Aims
To determine whether alanine aminotransferase or gamma‐glutamyltransferase levels, as markers of liver health and non‐alcoholic fatty liver disease, might predict cardiovascular events in people ...with Type 2 diabetes.
Methods
Data from the Fenofibrate Intervention and Event Lowering in Diabetes study were analysed to examine the relationship between liver enzymes and incident cardiovascular events (non‐fatal myocardial infarction, stroke, coronary and other cardiovascular death, coronary or carotid revascularization) over 5 years.
Results
Alanine aminotransferase measure had a linear inverse relationship with the first cardiovascular event occurring in participants during the study period. After adjustment, for every 1 sd higher baseline alanine aminotransferase measure (13.2 U/l), the risk of a cardiovascular event was 7% lower (95% CI 4–13; P = 0.02). Participants with alanine aminotransferase levels below and above the reference range 8–41 U/l for women and 9–59 U/l for men, had hazard ratios for a cardiovascular event of 1.86 (95% CI 1.12–3.09) and 0.65 (95% CI 0.49–0.87), respectively (P = 0.001). No relationship was found for gamma‐glutamyltransferase.
Conclusions
The data may indicate that in people with Type 2 diabetes, which is associated with higher alanine aminotransferase levels because of prevalent non‐alcoholic fatty liver disease, a low alanine aminotransferase level is a marker of hepatic or systemic frailty rather than health.
What's new?
Alanine aminotransferase and gamma‐glutamyltransferase are associated with measures of adiposity, metabolic syndrome, insulin resistance and poorer glycaemic control in people with Type 2 diabetes.
Lower alanine aminotransferase but not gamma‐glutamyltransferase levels predict a higher risk of a cardiovascular event over time and, as such, may be a marker of systemic or hepatic frailty in people with Type 2 diabetes, rather than liver health and absence of non‐alcoholic fatty liver disease.
The study highlights the fact that further study is needed into the mechanisms by which lower alanine aminotransferase levels are associated with adverse cardiovascular outcomes in various at‐risk groups, with a particular emphasis on formal assessment of comorbidity, biological frailty, non‐alcoholic fatty liver disease severity and lipid variables.
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, HbA1c 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 HbA1c 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, QTc 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 QTc was associated with higher HbA1c 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 HbA1c 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 HbA1c, 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.
Inappropriate sinus tachycardia (IST) is an incompletely understood condition, characterised by an elevation in heart rate (HR) accompanied by wide ranging symptoms in the absence of an underlying ...physiological stimulus. The condition often takes a chronic course with significant adverse effects on quality of life. Currently, there is no effective treatment for IST. Beta-blockers, generally considered the cornerstone of treatment, are often ineffective and poorly tolerated. Ivabradine is a novel sinus node If 'funny current' inhibitor, which reduces the HR. It has been approved for the treatment of beta-blocker refractory chronic systolic heart failure and chronic stable angina but more recently has shown promise in the treatment of IST. This review provides an overview of IST prevalence and mechanisms followed by an examination of the evidence for the role and efficacy of ivabradine in the treatment of IST.
Aims/hypothesis Low HDL-cholesterol (HDL-C) is frequently accompanied by high triacylglycerol levels in diabetic dyslipidaemia, increasing the risk of CHD. In the Fenofibrate Intervention and Event ...Lowering in Diabetes (FIELD) study, fenofibrate treatment lowered triacylglycerol levels, but the initial 5% increase in HDL-C attenuated over 5 years. We explored the changes in VLDL and HDL subspecies during fenofibrate treatment in a statin-free FIELD cohort. Methods We randomised 171 participants with type 2 diabetes mellitus, who had been recruited to the FIELD study in Helsinki, to micronised fenofibrate (200 mg/day) or placebo in double-blind study design. VLDL and HDL subspecies were separated by ultracentrifugation at baseline and at the second and fifth year. Apolipoprotein (apo)A-I and apoA-II were measured by immunoturbidometric methods and lipoprotein (Lp)A-I and LpAI-AII particles by differential immunoassay. Results Fenofibrate reduced plasma triacylglycerol levels by 26%, resulting from a marked reduction in VLDL1 triacylglycerol (0.62 vs 0.29 mmol/l, p < 0.001). Fenofibrate caused an increase in LDL size (Δ0.80 nm, p < 0.001). HDL-C was similar between the groups. HDL2-C was decreased by fenofibrate (-27.5% at 5th year, p < 0.001) and HDL3-C increased (13.0% at 5th year, p < 0.001). Fenofibrate had no effect on apoA-I, whereas apoA-II increased. Thus, LpA-I decreased while LpAI-AII increased. Activities of cholesteryl ester transfer protein, phospholipids transfer protein and lecithin:cholesterylacyl transferase were unchanged by fenofibrate. High homocysteine levels were associated with a slight decrease in HDL-C and apoA-I. Conclusions/interpretation Fenofibrate markedly reduced large VLDL particles and produced a clear shift in HDL subspecies towards smaller particles. The HDL3-C increase in conjunction with unchanged apoA-II levels is a dilemma with regard to cardiovascular disease.
Concerns have been expressed 'that the physician-researcher is a dying breed'. As yet there are few Australian data.
To compare over time: (i) research progress of Sydney Medical School (SMS) medical ...practitioner - PhD awardees; (ii) National Health and Medical Research Council (NHMRC) project grant success rates for physician-researchers; and (iii) compare current NHMRC, NSW University and NSW Public Hospital pay scales for physician-researchers.
We evaluated 303 medical practitioners awarded a University of Sydney/SMS PhD in 1989-2012 and their publications. We assessed 1990-2014 NHMRC grants to physicians and non-physicians (nationally) and compared physician salaries from NHMRC, the University of Sydney and NSW public hospitals.
SMS PhD completions by clinicians increased ≈2.4-fold since 1989, with a recent decline, whilst non-medical PhD awardees rose 10-fold. The median time of PhD award after medical degree completion was stable at 13 years. A lower percentage of the more recent physician-researchers had completed specialty training at PhD award (34% in 2011-2012 vs 71% in 1989-1990, P = 0.017). Publication rates were stable, but low. Although NHMRC funding increased >10-fold since 1990, national project grant success rates declined (35% in 1990, 17% in 2013 and 15% in 2014, P < 0.0001), with physician-led funded grants declining from 29% in 1989 to 21% in 2013, P = 0.002. Current NHMRC and University salaries are less than comparable-stage public hospital salaries.
Since 1989, more medical graduates are completing SMS PhDs, although more often prior to completing clinical Fellowships, and many have ongoing, albeit low, research activity. Nationally NHMRC project grant success rates have declined significantly, as has the proportion of funded physician-led projects. Medical practitioner salaries from NHMRC and from Universities are less than in public hospitals. The Australian physician-researcher is at-risk. Knowledge and actions are needed to protect our medical research capacity.
Given the concerns that physician-researchers are 'at risk', and ≈50% of Australian medical students are female, the evaluation of female physician-researchers is important.
To compare over time (i) ...research-related metrics of male and female physician-researchers from Sydney Medical School; and (ii) National Health and Medical Research Council (NHMRC) Project grant leadership by gender.
The Sydney Medical School (SMS) PhD award lists from 1989 to 2012 were cross-referenced with the Australian Health Practitioner Regulation Agency database, and registered medical practitioners were searched for in the Scopus database for publications and H-indexes. The gender of medical-practitioner Chief Investigator A (CIA) in Australia on funded NHMRC Project grants in 1990 to 2014 was also compared.
Of the medical practitioners awarded University of Sydney PhD, females increased from 14 to 55% in 1989-1990 and 2009-2010 and decreased to 38% in 2011-2012 (overall increase, P = 0.047). PhD award timings relative to MBBS and clinical fellowship completions were similar for both genders (P > 0.05). Post-PhD, as many women as men publish and have similar H-indexes, but women publish fewer papers (0.7 vs 1.0 publications per year, P = 0.028). On medical practitioner-led, funded NHMRC project grants between 1999 and 2014, female CIA increased from 7.5 to 19.5%, P < 0.0001. For the 17% of project grant applications funded to commence in 2014, 21% were medical practitioner-led, of whom 19.5% were female.
Since 1989, more female medical practitioners are completing SMS PhD at similar times in their careers to males. However, relative to their male peers, they publish less. Fewer female than male medical practitioner-researchers hold NHMRC Project Grant CIA status nationally, although the rates are increasing. In addressing physician-researcher workforce issues, including retention, attention should be given to factors impacting females.
Video-based consultation is the only telehealth service reimbursed by the Medicare Benefits Schedule in Australia, but the uptake of telehealth is still low and inconsistent. There is a clear need ...for the development of appropriate medical evidence to support implementation of telehealth services. With the ubiquitous use of mobile phones, mobile health becomes important in facilitating health services and impacting clinical outcomes anywhere.
Abstract
Background
The 2019 ESC/EAS Dyslipidemia Guidelines recommend an LDL-C goal of <1.4 mmol/L (∼55 mg/dl) for patients with very high-risk ASCVD, and <1 mmol/L (∼40 mg/dl) for those with ...recurrent events within 2 years despite taking maximally tolerated statin therapy. The addition of PCSK9 inhibitors to statin therapy can achieve LDL-C levels well below 1 mmol/L in many patients, yet the clinical benefit of LDL-C lowering beyond this level has recently been questioned.
Methods
FOURIER was a cardiovascular outcomes trial comparing evolocumab vs. placebo in patients with stable ASCVD on optimized statin therapy with a median follow-up of 2.2 years. We performed an exploratory analysis to determine the consistency of CV risk reduction with LDL-C lowering below ∼1 mmol/L (40 mg/dl) with evolocumab. We modeled the achieved LDL-C at 48 weeks in the two treatment arms as well as the percentage of LDL-C difference between the two arms that was due to LDL-C below ∼1 mmol/L (40 mg/dl) as a function of baseline LDL-C. We then modeled the hazard ratio (HR) for the composite of CV death, MI or stroke (per 1 mmol/L reduction in LDL-C) with evolocumab vs. placebo as a function of baseline LDL-C.
Results
All 27,564 patients from FOURIER were included in this analysis. Patients with lower baseline LDL-C achieved lower LDL-C levels following evolocumab therapy, with achieved LDL-C typically being below 1 mmol/L (40 mg/dl) once the baseline LDL-C was below 2.4 mmol/L (94 mg/dl) and reaching levels approaching 0.5 mmol/L (∼20 mg/dl). Accordingly, the further baseline LDL-C levels were below 2.4 mmol/L (94 mg/dl), the greater the proportion of the difference in achieved LDL-C between the evolocumab and placebo arms was due to LDL-C levels below ∼1 mmol/L (40 mg/dl), reaching nearly 40% of the difference in LDL-C between treatment arms (Upper Panel). Despite this, the clinical benefit of LDL-C lowering was not attenuated (p=0.78) (and even appeared greater), with robust reductions in risk of CV death, MI or stroke even when LDL-C was lowered to nearly 0.5 mmol/L (∼20 mg/dl) and having close to 40% of the LDL-C difference between treatment arms due to LDL-C lowering below ∼1 mmol/L (40 mg/dl) (Lower Panel).
Conclusion
PCSK9 inhibitors added to statin therapy can achieve LDL-C well below 1 mmol/L (40 mg/dl). There is no evidence for attenuation of the clinical benefit of lowering LDL-C below this threshold. These data support lowering LDL-C to below 1 mmol/L (40 mg/dl) in patients with ASCVD.
Funding Acknowledgement
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Institute of Health
Aim Cardiovascular disease (CVD) rates are substantially higher among patients with Type 2 diabetes than in the general population. The objective of this study was to identify the determinants of ...carotid intima media thickness (IMT) in patients with Type 2 diabetes.
Methods We measured the thickness of the intima media layer of the carotid artery, a strong predictor of the risk of future vascular events, in 397 Type 2 diabetic patients drawn from the Fenofibrate Intervention and Event Lowering in Diabetes study, prior to treatment allocation.
Results The mean IMT was 0.78 mm interquartile range (IQR) 0.23 mm, and the maximum IMT was 1.17 mm (IQR 0.36 mm). By multivariate analysis, age, sex, duration of diabetes, triglycerides, and total cholesterol were independently correlated with IMT, as was urine albumin–creatinine ratio (ACR) (P < 0.001). The effect of ACR on IMT was further examined by tertile. Clinically significant differences in IMT were associated with ACR > 0.65 mg/mmol, approximately one‐fifth the standard clinical threshold for microalbuminuria (P < 0.01). Long‐term diabetes, independent of other parameters, was associated with a 50% increase in age‐related thickening.
Conclusions IMT in people with Type 2 diabetes is independently and continuously related to urine albumin levels and to the duration of diabetes. These results support previous data linking urine albumin measurements within the normal range with increased ischaemic cardiac mortality in the setting of Type 2 diabetes, and strongly suggest that urine albumin levels within this range should trigger a formal evaluation for CVD.
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