The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab reduced LDL cholesterol and cardiovascular events in the FOURIER trial. In this prespecified analysis of FOURIER, we ...investigated the efficacy and safety of evolocumab by diabetes status and the effect of evolocumab on glycaemia and risk of developing diabetes.
FOURIER was a randomised trial of evolocumab (140 mg every 2 weeks or 420 mg once per month) versus placebo in 27 564 patients with atherosclerotic disease who were on statin therapy, followed up for a median of 2·2 years. In this prespecified analysis, we investigated the effect of evolocumab on cardiovascular events by diabetes status at baseline, defined on the basis of patient history, clinical events committee review of medical records, or baseline HbA
of 6·5% (48 mmol/mol) or greater or fasting plasma glucose (FPG) of 7·0 mmol/L or greater. The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, hospital admission for unstable angina, or coronary revascularisation. The key secondary endpoint was a composite of cardiovascular death, myocardial infarction, or stroke. We also assessed the effect of evolocumab on glycaemia, and on the risk of new-onset diabetes among patients without diabetes at baseline. HbA
was measured at baseline then every 24 weeks and FPG was measured at baseline, week 12, week 24, and every 24 weeks thereafter, and potential cases of new-onset diabetes were adjudicated centrally. In a post-hoc analysis, we also investigated the effects on glycaemia and diabetes risk in patients with prediabetes (HbA
5·7-6·4% 39-46 mmol/mol or FPG 5·6-6·9 mmol/L) at baseline. FOURIER is registered with ClinicalTrials.gov, number NCT01764633.
At study baseline, 11 031 patients (40%) had diabetes and 16 533 (60%) did not have diabetes (of whom 10 344 had prediabetes and 6189 had normoglycaemia). Evolocumab significantly reduced cardiovascular outcomes consistently in patients with and without diabetes at baseline. For the primary composite endpoint, the hazard ratios (HRs) were 0·83 (95% CI 0·75-0·93; p=0·0008) for patients with diabetes and 0·87 (0·79-0·96; p=0·0052) for patients without diabetes (p
=0·60). For the key secondary endpoint, the HRs were 0·82 (0·72-0·93; p=0·0021) for those with diabetes and 0·78 (0·69-0·89; p=0·0002) for those without diabetes (p
=0·65). Evolocumab did not increase the risk of new-onset diabetes in patients without diabetes at baseline (HR 1·05, 0·94-1·17), including in those with prediabetes (HR 1·00, 0·89-1·13). Levels of HbA
and FPG were similar between the evolocumab and placebo groups over time in patients with diabetes, prediabetes, or normoglycaemia. Among patients with diabetes at baseline, the proportions of patients with adverse events were 78·5% (4327 of 5513 patients) in the evolocumab group and 78·3% (4307 of 5502 patients) in the placebo group; among patients without diabetes at baseline, the proportions with adverse events were 76·8% (6337 of 8256 patients) in the evolocumab group and 76·8% (6337 of 8254 patients) in the placebo group.
PCSK9 inhibition with evolocumab significantly reduced cardiovascular risk in patients with and without diabetes. Evolocumab did not increase the risk of new-onset diabetes, nor did it worsen glycaemia. These data suggest evolocumab use in patients with atherosclerotic disease is efficacious and safe in patients with and without diabetes.
Amgen.
Aims To examine QT intervals corrected for heart rate (QTc) in adolescents with Type 1 diabetes compared with control subjects, and to determine associations with metabolic control and autonomic ...function. Methods Resting electrocardiogram recordings of 142 adolescents with Type 1 diabetes mean (sd) age 15.3 (2.0) years, diabetes duration 9.0 (3.5) years, HbA sub(1c) 71 (17) mmol/mol or 8.7 (1.6)% and 125 control subjects mean (sd) age 15.7 (2.5) years were used to calculate QTc duration and derive mean heart rate and heart rate variability (HRV) values. Linear and logistic regression models were used to examine the associations between QTc, metabolic control and autonomic function (HRV and pupillary function). Results QTc duration was not significantly different between subjects with Type 1 diabetes and control subjects (mean duration 392 vs 391 ms; P = 0.65). In the Type 1 diabetes group, QTc was positively associated with HbA sub(1c) beta = 4 (95% CI 2, 6); P < 0.001 and inversely associated with severe hypoglycaemic events beta = -10 (95% CI -20,-2); P = 0.01, less insulin/kg beta = -12 (95% CI -22, -2); P = 0.024 and less HRV. In the Type 1 diabetes group, QTc in the highest quintile ( greater than or equal to 409 ms) vs quintiles 1-4 had more pupillary abnormalities (83 vs 56%; P = 0.03), lower pupillary maximum constriction velocity (4.8 vs 5.3 mm/s; P = 0.04), higher heart rate (78 vs 72 beats per min; P = 0.02) and lower HRV (standard deviation of mean NN intervals 4.0 vs 4.3 ms, P = 0.004 and root-mean-square difference of successive NN intervals 3.7 vs 4.1 ms; P = 0.004). Conclusions Although there are concerns about hypoglycaemia in general in people with Type 1 diabetes, chronic hyperglycaemia, rather than intermittent hypoglycaemia, appears to be more deleterious to autonomic cardiac function, even in adolescence. Longer QTc was associated with higher HbA sub(1c) concentration, lower risk of hypoglycaemia and autonomic dysfunction. Longitudinal studies are warranted. What's new? * Longer QT interval corrected for heart rate (QTc) is associated with higher HbA sub(1c) concentration, less exogenous insulin and a lower rate of significant hypoglycaemia in adolescents with Type 1 diabetes. * This is the first study to show significant associations between abnormal pupillometry, cardiac autonomic dysfunction and longer QTc interval in adolescents with Type 1 diabetes. * A threshold of QTc > 409 ms in adolescents with Type 1 diabetes differentiates those most at risk of autonomic dysfunction, in addition to being female, having higher HbA sub(1c), BMI and total cholesterol. * Electrocardiogram screening to exclude long QTc syndromes and assess complication risk may be of value in routine complications assessment in young people with diabetes.
Abstract
Aims
To examine
QT
intervals corrected for heart rate (
QT
c) in adolescents with Type 1 diabetes compared with control subjects, and to determine associations with metabolic control and ...autonomic function.
Methods
Resting electrocardiogram recordings of 142 adolescents with Type 1 diabetes mean (
sd
) age 15.3 (2.0) years, diabetes duration 9.0 (3.5) years, HbA
1c
71 (17) mmol/mol or 8.7 (1.6)% and 125 control subjects mean (
sd
) age 15.7 (2.5) years were used to calculate
QT
c duration and derive mean heart rate and heart rate variability (HRV) values. Linear and logistic regression models were used to examine the associations between
QT
c, metabolic control and autonomic function (HRV and pupillary function).
Results
QT
c duration was not significantly different between subjects with Type 1 diabetes and control subjects (mean duration 392 vs 391 ms;
P
= 0.65). In the Type 1 diabetes group,
QT
c was positively associated with HbA
1c
β = 4 (95%
CI
2, 6);
P
< 0.001 and inversely associated with severe hypoglycaemic events β = ‐10 (95%
CI
‐20,‐2);
P
= 0.01, less insulin/kg β = ‐12 (95%
CI
‐22, ‐2);
P
= 0.024 and less HRV. In the Type 1 diabetes group,
QT
c in the highest quintile (≥409 ms) vs quintiles 1–4 had more pupillary abnormalities (83 vs 56%;
P
= 0.03), lower pupillary maximum constriction velocity (4.8 vs 5.3 mm/s;
P
= 0.04), higher heart rate (78 vs 72 beats per min;
P
= 0.02) and lower HRV (standard deviation of mean
NN
intervals 4.0 vs 4.3 ms,
P
= 0.004 and root‐mean‐square difference of successive
NN
intervals 3.7 vs 4.1 ms;
P
= 0.004).
Conclusions
Although there are concerns about hypoglycaemia in general in people with Type 1 diabetes, chronic hyperglycaemia, rather than intermittent hypoglycaemia, appears to be more deleterious to autonomic cardiac function, even in adolescence. Longer
QT
c was associated with higher HbA
1c
concentration, lower risk of hypoglycaemia and autonomic dysfunction. Longitudinal studies are warranted.
What's new?
Longer QT interval corrected for heart rate (QTc) is associated with higher HbA
1c
concentration, less exogenous insulin and a lower rate of significant hypoglycaemia in adolescents with Type 1 diabetes.
This is the first study to show significant associations between abnormal pupillometry, cardiac autonomic dysfunction and longer QTc interval in adolescents with Type 1 diabetes.
A threshold of QTc > 409 ms in adolescents with Type 1 diabetes differentiates those most at risk of autonomic dysfunction, in addition to being female, having higher HbA
1c
, BMI and total cholesterol.
Electrocardiogram screening to exclude long QTc syndromes and assess complication risk may be of value in routine complications assessment in young people with diabetes.
The ability of a genetic risk score to predict risk in established cardiovascular disease and identify individuals who derive greater benefit from PCSK9 (proprotein convertase subtilisin/kexin type ...9) inhibition has not been established.
We studied 14 298 patients with atherosclerotic cardiovascular disease from the FOURIER trial (Further Cardiovascular Outcomes Researh With PCSK9 Inhibition in Subjects With Elevated Risk). A 27-single-nucleotide polymorphism genetic risk score defined low (quintile 1), intermediate (quintiles 2-4), and high (quintile 5) genetic risk. Patients were also categorized by major atherosclerotic risk factors including diabetes mellitus, hypertension, low-density lipoprotein cholesterol ≥100 mg/dl, and smoking; multiple (≥2) risk factors was considered high clinical risk. Outcomes consisted of major coronary events (coronary heart death, myocardial infarction, or coronary revascularization) and major vascular events (major coronary events and ischemic stroke). Median follow-up was 2.3 years.
After we adjusted for clinical factors, the genetic risk score was associated with risk for both major vascular events (
=0.005) and major coronary events (
<0.0001). Individuals with intermediate and high genetic risk scores had 1.23- and 1.65-fold increased hazard for major coronary events, respectively. Elevated genetic risk was additive to major atherosclerotic risk factors and identified patients more likely to benefit from evolocumab. There was no benefit for major vascular events in patients without multiple clinical risk factors or high genetic risk (hazard ratio HR, 1.02; absolute risk reduction ARR, -0.2%,
=0.86). In contrast, there was a 13% relative risk reduction (HR, 0.87 0.75-0.998,
=0.047) and a 1.4% ARR in patients with multiple clinical risk factors but without high genetic risk and a 31% relative risk reduction (HR, 0.69 0.55-0.86,
=0.0012), and 4.0% ARR in patients with high genetic risk, irrespective of clinical risk (
for HR=0.017, ARR
=0.004). Patients with high genetic risk who received evolocumab had event rates similar to patients with a low burden of both genetic and clinical risk.
Patients without multiple clinical risk factors or high genetic risk had a low event rate and did not appear to derive benefit from evolocumab over 2.3 years. Conversely, patients with multiple clinical risk factors but without high genetic risk had intermediate risk and intermediate risk reduction. Patients with high genetic risk, regardless of clinical risk, had a high event rate and derived the greatest relative and absolute benefit from evolocumab, which mitigated this risk.
D-dimer, a degradation product of cross-linked fibrin, is a marker for hypercoagulability and thrombotic events. Moderately elevated levels of D-dimer are associated with the risk of venous and ...arterial events in patients with vascular disease. We assessed the role of D-dimer levels in predicting long-term vascular outcomes, cause-specific mortality, and new cancers in the LIPID trial (Long-Term Intervention with Pravastatin in Ischaemic Disease) in the context of other risk factors.
LIPID randomized patients to placebo or pravastatin 40 mg/d 5 to 38 months after myocardial infarction or unstable angina. D-dimer levels were measured at baseline and at 1 year. Median follow-up was 6.0 years during the trial and 16 years in total.
Baseline D-dimer levels for 7863 patients were grouped by quartile (≤112, 112-173, 173-273, >273 ng/mL). Higher levels were associated with older age, female sex, history of hypertension, poor renal function, and elevated levels of B-natriuretic peptide, high-sensitivity C-reactive protein, and sensitive troponin I (each P<0.001). During the first 6 years, after adjustment for up to 30 additional risk factors, higher D-dimer was associated with a significantly increased risk of a major coronary event (quartile 4 versus 1: hazard ratio HR, 1.45; 95% confidence interval, 1.21-1.74), major cardiovascular disease (CVD) event (HR, 1.45; 95% confidence interval, 1.23-1.71) and venous thromboembolism (HR, 4.03; 95% confidence interval, 2.31-7.03; each P<0.001). During the 16 years overall, higher D-dimer was an independent predictor of all-cause mortality (HR, 1.59), CVD mortality (HR, 1.61), cancer mortality (HR, 1.54), and non-CVD noncancer mortality (HR, 1.57; each P<0.001), remaining significant for deaths resulting from each cause occurring beyond 10 years of follow-up (each P≤0.01). Higher D-dimer also independently predicted an increase in cancer incidence (HR, 1.16; P=0.02).The D-dimer level increased the net reclassification index for all-cause mortality by 4.0 and venous thromboembolism by 13.6.
D-dimer levels predict long-term risk of arterial and venous events, CVD mortality, and non-CVD noncancer mortality independent of other risk factors. D-dimer is also a significant predictor of cancer incidence and mortality. These results support an association of D-dimer with fatal events across multiple diseases and demonstrate that this link extends beyond 10 years' follow-up.
Levels of atherogenic lipoproteins achieved with statin therapy are highly variable, but the consequence of this variability for cardiovascular disease risk is not well-documented.
The aim of this ...meta-analysis was to evaluate: 1) the interindividual variability of reductions in low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), or apolipoprotein B (apoB) levels achieved with statin therapy; 2) the proportion of patients not reaching guideline-recommended lipid levels on high-dose statin therapy; and 3) the association between very low levels of atherogenic lipoproteins achieved with statin therapy and cardiovascular disease risk.
This meta-analysis used individual patient data from 8 randomized controlled statin trials, in which conventional lipids and apolipoproteins were determined in all study participants at baseline and at 1-year follow-up.
Among 38,153 patients allocated to statin therapy, a total of 6,286 major cardiovascular events occurred in 5,387 study participants during follow-up. There was large interindividual variability in the reductions of LDL-C, non-HDL-C, and apoB achieved with a fixed statin dose. More than 40% of trial participants assigned to high-dose statin therapy did not reach an LDL-C target <70 mg/dl. Compared with patients who achieved an LDL-C >175 mg/dl, those who reached an LDL-C 75 to <100 mg/dl, 50 to <75 mg/dl, and <50 mg/dl had adjusted hazard ratios for major cardiovascular events of 0.56 (95% confidence interval CI: 0.46 to 0.67), 0.51 (95% CI: 0.42 to 0.62), and 0.44 (95% CI: 0.35 to 0.55), respectively. Similar associations were observed for non-HDL-C and apoB.
The reductions of LDL-C, non-HDL-C, and apoB levels achieved with statin therapy displayed large interindividual variation. Among trial participants treated with high-dose statin therapy, >40% did not reach an LDL-C target <70 mg/dl. Patients who achieve very low LDL-C levels have a lower risk for major cardiovascular events than do those achieving moderately low levels.
Type 2 diabetes (T2D) is associated with increased risk of cardiovascular disease (CVD). As disturbed angiogenesis and endothelial dysfunction are strongly implicated in T2D and CVD, we aimed to ...investigate the association between a novel anti-angiogenic protein, FK506-binding protein like (FKBPL), and these diseases. Plasma FKBPL was quantified by ELISA cross-sectionally in 353 adults, consisting of 234 T2D and 119 non-diabetic subjects with/without CVD, matched for age, BMI and gender. FKBPL levels were higher in T2D (adjusted mean: 2.03 ng/ml ± 0.90 SD) vs. non-diabetic subjects (adjusted mean: 1.79 ng/ml ± 0.89 SD, p = 0.02), but only after adjustment for CVD status. In T2D, FKBPL was negatively correlated with fasting blood glucose, HbA1c and diastolic blood pressure (DBP), and positively correlated with age, known diabetes duration, waist/hip ratio, urinary albumin/creatinine ratio (ACR) and fasting C-peptide. FKBPL plasma concentrations were increased in the presence of CVD, but only in the non-diabetic group (CVD: 2.02 ng/ml ± 0.75 SD vs. no CVD: 1.68 ng/ml ± 0.79 SD, p = 0.02). In non-diabetic subjects, FKBPL was positively correlated with an established biomarker for CVD, B-type Natriuretic Peptide (BNP), and echocardiographic parameters of diastolic dysfunction. FKBPL was a determinant of CVD in the non-diabetic group in addition to age, gender, total-cholesterol and systolic blood pressure (SBP). FKBPL may be a useful anti-angiogenic biomarker in CVD in the absence of diabetes and could represent a novel CVD mechanism.
Pulmonary vein isolation by cryoballoon ablation is an accepted method of treating atrial fibrillation. Little data exist regarding factors affecting late electrical reconnection of pulmonary veins ...following cryoballoon ablation.
To investigate factors determining pulmonary vein reconnection in patients undergoing repeat catheter ablation for recurrent atrial fibrillation following cryoballoon ablation.
Fifty-one consecutive patients undergoing repeat catheter ablation for recurrent atrial fibrillation following initial cryoballoon ablation underwent retrospective assessment of initial cryoablation characteristics, including balloon and vein sizes, venogram occlusion score, balloon freezing time from 0 to -30 °C, nadir temperature, and balloon warming time from -30 to +15 °C, recorded during the initial cryoballoon procedure.
Of 199 veins assessed, 91 had reconnected (1.8 per patient). Balloon warming time (odds ratio OR 3.21; 95% confidence interval CI 2.00-5.13; P < .0001), nadir temperature (OR 1.94; 95% CI 1.42-2.66; P < .0001), vein occlusion score (OR 1.74; 95% CI 1.29-2.34; P = .0003), and balloon freezing time (OR 1.58; 95% CI 1.03-2.42; P = .037) predicted pulmonary vein reconnection. On multivariate analysis, balloon warming time (OR 3.71; 95% CI 2.2-6.24; P ≤ .0001), pulmonary vein size (OR 1.63; 95% CI 1.08-2.43; P = .020), and vein occlusion score (OR 1.48; 95% CI 1.06-2.08; P = .021) remained statistically significant independent predictors of pulmonary vein reconnection. The receiver operating characteristic for the multivariate model yielded an area under the curve of 0.82.
Balloon warming time, vein occlusion score, and pulmonary vein size predict pulmonary vein reconnection. Balloon warming time was the most important predictive factor, and the manipulation of balloon warming may be a novel therapeutic strategy for improving outcomes of cryoballoon ablation for atrial fibrillation.
The EBBINGHAUS (Evaluating PCSK9 Binding Antibody Influence on Cognitive Health in High Cardiovascular Risk Subjects) trial demonstrated that evolocumab added to a background statin did not affect ...cognitive performance in a subset of 1,204 patients enrolled in FOURIER (Further Cardiovascular Outcomes Research With PCSK9 inhibitors in Subjects With Elevated Risk).
The authors describe patient-reported cognition in the entire FOURIER trial using a self-survey.
FOURIER was a randomized, double-blind, placebo-controlled trial involving patients with atherosclerotic cardiovascular disease and low-density lipoprotein cholesterol (LDL-C) levels ≥70 mg/dl or non-high-density cholesterol ≥100 mg/dl despite statin therapy. At the final visit, patients completed a 23-item survey on memory and executive domains from the Everyday Cognition (ECog) scale. Patients compared their levels of everyday function at the end of the trial with their levels at the beginning and scored as 1 (no change or improvement), 2 (occasionally worse), 3 (consistently little worse), or 4 (consistently much worse). ECog scores were compared by the 2 randomized treatment arms and by achieved LDL-C at 4 weeks.
A total of 22,655 patients completed ECog after a median duration of 2.2 years. The proportions of patients reporting cognitive decline (ECog score ≥2) at the end of the study were similar for placebo versus evolocumab, both for total score 3.6% versus 3.7% (p = 0.62) and for subdomains (memory, 5.8% vs. 6.0%; total executive, 3.6% vs. 3.7%). The proportion of patients reporting a decline in total cognitive score was similar among the 2,338 patients who achieved very low LDL-C levels (<20 mg/dl) compared to the 3,613 patients with LDL-C ≥100 mg/dl (3.8% vs. 4.5%, p = 0.57).
The addition of evolocumab to maximally tolerated statin therapy had no impact on patient-reported cognition after an average of 2.2 years of treatment, even among patients who achieved LDL-C <20 mg/dl.
Display omitted
Implementing gear-based solutions to reduce bycatch in trawl fisheries can be difficult owing to fishers’ concerns over the fleet-wide applicability of results from discrete, highly controlled ...experiments associated with the development of such innovations. In New South Wales, Australia, a codend comprising a posterior section made from 35-mm square-shaped mesh (i.e. hung on the bar) was developed and subsequently recommended for partial implementation in a multi-species demersal trawl fishery (i.e. for use when eastern king prawn –Melicertus plebejus – is the primary target species). However, industry concerns over this design have to date prevented its implementation. Here, using direct twin-tow comparisons onboard a subset of the fleet, we quantitatively assessed the performance of the square-mesh codend, relative to the range of diamond-mesh codend designs currently being used, in terms of reductions in bycatch rates and shortfalls in catch rates of retained animals. Generalised linear mixed-effects modelling across all vessels showed that when eastern king prawn was the target species, the square-mesh codend significantly reduced bycatch rates (by ∼48%), but with an accompanying significant shortfall in catch rates of eastern king prawn (∼7%) and a substantial (though not statistically significant) shortfall in catch rates of an important component of the retained byproduct (whiting, Sillago spp., ∼36%). Partitioning of data by vessel revealed that such shortfalls in retained catch were evident for only some vessels, while the square-mesh codend performed as intended for the others. When school prawn (Metapenaeus macleayi) was the target species, substantial shortfalls in catches of school prawn (∼54%) in the 35-mm square-mesh codend confirmed that a codend of a smaller square mesh might be a more appropriate design under those circumstances. Potential strategies to address intra-vessel inconsistencies in performance of the square-mesh codend and thereby facilitate implementation of square-mesh codends in the fishery are discussed.
PDF
