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PubMed2002

[Statins for cardiovascular prevention. Lowering LDL cholesterol, the primary objective].

A MAJOR CARDIOVASCULAR RISK FACTOR: LDL-cholesterol is unquestionably the principle cardiovascular risk factor, showing a continuous relationship without threshold value with the incidence of cardiovascular events. Interventional studies conducted with statins showed a significant reduction in cardiovascular risk and total mortality, which was enhanced when the absolute risk was high in the population studied. Moreover, there was a linear relationship between the decrease in cholesterol and the reduction of coronary events. FOR OPTIMAL CARDIOVASCULAR PREVENTION: Many arguments are in favor of a drastic reduction in LDL-cholesterol (< 1 g/l) for secondary prevention and in patients at high vascular risk (absolute cardiovascular risk greater than 20% over 10 years), without the possibility, today, of clearly defining the optimal target level in these patients. However, in daily practice the therapeutic aims established by national and international recommendations are rarely reached, as is shown by several epidemiological surveys. NEW THERAPEUTIC STRATEGIES: To obtain even lower levels of LDL-cholesterol, two strategies are possible, either combined with other hypolipidemic substances, such as intestinal cholesterol absorption inhibitors, or administration of more potent statins (rosuvastatin, pitavastatin). Nonetheless, the other risk factors must also be treated in order to reduce the patients' global cardiovascular risk score.

Anticholesteremic Agents↗
PubMed2003

Plant sterols lower LDL cholesterol without improving endothelial function in prepubertal children with familial hypercholesterolaemia.

In adults with familial hypercholesterolaemia (FH), cholesterol lowering with statins has been shown to improve the endothelial function, a hallmark of early atherogenesis. Currently, therapeutic options for treating high cholesterol levels in FH children are limited. Plant sterols safely and effectively reduce serum cholesterol concentrations by inhibiting cholesterol absorption. Therefore, we evaluated the effect of plant sterols on cholesterol and vascular function in prepubertal children with FH. We included 41 children (5-12 years old) with FH in a double-blind crossover trial using spreads containing 2.3 g of plant sterols (mainly sitosterol and campesterol) per 15 g spread and a placebo spread for a 4-week period, separated by a 6-week washout period. Lipid levels and endothelial function were assessed after both 4-week treatment periods. Endothelial function was assessed as flow-mediated dilation (FMD) of the brachial artery using a wall tracking system. Data were compared to those of 20 healthy controls. Intake of 2.3 g plant sterols per day decreased total cholesterol (-11%) and low-density cholesterol (-14%) as compared to placebo spread in FH children. FH children treated with placebo spread were characterized by an impaired FMD compared to healthy control children (7.2% +/- 3.4% versus 10.1% +/- 4.2%, p < 0.005). However, the reduction of LDL in FH children did not improve FMD (placebo: 7.2% +/- 3.4% versus plant sterols: 7.7% +/- 4.1%). In conclusion, the present study shows a clear reduction of LDL cholesterol by plant sterol treatment. However, short-term plant sterol treatment does not improve the endothelial function in FH children.

Brachial Artery↗
PubMed1989

HMG CoA reductase inhibitors lower LDL cholesterol without reducing Lp(a) levels.

Lp(a) is a plasma lipoprotein particle consisting of a plasminogenlike protein [apo(a)] disulfide bonded to the apo B moiety of low-density lipoprotein (LDL). Increased plasma levels of Lp(a), either independently or interactively with LDL levels, have been shown to be a risk factor for atherosclerosis. Recently, a new class of lipid-lowering drugs, HMG CoA reductase inhibitors, have been introduced. These drugs act by decreasing liver cholesterol synthesis resulting in up-regulation of LDL receptors, increased clearance of LDL from plasma, and diminution of plasma LDL levels. In this study, we examined the effect of HMG CoA reductase inhibitors on Lp(a) levels in three groups of subjects, five volunteers and two groups of five and 14 patients. In all 24 subjects, mean decreases were observed in total cholesterol (43 +/- 5%), total triglyceride (35 +/- 8%), very low-density lipoprotein (45 +/- 9%), and LDL cholesterol (43 +/- 5%). The mean change in high-density lipoprotein cholesterol was an increase of 7 +/- 8%. Despite the very significant decrease in LDL cholesterol levels (p less than 0.001), Lp(a) levels increased by 33 +/- 12% (p less than 0.005). This was not associated with a measurable change in the chemical composition or size of the Lp(a) particle. This emphatically suggests that Lp(a) particles, despite consisting principally of LDL, are cleared from plasma differently than LDL. The surprising finding of an increase in Lp(a) levels suggests this class of drugs may have a direct effect on Lp(a) synthesis or clearance independent of its effect on LDL receptors.

Adult↗
PubMed2006

Effect of lowering LDL cholesterol substantially below currently recommended levels in patients with coronary heart disease and diabetes: the Treating to New Targets (TNT) study.

OBJECTIVE: The Treating to New Targets study showed that intensive lipid-lowering therapy with atorvastatin 80 mg/day provides significant clinical benefit beyond that afforded by atorvastatin 10 mg/day in patients with stable coronary heart disease (CHD). The objective of our study was to investigate whether similar benefits of high-dose intensive atorvastatin therapy can be achieved in patients with CHD and diabetes. RESEARCH DESIGN AND METHODS: A total of 1,501 patients with diabetes and CHD, with LDL cholesterol levels of <130 mg/dl, were randomized to double-blind therapy with either atorvastatin 10 (n = 753) or 80 (n = 748) mg/day. Patients were followed for a median of 4.9 years. The primary end point was the time to first major cardiovascular event, defined as death from CHD, nonfatal non-procedure-related myocardial infarction, resuscitated cardiac arrest, or fatal or nonfatal stroke. RESULTS: End-of-treatment mean LDL cholesterol levels were 98.6 mg/dl with atorvastatin 10 mg and 77.0 mg/dl with atorvastatin 80 mg. A primary event occurred in 135 patients (17.9%) receiving atorvastatin 10 mg, compared with 103 patients (13.8%) receiving atorvastatin 80 mg (hazard ratio 0.75 [95% CI 0.58-0.97], P = 0.026). Significant differences between the groups in favor of atorvastatin 80 mg were also observed for time to cerebrovascular event (0.69 [0.48-0.98], P = 0.037) and any cardiovascular event (0.85 [0.73-1.00], P = 0.044). There were no significant differences between the treatment groups in the rates of treatment-related adverse events and persistent elevations in liver enzymes. CONCLUSIONS: Among patients with clinically evident CHD and diabetes, intensive therapy with atorvastatin 80 mg significantly reduced the rate of major cardiovascular events by 25% compared with atorvastatin 10 mg.

Aged↗
PubMed2005

A promoter polymorphism in cholesterol 7alpha-hydroxylase interacts with apolipoprotein E genotype in the LDL-lowering response to atorvastatin.

Bile-acid biosynthesis is a key determinant of intracellular cholesterol and, in turn, cholesterol synthesis rate in hepatocytes. This suggests that variation in the cholesterol 7alpha-hydroxylase gene (CYP7A1), a key enzyme in bile-acid biosynthesis, may influence the statin response. To test this hypothesis, a promoter polymorphism (A-204C) in CYP7A1 was examined in 324 hypercholesterolemic patients treated with atorvastatin 10mg. The variant C allele was significantly and independently associated with poor LDL cholesterol reductions; -39% in wild type allele homozygotes, -37% in variant allele heterozygotes, and -34% in variant allele homozygotes (p<0.0001 for trend). Differences were more striking in men, and were enhanced by the coexistence of common variants of apolipoprotein E gene (APOE), epsilon2 or epsilon4. In subjects having wild type alleles at both loci, the mean reduction in LDL cholesterol was -40%, while the value in subjects having two CYP7A1 variant alleles and at least one variant APOE allele was -31% (p<0.0001). Combination analysis of these two loci more accurately predicted the achievement of goal LDL cholesterol, than did both single locus analysis. We concluded that the CYP7A1 A-204C promoter variant was associated with poor response to atorvastatin, which were additively enhanced by common variants in another locus, APOE.

Aged↗
PubMed2003

Emerging non-statin LDL-lowering therapies for dyslipidemia and atherosclerosis.

Elevated low-density lipoprotein cholesterol is an important risk factor for atherothrombotic arterial disease. HMG-CoA reductase inhibitors, or statins, are very effective in lowering cholesterol levels, and several trials using statins have shown reductions in mortality and cardiovascular events, leading to the recent recommendations that all patients with known vascular disease, or who are at high risk for vascular disease, should be considered candidates for statin therapy. Yet statins reduce cardiovascular events by only about 20%-40%. Nonstatin therapies (either as monotherapy or in addition to statins) to reduce LDL cholesterol by mechanisms that do not involve inhibition of HMG-CoA reductase are likely to be useful for patients in need of LDL reduction; particularly those who either cannot take statins or respond only partially or not at all to statins alone. These therapies include cholesterol absorption inhibitors, Acyl-CoA cholesterol acyl transferase inhibitors, farnesoid X receptor antagonists, sterol-regulating binding protein cleavage activating protein, and microsomal triglyceride transfer protein.

Arteriosclerosis↗
PubMed1993

Positive correlation between probucol in low density lipoprotein and LDL-lowering.

The relationship between the content of probucol in plasma and lipid lowering was studied after administration of probucol. The study group consisted of 44 patients with Type II hyperlipidaemia (mean age 56 y). Total cholesterol level was decreased from 293 to 232 mg.dl-1 by the administration of probucol. The plasma probucol concentration was 2.03 mg.dl-1 after 4 weeks of administration of 500 mg b.d. Although there was no relationship between the change in total cholesterol and the plasma probucol, a linear relation was observed between the decrease in LDL-cholesterol concentration and the probucol concentration in LDL. Neither the VLDL nor the HDL-probucol content were related to the magnitude of the decrease in lipoprotein cholesterol. The present study has demonstrated that an increase in the probucol content in LDL was associated with a decrease in plasma LDL-cholesterol.

Adult↗
PubMed1999

Therapeutic strategies for coronary artery disease beyond low density lipoprotein (LDL)--lowering.

Coronary artery disease (CAD) ranks as the leading cause of death in the Western world. The most widely used therapeutics utilized for the treatment of CAD are the lipid-lowering drugs, which lower plasma cholesterol. However lowering cholesterol alone may not be sufficient to provide benefit to all patient populations at risk for CAD. This creates an unmet medical need. Emerging knowledge of the genesis, progression and regression of atherosclerosis, that leads to CAD permits evaluation of other therapeutic strategies. This review will evaluate two such naturally occurring paradigms, the nitric oxide pathway and the high-density lipoprotein system which are nature's defense mechanisms against atherosclerosis and may lead to next generation therapeutics against CAD.

Animals↗
PubMed2005

Treatment of multiple-risk patients: using combination therapy to treat beyond LDL lowering.

During the past 25 years, the role of traditional "risk factors" in the genesis of atherosclerotic vascular disease has been convincingly validated. The impact of elevated low-density lipoprotein cholesterol, hypertension, type II diabetes, and metabolic syndrome are now well accepted. However, until recently, there was guilt by association without a clear understanding of the manner in which the crime was committed. It is now acknowledged that the presence of multiple risk factors can increase the likelihood of an ischemic event. This has become a great concern, given the very high prevalence of patients who fall into this category. In light of this information, the mandate for appropriate guideline-driven therapy has become even stronger, and we must consider the use of multiple medications to effectively neutralize this risk.

Cholesterol, LDL↗
PubMed1999

Monounsaturated diet lowers LDL oxidisability in type IIb and type IV dyslipidemia without affecting coenzyme Q10 and vitamin E contents.

The purpose of the present study was to evaluate the effects of MUFA vs PUFA enriched diets on the plasma and LDL lipid profile and antioxidant contents in mild hypercholesterolemic and triglyceridemic subjects. The study was divided in two consecutive diet periods. Two groups of 11 dyslipidemic patients each (type IIb and type IV) were recruited and during the first period (lasting four weeks) received a linoleic rich diet while during the following four weeks took an oleate rich diet. Both groups showed no significant changes in cholesterol and TG concentration either in plasma or in LDL. Coenzyme Q10 and vitamin E were also unaffected by the dietary treatments. LDL proneness to be oxidatively modified increased after dietary PUFA administration and markedly decreased following the virgin olive oil enriched diet. In fact, LDL from hypertrigliceridemic subjects on a oleate-enriched diet displayed a 26% (p < 0.05) longer lag-phase in conjugated dienes generation than during linoleate-enriched diet and at recruitment. In hypercholesterolemic subjects similar results were obtained: the lag-phase was 28% longer after MUFA diet that after PUFA diet. No differences were found in the maximum propagation rate and maximum concentration of conjugated dienes among dietary periods and at recruitment. Since we found that the vit. E and CoQ10 levels in plasma and in LDL particles remained unchanged during the course of the study, we may conclude that LDL proneness to undergo oxidative modifications is mainly the result of compositional change due to the enrichment from the different diets of the relative fats.

Cholesterol↗
PubMed2005

An ezetimibe-policosanol combination has the potential to be an OTC agent that could dramatically lower LDL cholesterol without side effects.

Although many risk factors influence atherogenesis, LDL appears to play a primary role in this process. In prospective epidemiology, coronary risk increases as LDL cholesterol increases, throughout the entire range of concentrations encountered in healthy humans. Coronary risk is minimal in individuals and populations whose serum cholesterol remains quite low throughout life. Thus, practical strategies for achieving large reductions of LDL cholesterol in the general population could have a dramatic impact on coronary mortality rates. Dietary measures have limited potential in this regard; modest restriction of saturated fat has a rather trivial effect on LDL cholesterol, and the very-low-fat quasi-vegan diets that do have a notable effect in this regard currently have little appeal to the majority of the population. With respect to pharmacotherapy, most available hypolipidemic agents with reasonably potent activity entail side effects or compliance difficulties that would render their use too expensive or impractical for population-wide application. However, two agents may have great potential in this regard: policosanol and ezetimibe. The former, a mixture of long-chain alcohols derived from sugar cane wax, has effects on serum lipids comparable to those of statins, and may work by down-regulating expression of HMG-CoA reductase. However, unlike statins, policosanol appears to be devoid of side effects or risks. Ezetimibe is a newly approved drug that is a potent and highly specific inhibitor of an intestinal sterol permease; in daily doses as low as 10 mg, it suppresses intestinal absorption of cholesterol and decreases serum LDL cholesterol by approximately 18%. No side effects have been seen in clinical doses, and the fact that its hypolipidemic activity is additive to that of statins has generated considerable interest. Both policosanol and ezetimibe can be administered once daily. Future studies should determine whether policosanol, like statins, interacts additively with ezetimibe. If so, it may be feasible someday to produce a tablet combining policosanol and ezetimibe that could reduce LDL cholesterol by about 40%, without side effects, and that could be recommended to virtually anyone whose LDL cholesterol levels were not already ideal.

Anticholesteremic Agents↗