The Role of Nutraceuticals in Statin Intolerant Patients.

Statins are the most common drugs administered for patients with cardiovascular disease. However, due to statin-associated muscle symptoms, adherence to statin therapy is challenging in clinical practice. Certain nutraceuticals, such as red yeast rice, bergamot, berberine, artichoke, soluble fiber, and plant sterols and stanols alone or in combination with each other, as well as with ezetimibe, might be considered as an alternative or add-on therapy to statins, although there is still insufficient evidence available with respect to long-term safety and effectiveness on cardiovascular disease prevention and treatment. These nutraceuticals could exert significant lipid-lowering activity and might present multiple non-lipid-lowering actions, including improvement of endothelial dysfunction and arterial stiffness, as well as anti-inflammatory and antioxidative properties. The aim of this expert opinion paper is to provide the first attempt at recommendation on the management of statin intolerance through the use of nutraceuticals with particular attention on those with effective low-density lipoprotein cholesterol reduction.

Lipid-lowering nutraceuticals in clinical practice: position paper from an International Lipid Expert Panel.

In recent years, there has been growing interest in the possible use of nutraceuticals to improve and optimize dyslipidemia control and therapy. Based on the data from available studies, nutraceuticals might help patients obtain theraputic lipid goals and reduce cardiovascular residual risk. Some nutraceuticals have essential lipid-lowering properties confirmed in studies; some might also have possible positive effects on nonlipid cardiovascular risk factors and have been shown to improve early markers of vascular health such as endothelial function and pulse wave velocity. However, the clinical evidence supporting the use of a single lipid-lowering nutraceutical or a combination of them is largely variable and, for many of the nutraceuticals, the evidence is very limited and, therefore, often debatable. The purpose of this position paper is to provide consensus-based recommendations for the optimal use of lipid-lowering nutraceuticals to manage dyslipidemia in patients who are still not on statin therapy, patients who are on statin or combination therapy but have not achieved lipid goals, and patients with statin intolerance. This statement is intended for physicians and other healthcare professionals engaged in the diagnosis and management of patients with lipid disorders, especially in the primary care setting.

Candidate gene sequencing of SLC11A2 and TMPRSS6 in a family with severe anaemia: common SNPs, rare haplotypes, no causative mutation.

BACKGROUND: Iron-refractory iron deficiency anaemia (IRIDA) is a rare disorder which was linked to mutations in two genes (SLC11A2 and TMPRSS6). Common polymorphisms within these genes were associated with serum iron levels. We identified a family of Serbian origin with asymptomatic non-consanguineous parents with three of four children presenting with IRIDA not responding to oral but to intravenous iron supplementation. After excluding all known causes responsible for iron deficiency anaemia we searched for mutations in SLC11A2 and TMPRSS6 that could explain the severe anaemia in these children. METHODOLOGY/RESULTS: We sequenced the exons and exon-intron boundaries of SLC11A2 and TMPRSS6 in all six family members. Thereby, we found seven known and fairly common SNPs, but no new mutation. We then genotyped these seven SNPs in the population-based SAPHIR study (n = 1,726) and performed genetic association analysis on iron and ferritin levels. Only two SNPs, which were top-hits from recent GWAS on iron and ferritin, exhibited an effect on iron and ferritin levels in SAPHIR. Six SAPHIR participants carrying the same TMPRSS6 genotypes and haplotype-pairs as one anaemic son showed lower ferritin and iron levels than the average. One individual exhibiting the joint SLC11A2/TMPRSS6 profile of the anaemic son had iron and ferritin levels lying below the 5(th) percentile of the population's iron and ferritin level distribution. We then checked the genotype constellations in the Nijmegen Biomedical Study (n = 1,832), but the profile of the anaemic son did not occur in this population. CONCLUSIONS: We cannot exclude a gene-gene interaction between SLC11A2 and TMPRSS6, but we can also not confirm it. As in this case candidate gene sequencing did not reveal causative rare mutations, the samples will be subjected to whole exome sequencing.

Effect of folate supplementation on N-terminal pro-brain natriuretic peptide.

BACKGROUND: Increased plasma homocysteine (HCY) has been suggested as a novel risk factor for chronic heart failure (CHF). This study investigated the effect of a HCY lowering therapy by folic acid (FA) supplementation on N-terminal pro-brain natriuretic peptide (NT-proBNP) in healthy subjects. METHODS: We treated 61 healthy individuals (median age [25th-75th percentile]: 57 [53-69] years with placebo, 0.4, 1.0 or 5.0 mg FA daily for 2 months. Fasting blood samples were taken after 0, 4 and 8 weeks. Serum HCY, folate, vitamin B12 and NT-proBNP were studied. RESULTS: Baseline HCY, folate and NT-proBNP levels were 13.6 (10.0-16.4) micromol/L, 5.0 (3.8-6.4) microg/L and 40.4 (21.8-67.3) ng/L, respectively. Serum folate increased during supplementation (4 weeks of placebo, 0.4, 1.0, 5.0 mg of FA: -9%, +131%, +150%, +314%; 8 weeks: -72%, +152%, +185%, +62%) and HCY decreased (4 weeks: +2%, -12%, -20%, -15%; 8 weeks: -2%, -9%, -17%, -15%) in the treatment groups. NT-proBNP did not change within groups. Pooling FA treated subjects, individuals with a baseline NT-proBNP above the median of 40 ng/L exhibited a 20% decrease of NT-proBNP (significant on a 10% level) while HCY decreased by 15%. CONCLUSION: FA supplementation with doses between 0.4 and 5 mg does not affect NT-proBNP in healthy subjects with an NT-proBNP concentration <40 ng/L, but possibly lowers NT-proBNP in individuals with NT-proBNP levels >40 ng/L.

Folate supplementation does not affect biochemical markers of bone turnover.

BACKGROUND: Recently, increased plasma homocysteine (HCY) has been suggested as a novel independent risk factor for osteoporotic fractures. This study aimed to analyze the effect of a HCY lowering therapy by folic acid (FA) supplementation on biochemical bone markers in healthy subjects. MATERIAL AND METHODS: We treated 61 healthy individuals (mean age: 58+/-8 years) with placebo, 0.4, 1 or 5 mg FA daily for 2 months. Fasting blood samples were taken after 0, 4 and 8 weeks. Serum HCY, folate, vitamin B12, osteocalcin (OC), procollagen type I N-terminal propeptide (PINP) and C-terminal telopeptides of human collagen type I (CTX) were studied. RESULTS: Overall baseline HCY and folate levels were 13.4 +/- 3.6 micromol/L and 5.7 +/- 3.0 microg/L, respectively. Participants exhibited normal baseline OC, PINP and CTX levels. Serum folate increased during supplementation (4 weeks of placebo, 0.4, 1 and 5 mg of FA: -7, +160, +162 and +436 %; 8 weeks: -6, +305, +340 and +216 %) and HCY decreased (4 weeks of placebo, 0.4, 1 and 5 mg of FA: +2, -14, -21 and -17 %; 8 weeks: +2, -8, -20 and -17 %) in the treatment groups, but not in the placebo group. OC (placebo: 22.8 vs. 23.0 vs. 23.6; 0.4 mg FA: 21.6 vs. 22.1 vs. 24.1; 1 mg FA: 23.7 vs. 22.6 vs. 23.4; 5 mg FA: 24.1 vs. 20.5 vs. 20.9 microg/L), PINP (placebo: 43.5 vs. 51.3 vs. 46.5; 0.4 mg FA: 34.0 vs. 34.1 vs. 39.5; 1 mg FA: 43.6 vs. 39.7 vs. 43.2; 5 mg FA: 41.1 vs. 38.7 vs. 37.4 microg/L) and CTX (placebo: 258 vs. 360 vs. 321; 0.4 mg FA: 229 vs. 290 vs. 315; 1 mg FA: 319 vs. 325 vs. 301; 5 mg FA: 293 vs. 321 vs. 304 ng/L) did not change throughout the study. CONCLUSION: Short-term FA supplementation does not affect biochemical bone markers in non-osteoporotic subjects with a low folate status.