse events related to volume depletion, renal dysfunction, and hypoglycemia did not differ between treatment groups. CONCLUSIONS: Among patients with heart failure and a reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes. (Funded by AstraZeneca; DAPA-HF ClinicalTrials.gov number, NCT03036124.).


Assuntos
Compostos Benzidrílicos/uso terapêutico , Glucosídeos/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Idoso , Compostos Benzidrílicos/efeitos adversos , Fármacos Cardiovasculares/uso terapêutico , Doenças Cardiovasculares/mortalidade , Terapia Combinada , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Quimioterapia Combinada , Feminino , Glucosídeos/efeitos adversos , Hemoglobina A Glicada/análise , Insuficiência Cardíaca/complicações , Hospitalização , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Volume Sistólico/efeitos dos fármacos , Disfunção Ventricular Esquerda/complicações , Disfunção Ventricular Esquerda/tratamento farmacológico
14.
Circulation ; 140(18): 1463-1476, 2019 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-31524498

RESUMO

BACKGROUND: Outcome trials in patients with type 2 diabetes mellitus have demonstrated reduced hospitalizations for heart failure (HF) with sodium-glucose co-transporter-2 inhibitors. However, few of these patients had HF, and those that did were not well-characterized. Thus, the effects of sodium-glucose co-transporter-2 inhibitors in patients with established HF with reduced ejection fraction, including those with and without type 2 diabetes mellitus, remain unknown. METHODS: DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients with HF with Reduced Ejection Fraction) was an investigator-initiated, multi-center, randomized controlled trial of HF patients with left ventricular ejection fraction ≤40%, New York Heart Association (NYHA) class II-III, estimated glomerular filtration rate ≥30 mL/min/1.73m2, and elevated natriuretic peptides. In total, 263 patients were randomized to dapagliflozin 10 mg daily or placebo for 12 weeks. Dual primary outcomes were (1) mean NT-proBNP (N-terminal pro b-type natriuretic peptide) and (2) proportion of patients with ≥5-point increase in HF disease-specific health status on the Kansas City Cardiomyopathy Questionnaire overall summary score, or a ≥20% decrease in NT-proBNP. RESULTS: Patient characteristics reflected stable, chronic HF with reduced ejection fraction with high use of optimal medical therapy. There was no significant difference in average 6- and 12-week adjusted NT-proBNP with dapagliflozin versus placebo (1133 pg/dL (95% CI 1036-1238) vs 1191 pg/dL (95% CI 1089-1304), P=0.43). For the second dual-primary outcome of a meaningful improvement in Kansas City Cardiomyopathy Questionnaire overall summary score or NT-proBNP, 61.5% of dapagliflozin-treated patients met this end point versus 50.4% with placebo (adjusted OR 1.8, 95% CI 1.03-3.06, nominal P=0.039). This was attributable to both higher proportions of patients with ≥5-point improvement in Kansas City Cardiomyopathy Questionnaire overall summary score (42.9 vs 32.5%, adjusted OR 1.73, 95% CI 0.98-3.05), and ≥20% reduction in NT-proBNP (44.0 vs 29.4%, adjusted OR 1.9, 95% CI 1.1-3.3) by 12 weeks. Results were consistent among patients with or without type 2 diabetes mellitus, and other prespecified subgroups (all P values for interaction=NS). CONCLUSIONS: In patients with heart failure and reduced ejection fraction, use of dapagliflozin over 12 weeks did not affect mean NT-proBNP but increased the proportion of patients experiencing clinically meaningful improvements in HF-related health status or natriuretic peptides. Benefits of dapagliflozin on clinically meaningful HF measures appear to extend to patients without type 2 diabetes mellitus. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02653482.

15.
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
17.
Diabetes Obes Metab ; 21(11): 2474-2485, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31297947

RESUMO

AIM: To evaluate treatment data from DISCOVER (NCT02322762 and NCT02226822), a global, prospective, observational study programme of patients with type 2 diabetes initiating a second-line glucose-lowering therapy. MATERIALS AND METHODS: Data were collected using a standardized case report form. First- and second-line treatments were assessed in 14 668 patients from 37 countries across six regions. Among patients prescribed first-line metformin monotherapy, Firth logistic regression models were used to assess factors associated with second-line treatment choices. RESULTS: The most common first-line therapies were metformin monotherapy (57.9%) and combinations of metformin with a sulphonylurea (14.6%). The most common second-line therapies were combinations of metformin with other agents (72.2%), including dipeptidyl peptidase-4 (DPP-4) inhibitors (25.1%) or sulphonylureas (21.3%). Among patients prescribed first-line metformin monotherapy, the most common second-line therapies were combinations of metformin with a DPP-4 inhibitor [32.8%; across-region range (ARR): 2.4%-51.3%] or a sulphonylurea (30.0%; ARR: 18.3%-63.6%); only a few patients received combinations of metformin with sodium-glucose co-transporter-2 inhibitors (6.7%; ARR: 0.0%-10.8%) or glucagon-like peptide-1 receptor agonists (1.9%; ARR: 0.1%-4.5%). Both clinical and non-medical factors were associated with choice of second-line therapy after metformin monotherapy. CONCLUSIONS: Fewer patients than expected received metformin monotherapy at first line, and the use of newer therapies at second line was uncommon in some regions of the world. Patients' socioeconomic status was associated with treatment patterns, suggesting that therapy choices are influenced by cost and access.

18.
Eur J Heart Fail ; 21(11): 1402-1411, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31309699

RESUMO

BACKGROUND: The aims of this study were to: (i) report the baseline characteristics of patients enrolled in the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure (DAPA-HF) trial, (ii) compare DAPA-HF patients to participants in contemporary heart failure (HF) registries and in other recent HF trials, and (iii) compare individuals with diabetes, pre-diabetes and a normal glycated haemoglobin (HbA1c) in DAPA-HF. METHODS AND RESULTS: Adults with HF in New York Heart Association functional class ≥ II, a left ventricular ejection fraction ≤ 40%, an elevated N-terminal pro-B-type natriuretic peptide concentration and receiving standard treatment were eligible for DAPA-HF, which is comparing dapagliflozin 10 mg once daily to matching placebo. In patients without a history of diabetes, previously undiagnosed diabetes was defined as a confirmed HbA1c ≥ 6.5%. Among patients without known or undiagnosed diabetes, pre-diabetes was defined as a HbA1c ≥ 5.7% The remainder of patients, with a HbA1c < 5.7%, were defined as normoglycaemic. Of the 4744 patients (mean age 66 years; 23% women) randomized, 42% had known diabetes and 3% undiagnosed diabetes. Of the remainder, 67% had pre-diabetes and 33% normal HbA1c. Overall, DAPA-HF patients were generally similar to those in recent registries and in relevant trials and had high levels of background therapy: 94% angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitor, 96% beta-blocker, and 71% mineralocorticoid receptor antagonist; 26% had a defibrillator. Patients with diabetes had worse HF status, more co-morbidity, and greater renal impairment but received similar HF therapy. Patients with diabetes received non-insulin hypoglycaemic therapy alone in 49%, insulin alone in 11%, both in 14%, and none in 26%. CONCLUSIONS: Patients randomized in DAPA-HF were similar to those in other contemporary HF with reduced ejection fraction (HFrEF) registries and trials. These patients were receiving recommended HFrEF therapy and those with diabetes were also treated with conventional glucose-lowering therapy. Consequently, DAPA-HF will test the incremental efficacy and safety of dapagliflozin in HFrEF patients with and without diabetes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03036124.

19.
Circulation ; 140(7): e294-e324, 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31167558

RESUMO

Type 2 diabetes mellitus is a risk factor for incident heart failure and increases the risk of morbidity and mortality in patients with established disease. Secular trends in the prevalence of diabetes mellitus and heart failure forecast a growing burden of disease and underscore the need for effective therapeutic strategies. Recent clinical trials have demonstrated the shared pathophysiology between diabetes mellitus and heart failure, the synergistic effect of managing both conditions, and the potential for diabetes mellitus therapies to modulate the risk of heart failure outcomes. This scientific statement on diabetes mellitus and heart failure summarizes the epidemiology, pathophysiology, and impact of diabetes mellitus and its control on outcomes in heart failure; reviews the approach to pharmacological therapy and lifestyle modification in patients with diabetes mellitus and heart failure; highlights the value of multidisciplinary interventions to improve clinical outcomes in this population; and outlines priorities for future research.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA