Ursula Kassner

Evaluation of the safety and tolerability of prolonged-release nicotinic acid in a usual care setting: the NAUTILUS study

ABSTRACT Objective: The main objective was to evaluate the safety and tolerability of prolonged-release nicotinic acid (niacin; Niaspan*) in an usual care setting with patients receiving treatment for dyslipidaemia in Germany: the multiceNtre, open, uncontrolled sAfety and tolerability stUdy of a modified-release nicoTinic acId formuLation in sUbjects with dySlipidaemia and low HDL-cholesterol (NAUTILUS). * Niaspan is a registered trade name of Merck KGaA, Darmstadt, Germany Research design and methods: This was a multicentre, open-label, 15‐week study. Eligible patients had a diagnosis of dyslipidaemia with lipids inadequately controlled by 4 weeks of diet treatment. Additionally, patients had low HDL-cholesterol (< 1.03 mmol/L [< 40 mg/dL]) in men and < 1.29 mmol/L [< 50 mg/dL] in women), and had triglycerides < 9.03 mmol/L (< 800 mg/dL). Exclusion criteria included uncontrolled diabetes (HbA1C > 9%), significant hepatic, vascular or renal disease. The target dose was 2000 mg once daily. Main outcome measures: The main objective was to evaluate the safety and tolerability of prolonged-release nicotinic acid [incidence of adverse events (AE) and serious AE] in the overall population (the safety population). Efficacy parameters (lipid parameters) were also measured in the intent-to-treat population. Results: A total of 566 patients were recruited, mostly with metabolic syndrome (39.4%), mixed hypercholesterolaemia (31.6%), isolated low HDL-cholesterol and markedly elevated cardiovascular risk for other reasons (10.8%), and primary hypercholesterolaemia (8.8%), according to NCEP/ATP III guidelines. The target dose was achieved by 65% of patients. Flushing was the most common side-effect (42%), as expected, and 9.7% withdrew for flushing. Other drug-related AEs occurred at low frequency (18.6%), and 8.7% withdrew for an AE other than flushing. Most AEs were mild or moderate in severity. Serious AEs considered possibly related to treatment occurred in three patients (0.5%); all resolved following treatment withdrawal. There was no hepatotoxicity or serious muscle AE. Conclusions: Prolonged-release nicotinic acid was well tolerated, and these results support its use in the management of patients at elevated cardiovascular risk due to low HDL-cholesterol.

Therapeutic Potential of Mipomersen in the Management of Familial Hypercholesterolaemia

High levels of low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) [Lp(a)] are associated with early morbidity and mortality caused by cardiovascular disease (CVD). There are hints that a reduction of LDL-C levels beyond currently advocated targets, and the use of drugs that also have Lp(a)-lowering potential, could provide further clinical benefit. Today, LDL apheresis is the only available treatment option to achieve further lowering of apolipoprotein-B (apo-B)-containing lipoproteins, especially Lp(a).Mipomersen is currently being studied in patients with mild to severe hypercholesterolaemia as add-on therapy to other lipid-lowering therapy, as monotherapy in patients who are intolerant of HMG-CoA reductase inhibitors (statins) and who are at high risk for CVD. Patients affected by homozygous or heterozygous familial hypercholesterolaemia (FH), which are inherited autosomal co-dominant disorders characterized by a marked elevation of serum LDL-C concentration, remain a clinical challenge, especially when their CVD risk is aggravated by additionally elevated Lp(a) levels.Mipomersen is a 20-mer oligonucleotide [2′-O-(2-methoxy) ethyl-modified oligonucleotide], a second-generation antisense oligonucleotide (AOS), complementary to the coding region for human-specific apo-B-100 messenger RNA (mRNA). Mipomersen inhibits apo-B-100 synthesis and is consequently a new treatment strategy to lower apo-B-containing lipoproteins like LDL-C and Lp(a) in patients at high risk for CVD not on target or intolerant to statins.This article focuses on mipomersen and gives an overview of the current status of mipomersen as a promising treatment option. Recent studies have shown a decrease in LDL-C levels of 22–42.2% and in Lp(a) of 19.6–31.1% from baseline, depending on study design. Dose-dependent reductions of very low-density lipoprotein cholesterol (VLDL-C) and triglyceride levels have also been observed.Although the short-term efficacy and safety of mipomersen have been proven, side effects like injection-site reactions (up to 90–100%), increased liver enzymes, cephalgias, nasopharyngitis, myalgia, nausea and fatigue must be mentioned and critically discussed. Furthermore, we need more data on the long-term side effects, especially regarding the long-term potential for hepatic steatosis. Data on cardiovascular outcomes with mipomersen are also not yet available.

Lipoprotein(a) – An independent causal risk factor for cardiovascular disease and current therapeutic options

It is widely accepted that elevated levels of lipoprotein(a) (Lp(a)) are associated with an increased risk for cardiovascular diseases. Several studies have identified Lp(a) as independent cardiovascular risk factor. Consequently, therapeutic concepts are targeting at lowering Lp(a) serum levels. To date, in Europe no pharmaceutical treatment to lower levels of Lp(a) is available. Current developments of pharmaceutical agents like the apolipoprotein-(B-100)-antisense mipomersen, inhibitors of PCSK9 and apolipoprotein-(a)-antisense have shown promising results in lowering Lp(a). Presently, the only available therapy to effectively reduce levels of Lp(a) is regular extracorporeal lipoprotein apheresis. Different apheresis methods show a similar lowering effect of about 60-70 % by a single session. Apart from one small-scale study there has been no randomized, controlled study which could prove that lowering Lp(a) will result in a risk reduction for cardiovascular disease. This review looks into the current scientific evidence of.

Single lipoprotein apheresis session improves cardiac microvascular function in patients with elevated lipoprotein(a): detection by stress/rest perfusion magnetic resonance imaging.

The aim of this study was to explore the effects of a single lipoprotein apheresis session on myocardial stress/rest (S/R) perfusion in patients with elevated lipoprotein(a) (Lp(a)) and coronary artery disease using cardiac magnetic resonance imaging. Twenty patients with Lp(a) > 60 mg/dL and coronary artery disease were randomized into a control or a treatment group. Both groups underwent cardiac magnetic resonance imaging with assessment of left ventricular function, perfusion and viability, and the treatment group underwent lipoprotein apheresis immediately afterwards. Repeat magnetic resonance imaging was performed at 24 h for both groups and at 96 h for just the treatment group. The transmyocardial perfusion gradient (i.e. endo‐epi ratio [EER]) was determined and a comprehensive parameter of resting and adenosine‐induced stress perfusion was derived (EER‐S/R). While the hematocrit remained unchanged, apheresis reduced lipoproteins and rheological parameters: Lp(a) − 55.1%, total cholesterol − 34.5%, low density lipoprotein (LDL) − 54.6%, Lp(a)‐corrected LDL − 54.3%, high density lipoprotein − 17.4%, apolipoprotein B − 39.2%, plasma viscosity − 10.7%, and fibrinogen − 30.6% at 24 h (P < 0.05 for all). At 96 h these parameters, except for plasma viscosity, apolipoprotein B and Lp(a)‐corrected LDL, recovered but did not reach baseline values (P < 0.05 for all). The EER‐S/R at 24 h was lowered by therapy (ΔEER‐S/R 5%; P < 0.03), whereas this effect disappeared at 96 h. The ejection fraction (EF) was slightly improved at 24 h (67.07 ± 6.28% vs. 64.89 ± 6.39%; ΔEF 2.2%, P < 0.05) and returned to baseline at 96 h. In the control group no corresponding changes were detected. In conclusion, cardiac magnetic resonance imaging detects subtle treatment‐related changes in regional myocardial perfusion in patients with elevated Lp(a) and coronary artery disease undergoing lipoprotein apheresis.

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.

Designing a study to evaluate the effect of apheresis in patients with elevated lipoprotein(a)

Lipoprotein(a) (Lp(a)) is a risk factor for premature coronary artery disease. Lp(a) levels can neither be influenced sufficiently by standard hypolipemic diet nor by drug therapy. Currently, lipid apheresis is the only option to effectively lower Lp(a) levels in patients with elevated Lp(a) and progressive CVD. The lipid-clinic at the Charité University hospital Berlin and other German apheresis centres have longstanding positive experience with this therapeutic regimen. Lately, in Germany lipid apheresis was accepted as the treatment of choice for patients with elevated Lp(a) levels > 60 mg/dl and progressive CVD. At the same time, care providers were obliged to conduct a controlled trial to prove the efficacy of lipid apheresis for this indication. Therefore, we designed a prospective, randomized, controlled trial to prove the hypothesis that lipid apheresis decreases vascular events.

Autosomal recessive hypercholesterolemia in three sisters with phenotypic homozygous familial hypercholesterolemia: diagnostic and therapeutic procedures.

Abstract:  Familial hypercholesterolemia is an autosomal‐dominant inherited disorder caused by mutations in the low‐density lipoprotein (LDL) receptor gene. The homozygous form is characterized by high‐serum LDL cholesterol concentrations, xanthoma formation and premature atherosclerosis. Recently, another molecular defect that also results in severely elevated LDL cholesterol levels was identified: autosomal recessive hypercholesterolemia. This inherited disorder is caused by a mutation in a putative LDL receptor adaptor protein. In our lipid clinic, three sisters with phenotypic homozygous hypercholesterolemia were recently diagnosed as having autosomal recessive hypercholesterolemia. They presented in 1990 with massive tuberous xanthomas at the knees, thighs, elbows and buttocks. LDL receptor and apolipoprotein B gene defects were excluded through mutation analysis. From 1992 onward they underwent LDL‐apheresis on a weekly basis. To date the clinical outcome is very satisfying with no evidence of coronary heart disease or aortic valve lesions  and  almost  complete  regression  of  xanthomatosis.

Correction of low HDL cholesterol to reduce cardiovascular risk: practical considerations relating to the therapeutic use of prolonged‐release nicotinic acid (Niaspan®)

Background:  Substantial residual cardiovascular risk persists despite effective LDL lowering treatment in populations at elevated risk for adverse cardiovascular outcomes. Low HDL cholesterol is an independent cardiovascular risk factor and occurs in about one‐third of patients treated for dyslipidaemia in Europe. Moreover, randomised intervention studies have shown that increasing HDL cholesterol improves cardiovascular outcomes. Correcting low HDL cholesterol therefore presents a rational and proven strategy for intervention to produce further reductions in cardiovascular risk beyond those possible with a statin alone. Nicotinic acid (niacin in the USA) is the most effective agent currently available for increasing levels of HDL cholesterol.

Clinical utility gene card for: Hyperlipoproteinemia, TYPE II

1.5 Mutational spectrum About 1.300 variants in the most commonly affected gene in the autosomal dominant form of Familial Hypercholesterolemia (FH), LDLR, are listed in the UCL LDLR variant database (http://www. ucl.ac.uk/ldlr/Current/index.php?select_db=LDLR) and the LOVDv2.0 platform (https://grenada.lumc.nl/LOVD2/UCL-Heart/home.php? select_db=LDLR). These variants are equally distributed over the gene and include exonic substitutions, small exonic rearrangements, large rearrangements, promoter variants, intronic variants and a variant in the 3’ untranslated sequence, point mutations, splice site mutations, large deletions, with approximately 80% being likely to be disease causing.1 Another reference database with known LDLR variants is maintained by Inserm (http://www.umd.be/LDLR/). One major disease causing mutation in the APOB gene, c.10580 G4A (p.Arg3527Gln).2–4 Only a few PCSK9 mutations, all of the missense type and resulting in a ‘gain of function’, have been found to be associated with the Hypercholesterolaemia phenotype, with some of them being restricted to certain ethnic groups.5

Immunoadsorption of Agonistic Autoantibodies Against α1-Adrenergic Receptors in Patients with Mild to Moderate Dementia.

Dementia has been shown to be associated with agonistic autoantibodies. The deleterious action of autoantibodies on the α1‐adrenergic receptor for brain vasculature has been demonstrated in animal studies. In the current study, 169 patients with dementia were screened for the presence of agonistic autoantibodies. 47% of patients suffering from mild to moderate Alzheimers disease and/or vascular dementia carried these autoantibodies. Eight patients positive for autoantibodies underwent immunoadsorption. Patients treated on four consecutive days were subsequently negative for autoantibodies and displayed stabilization of cognitive and mental condition during 12–18 months’ follow‐up. In patients treated for 2–3 days, autoantibodies were reduced by only 78%. They suffered a rebound of autoantibodies during follow‐up, benefited from immunoadsorption too, but their mental parameters worsened. We provide first data on the clinical relevance of agonistic autoantibodies in dementia and show that immunoadsorption is safe and efficient in removing autoantibodies with overall benefits for patients.