-
1.
Clinical Approach in the Management of Paediatric Patients with Familial Hypercholesterolemia: A National Survey Conducted by the LIPIGEN Paediatric Group.
Pederiva, C, Gazzotti, M, Arca, M, Averna, M, Banderali, G, Biasucci, G, Brambilla, M, Buonuomo, PS, Calabrò, P, Cipollone, F, et al
Nutrients. 2023;(15)
Abstract
Detection and treatment of patients with familial hypercholesterolemia (FH) starting from childhood is fundamental to reduce morbidity and mortality. The activity of National realities such as the LIPIGEN (LIpid transPort disorders Italian GEnetic Network) Paediatric Group, founded in 2018, is a milestone in this context. The aim of this exploratory survey, conducted in October 2021 among Italian lipid clinics included in the LIPIGEN Paediatric Group, was to investigate the current clinical approach in the management and treatment of paediatric patients with suspected FH. A digital questionnaire composed of 20 questions investigating nutritional treatment and nutraceutical and pharmacological therapy for children and adolescents with FH was proposed to the principal investigators of 30 LIPIGEN centres. Twenty-four centres responded to the section referring to children aged < 10 years and 30 to that referring to adolescents. Overall, 66.7% of children and 73.3% of adolescents were given lipid-lowering nutritional treatment as the first intervention level for at least 3-4 months (29.2% and 23.3%) or 6-12 months (58.3% and 53.3%). Nutraceuticals were considered in 41.7% (regarding children) and 50.0% (regarding adolescents) of the centres as a supplementary approach to diet. Lipid-lowering drug therapy initiation was mainly recommended (91.7% and 80.0%). In 83.3% of children and 96.7% of adolescents, statins were the most frequently prescribed drug. We highlighted several differences in the treatment of paediatric patients with suspected FH among Italian centres; however, the overall approach is in line with the European Atherosclerosis Society (EAS) recommendations for FH children and adolescents. We consider this survey as a starting point to reinforce collaboration between LIPIGEN centres and to elaborate in the near future a consensus document on the management of paediatric patients with suspected FH so as to improve and uniform detection, management, and treatment of these patients in our country.
-
2.
A subgroup analysis of the ODYSSEY APPRISE study: Safety and efficacy of alirocumab in the Italian cohort.
Cefalù, AB, Garbelotto, R, Mombelli, G, Pirro, M, Rubba, P, Arca, M, Borghi, C, Bonomo, K, Gonnelli, S, Massaroni, K, et al
Nutrition, metabolism, and cardiovascular diseases : NMCD. 2022;(11):2638-2646
Abstract
BACKGROUND AND AIMS ODYSSEY APPRISE trial evaluated efficacy and safety of alirocumab in 994 patients with hypercholesterolemia and high CV risk in a real-life setting. The aim of the present report is to detail on the Italian cohort enrolled and treated in the trial. METHODS AND RESULTS The methodology of the of the multinational, single-arm, Phase 3b open-label ODYSSEY APPRISE (Clinicaltrials.gov: NCT02476006) has been previously reported. 255 Italian patients were enrolled and treated according to the trial protocol. Overall mean exposure to alirocumab was 83.3 ± 27.7 weeks. At week 12, LDL-C decreased by 51.3 ± 23.1% and this reduction was overall maintained for the duration of the study. A similar reduction was observed in patients with and without heterozygous familial hypercholesterolemia (HeFH 50.7% ± 23.9 vs. non-FH, 53.6% ± 19.6). LDL-C was reduced below 1.8 mmol/L and/or by ≥ 50% reduction from baseline in 62% of patients overall (61% in HeFH and 67% in non-FH). Alirocumab was similarly well tolerated in the Italian cohort as in the entire study population and the more common treatment emergent adverse events (TEAEs) were influenza, myalgia and nasopharyngitis. The incidence LDL-C levels <25 mg/dl and <15 mg/dl, was 8.2% and 2.9% respectively. CONCLUSION The efficacy and safety of alirocumab in a real-life setting, in the Italian subgroup of patients are consistent with findings in the entire study population and confirm that alirocumab is a beneficial approach to further reduce LDL-C levels in patients at high CV risk on maximally tolerated conventional lipid lowering treatment. GOV IDENTIFIER NCT02476006.
-
3.
Effects of PCSK9 inhibitors on HDL cholesterol efflux and serum cholesterol loading capacity in familial hypercholesterolemia subjects: a multi-lipid-center real-world evaluation.
Palumbo, M, Giammanco, A, Purrello, F, Pavanello, C, Mombelli, G, Di Pino, A, Piro, S, Cefalù, AB, Calabresi, L, Averna, M, et al
Frontiers in molecular biosciences. 2022;:925587
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9), beyond regulating LDL cholesterol (LDL-c) plasma levels, exerts several pleiotropic effects by modulating lipid metabolism in extrahepatic cells such as macrophages. Macrophage cholesterol homeostasis depends on serum lipoprotein functions, including the HDL capacity to promote cell cholesterol efflux (CEC) and the serum capacity to promote cell cholesterol loading (CLC). The aim of this observational study was to investigate the effect of PCSK9 inhibitors (PCSK9-i) treatment on HDL-CEC and serum CLC in patients with familial hypercholesterolemia (FH). 31 genetically confirmed FH patients were recruited. Blood was collected and serum isolated at baseline and after 6 months of PCSK9-i treatment. HDL-CEC was evaluated through the main pathways with a radioisotopic cell-based assay. Serum CLC was assessed fluorimetrically in human THP-1 monocyte-derived macrophages. After treatment with PCSK9-i, total cholesterol and LDL-c significantly decreased (-41.6%, p < 0.0001 and -56.7%, p < 0.0001, respectively). Total HDL-CEC was not different between patients before and after treatment. Conversely, despite no changes in HDL-c levels between the groups, ABCG1 HDL-CEC significantly increased after treatment (+22.2%, p < 0.0001) as well as HDL-CEC by aqueous diffusion (+7.8%, p = 0.0008). Only a trend towards reduction of ABCA1 HDL-CEC was observed after treatment. PCSK9-i significantly decreased serum CLC (-6.6%, p = 0.0272). This effect was only partly related to the reduction of LDL-c levels. In conclusion, PCSK9-i treatment significantly increased HDL-CEC through ABCG1 and aqueous diffusion pathways and reduced the serum CLC in FH patients. The favorable effect of PCSK9-i on functional lipid profile could contribute to the cardiovascular benefit of these drugs in FH patients.
-
4.
Interactions of Oxysterols with Atherosclerosis Biomarkers in Subjects with Moderate Hypercholesterolemia and Effects of a Nutraceutical Combination (Bifidobacterium longum BB536, Red Yeast Rice Extract) (Randomized, Double-Blind, Placebo-Controlled Study).
Cicolari, S, Pavanello, C, Olmastroni, E, Puppo, MD, Bertolotti, M, Mombelli, G, Catapano, AL, Calabresi, L, Magni, P
Nutrients. 2021;(2)
Abstract
BACKGROUND Oxysterol relationship with cardiovascular (CV) risk factors is poorly explored, especially in moderately hypercholesterolaemic subjects. Moreover, the impact of nutraceuticals controlling hypercholesterolaemia on plasma levels of 24-, 25- and 27-hydroxycholesterol (24-OHC, 25-OHC, 27-OHC) is unknown. METHODS Subjects (n = 33; 18-70 years) with moderate hypercholesterolaemia (low-density lipoprotein cholesterol (LDL-C:): 130-200 mg/dL), in primary CV prevention as well as low CV risk were studied cross-sectionally. Moreover, they were evaluated after treatment with a nutraceutical combination (Bifidobacterium longum BB536, red yeast rice extract (10 mg/dose monacolin K)), following a double-blind, randomized, placebo-controlled design. We evaluated 24-OHC, 25-OHC and 27-OHC levels by gas chromatography/mass spectrometry analysis. RESULTS 24-OHC and 25-OHC were significantly correlated, 24-OHC was correlated with apoB. 27-OHC and 27-OHC/total cholesterol (TC) were higher in men (median 209 ng/mL and 77 ng/mg, respectively) vs. women (median 168 ng/mL and 56 ng/mg, respectively); 27-OHC/TC was significantly correlated with abdominal circumference, visceral fat and, negatively, with high-density lipoprotein cholesterol (HDL-C). Triglycerides were significantly correlated with 24-OHC, 25-OHC and 27-OHC and with 24-OHC/TC and 25-OHC/TC. After intervention, 27-OHC levels were significantly reduced by 10.4% in the nutraceutical group Levels of 24-OHC, 24-OHC/TC, 25-OHC, 25-OHC/TC and 27-OHC/TC were unchanged. CONCLUSIONS In this study, conducted in moderate hypercholesterolemic subjects, we observed novel relationships between 24-OHC, 25-OHC and 27-OHC and CV risk biomarkers. In addition, no adverse changes of OHC levels upon nutraceutical treatment were found.
-
5.
Nutraceutical approach for the management of cardiovascular risk - a combination containing the probiotic Bifidobacterium longum BB536 and red yeast rice extract: results from a randomized, double-blind, placebo-controlled study.
Ruscica, M, Pavanello, C, Gandini, S, Macchi, C, Botta, M, Dall'Orto, D, Del Puppo, M, Bertolotti, M, Bosisio, R, Mombelli, G, et al
Nutrition journal. 2019;18(1):13
-
-
-
Free full text
Plain language summary
Probiotics have been shown to reduce total cholesterol (TC) and low-density lipoprotein (LDL-C – often called ‘bad’ cholesterol) in people with moderately raised cholesterol levels. A specific strain of probiotic called Bifidobacterium longum BB536, may decrease TC and LDL-C by reducing the reabsorption of cholesterol from the intestine, and, combined with other natural supplements, may be useful to manage high cholesterol in people at low risk of heart disease. This study was conducted to evaluate the effect of a nutraceutical (Lactoflorene Colesterolo®), containing Bifidobacterium longum BB536 (1bn CFUs) combined with red yeast rice (RYR) extract (10 mg/day monacolin K), niacin (16mg) and coenzyme Q10 (20mg) on levels of cholesterol and fats in the blood. This was a 12-week randomised, parallel, double-blind, placebo-controlled study, in which 33 adults at low risk of heart disease were given either the Bifidobacterium combination, or a placebo. Treatment with the Bifidobacterium combination significantly reduced total cholesterol by 16.7%, LDL-C by 25.7%, non-HDL-C by 24% and apolipoprotein-B by 17%. Triglycerides, HDL-C, apolipoprotein AI, lipoprotein (a) and proprotein convertase subtilisin/kexin type 9 (PCSK9) were unchanged. Markers of cholesterol synthesis and absorption suggested that a reduction in the synthesis of cholesterol had occurred without increased absorption of cholesterol. No adverse effects were reported in the study and the compliance rate was high at 97%. The use of nutraceuticals in the prevention of cardiovascular disease, as well as in other areas related to chronic diseases like cancer, is currently expanding.
Abstract
BACKGROUND Probiotics incorporated into dairy products have been shown to reduce total (TC) and LDL cholesterolemia (LDL-C) in subjects with moderate hypercholesterolemia. More specifically, probiotics with high biliary salt hydrolase activity, e.g. Bifidobacterium longum BB536, may decrease TC and LDL-C by lowering intestinal cholesterol reabsorption and, combined with other nutraceuticals, may be useful to manage hypercholesterolemia in subjects with low cardiovascular (CV) risk. This study was conducted to evaluate the efficacy and safety of a nutraceutical combination containing Bifidobacterium longum BB536, red yeast rice (RYR) extract (10 mg/day monacolin K), niacin, coenzyme Q10 (Lactoflorene Colesterolo®). The end-points were changes of lipid CV risk markers (LDL-C, TC, non-HDL-cholesterol (HDL-C), triglycerides (TG), apolipoprotein B (ApoB), HDL-C, apolipoprotein AI (ApoAI), lipoprotein(a) (Lp(a), proprotein convertase subtilisin/kexin type 9 (PCSK9)), and of markers of cholesterol synthesis/absorption. METHODS A 12-week randomized, parallel, double-blind, placebo-controlled study. Thirty-three subjects (18-70 years) in primary CV prevention and low CV risk (SCORE 0-1% in 24 and 2-4% in 9 subjects; LDL-C: 130-200 mg/dL) were randomly allocated to either nutraceutical (N = 16) or placebo (N = 17). RESULTS Twelve-week treatment with the nutraceutical combination, compared to placebo, significantly reduced TC (- 16.7%), LDL-C (- 25.7%), non-HDL-C (- 24%) (all p < 0.0001), apoB (- 17%, p = 0.003). TG, HDL-C, apoAI, Lp(a), PCSK9 were unchanged. Lathosterol:TC ratio was significantly reduced by the nutraceutical combination, while campesterol:TC ratio and sitosterol:TC ratio did not change, suggesting reduction of synthesis without increased absorption of cholesterol. No adverse effects and a 97% compliance were observed. CONCLUSIONS A 12-week treatment with a nutraceutical combination containing the probiotic Bifidobacterium longum BB536 and RYR extract significantly improved the atherogenic lipid profile and was well tolerated by low CV risk subjects. TRIAL REGISTRATION NCT02689934 .
-
6.
Effect of a food supplement containing berberine, monacolin K, hydroxytyrosol and coenzyme Q10 on lipid levels: a randomized, double-blind, placebo controlled study.
D'Addato, S, Scandiani, L, Mombelli, G, Focanti, F, Pelacchi, F, Salvatori, E, Di Loreto, G, Comandini, A, Maffioli, P, Derosa, G
Drug design, development and therapy. 2017;:1585-1592
Abstract
PURPOSE To evaluate the ability of the new food supplement, Body Lipid (BL), containing red yeast rice, berberine, coenzyme Q10 and hydroxytyrosol, to lower the LDL-C in patients with mild-to-moderate hypercholesterolemia and to assess the overall safety profile of the product. METHODS In this multicenter, randomized, double-blind, placebo and active comparator (the marketed Armolipid Plus® [AM]) controlled study, 158 hypercholesterolemic patients were randomized following a 4-week dietary run-in period. After 4 weeks of treatment with a daily oral dose of the new food supplement BL, AM or placebo, plus diet, the main outcome was the decrease of LDL-C, total cholesterol (TC), and triglyceride levels. FINDINGS The absolute changes of LDL-C and TC levels from baseline, at week 4 were: -39.1 mg/dL ±17.76 and -45.9 mg/dL ±21.54, respectively in the BL group; 5.7 mg/dL ±14.98 and 2.4 mg/dL ±18.43, respectively in the placebo group. Results were statistically significant. In terms of mean percentage, BL was shown to be more effective in lowering LDL-C levels as compared to placebo and the active comparator (AM), with a reduction of -26.3%, +4.2%, -18.3%, respectively. Five adverse events (AEs) were reported by five patients after the initiation of the study treatment: two in the BL group (influence and insomnia), two in the AM group (ear pain and rash), and one in the placebo group (back pain). All AEs were mild in intensity, except for back pain (severe). The case of insomnia in the BL group and the case of rash in the AM group were judged as treatment related. The safety review of the laboratory (blood and urine) analyses, vital signs and physical findings did not show any clinical effect of the study products on any of the parameters. IMPLICATIONS BL showed a good efficacy and safety profile and, for this reason, it can be considered an alternative to pharmacological treatment, for patients with mild-to-moderate hypercholesterolemia.
-
7.
Nutraceutical approach to moderate cardiometabolic risk: results of a randomized, double-blind and crossover study with Armolipid Plus.
Ruscica, M, Gomaraschi, M, Mombelli, G, Macchi, C, Bosisio, R, Pazzucconi, F, Pavanello, C, Calabresi, L, Arnoldi, A, Sirtori, CR, et al
Journal of clinical lipidology. 2014;(1):61-8
Abstract
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.
-
8.
Novel therapeutic strategies for the homozygous familial hypercholesterolemia.
Mombelli, G, Pavanello, C
Recent patents on cardiovascular drug discovery. 2013;(2):143-50
Abstract
HoFH is an autosomal co-dominant disease with a prevalence of one in 1,000,000. Mutations of LDL-R gene are responsible for this disease. HoFH needs to be distinguished from autosomal recessive hypercholesterolemia protein (ARH) that causes a similar clinical phenotype. HoFH induces aggressive cardiovascular disease that can develop from birth. These patients possess high LDL-C levels, cutaneous and tendon xanthomas, and accelerated atherosclerosis shown in the first 2 decades of life. Current treatment modalities include life-style modifications, lipid-lowering therapy and LDL-apheresis. However, the treatment goal cannot be achieved only by statin therapy. New therapeutic strategies to lower LDL-C have been developed over recent years. These include monoclonal antibodies binding to PCSK9, inhibition of ApoB production and MTP-inhibitors. This review is focused on new treatments for HoFH and their patents. It is known to be an important contribution in this rare disease, which is difficult to manage.
-
9.
Hypocholesterolaemic effects of lupin protein and pea protein/fibre combinations in moderately hypercholesterolaemic individuals.
Sirtori, CR, Triolo, M, Bosisio, R, Bondioli, A, Calabresi, L, De Vergori, V, Gomaraschi, M, Mombelli, G, Pazzucconi, F, Zacherl, C, et al
The British journal of nutrition. 2012;(8):1176-83
Abstract
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.
-
10.
Does bicarbonate transfer have relevant hemodynamic consequences in standard hemodialysis?
Gabutti, L, Ross, V, Duchini, F, Mombelli, G, Marone, C
Blood purification. 2005;(5):365-72
Abstract
BACKGROUND In a previous study we demonstrated that mild metabolic alkalosis resulting from standard bicarbonate hemodialysis induces hypotension. This study aimed to compare hemodynamic consequences of either a decrease in the dialysate bicarbonate from 32 to 26 mmol/l or an increase in the dialysate calcium of 0.25 mmol/l and to verify whether the calcium shift secondary to alkalemia explains the consequences on blood pressure. METHODS In this randomized controlled trial with a single-blind, cross-over design, we used dialysis liquids with two different bicarbonate (32 mmol/l in modalities A and C, and 26 mmol/l in modality B) and calcium (1.25 mmol/l in modalities A and B, and 1.50 mmol/l in modality C) concentrations, and in 27 patients, 243 dialysis sessions, compared blood pressure, heart rate and the incidence of hypotension. RESULTS No significant differences were seen between A and B while an increase in systolic and diastolic blood pressures and a decrease in the incidence of hypotension (10.5 vs. 1.2%, p < 0.05) were documented in C. The subgroup of patients who with A showed a lower mean systolic blood pressure received more angiotensin-converting enzyme inhibitors or angiotensin II type-1 receptor blockers (36 vs. 0%, p<0.05) and in C showed a less important increase in systolic and diastolic pressures, but the incidence of hypotensive episodes between A and B was not significantly different (9.1 vs. 15.1%). CONCLUSIONS In the present study it was not possible to demonstrate hemo dynamic instability associated with mild metabolic alkalosis. Even in the subgroup showing a lower blood pressure with a higher dialysate bicarbonate, significant hemodynamic or clinical consequences were not noticed. The calcium shift (0.05 mmol/l) related to alkalemia would justify a mean decrease in systolic blood pressure of only about 1 mm Hg.