Efficacy of Dapagliflozin According to Geographic Location of Patients With Heart Failure

Background: Because clinical characteristics and prognosis vary by geographic region in patients with heart failure (HF), the response to treatment may also vary. A previous report suggested that the efficacy of sodium-glucose cotransporter-2 inhibitor efficacy in heart failure with reduced ejection fraction (HFrEF) may be modified by region. Objectives: The goal of this study was to examine the efficacy and safety of dapagliflozin in patients with HF according to geographic region. Methods: We conducted a patient-level pooled analysis of the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure) trials, which evaluated the effects of dapagliflozin in HFrEF and heart failure with mildly reduced ejection fraction (HFmrEF)/heart failure with preserved ejection fraction (HFpEF), respectively. The primary outcome was the composite of worsening HF or cardiovascular death. Results: Among 11,007 patients, 5,159 (46.9%) were enrolled in Europe, 1,528 (13.9%) in North America, 1,998 (18.2%) in South America, and 2,322 (21.1%) in Asia. The rate of the primary outcome (per 100 person-years) was higher in North America (13.9 [95% CI: 12.5-15.4]) than in other regions: Europe 10.8 (95% CI: 10.1-11.5), South America 10.0 (95% CI: 9.0-11.1), and Asia 10.5 (95% CI: 9.5-11.5). The benefit of dapagliflozin on the primary outcome was not modified by region: dapagliflozin vs placebo HR: Europe, 0.85 (95% CI: 0.75-0.96); North America, 0.75 (95% CI: 0.61-0.93); South America, 0.72 (95% CI: 0.58-0.89); and Asia, 0.74 (95% CI: 0.61-0.91) (P interaction = 0.40). This was the same when evaluated separately for HFrEF (P interaction = 0.39) and HFmrEF/HFpEF (P interaction = 0.84). Patients in North America discontinued randomized treatment more frequently than did those elsewhere (placebo discontinuation: 21.8% in North America vs 6.4% in South America), but discontinuation rates did not differ between placebo and dapagliflozin by region. Conclusions: The efficacy and safety of dapagliflozin were consistent across global regions despite geographic differences in patient characteristics, background treatment, and event rates.</p

Dapagliflozin and quality of life measured using the EuroQol 5-Dimension questionnaire in patients with HFrEF and HFmrEF/HFpEF

Aims: Although much is known about the usefulness of heart failure (HF)-specific instruments for assessing patient well-being, less is known about the value of generic instruments for the measurement of health-related quality of life (HRQL) in HF. The aim of this study was to assess the relationship between the EuroQol 5-dimension 5-level (EQ-5D-5L) visual analogue scale (VAS) and index scores, clinical characteristics, and outcomes in patients with HF and the effect of dapagliflozin on these scores. Methods and results: We performed a patient-level pooled analysis of the DAPA-HF and DELIVER trials, which investigated the effectiveness and safety of dapagliflozin in patients with HF and reduced ejection fraction (HFrEF) and mildly reduced/preserved ejection fraction (HFmrEF/HFpEF), respectively. Patients reporting higher (better) EQ-5D-5L VAS and index scores had a lower prevalence of comorbidities, including atrial fibrillation and hypertension, than patients with a worse score. They were also more likely to have better investigator-reported (New York Heart Association class) and patient-self-reported (Kansas City Cardiomyopathy Questionnaire) health status and lower median N-terminal pro-B-type natriuretic peptide levels. Compared to patients with the lowest scores (Q1), those with higher EQ-5D-5L VAS scores had better outcomes: the hazard ratio for the composite of cardiovascular death or worsening HF was 0.81 (95% confidence interval 0.72–0.91) in Q2, 0.74 (0.65–0.84) in Q3, and 0.62 (0.54–0.72) in Q4. The risk of each component of the composite outcome, and all-cause death, was also lower in patients with better scores. Similar findings were observed for the index score. Treatment with dapagliflozin improved both EQ-5D-5L VAS and index scores across the range of ejection fraction. Conclusions: Both higher (better) EQ-5D-5L VAS and index scores were associated with better outcomes. Dapagliflozin treatment improved EQ-5D-5L VAS and index scores, irrespective of ejection fraction

Efficacy and safety of dapagliflozin according to frailty in patients with heart failure: a prespecified analysis of the DELIVER trial

Background: Frailty is increasing in prevalence and because frail patients are often perceived to have a less favorable benefit/risk profile, they may be less likely to receive new pharmacological treatments. We investigated the efficacy and tolerability of dapagliflozin according to frailty status in patients with heart failure and mildly reduced and preserved ejection fraction randomized in DELIVER. Methods: Frailty was measured using the Rockwood cumulative deficit approach. The primary endpoint was time to a first worsening heart failure event or cardiovascular death. Results: Of the 6263 patients randomized, a Frailty Index (FI) was calculable in 6258. In total, 2,354 (37.6%) patients had class 1 frailty (FI &lt;0.210, i.e., not frail), 2,413 (38.6%) were in class 2 (FI 0.211-0.310, i.e., more frail), and 1,491 (23.8%) had class 3 frailty (FI &gt;0.311, i.e., most frail). Greater frailty was associated with a higher rate of the primary endpoint (per 100 person years): FI class 1, 6.3 (95% CI 5.7-7.1); class 2, 8.3 (7.5-9.1); and class 3, 13.4 (12.1-14.7), P&lt;0.001. The effect of dapagliflozin (as a hazard ratio) on the primary endpoint from FI class 1 to 3 was: 0.85 (95% CI, 0.68-1.06); 0.89 (0.74-1.08); and 0.74 (0.61-0.91), respectively (Pinteraction=0.40). Although frailer patients had worse KCCQ scores at baseline, the improvement with dapagliflozin was greater than in less frail patients: placebo-corrected improvement in KCCQ-OSS at 4 months FI class 1, 0.3 (95% CI -0.9 to 1.4); class 2, 1.5 (0.3-2.7); and class 3, 3.4 (1.7-5.1) [Pinteraction=0.021]. Adverse reactions and treatment discontinuation, while more frequent in frailer patients, were not more common with dapagliflozin than placebo, irrespective of frailty class. Conclusions: In DELIVER, frailty was common and associated with worse outcomes. The benefit of dapagliflozin was consistent across the range of frailty studied. The improvement in health-related quality of life with dapagliflozin occurred early and was greater in patients with greater frailty

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p&lt;0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (&lt;1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (&lt;1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Clinical correlates of white matter lesions in younger alcohol addicts

Einleitung: Zahlreiche Untersuchungen haben belegt, dass die bekannten zerebrovaskulären Risikofaktoren mit einem vermehrten Auftreten von Läsionen der weißen Substanz (WSL) verknüpft sind. Die Datenbasis bezüglich der Rolle des Alkohols bei der Entstehung von WSL ist bis heute schlecht. Ziel dieser Untersuchung ist es, die Prävalenz von WSL bei jüngeren Alkoholkranken unter Berücksichtigung anderer bekannter sowie potentieller Risikofaktoren zu ermitteln. Methoden: N=100 Patienten im Alter von 25-60 Jahren (Durchschnittsalter 44 Jahre), welche die Diagnosekriterien einer Alkoholabhängigkeit (ICD F10.2) erfüllten, wurden mit einem 1,5 Tesla Magnetresonanstomographen (MRT), nach einem standardisierten Protokoll, auf das Vorkommen von WSL sowie deren Lokalisation und Ausbreitung hin untersucht. Alle Patienten befanden sich in freiwilliger stationärer Behandlung. Es wurden Daten zu Vorerkrankungen, Bildung, Beruf, Schadstoffexposition, Ernährung, Rauchen, Laborwerte, Vitaminspiegel, ApoE-Genotyp sowie Daten zu Parametern der Alkoholkrankheit und zum Konsum anderer Rauschmittel als Alkohol erhoben. Ergebnisse: WSL konnten bei 39 Patienten gefunden werden. 34 hatten subkortikale fokale WSL (≤ 5 mm), 13 periventrikuläre WSL (zwölf ≤ 5 mm, einer 6-10 mm). 26 hatten ausschließlich subkortikale, fünf ausschließlich periventrikuläre und acht WSL beider Lokalisationen. Signifikante positive Assoziationen fanden sich zu höherem Alter, größerer täglicher Trinkmenge, niedrigerem Hämatokrit und niedrigerer Kreatinkinase. Grenzsignifikante Assoziationen fanden sich zu häufigerer Malnutrition, seltenerem Verzehr von Milchprodukten und einem niedrigeren Hämoglobinwert. Die Patienten der fünften Lebensdekade hatten signifikant häufiger WSL und gaben signifikant größere tägliche Trinkmengen an. Die bekannten zerebrovaskulären Risikofaktoren waren nicht mit WSL assoziiert. Diskussion: Die Daten dieser Studie an jüngeren Alkoholkranken deuten darauf hin, dass Menge und Dauer eines erhöhten Alkoholkonsums, in Kombination m it einem höheren Lebensalter, schon ab der fünften Lebensdekade ein Risikofaktor für WSL sind. Die meisten Patienten hatten subkortikale WSL. Diese werden eher mit zerebrovaskulären Risikofaktoren als mit einem höheren Lebensalter in Verbindung gebracht. Auch die Ernährung scheint eine Rolle zu spielen. Der Verzehr von Milchprodukten könnte einen protektiven Effekt haben. Die signifikant niedrigeren Werte für Hämatokrit und Kreatinkinase sowie der grenzsignifikant niedrigere Hämoglobinwert könnten die Folge eines alkoholinduzierten Diabetes insipidus sein. Die von anderen Autoren formulierte Annahme, dass es einen Zusammenhang zwischen Veränderungen des Blutbildes sowie der Hirnmorphologie und der Alkoholkrankheit gibt, können wir mit unseren Daten unterstützen. Ebenso die These, dass ein erhöhter Alkoholkonsum ein Risikofaktor für eine im späteren Leben erhöhte Vulnerabilität der weißen Substanz ist. Wir nehmen an, dass ein erhöhter Alkoholkonsum Alterungsprozesse des zentralen Nervensystems beschleunigt und das Risiko, WSL bereits in jüngeren Jahren zu entwickeln, erhöht

Metabolically healthy obesity (MHO) in the Malmö diet cancer study - Epidemiology and prospective risks

BACKGROUND/AIMS: Metabolically healthy obesity (MHO) remains controversial, since the underlying mechanisms behind this phenotype remain unclear. We aimed to investigate the characteristics of MHO, as well as prospective risks.METHOD: A cross-sectional analysis was carried out in a subsample of 3812 obese subjects selected from the Malmo diet cancer study (n=28,403). Subjects with MHO (n=1182) were defined by having no records of hospitalization for somatic disorders prior to baseline examination. MHO subjects were further compared to subjects with metabolically unhealthy obesity, MUO (obese individuals with at least one recorded hospitalization: n=2630), and all non-obese cohort controls (NOC; n=24,591). Moreover, prospective risk analyses for incident cardiovascular (CV) morbidity and mortality were carried out.RESULTS: Compared to MUO individuals, MHO individuals reported a significantly lower proportion of sedentary life style (p=0.009), but also significantly lower HbA1c (p=0.012), fasting glucose (p=0.001) and triglyceride levels (p=0.011) than MUO. Cox-regression analysis (follow-up 20±6 years) showed both a significantly lower all-cause mortality risk for MHO individuals as compared to MUO (p=0.001), as well as lower incident CV morbidity risk (p=0.001). When comparing MHO individuals to NOC, there were no significant differences in neither mortality risk nor incident CV morbidity risk.CONCLUSION: Compared to MUO individuals, MHO individuals presented with a higher level of physical activity, a more favorable lipid- and glucose profile and a lower prospective risk of total mortality and CV morbidity during 20-years follow-up. Notably, no significant differences could be seen in mortality and CV morbidity risks when comparing MHO subjects to non-obese controls

Orthostatic Hypotension and Cardiac Changes After Long-Term Follow-Up.

Orthostatic hypotension (OH) increases the risk of incident cardiovascular disease (CVD) and all-cause mortality in population-based cohort studies. Whether OH is associated with development of cardiac anomalies has not been sufficiently explored

Physical Inactivity Is Associated With Post-discharge Mortality and Re-hospitalization Risk Among Swedish Heart Failure Patients-The HARVEST-Malmö Study

BackgroundSeveral studies have examined the role of physical activity as a predictor of heart failure (HF) mortality and morbidity. Here, we aimed to evaluate the role of self-reported physical activity as an independent risk factor of post-discharge mortality and re-hospitalization in patients hospitalized for HF, as well as study the association between physical activity and 92 plasma proteins associated with cardiovascular disease (CVD). MethodsFour-hundred-and-thirty-four patients hospitalized for HF (mean age 75 years; 32% women) were screened for physical activity derived from questionnaires in the Swedish national public health survey. The median follow-up time to death and re-hospitalization was 835 (interquartile range, 390-1,432) and 157 (43-583) days, respectively. Associations between baseline reported physical activity, mortality and re-hospitalization risk were analyzed using multivariable Cox regression analysis. Plasma samples from 295 study participants were analyzed with a proximity extension assay consisting of 92 proteins. Associations between proteins and physical activity were explored using a false discovery rate of &lt;5%, and significant associations were taken forward to multivariate analyses. ResultsIn the multivariate Cox regression model, physical inactivity, defined as physical activity time &lt;1 h throughout the week was associated with increased risk of all-cause mortality (HR 1.71; CI95% 1.26-2.31; p = 5.9 x 10(-4)) as well as all-cause re-hospitalization (HR 1.27; CI95% 1.01-1.60; p = 0.038). Further, physical inactivity was associated with elevated plasma levels of Metalloproteinase inhibitor 4, Soluble interleukin 1 receptor-like 1, Elafin and Transferrin receptor protein 1, which are implicated in myocardial fibrosis, migration and apoptosis. ConclusionsSelf-reported low weekly physical activity is associated with increased risk of mortality and re-hospitalization in patients hospitalized for HF independent of traditional risk factors. Furthermore, physical inactivity was associated with elevated levels of 4 proteins linked to cardiovascular disease