Systematic Lab Knowledge Integration for Management of Lipid Excess in High-Risk Patients: Rationale and Design of the SKIM LEAN Project.

SKIM LEAN aims at exploiting Electronic Health Records (EHRs) to integrate knowledge derived from routine laboratory tests with background analysis of clinical databases, for the identification and early referral to specialist care, where appropriate, of patients with hypercholesterolemia, who may be inadequately controlled according to their cardiovascular (CV) risk level. SKIM LEAN addresses gaps in care that may occur through the lack of coordination between primary and specialist care, incomplete adherence to clinical guidelines, or poor patient's compliance to the physician's prescriptions because of comorbidities or drug side effects. Key project objectives include: (1) improved health professionals' competence and patient empowerment through a two-tiered educational website for general practitioners (GPs) and patients, and (2) implementation of a hospital-community shared care pathway to increase the proportion of patients at high/very-high CV risk (Familial Hypercholesterolemia, previous CV events) who achieve target LDL cholesterol (LDL-C) levels. Thanks to a close collaboration between clinical and information technology partners, SKIM LEAN will fully exploit the value of big data deriving from EHRs, and filter such knowledge using clinically-derived algorithms to risk-stratify patients. Alerts for GPs will be generated with interpreted test results. GPs will be able to refer patients with uncontrolled LDL-C within the shared pathway to the lipid or secondary prevention outpatient clinics of NIG hospital. Metrics to verify the project achievements include web-site visits, the number of alerts generated, numbers of patients referred by GPs, the proportion of secondary prevention patients who achieve LDL-C <100 mg/dl or a >50% decrease from baseline.

Indicators of Cardiovascular Risk in Metabolic Syndrome: Long Term Follow-up in Italian Patients.

BACKGROUND: Cardiovascular risk (CV) factors associated with the metabolic syndrome (MetS) may vary in different populations. In some, hypertension may be the major determinant, in others are low high-density lipoprotein cholesterol (HDL-C), high triglycerides, or another component. SUBJECTS AND METHODS: Subjects included in this analysis were identified in 2006, among those attending the Lipid Clinic of the Niguarda Hospital, and followed up through to 2013. Patient characteristics (including the occurrence of CV events) were obtained from electronic medical records. MetS was diagnosed according to the American Heart Association/National Heart, Lung and Blood Institute (AHA/NHLBI) guidelines. The carotid intima media thickness (cIMT) was also followed in these patients over the years. RESULTS: After 7 years a total of 858 subjects had a complete follow-up; 271 of those had MetS. Patients developing a CV event showed elevated baseline cIMT (e.g. cIMTmax ≥ 2.4 mm in males and ≥ 2.2 mm in females); moreover the cIMT in MetS patients was higher at baseline and the rise over 7 years was larger compared with patients without MetS. By examining each body variable for MetS we found that a waist to height ratio (WHtR) ≥ 0.5 was present in nearly all subjects with a CV event. CONCLUSION: The follow-up data of a series of Italian patients with and without MetS, clearly indicates that the former have a raised cIMT and their arterial IMT progression is greater and the presence of a larger WHtR is apparently linked to a higher incidence of CV events.

Gender-related lipid and/or lipoprotein responses to statins in subjects in primary and secondary prevention.

BACKGROUND: Cardiovascular risk in men rises around the fourth decade of life, whereas women appear to be protected by sex hormones until menopause. This, in turn, tends to negatively affect the lipid profile. Since the 1980s, the incidence of cardiovascular diseases has been reported to progressively decline in men, but it has persisted almost unchanged in women. Major clinical trials on statins have been mostly conducted in men and have fostered the introduction of these agents into clinical practice worldwide. However, only few reports have examined a possible differential activity of statins in the 2 genders, providing in some cases opposite findings. OBJECTIVE: To evaluate gender-related differences in statin responses. METHODS: Variations of lipid profile after 1-year of treatment with different statins in 337 dyslipidemic patients (171 men and 166 women). RESULTS: In this series of patients, a significantly attenuated reduction of total cholesterol and low-density lipoprotein cholesterol in women vs men on drug treatment was noted after adjustment for dose and statin power (low-density lipoprotein cholesterol: -28.5 ± 11.8% in men vs -22.7 ± 11.8% in women; P < .001). CONCLUSIONS: The present study indicates that statin treatment has a reduced effectiveness in improving the plasma lipid profile in dyslipidemic women vs men. Whether such gender-related differences may have an impact on clinical outcomes remains to be elucidated.

Nutraceutical approach to moderate cardiometabolic risk: results of a randomized, double-blind and crossover study with Armolipid Plus.

BACKGROUND: Primary cardiovascular prevention may be achieved by lifestyle/nutrition improvements and specific drugs, although a relevant role is now emerging for specific functional foods and nutraceuticals. OBJECTIVES: The aim of this study was to evaluate the usefulness of a nutraceutical multitarget approach in subjects with moderate cardiovascular risk and to compare it with pravastatin treatment. SUBJECTS: Thirty patients with moderate dyslipidemia and metabolic syndrome (according to the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults) were included in an 8-week randomized, double-blind crossover study and took either placebo or a nutraceutical combination that contained red yeast rice extract, berberine, policosanol, astaxanthin, coenzyme Q10, and folic acid (Armolipid Plus). Subsequently, they were subjected to another 8-week treatment with pravastatin 10 mg/d. This dosage was selected on the basis of its expected -20% efficacy in reducing low-density lipoprotein-cholesterol. RESULTS: Treatment with Armolipid Plus led to a significant reduction of total cholesterol (-12.8%) and low-density lipoprotein-cholesterol (-21.1%), similar to pravastatin (-16% and -22.6%, respectively), and an increase of high-density lipoprotein-cholesterol (4.8%). Armolipid Plus improved the leptin-to-adiponectin ratio, whereas adiponectin levels were unchanged. CONCLUSIONS: These results indicate that this nutraceutical approach shows a lipid-lowering activity comparable to pravastatin treatment. Hence, it may be a safe and useful option, especially in conditions of moderate cardiovascular risk, in which a pharmacologic intervention may not be appropriate.

Hypocholesterolaemic effects of lupin protein and pea protein/fibre combinations in moderately hypercholesterolaemic individuals.

The present study was aimed to evaluate the effect of plant proteins (lupin protein or pea protein) and their combinations with soluble fibres (oat fibre or apple pectin) on plasma total and LDL-cholesterol levels. A randomised, double-blind, parallel group design was followed: after a 4-week run-in period, participants were randomised into seven treatment groups, each consisting of twenty-five participants. Each group consumed two bars containing specific protein/fibre combinations: the reference group consumed casein+cellulose; the second and third groups consumed bars containing lupin or pea proteins+cellulose; the fourth and fifth groups consumed bars containing casein and oat fibre or apple pectin; the sixth group and seventh group received bars containing combinations of pea protein and oat fibre or apple pectin, respectively. Bars containing lupin protein+cellulose ( - 116 mg/l, - 4·2%), casein+apple pectin ( - 152 mg/l, - 5·3%), pea protein+oat fibre ( - 135 mg/l, - 4·7%) or pea protein+apple pectin ( - 168 mg/l, - 6·4%) resulted in significant reductions of total cholesterol levels (P<0·05), whereas no cholesterol changes were observed in the subjects consuming the bars containing casein+cellulose, casein+oat fibre or pea protein+cellulose. The present study shows the hypocholesterolaemic activity and potential clinical benefits of consuming lupin protein or combinations of pea protein and a soluble fibre, such as oat fibre or apple pectin.

Paradoxical decrease in high-density lipoprotein cholesterol with fenofibrate: a quite rare phenomenon indeed.

Some recent clinical reports have suggested that paradoxical decreases in high-density lipoprotein cholesterol (HDL-C) levels after fenofibrate treatment may be quite common. These appear to occur mainly in patients with combined fibrate/statin therapy and possibly in those with low baseline HDL-C. Reports on HDL-C reductions after fenofibrate are possibly supported by the disappointing results in terms of HDL-C responses from the recent FIELD study. A survey on 581 patients treated for 1 year or longer was carried out in our Clinical Center. This indicated that paradoxical HDL-C reductions are a relatively uncommon phenomenon. Not more than 15.3% of the present series showed an HDL-C reduction, mostly of a modest degree. Further, reductions of HDL-C appear to occur mainly in individuals with significant HDL-C elevations (>50 mg/dL), almost never in patients with low HDL-C. Otherwise, there seems to be no impact of a previous diagnosis of diabetes or hypertension on the HDL-C changes. From a very recent pharmacogenomic study on the apo A1/C3/A4/A5 gene cluster, genetic influences appear only to reduce the positive impact of fenofibrate on HDL-C, but do not indicate any risk of occurrence of HDL-C reductions. Also based on our very long experience with this drug, it appears that fenofibrate raises HDL-C levels in the vast majority of treated patients, with a particularly dramatic effect in individuals with low HDL-C and hypertriglyceridemia.

Serum from hypercholesterolemic patients treated with atorvastatin or simvastatin inhibits cultured human smooth muscle cell proliferation.

We evaluated the pharmacological activity of whole-blood serum from atorvastatin- vs. simvastatin- (both 40 mg/day) treated hypercholesterolemic patients (n=10) on cultured smooth muscle cell (SMC) proliferation and cholesterol biosynthesis, as related to lipid-lowering effect. Patients received either single or 2-weeks repeated doses of both simvastatin and atorvastatin, following a randomised, double-blind, cross-over design. Blood samples were collected before drug administration and at the scheduled intervals after administration, and the obtained serum was separated by centrifugation, sterilized and frozen until assayed. Cultured SMC were supplemented with medium plus 15% of separate serum sampled from the patients, and grown for 72 h. Proliferation was assayed by a Coulter Counter, while cholesterol biosynthesis was measured by the incorporation of 14C-acetate into cholesterol, under the same experimental conditions. Atorvastatin was more active vs. simvastatin in reducing total- (-28.3% vs. -20.7%; p=0.045) and LDL-cholesterol (-39.8% vs. -30.1%; p=0.011) after a 2-weeks regimen. Serum from atorvastatin-treated patients inhibited SMC proliferation vs.t=0 after both single (AUC -21.6%) and repeated (AUC -26.9%) doses, while serum from simvastatin-treated patients inhibited SMC proliferation only after repeated doses (AUC -24.5%). Interestingly, in the same experimental conditions, the serum concentrations of both statins (and of their active metabolites) were constantly below the detection limits, as shown from the lack of inhibition of cholesterol biosynthesis. The absence of any significant association between the lipid-lowering effects and the inhibition of SMC proliferation, together with no detectable active statin in the serum, suggests that these effects are elicited through independent mechanisms.

Pharmacokinetic interactions between omeprazole/pantoprazole and clarithromycin in health volunteers.

The association omeprazole/clarithromycin is of current wide use in the treatment of Helicobacter pylori associated gastroduodenal ulcer. This combination may result in increased levels of omeprazole with potential interactions with commonly associated drugs. Kinetic/metabolic changes occurring after omeprazole/clarithromycin were compared to those occurring after pantoprazole/clarithromycin in healthy volunteers. Eight healthy volunteers, all males, age 25-34 years, all EM for CYP2C19, participated in a randomized, double blind crossover study in two periods of 7 days, separated by a 14-day washout. In each treatment period, subjects took either omeprazole 20mg b.i.d. together with clarithromycin 500 mg b.i.d., or pantoprazole 40 mg b.i.d. with the same dose of the antibiotic. The pharmacokinetic parameters of omeprazole and pantoprazole were compared to those after intake of both agents alone. Kinetics of unchanged clarithromycin was evaluated at the end of the two periods. The mean value of the area under the plasma concentration versus time curve (AUC) of unchanged omeprazole increased almost two-fold after concomitant administration of clarithromycin; the average 5-OH-omeprazole AUC was instead significantly reduced by 42%. Omeprazole clearance and volume of distribution were reduced significantly by 75 and 56%, respectively, after administration of the drug with clarithromicyn. No significant changes of the kinetic of pantoprazole and metabolites were observed. Kinetics of clarithromycin did not differ after the two associated treatments. The administration of clarithromycin with two different proton pump inhibitors indicates that the antibiotic can markedly increase omeprazole, not pantoprazole, levels. This observation may result in a better therapeutic response to omeprazole, but it may also potentially affect either the metabolism of CYP3A4 substrates or interfere with the absorption of drugs requiring an intact gastric digestion system.

Enantioselective liquid chromatographic-electrospray mass spectrometric assay of beta-adrenergic blockers: application to a pharmacokinetic study of sotalol in human plasma.

An enantioselective high performance liquid chromatographic-electrospray ionization mass spectrometric (HPLC-ESI-MS) method for the direct determination of several beta-adrenergic blockers was developed and validated. The method is based on the direct separation of the enantiomers of drugs on a laboratory-made chiral stationary phase (CSP) containing covalently bonded teicoplanin (TE) as chiral selector. Detection of the effluent was performed by electrospray ionization mass spectrometry, run in the selected-ion recording (SIR) mode. The method was applied to the pharmacokinetic monitoring of sotalol (STL) in the plasma of five young healthy volunteers, dosed with racemic drug. The limits of quantitation (LOQ) reached 4 ng/ml for both sotalol enantiomers. Such a method, fully validated, offers a novel, fast and very efficient tool for the direct determination of sotalol enantiomers in human plasma, and can be generally applied to the beta-adrenergic blockers stereoselective pharmacokinetics.

Soy milk with a high glycitein content does not reduce low-density lipoprotein cholesterolemia in type II hypercholesterolemic patients.

In order to evaluate acceptability and effectiveness of a partial addition of soy protein to the daily diet in well-established type II hypercholesterolemic individuals, a double-blind study was carried out with a soy milk providing 25 g/day of protein versus an identically formulated cow's milk. Twenty patients with type II hypercholesterolemia, 4 males and 16 females, age range 38-76 years, all with cholesterol levels >7 mmol/l and low-density lipoprotein cholesterol <5.5 mmol/l, were selected. Significant triglyceride elevations (WHO Fredrickson type IIB) were present in 4 patients, and the body mass index was 24.2 +/- 3.47 kg/m(2). Different from prior studies, either with isoflavone-free products or with a moderately isoflavone-rich milk, the milk in the present study did not reduce total and low-density lipoprotein cholesterolemia. A detailed analysis of the composition showed significant differences in the isoflavone content versus products used in prior studies with a positive outcome. Soy milk isoflavones were, in fact, characterized by a high glycitein content and a low genistein/daidzein ratio. Glycitein is a minor component in most soy products, and its role in cholesterol regulation is unclear. In view of the high interest in the use of soy products for the prevention of coronary diseases, the metabolic behavior of different isoflavones in man should be better characterized, and the role of isoflavone composition of soy products given for the control of cholesterolemia needs further clarification.