Prolonged-release nicotinic acid for the management of dyslipidemia: an update including results from the NAUTILUS study

Low HDL-cholesterol (<1.02 mmol/L [40 mg/dL] in men or <1.29 mmol/L [50 mg/dL] in women) occurs in about one-third of European patients with dyslipidemia and is an independent cardiovascular risk factor. Simultaneous correction of low HDL-cholesterol and high total-cholesterol and LDL-cholesterol may provide reductions in cardiovascular morbidity and mortality beyond those possible with statins alone. Nicotinic acid (niacin in the US) is the most effective means of increasing HDL-cholesterol available and has been shown to reduce cardiovascular event rates significantly. Niaspan® (prolonged-release nicotinic acid) provides a convenient, once-daily means of administering nicotinic acid. Clinical studies with Niaspan® have demonstrated marked, long-term increases in HDL-cholesterol with additional useful benefits on triglycerides, LDL-cholesterol, and lipid sub-profiles. The NAUTILUS study demonstrated the beneficial efficacy and tolerability profiles of Niaspan® in a usual-care setting. The most common side-effect of Niaspan® is flushing, which infrequently causes treatment discontinuation and which usually subsides over continued treatment. The ARBITER 2 and ARBITER 3 studies showed 1–2 years of treatment with Niaspan® plus a statin induced regression of atherosclerosis in patients with coronary artery disease. The effect of Niaspan®-statin treatment, relative to a statin alone, on clinical cardiovascular outcomes is currently under evaluation. Niaspan® represents a practical means of correcting low HDL-cholesterol, an independent risk factor for adverse cardiovascular outcomes

Clinical outcome of a patient with lysosomal acid lipase deficiency and first results after initiation of treatment with Sebelipase alfa: A case report

We report on a case of very rare autosomal recessive cholesteryl ester storage disease due to lysosomal acid lipase deficiency (LALD). LALD is caused by mutations in the lysosomal acid lipase A (LIPA) gene resulting in cholesteryl ester accumulation in liver, spleen, and macrophages. It can lead to liver failure, accelerated atherosclerosis and premature death. Until recently, treatment options were limited to lipid-lowering medications to control dyslipidemia. Presently, a long-term enzyme replacement therapy with Sebelipase alfa, a recombinant human lysosomal acid lipase, is available for patients with LALD. Our patient's condition became conspicuous at the age of two due to a xanthogranuloma of the chin together with increased lipid levels, elevated liver enzymes and hepatomegaly. It took another five years until our patient was diagnosed with LALD after genetic testing. A bi-weekly therapy with intravenous Sebelipase alfa was started at the age of 26 years. It led to normalization of lipid levels, reduction of liver enzymes and beginning regression of hepatomegaly in the absence of adverse drug reactions after 46 infusions. Since LALD can take a fatal course even in patients with a long-term stable condition, it is essential to identify affected patients early and to treat them appropriately by enzyme replacement therapy. LALD should be suspected in patients with low high-density lipoprotein cholesterol (HDL-C) and high low-density lipoprotein cholesterol (LDL-C) in conjunction with elevated liver enzymes or hepatomegaly. A registry for LALD patients shall help to advance our understanding of the disease as well as improve patient care (NCT01633489)

Hyperlipidemias in elderly patients: results from the Berlin Aging Study II (BASEII), a cross-sectional study

Background: Hyperlipidemias are common and the last decades have seen substantially growing evidence of their causative role in the development of atherosclerosis and subsequent cardiovascular diseases. Since hyperlipidemias usually do not cause direct clinical symptoms, they often remain undiagnosed until a serious cardiovascular event occurs. Especially for LDL-hypercholesteremia, there are well-established treatment options available to prevent the occurrence of atherosclerosis. However, there is a lack of knowledge regarding the proper treatment of elderly patients. The goal of this study was to assess the prevalence of hyperlipidemia in a group of young and a group of elderly community-dwelling participants and to determine to what extent treatment of hyperlipidemia should be initiated or required. Methods: Crossectional data from a total of 2151 subjects (1657 in the elderly group, mean age 69, and 494 in the young group (control group), mean age 29) of the Berlin Aging Study II (BASE-II) were available. Medical history was assessed and recorded by trained physicians and prevalence of lipid disorders was determined with laboratory tests, including a lipid-profile. Results: A large proportion of subjects (39%) were unaware of an existing lipid disorder. The prevalence of hyperlipidemia was more frequent in the elderly group (76%) compared to the young group (41%). Hypercholesterolemia was the most common diagnosed disorder (64%), followed by hyperlipoproteinemia(a) (18%), hypertriglyceridemia (7%) and combined hyperlipoproteinaemia (5%). Only a minority of this cohort was treated with lipid-lowering medication (17%) and of those treatment targets according to ESC guidelines were reached only in 16.5 %. Conclusions: Hyperlipidemias appear underdiagnosed and undertreated. As the prevalence of these disorders increases with age and with regard to their role as a major modifiable risk factor for cardiovascular disease it seems to be advisable to aim for more consistent and sustainable screening and treatment of these common disorders. Trial registration: BASE-II registered with the clinical trial registry Deutsches Register Klinischer Studien (DRKS00009277)

Higher Lipoprotein (a) Levels Are Associated with Better Pulmonary Function in Community-Dwelling Older People - Data from the Berlin Aging Study II

Reduced pulmonary function and elevated serum cholesterol levels are recognized risk factors for cardiovascular disease. Currently, there is some controversy concerning relationships between cholesterol, LDL-cholesterol, HDL-cholesterol, serum triglycerides and lung function. However, most previous studies compared patients suffering from chronic obstructive pulmonary disease (COPD) with healthy controls, and only a small number examined this relationship in population-based cohorts. Moreover, lipoprotein a [Lp(a)], another lipid parameter independently associated with cardiovascular diseases, appears not to have been addressed at all in studies of lung function at the population level. Here, we determined relationships between lung function and several lipid parameters including Lp(a) in 606 older community-dwelling participants (55.1% women, 68±4 years old) from the Berlin Aging Study II (BASE-II). We found a significantly lower forced expiration volume in 1 second (FEV1) in men with low Lp(a) concentrations (t-test). This finding was further substantiated by linear regression models adjusting for known covariates, showing that these associations are statistically significant in both men and women. According to the highest adjusted model, men and women with Lp(a) levels below the 20th percentile had 217.3ml and 124.2ml less FEV1 and 239.0ml and 135.2ml less FVC, respectively, compared to participants with higher Lp(a) levels. The adjusted models also suggest that the known strong correlation between pro-inflammatory parameters and lung function has only a marginal impact on the Lp(a)-pulmonary function association. Our results do not support the hypothesis that higher Lp(a) levels are responsible for the increased CVD risk in people with reduced lung function, at least not in the group of community-dwelling older people studied here

Evaluation of the role of STAP1 in Familial Hypercholesterolemia

Familial hypercholesterolemia (FH) is characterised by elevated serum levels of low-density lipoprotein cholesterol (LDL-C) and a substantial risk for cardiovascular disease. The autosomal-dominant FH is mostly caused by mutations in LDLR (low density lipoprotein receptor), APOB (apolipoprotein B), and PCSK9 (proprotein convertase subtilisin/kexin). Recently, STAP1 has been suggested as a fourth causative gene. We analyzed STAP1 in 75 hypercholesterolemic patients from Berlin, Germany, who are negative for mutations in canonical FH genes. In 10 patients with negative family history, we additionally screened for disease causing variants in LDLRAP1 (low density lipoprotein receptor adaptor protein 1), associated with autosomal-recessive hypercholesterolemia. We identified one STAP1 variant predicted to be disease causing. To evaluate association of serum lipid levels and STAP1 carrier status, we analyzed 20 individuals from a population based cohort, the Cooperative Health Research in South Tyrol (CHRIS) study, carrying rare STAP1 variants. Out of the same cohort we randomly selected 100 non-carriers as control. In the Berlin FH cohort STAP1 variants were rare. In the CHRIS cohort, we obtained no statistically significant differences between carriers and non-carriers of STAP1 variants with respect to lipid traits. Until such an association has been verified in more individuals with genetic variants in STAP1, we cannot estimate whether STAP1 generally is a causative gene for FH

Mutation spectrum and polygenic score in German patients with familial hypercholesterolemia

Autosomal-dominant familial hypercholesterolemia (FH) is characterized by increased plasma concentrations of low-density lipoprotein cholesterol (LDL-C) and a substantial risk to develop cardiovascular disease. Causative mutations in three major genes are known: the LDL receptor gene (LDLR), the apolipoprotein B gene (APOB) and the proprotein convertase subtilisin/kexin 9 gene (PCSK9). We clinically characterized 336 patients suspected to have FH and screened them for disease causing mutations in LDLR, APOB, and PCSK9. We genotyped six single nucleotide polymorphisms (SNPs) to calculate a polygenic risk score for the patients and 1985 controls. The 117 patients had a causative variant in one of the analyzed genes. Most variants were found in the LDLR gene (84.9%) with 11 novel mutations. The mean polygenic risk score was significantly higher in FH mutation negative subjects than in FH mutation positive patients (P < .05) and healthy controls (P < .001), whereas the score of the two latter groups did not differ significantly. However, the score explained only about 3% of the baseline LDL-C variance. We verified the previously described clinical and genetic variability of FH for German hypercholesterolemic patients. Evaluation of a six-SNP polygenic score recently proposed for clinical use suggests that it is not a reliable tool to classify hypercholesterolemic patients

Dusty Punch Cards and an Eternal Enigma: High-Density Lipoproteins and Atherosclerosis

Epidemiological, clinical, and experimental evidence has accumulated during the last decades suggesting that high-density lipoproteins (HDLs) may protect from atherosclerosis and its clinical consequences. However, more than 55 years after the first description of the link between HDL and heart attacks, many facets of the biochemistry, function, and clinical significance of HDL remain enigmatic. This applies particularly to the completely unexpected results that became available from some recent clinical trials of nicotinic acid and of inhibitors of cholesteryl ester transfer protein (CETP). The concept that raising HDL cholesterol by pharmacological means would decrease the risk of vascular disease has therefore been challenged

Prevention of Coronary Artery Disease by Lipidscreening in Families with Hereditary with Lipid Disorders: A Comparison between Patients with Hypercholesterolemia and Patients with Hyperlipoproteinemia(a)

Titelblatt und Inhaltsverzeichnis Einleitung Theoretische Grundlagen Einteilung der Fettstoffwechselstörungen LDL-Cholesterin und Lipoprotein(a) Screeninguntersuchungen und Präventivmaßnahmen zur Verhinderung Herleitung der Fragestellung Fragestellung Material und Methoden Ergebnisse Diskussion Zusammenfassung und Ausblick Literaturverzeichnis AnlagenDie vorliegende Arbeit hatte zwei Schwerpunkte. Einerseits haben wir die Indexpatienten hinsichtlich der Risikofaktoren Hypercholesterinämie und einer Hyperlipoproteinämie(a) charakterisiert. Auf der anderen Seite wollten wir herausfinden, ob sich das Präventionsverhalten einer Population mit einer allgemein bekannten Fettstoffwechselstörung (Hypercholesterinämie) von einer Population mit einer weitgehend unbekannten Fettstoffwechselstörung (Hyperlipoproteinämie(a)) unterscheidet und ob Patienten die Empfehlungen umsetzen, die ihnen anhand von schriftlichen Befundübermittlungen zugehen. Außerdem sollte das Konzept eines Familienscreenings unter Praxisbedingungen kritisch überprüft werden. Bei den Indexpatienten spielen die Hypercholesterinämie und die Hyperlipoproteinämie(a) in der Lipidambulanz der Charité dominierende Rollen. Die Prävalenzraten lagen jeweils über 50%. Eine Hyperlipoproteinämie(a) fand sich überwiegend mit anderen Dyslipoproteinämien, in 5% der Fälle aber auch isoliert. Die medikamentöse Behandlungsprävalenz beider Dyslipoproteinämien lag höher als die in der Literatur zu finden, was mit den besonderen Bedingungen einer Spezialambulanz erklärt werden kann. Ein nicht zu vernachlässigender Teil von Patienten, auch Patienten mit KHK, war trotzdem nicht medikamentös-lipidsenkend therapiert. Patienten mit Hypercholesterinämie und KHK waren in 86% der Fälle medikamentös-lipidsenkend vorbehandelt, Patienten mit isolierter Hyperlipoproteinämie(a) erhielten in 62,5% der Fälle eine Therapie. Medikamentöse Behandlungen mit HMG-CoA- Reduktasehemmern (Statinen) dominierten mit 86%. Durch die vorliegende Untersuchung wurde deutlich, daß ein gezieltes Familienscreening sinnvoll in Bezug auf die Identifizierung von Risikopersonen ist. Es wurden mehr Patienten identifiziert, als statistisch zu erwarten war (63% bei Frauen, 70% bei Männern). Auch hier dominierten die Hypercholesterinämie und die Hyperlipoproteinämie(a). In der Follow-up-Befragung gaben mehr als 50% der Angehörigen an, aufgrund der Ergebnisse ihre Ernährung umgestellt zu haben. Auch die Anzahl der medikamentös behandelten Personen nahm signifikant zu. Das Projekt stellt einen sinnvollen Ansatz für präventive Maßnahmen bei Personen mit Hypercholesterinämie und Hyperlipoproteinämie(a) dar. Die Hyperlipoproteinämie(a) ist derzeit zwar durch klinisch etablierte Maßnahmen nicht direkt beeinflußbar, jedoch kann das individuelle Risiko durch Management begleitender Risikofaktoren gesenkt werden. Patienten mit Hypercholesterinämie waren häufiger vorbehandelt. Auch konnte gezeigt werden, daß insbesondere Personen, die eine Kombination aus Hypercholesterinämie und Hyperlipoproteinämie(a) aufweisen, ein erhöhtes Risikobewußtsein entwickeln, was sich in einer hohen Anzahl von Kontrollen widerspiegelt.The present work had two focusses. On the one hand we characterized Indexpatients according to their riskfactors Hypercholesterolemia and Hyperlipoproteinemia(a). On the other hand we wanted to find out whether preventive behaviour in a population with a wellknown lipiddisorder (Hypercholesterolemia) differs from a population with a widely unknown lipiddisorder (Hyperlipoproteinemia(a)) and if patients implement recommendations they receive via diagnostic fundings in writing. In addition we wanted to prove the concept of familyscreening in daily life practice. Within the lipidclinic of the Charité in the group of the indexpatients Hypercholesterolemia and Hyperlipoproteinemia(a) played dominating roles. The prevalence rates for both lipiddisorders were beyond 50%. Hyperlipoproteinemia(a) was mainly found in combination with other lipiddisorders but in 5% of the cases we even found an isolated Lipoprotein(a) elevation. The prevalence of drug treatment was higher than expected according to medical literature, which can be explained by the particular conditions of a spezialized clinic. But still a not to be disregarded percentage of the patients, even with Coronary Artery Disease(CAD), was not treated with lipidlowering drugs. 86% of the patients with Hypercholesterolemia and CAD were treated with lipidlowering drug. Whereas 62,5% of the Patients with isolated Hyperlipoproteinemia(a) received drug treatment. The main proportion of lipidlowering drugs (86%) was covered by HMG-CoA-Reductase-Inhibitors (Statins). The present work shows that targeted familyscreening is a good tool to identifie persons at high risk for cardiovascular diseases. We traced more persons at risk than statistically expected ( 63% of the female relatives and 70% of the male relatives). Also within this group the main proportion of the lipiddisorders was covered by Hypercholesterolemia and Hyperlipoproteinemia(a). According to the follow up questionaire more than 50% of the affected relatives stated that they changed their eating habits due to the medical findings. Also the number of persons with drug treatment increased significantly. The project is a reasonable approach towards preventive measures in persons with Hypercholesterolemia and Hyperlipoproteinemia(a)

PCSK9 Inhibitors in a German Single-Center Clinical Practice: Real-World Treatment of Patients at High Cardiovascular Risk Over 68 Weeks

Aims: Several the use of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) for patients at high/very high cardiovascular risk who are inadequately treated with maximally tolerated lipid-lowering therapies (LLTs). Objectives: We assessed the effectiveness and safety of the PCSK9i alirocumab and evolocumab in a single-center clinical practice for up to 68 weeks. Methods: In this prospective, open-label study conducted in Germany, 635 enrolled patients were treated with alirocumab [75 or 150 mg every 2 weeks (Q2W)] or evolocumab (140 mg Q2W) according to European Society of Cardiology/European Atherosclerosis Society guidelines (low-density lipoprotein cholesterol [LDL-C] > 1.81/2.59 mmol/L (70/100 mg/dL), depending on cardiovascular risk]. Investigators were able to adjust LLTs, including PCSK9i, according to their own clinical judgment. The primary effectiveness endpoint was LDL-C reduction from baseline to week 68. Results: At baseline, approximately 50% of patients were statin intolerant, and approximately 90% reported a history of cardiovascular disease. LDL-C reductions remained generally unchanged from weeks 4 to 68 in each treatment group. At week 68, LDL-C mean percentage changes from baseline were - 41.7% (alirocumab 75 mg Q2W), - 53.7% (alirocumab 150 mg Q2W), and - 54.1% (evolocumab 140 mg Q2W). LDL-C reduction was 7.1% greater in patients receiving statins than in those not receiving statins because of statin intolerance (P < 0.0001). PCSK9i consistently improved levels of other lipoproteins throughout. Overall, 47.1% of patients reported adverse events at week 68. Conclusions: Consistent with clinical trial findings, alirocumab and evolocumab improved lipid levels in a real-world setting in patients with high baseline LDL-C levels despite receiving maximally tolerated LLTs. PCSK9i were generally well-tolerated

Dusty punch cards and an eternal enigma: high-density lipoproteins and atherosclerosis

Epidemiological, clinical, and experimental evidence has accumulated during the last decades suggesting that high-density lipoproteins (HDLs) may protect from atherosclerosis and its clinical consequences. However, more than 55 years after the first description of the link between HDL and heart attacks, many facets of the biochemistry, function, and clinical significance of HDL remain enigmatic. This applies particularly to the completely unexpected results that became available from some recent clinical trials of nicotinic acid and of inhibitors of cholesteryl ester transfer protein (CETP). The concept that raising HDL cholesterol by pharmacological means would decrease the risk of vascular disease has therefore been challenged