Lipid Lowering Drugs Statins Fibrates

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Hydroxymethylglutaryl coenzyme-A (HMGCoA) reductase inhibitors, better known as "statins," are the most potent lipid-lowering agents, consistently documented to prevent or reduce cardiovascular events in primary and secondary prevention (168-170). The therapeutic potential of this type of drug is probably far greater than previously anticipated (171). Many of the nonlipid lowering effects of statins could be of major relevance to a variety of disease processes. For example, statins enhance nitric oxide production and improve endothelial function, display anti-inflammatory potency, inhibit integrins, and lower circulating adhesion molecules (172,173). As with statins, fibrates have also been shown to reduce coronary risk (LOCAT study); the beneficial nonlipid effects with respect to atherosclerotic prevention include antithrombotic effects (decrease in fibrinogen and PAI1), anti-inflammatory activity (inhibition of TNF-a-induced endothelial expression of VCAM-1 and IL6), and decrease in plasma uric acid (174).

A number of studies of candidate genes involved in the lipid pathway have identified genetic polymorphisms influencing the clinical response to statins, not only on LDL plasma levels but also in terms of lipid-lowering outcomes and/or clinical events (Table 3).

Table 3 Examples of Genetic Polymorphisms Affecting Responses to Therapeutic Agents

Gene/gene product Medication Drug effect associated with polymorphism References

Angiotensin-Converting ACE inhibitors Left ventricular mass reduction (150)

enzyme (ACE) Blood pressure reduction (152,196)

Endothelial function improvement (196)

Arterial stiffness (153)

Survival after cardiac transplantation (29)

Renal protection (31)

ACE inhibitor-related cough (197)

Angiotensinogen (AGT) ACE inhibitors Blood pressure reduction (18)

Bradykinin B2 receptor (BDKRB2) ACE inhibitors ACE inhibitor-induced cough (198)

/^-Adrenergic receptor /32-Agonists Cardiovascular effects (increased heart rate, cardiac index, (41)

(.ADRB2) peripheral vasodilation) (199)

Susceptibility to agonist-induced desensitization (48)

Bronchodilation (42)

Angiotensin-Converting Statins Lipid changes (reductions in total cholesterol, LDL (183)

enzyme {ACE) cholesterol, increase HDL and APOB concentrations) (201)

Apolipoprotein E (APOE) Progression/regression of atherosclerotic lesions, decrease (177)

Choslesteryl ester transfer in coronary artery diameter, death (176)

protein (CETP) (105)

Stromelysin-1 (MMP3) Statins Cardiovascular events reduction (death, myocardial (87)

infarction, stroke, angina) Decreased risk of repeated angioplasty

Prothrombin (F2) Oral contraceptives Increased risk of deep vein and cerebral vein thrombosis (184)

Abbreviations'. LDL, low-density lipoproteins; HDL, high-density lipoproteins.

Although a number of variants have been identified, this section deals with polymorphisms (e.g., APOE and CETP) associated with lipid-lowering therapy. In addition, the pharmaco-genetic interaction of statins with ACE I/D (175) and MMP3 (84) is also discussed.

Despite a majority of publications describing a cholesterol reduction in APO E4 carriers (105,106,176-178), there are some contradictory reports (100,102) on the effects of APOE polymorphism on the efficacy of hypolipidemic drugs. APOE genotype probably plays a key role in the LDL cholesterol-lowering response to statins. As discussed earlier, in the 4S study, the risk of death or coronary event in survivors of myocardial infarction was related to the APOE genotype (100). Among patients who received placebo and who had at least one APO E4 allele, the relative risk of death from all causes was 1.9. The detrimental impact of the E4 allele was not evident among patients who received simvastatin. From the literature, it is evident that APO E4 allele is also associated with an enhanced response (in terms of LDL reduction) to dietary intervention but a reduced response to statin-induced LDL cholesterol-lowering. This modest effect of LDL cholesterol reduction in response to statins seen in APO E4 individuals may actually be due to the low HMGCo-A reductase activity itself (179).

CETP provides another example of a pharmacogenetic intervention interacting with the genotype to bring about lipid-lowering. CETP plays a key role in distributing choles-teryl esters among HDLs, LDLs, and very low-density lipoproteins (VLDLs). As mentioned previously, one variant in the CETP gene is referred to as B1 and its absence as B2. The B2 allele of the TaqIB polymorphism has been shown to be associated with decreased CETP activity, increased HDL cholesterol, and faster progression of coronary atherosclerosis (105). However, there was no difference in plasma lipoprotein response to statins between the genotypes (B1B1, B1B2, B2B2). Moreover, B2B2 carriers with low CETP and high HDL levels did not respond to therapy in terms of disease regression. The pravastatin-treated patients with a B2B2 genotype derived no benefit from the treatment, as measured by changes in mean coronary artery lumen, whereas B1B1 genotype-treated patients had significantly less atherosclerotic progression than the placebo group. The WOSCOPS study also did not find any interaction between CETP genotype and statin therapy (180). However, untreated patients with angiographic coronary artery disease who carried the B2 allele had higher rates of death/nonfatal myocardial infarction over 2.4 years follow-up (181). Statin therapy was associated with greater benefit in these high-risk B2 carriers than in the B1B1 homozygotes. Although both APOE and CETP variants are promising as drug targets, additional clarification of risk and pharmacogenetic associations is needed.

From this literature, it is clear that the response to statins is not based on lipid levels but rather upon genotypes. These studies have identified genetic subgroups of placebo-treated patients with ischemic heart disease who had an increased risk of major coronary events. In general, treatment abolished the harmful effects associated with the genetic variant. The evidence is based on clinical outcome data. Therefore, future large-scale population studies are required to complement the results from the clinical trials and small-scale selected population cohorts.

It has also been demonstrated that statins may reduce ACE activity (175). However, the data regarding the influence of the ACE I/D polymorphism on the effectiveness of statins are controversial (182,183). In the LCAS study, subjects with the DD genotype displayed the strongest reduction of coronary atherosclerosis with statin therapy, whereas in the REGRESS trial, statins reduced coronary atherosclerosis less strongly in DD than ID or II genotypes. A CARE substudy focused upon whether the glycoprotein IIIa (ITGB3) PIA1A2 and ACE I/D polymorphisms were associated with fatal coronary events or non-fatal myocardial infarction (183). In this study, the greatest benefit of pravastatin treatment occurred in patients with a glycoprotein Ilia PIA1A2 genotype who also carried at least one D allele of the ACE gene.

A functional polymorphism in the stromelysin-1 (MMP3) gene (5A/6A) has been described (84). Evidence suggests that stromelysin activity is important in connective tissue remodeling associated with atherogenesis and plaque rupture. In this study, patients homozygous for the 6A allele displayed greater progression of angiographic disease than those with other genotypes. de Maat et al. (87) in their REGRESS study, investigated the influence of 5A/6A polymorphism on statins and showed no differences in prognostic baseline characteristics, disease severity, or lipid values among the three genotypic groups (5A5A, 5A6A, 6A6A). But, pravastatin therapy reduced clinical events most effectively among the 6A allele carriers (5A6A or 6A6A genotypes). Moreover, these beneficial changes were independent of the effects of pravastatin on lipid levels, raising the possibility that this agent exerts a pleiotropic effect not merely on stromelysin expression or activity. Similar findings were observed in the LOCAT study (88). These results indicate that the stromelysin-1 gene promoter polymorphism confers a genotype-specific response to statins.

Although statins decrease the secretion of MMPs in vitro models, their role in reducing MMPs in vivo is unclear. The only data from aneurysm patients demonstrated a reduction in both total and active MMP levels in the tissue with statins (89). To our knowledge, there are no reports of variants in other MMPs, such as MMP2, 9, or 12, that could be modulated by drugs. Should this be the case, then such treatment may provide new ways to manipulate and target arterial wall remodeling in specific arterial beds in individual patients.

Polymorphisms in the lipid pathway associated with adverse reactions to statins: In general, HMGCo-A reductase inhibitors are well tolerated, although in a minority of patients severe adverse effects, such as myopathy or rhabdomyolysis, may develop. The incidence of these potentially life-threatening side effects increases with (i) coadministra-tion of drugs that are metabolized via the same pharmacokinetic pathways and (ii) highdose statin therapy (e.g., dementia).

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