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Highlighted articles May

Volume 272 Issue May 2018

By Simona Negrini and Arnold von Eckardstein (Editor–in-Chief).

Hypertriglyceridemia, hyperglycemia and hyperuricemia are frequently found in patients with manifest atherosclerotic cardiovascular disease or asymptomatic individuals who will develop ASCVD later in life. However, because of their mutual confounding and their association with many other risk factors, there has been a long controversy on their causal role in the pathogenesis of ASCVD. Data from recent Mendelian randomization studies or randomized intervention studies provide some evidence for causality at least for triglyceride-rich lipoproteins and hyperglycemia. This issue of Atherosclerosis provides several review articles and original reports addressing this interesting topic.

Issue highlights


    Highlighted articles

    Treatment patterns in hyperlipidaemia patients based on administrative claim databases in Japan

    Hyperlipidaemia (HLD) or hyperlipoproteinaemia is defined as an abnormally elevated level of any or all lipids and/or lipoproteins in the blood. HLD increases the risk of atherosclerotic cardiovascular disease (CVD), especially coronary artery disease, and is a major contributor to increased mortality. Real-world evidence on treatment of hyperlipidaemia (HLD) in Japan is limited.

    In this observational cohort study, Wake et al. aimed to describe treatment patterns, persistence with, and adherence to treatment in Japanese patients with HLD.

    Retrospective analyses of adult HLD patients receiving drug therapy in 2014–2015 were conducted using the Japan Medical Data Center (JMDC) and Medical Data Vision (MDV) databases. Data were analyzed for >100,000 untreated (UT) and previously treated (PT) patients (defined based on their HLD treatment history) followed for at least 12 months. Outcomes of interest included prescribing patterns of HLD drug classes, persistence with treatment at 12 months, and adherence to treatment.

    First-line HLD prescriptions for UT patients were predominantly for moderate statins while PT patients most commonly received combination therapy. Approximately half of the UT patients discontinued treatment during observation. Within each cohort, persistence rates were lower in UT patients than in PT patients. Adherence was ≥80% across almost all HLD drug classes.

    The high discontinuation rate of HLD therapy in UT patients warrants further investigation and identification of methods to encourage and support long-term persistence.

    Resolution of fatty liver and weight loss: Independent associations with changes in serum lipids and apolipoprotein

    Recent evidence shows that non-alcoholic fatty liver disease (NAFLD) is an independent cardiovascular disease (CVD) risk factor. Accumulation of liver fat is used to diagnose NAFLD, however, it is not clear whether resolution of fatty liver can improve cardiovascular disease risk factors, independently of changes in body mass index (BMI). Sung et al. tested whether resolution of fatty liver was associated with improvements in components of the lipid profile, independently of changes in BMI, and quantified and compared the magnitude of benefit of resolution of liver fat, and decreases in BMI on the lipid profile.

    36,195 subjects with fatty liver were studied. Persistence/resolution of fatty liver was determined by ultrasound at follow up. Total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and apolipoproteins were measured at baseline and follow up.

    Regression modelling was used to test the independence of associations between change in fatty liver status or change in BMI, with any change in lipid profile concentrations between baseline and follow up.
    Resolution of fatty liver occurred in 7,086 and persisted in 29,109 subjects. Both resolution of fatty liver and decrease in BMI were independently associated with improvements in all components of the lipid profile and there was a similar magnitude of benefit associated with resolution of fatty liver, or 1 kg/m2 decrease in BMI.

    Resolution of fatty liver improves the lipid profile, independently of weight loss.

    Plasma levels of n-3 fatty acids and risk of coronary heart disease among Japanese: The Japan Public Health Center-based (JPHC) study

    Higher intake of fish or n-3 polyunsaturated fatty acids (PUFAs) has been associated with reduced risk of coronary heart disease (CHD). Japanese consume high amounts of fish and have a low prevalence of CHD compared with Western people. However, there has been no nationwide community-based prospective research on the relationship between plasma levels of n-3 PUFAs and risk of CHD in a Japanese population with high fish intake. Hamazaki et al. conducted a nested case-control study among participants in the Japan Public Health Center (JPHC)-based Study Cohort to examine the relationship between circulating levels of n-3 PUFAs (eicosapentaenoic acid + docosapentaenoic acid + docosahexaenoic acid) and risk of CHD.

    Plasma n-3 PUFA phospholipid levels were measured at baseline by gas chromatography in 209 cases with CHD and 418 controls matched for sex, age, date of blood draw, time elapsed since last meal before blood collection, and study location. The CHD cases comprised 168 cases of myocardial infarction and 41 of sudden cardiac death, otherwise classified as 157 non-fatal and 52 fatal coronary events, respectively. Mean duration of follow-up was 13.5 years.

    Multivariate conditional logistic analysis showed no significant association between n-3 PUFAs and risk of total CHD. The odds ratio (OR) for the highest versus lowest quartiles of plasma n-3 PUFAs was 0.79. Subtype analysis of CHD revealed that the multivariate ORs for the highest versus lowest quartiles for n-3 PUFAs were 0.91 for myocardial infarction, 0.08 for sudden cardiac death, 0.89 for nonfatal coronary events, and 0.12 for fatal coronary events.

    Plasma n-3 PUFA levels were not associated with risk of total CHD but were inversely associated with risks of sudden cardiac death and fatal coronary events among middle-aged Japanese individuals.

    In his editorial, W. S Harrys emphasizes that while many studies have examined the associations between the intake of omega-3 fatty acids and risk for CHD in Japan, only a few have used circulating fatty acids biomarkers as their exposure variable.

    Overexpressing human GPR109A leads to pronounced reduction in plasma triglyceride levels in BAC transgenic rats

    Nicotinic acid has been used clinically for more than 50 years since it has anti-atherogenic effects, including the ability to reduce triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C), and elevate high-density lipoprotein cholesterol (HDL-C). GPR109A, a G-protein-coupled receptor located mainly on adipocyte cell membranes, has anti-lipolytic activity and was reported to be a molecular target for nicotinic acid. However, recent clinical reports have shown that most GPR109A agonists failed to induce clinically meaningful plasma lipid changes. In addition, a recent study has shown that the TG lowering effect of nicotinic acid was not diminished in Gpr109a deficient mice, which is different from the original finding. Therefore, whether GPR109A activation can lead to plasma lipid changes is unclear. Masuda et al. created a bacterial artificial chromosome (BAC) transgenic rat expressing human GPR109A (Tg rat) and examined the in vivo role of GPR109A.

    The results showed that under fasted conditions, plasma NEFA and triglyceride levels in Tg rats were lower than in non-Tg rats. In this condition, a positive correlation between plasma NEFA and triglyceride or β-hydroxybutyrate levels was observed. Furthermore, insulin levels in Tg rats were lower than in non-Tg rats only when a reduction in NEFAs was observed, which is a phenomenon also reported for nicotinic acid. Interestingly, body weight gain in Tg rats was significantly lower than in non-Tg rats.

    These results suggest that GPR109A signaling leads to a reduction in triglyceride and insulin levels, and that the triglyceride-lowering effect of nicotinic acid is at least partially mediated by GPR109A signaling.

    New medications targeting triglyceride-rich lipoproteins: Can inhibition of ANGPTL3 or apoC-III reduce the residual cardiovascular risk?

    Remarkably good results have been achieved in the treatment of atherosclerotic cardiovascular diseases (CVD) by using statin, ezetimibe, antihypertensive, antithrombotic, and PCSK9 inhibitor therapies and their proper combinations. However, despite this success, the remaining CVD risk is still high. To target this residual risk and to treat patients who are statin-intolerant or have an exceptionally high CVD risk, for instance due to familial hypercholesterolemia (FH), new therapies are intensively sought. One pathway of drug development is targeting the circulating triglyceride-rich lipoproteins (TRL) and their lipolytic remnants, which, according to the current view, confer a major CVD risk. Angiopoietin-like protein 3 (ANGPTL3) and apolipoprotein C-III (apoC-III) are at present the central molecular targets for therapies designed to reduce TRL, and there are new drugs emerging that suppress their expression or inhibit the function of these two key proteins. The medications targeting these components are biologicals, either human monoclonal antibodies or antisense oligonucleotides. In this review, Olkkonen et al. discuss the mechanisms of action of ANGPTL3 and apoC-III, the reasons why they have been considered promising targets of novel therapies for CVD, as well as the current status and the most important results of their clinical trials.


    Clinical implications of current cardiovascular outcome trials with sodium glucose cotransporter-2 (SGLT2) inhibitors

    The final goal in the management of patients with type 2 diabetes (T2D) is reduction in cardiovascular (CV) complications and total mortality. Various factors including hyperglycemia contribute to these complications and mortality directly and indirectly. In recent years, large-scale CV outcome trials with new antidiabetic medications, such as dipeptidyl peptidase-4 (DPP4) inhibitors, glucagon-like peptide-1 (GLP1) receptor agonists, and sodium glucose cotransporter-2 (SGLT2) inhibitors, have been completed. Most clinical trials with DPP4 inhibitors have shown no inferiority compared with placebo treatments in terms of CV safety. However, they did not show benefits in terms of adverse CV events or mortality. CV outcome trials with GLP1 receptor agonists showed inconsistent results: lixisenatide did not show benefits in preventing major adverse CV events. In contrast, liraglutide and semaglutide (longer acting GLP1 receptor agonists) proved to be superior in terms of alleviating CV morbidity and mortality. Two large-scale CV outcome trials with SGLT2 inhibitors showed significant results: empagliflozin proved to be superior in preventing CV and all-cause mortality, and canagliflozin proved to be superior in preventing CV mortality but not all-cause mortality. So far, controlling cardiometabolic risk factors such as hemodynamic changes and weight loss by SGLT2 inhibitors are suggested to be the main mechanisms for these results. However, the risk–benefit profile for these new drugs will need further elucidation, and more studies are warranted to reveal the possible mechanisms. It will also be important to confirm these results in other ongoing trials with SGLT2 inhibitors. In this review, Lim et al. discuss the clinical implications of results of recent trials with SGLT2 inhibitors. Moreover, the advantages and disadvantages of treatment with these drugs are also discussed from a clinical viewpoint.

    Elevated serum uric acid predicts the development of moderate coronary artery calcification independent of conventional cardiovascular risk factors

    Serum uric acid (SUA) is the end product of purine metabolism. Although it has not been established whether SUA is a marker or cause of metabolic disorders, SUA has been significantly associated with metabolic syndrome, type 2 diabetes (T2D), hypertension, and dyslipidemia, all of which contribute to cardiovascular disease (CVD). SUA is an independent risk factor for CVD events such as coronary heart disease (CHD), congestive heart failure, stroke, and even cardiovascular mortality in a high risk or general population. Since hyperuricemia was frequently oberved in subjects with a high risk of cardiovascular disease (CVD), Jun et al. aimed to elucidate whether serum uric acid (SUA) is associated with development of moderate coronary artery calcification in generally healthy adults.

    A total of 9297 subjects underwent multidetector CT for the evaluation of CAC at least two times during their annual health examinations. Among them, 4461 participants without CVD history and who had no or minimal CAC in their first examination at enrollment. The association between SUA as a continuous and categorical variable and development of moderate coronary artery calcification was assessed by Cox regression analysis. Receiver-operating characteristic (ROC) curves were constructed to investigate the diagnostic efficacy of SUA.

    During a median follow-up of 4.1 years, 131 incident cases of moderate calcification developed. Baseline SUA concentration was significantly higher in subjects with progression to moderate coronary artery calcification. SUA as a continuous variable and divided into quartiles was positively associated with a higher risk of development of moderate calcification after adjustment for conventional CVD risk factors. The addition of SUA to the conventional CVD risk factors improved the predictive power for development of moderate coronary artery calcification.
    In conclusion, this study shows that SUA is an independent predictor for development of moderate coronary artery calcification in subjects with no or minimal calcification. SUA might be a potentially useful monitoring tool for subclinical atherosclerosis detection.

    Elevated serum uric acid levels are associated with endothelial dysfunction in HIV patients receiving highly-active antiretroviral therapy

    Elevated serum uric acid (SUA) levels may be associated with endothelial dysfunction. Metabolic syndrome (MS) and increased SUA levels are prevalent conditions in treated human immunodeficiency virus (HIV) patients. Pirro et al. investigated whether SUA levels are associated with endothelial dysfunction in HIV positive patients receiving highly-active antiretroviral therapy (HAART) irrespective of MS.

    In this cross-sectional study of 250 HIV positive patients receiving stable HAART, they evaluated the relationship between MS, SUA levels and endothelial function. SUA levels and brachial artery flow-mediated dilation (bFMD) were measured. The relationship between logarithmic (LG)-transformed SUA levels and bFMD was evaluated after correction for MS.

    MS was detected in 28.4% of patients and elevated SUA levels in 25.2%. MS was associated with higher LG-SUA levels. The crude linear association between LG-SUA levels and LG-bFMD was abolished after correction for MS. When SUA levels were used as a categorical variable, the association between LG-SUA levels and LG-bFMD remained significant after adjustment for MS.

    MS significantly affects SUA levels in HAART-treated HIV infected patients. The negative association between uric acid levels and endothelial function is attenuated by the metabolic syndrome. The association between uricemia and FMD is independent of the metabolic syndrome only for elevated uric acid levels.

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