Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, also known as statins, are competitive inhibitors of the rate-limiting step of hepatic cholesterol synthesis. This leads to a reduction in hepatocyte cholesterol concentration with subsequent upregulation of low-density lipoprotein (LDL) receptors that enhance clearance of LDL. Statins lower both large and small LDL subclasses. In addition to its effects on LDL, intermediate-density lipoprotein (IDL) and very-low-density lipoprotein (VLDL) are decreased by statin therapy. Both fractions are decreased to similar percentages by statin therapy; thus statins are effective drugs for lowering both elevated LDL cholesterol (LDL-c) and triglyceride-rich lipoproteins. Statins are indicated in individuals with elevations of these lipoproteins because of genetics, as in familial hypercholesterolemia, familial defective apolipoprotein B (ApoB), familial combined hyperlipidemia, and type 3 hyperlipoproteinemia (remnant removal disease). They are also indicated in most adults with diabetes, renal dysfunction, and for the dyslipidemia found in renal and cardiac transplantation recipients. The Adult Treatment Panel III (ATP III) recommends statins as the most effective class of drugs for lowering LDL-c to reduce the risk for coronary heart disease (CHD) in both primary and secondary prevention.
A current controversy is whether statins are as effective in the primary prevention of cardiovascular disease (CVD) as they are in the secondary prevention of CVD, especially for women. These meta-analyses must be analyzed carefully; inclusions and exclusions, as well as length of exposure to statin therapy, must be considered to put this controversy in perspective. Statins do not always lower risk in those at very high risk (>5% per year), as demonstrated by clinical trials of statins, which fail to show significant benefit in patients on long-term hemodialysis with end-stage renal disease and in those with chronic, symptomatic, systolic ischemic heart failure or those with heart failure of any cause. These studies raise the issue as to whether mechanisms other than the prevention of plaque rupture in those with atherosclerotic vascular disease, for which the evidence for statin benefit appears strong, are operable and for which statin therapy is not an important solution (e.g., fatal arrhythmia, recurrent reperfusion injury, and/or progressive left ventricular dysfunction). Preprocedural statin use to reduce the incidence of myocardial infarction (MI) after invasive procedures—such as angioplasty, coronary artery bypass grafting (CABG), or noncardiac surgery—has been proposed. Emerging data suggest that the administration of statin therapy, if the preventive data hold up, should precede percutaneous coronary angioplasty (PCI) by approximately 1 to 7 days, or it should occur approximately 4 weeks before noncardiac surgical procedures to result in a reduced incidence of postoperative MI. For noncardiac surgical trials, fluvastatin was used in more than 90% of studies and conferred benefit despite its less potent LDL-c lowering effects compared with other statins. One speculation is that its longer half-life allows it to be withheld the first postoperative day without a diminution in its effects. Caution must be exercised, however, about attributing benefits of statin or any other therapy based on short-term trial results. Although short-term trials that used more sensitive atrial fibrillation (AF) detection methods suggest statin therapy can reduce the risk of AF, a recent meta-analysis that looked at longer term studies as well could not confirm this effect.
Effects on Lipids and Lipoproteins
All members of the statin class reduce LDL-c levels in a dose-dependent fashion. This dose/response relationship is log linear, which means that although the initial dose lowers LDL-c from 25% to 45%, additional doublings of the statin dose result in only an additional 6% to 7% of LDL-c lowering. Responsiveness to statins by individuals varies, and individuals who are hyporesponsive or hyperresponsive to one statin maintain that response with other statins. In familial combined hyperlipidemia, use of a moderate dosage of a potent statin generates lowered cholesterol not only in LDL but also in triglyceride-rich remnant lipoproteins (TGRLs) in both the fasting and fed state. This allows attainment of both LDL and non–high-density lipoprotein (HDL) goals.
The initially available statins—lovastatin, pravastatin, and simvastatin—were derived from fungal fermentation. Subsequently, synthetic forms such as fluvastatin, atorvastatin, cerivastatin, and rosuvastatin have become available. The newest available synthetic statin, pitavastatin, has a unique cyclopropyl group on its base structure that potently inhibits HMG-CoA reductase and inhibits synthesis of cholesterol in the liver. It is not a substrate for 3A4 cytochrome P450, but the Medical Letter noted that pitavastatin’s use is contraindicated with cyclosporine and ritonavir/lopinavir. The concentration of pitavastatin can be raised 30% by adding rifampin, atazanavir, and gemfibrozil. No large-scale clinical trial data are currently available on outcome and safety data from such trials. Finally, cerivastatin, the most potent of all the statins introduced to date, was withdrawn from the market after it was found to have an unacceptable incidence of myositis and rhabdomyolysis. The latter reaction was more likely when cerivastatin was combined with gemfibrozil.
A review of clinical trial data indicated that initial doses of statins should provide at least a 30% reduction in LDL-c. Table 24-1 shows the dose of currently available statins that would provide this. Triglycerides are lowered with statins approximately proportional to the degree of LDL-c lowering. This is a modest effect (15% to 30%) and is usually not adequate to normalize moderate elevations of triglycerides. Statin therapy does not result in removal of triglyceride-laden chylomicrons; thus statins should not be used when severe hypertriglyceridemia suggesting chylomicronemia is present. Statins affect HDL-c levels to a variable degree, and no relationship has been found between degree of LDL-c lowering and change in HDL-c. Rosuvastatin, simvastatin, and pravastatin appear to raise HDL-c more than atorvastatin, for example. In the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction (PROVE-IT–TIMI) 22 trial, standard LDL-c lowering with pravastatin in subjects with acute coronary syndrome (ACS) was associated with a greater percent increase in HDL-c than that seen with the intensive LDL-c lowering with atorvastatin. In PROVE-IT–TIMI 22, those individuals with the greatest LDL-c lowering had the greatest event reduction. Statins in moderate doses do not lower lipoprotein A [Lp(a)], which can account for apparent reduced effectiveness of statin therapy in reducing LDL-c if the latter is determined by the Friedewald formula. Statins lower markers of inflammation and oxidation, such as high-sensitivity C-reactive protein (hs-CRP), and they reduce lipoprotein-associated phospholipase A2 (Lp-PLA2). Statins lower hs-CRP in primary and secondary prevention patients, a result seen in as little as 12 weeks. For hs-CRP, the lowering is mainly independent of LDL-c lowering, unlike that seen with Lp-PLA2, which is largely mediated by the statin-induced reduction in LDL-c. Lovastatin was effective among individuals with a ratio of total cholesterol to HDL-c that was lower than the median and an hs-CRP level higher than the median in a primary prevention trial. In contrast, lovastatin was ineffective among subjects in this trial, with both a ratio of total cholesterol to HDL-c and an hs-CRP level that were lower than the median. Also, patients with ACS who have low hs-CRP levels after statin therapy have better clinical outcomes than those with higher hs-CRP levels, regardless of the resultant level of LDL-c. The primary prevention study Justification for the use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) used an hs-CRP of 2.0 mg/L or more as an entry criteria in men aged 50 years and older and women aged 60 years and older. All the subjects had LDL-c below 130 mg/dL. Controversy is ongoing as to the merits of using hs-CRP to identify those who should receive statin therapy.
| STATIN | DAILY DOSE (mg) To LOWER LDL >30% | MAXIMAL DOSE (MG) |
|---|---|---|
| Lovastatin | 40 | 80 |
| Pravastatin | 40 | 80 |
| Simvastatin | 20 | 40 |
| Fluvastatin XL | 80 | 80 |
| Atorvastatin | 10 | 80 |
| Rosuvastatin | 5 | 40 |
| Pitavastatin | 2 | 4 |
Pharmacokinetic Properties
The available statins differ in terms of lipid solubility, half-life, and hepatic and renal clearance (see Table 24-2 ). These properties can have clinical importance; for example, in patients with impaired renal function, atorvastatin and fluvastatin are important choices because of their limited renal clearance.
| STATIN | ATORVASTATIN | FLUVASTATIN/XL | LOVASTATIN | PITAVASTATIN | PRAVASTATIN | ROSUVASTATIN | SIMVASTATIN |
|---|---|---|---|---|---|---|---|
| Origin | Synthetic | Synthetic | Fungal | Synthetic | Semisynthetic | Synthetic | Semisynthetic |
| Lipophilicity | Yes | Yes | Yes | No | No | No | Yes |
| Protein binding | >98% | >99% | >95% | >99% | 50% | 88% | 95% |
| CYP | 3A4 | 2C9 | 3A4 | Minimal | None | 2C9 minor | 3A4 |
| T 1/2 | Long acting | Short acting | Short acting | Long acting | Short acting | Long acting | Short acting |
| Renal adjustments to statin dosage | None | If severe impairment, use with caution | If severe impairment, use doses >20 mg/day with caution | Maximum 2 mg/day | Monitor if impairment | No more than 10 mg/day if severe impairment | Monitor if severe impairment |
Drug Interactions
Table 24-3 shows various drug interactions for simvastatin; however, it should be recognized that safety is not a class effect because statins vary in their routes of excretion and in their metabolism by other drugs, especially those that affect the P450 system. Knowledge of drug interactions is important in all patients, but it is critical in older patients, who are prone to acquire a long list of medications from multiple physicians. Fluvastatin is metabolized by P450 2C9, whereas lovastatin, simvastatin, and atorvastatin are metabolized by P450 3A4. Rosuvastatin is only weakly metabolized by 2C9, and pravastatin concentrations are not affected by the P450 system at all. Drugs such as erythromycin, clarithromycin, or ketoconazole—but not azithromycin or fluoconazole—affect statins metabolized by the P450 3A4 pathway, and this should influence the choice of a statin. Large amounts of grapefruit juice can inhibit intestinal P450 3A4 irreversibly, with effects that last up to 3 days, which may increase steady-state concentrations of statins with the potential to cause rhabdomyolysis. Drug interactions with grapefruit juice are likely to be clinically significant for drugs with a narrow therapeutic index and/or in cases where the magnitude of the interaction is large.
| PREVIOUS SIMVASTATIN LABEL | current SIMVASTATIN LABEL |
|---|---|
Avoid simvastatin with:
| Contraindicated with simvastatin:
|
Do not exceed 10 mg/day simvastatin with:
| Do not exceed 10 mg/day simvastatin with * :
|
Do not exceed 20 mg/day simvastatin with:
| Do not exceed 20 mg/day simvastatin with:
|
Do not exceed 40 mg/day simvastatin with:
| |
| Avoid large quantities of grapefruit juice (>1 quart/day) | Avoid large quantities of grapefruit juice (>1 quart/day) |
* These drugs are contraindicated with Simcor, which is only available with 20 mg or 40 mg of simvastatin.
A clinically useful tactic is to substitute pravastatin for a statin metabolized by the 3A4 system, if a prolonged course of therapy with a known inhibitor of the 3A4 system is needed, as may occur in the common example of sinusitis treated with a prolonged course of clarithromycin.
Certain populations need to be especially aware of drug-drug interactions when given statins. A detailed review of patients with CHD and human immunodeficiency virus (HIV) advised that, because protease inhibitors (PIs) inhibit the P450 3A4 cytochrome system, lovastatin and simvastatin are contraindicated to avoid elevated statin concentrations. The authors instead recommended pravastatin and rosuvastatin for patients taking PIs. Of note, this expert review proposed that atorvastatin was an acceptable choice with PIs, in that it does not seem to be affected as greatly as lovastatin and simvastatin by inhibitors of the P450 3A4 system. They further suggested that clinicians who treat patients taking PIs who require statins be aware of the following limitations of such therapy:
- •
Pravastatin should not be prescribed with boosted darunavir.
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Ritonavir and ritonavir-boosted PI combinations cause the most significant increases in lipids.
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Fluvastatin data are limited.
- •
Efavirenz, not a PI, in contrast to effects seen with a PI, lowers levels of simvastatin, pravastatin, and atorvastatin.
Cardiac patients are another group for whom vigilance is required to avoid statin-drug interactions; these are detailed in Table 24-3 . Both amiodarone and verapamil inhibit the P450 3A4 system; when either is started, it is important to consider whether a statin-drug interaction is likely. The U.S. Food and Drug Administration (FDA) has warned that the dose of simvastatin used should not exceed 10 mg/day with these drugs to avoid myopathy and its most serious consequence, rhabdomyolysis. Safer statins include pravastatin, fluvastatin, or rosuvastatin. All statins may interact with cyclosporine and with other lipid-lowering drugs such as fibrates, nicotinic acid, warfarin, and digoxin. Cyclosporine is used extensively in transplant recipients; it is highly lipid soluble, a significant portion is bound to lipoproteins, and it increases LDL-c and Lp(a) concentrations, although it affects fluvastatin less so. Gemfibrozil affects glucuronidation of statins and results in a higher concentration of statins and increased toxicity in turn, which results in an unacceptably high incidence of rhabdomyolysis when gemfibrozil was combined with a statin, especially cerivastatin. Coadministered fenofibrate does not raise statin concentrations and is therefore considered the fibrate of choice when fibrate and statin therapy are combined. Both fluvastatin and warfarin are metabolized by the P450 2C9 pathway. Because case reports have indicated changes in warfarin levels with other statins not metabolized this way, until more definitive data are available, patients on warfarin should have their international normalized ratio (INR) monitored closely after starting statin therapy because statins may increase digoxin concentrations by inhibiting P-glycoprotein transport.
Although there were early reports of myositis with statin and nicotinic acid combinations, this has not been reported in studies of an extended-release form of nicotinic acid. This may relate to the higher incidence of hepatotoxicity with long-acting forms of nicotinic acid and the increased levels of statins that results from hepatic damage.
Efficacy
Angiographic Trials
A decade of double-blind, randomized, controlled angiographic trials has demonstrated that treatment with statins could significantly decrease progression of atherosclerosis. Thompson emphasized the importance of statins in lowering non-HDL and LDL cholesterol in these trials. The Post Coronary Artery Bypass Graft Trial (Post CABG) demonstrated the value of lower LDL-c attained with more intensive statin (lovastatin) therapy in subjects who had undergone CABG. The higher dose lovastatin group attained an LDL-c of approximately 100 mg/dL compared with the reduction of LDL-c to only 132 to 136 mg/dL. The investigators found delayed atherosclerotic progression in the grafts at 4 to 5 years. An informative angiographic trial enrolled 341 subjects with stable coronary disease, relatively normal left ventricular function, and an LDL-c higher than 115 mg/dL who were referred for angioplasty. Those assigned to the high-dose statin therapy (atorvastatin) had a significantly longer time to the first ischemic CHD event compared with those who were assigned to angioplasty and usual medical care.
Although the CHD event rate was 36% lower in the statin group, the P value obtained was not statistically significant because of the adjustment for multiple on-trial analyses. On closer inspection, the intensive statin therapy had its greatest effect in reducing revascularization procedures and hospitalizations for worsening angina. With the use of intravascular ultrasound, a multicenter study showed that intensive statin therapy (atorvastatin 80 mg/day) had a significantly greater effect on the primary endpoint, the percentage change in atheroma volume, than a moderate dose of a statin (pravastatin 40 mg/day). Importantly, progression did not occur in those assigned to atorvastatin 80 mg/day, whereas it did in those assigned to pravastatin 40 mg/day. Of note, those assigned to atorvastatin 80 mg/day had significantly lower hs-CRP levels than those assigned to pravastatin 40 mg/day. O’Keefe and colleagues plotted out the results of major angiographic trials showing the increasing benefit of LDL-c lowering down to an LDL-c of less than 80 mg/day ( Figure 24-1 ).
Surface/transesophageal magnetic resonance imaging (MRI) has been used to monitor statin-induced atherosclerotic plaque (AP) reduction. AP regression and reverse remodeling was detected accurately by MRI in just 6 months after statin therapy initiation and, not surprisingly, was associated with LDL-c reduction.
Large-Scale Clinical Trials
Statins have proven effective in primary prevention and secondary prevention trials ( Tables 24-4 and 24-5 ). As might be expected, the absolute risk reduction is greater in the secondary prevention trials, resulting in a steeper LDL-c event reduction curve than that seen in primary prevention trials. The large Heart Protection Study (HPS) demonstrated significant benefit for total mortality rate and CHD events in subjects at high risk of a coronary event who were assigned to simvastatin 40 mg/day compared with placebo. This substantial benefit occurred regardless of baseline LDL-c, and it was seen in all subgroups, including women and the elderly, and benefit increased with duration of therapy. Ischemic stroke incidence was also substantially reduced by statin therapy. No significant increase in liver or muscle toxicity was reported, and statin therapy was not associated with an increase in cancer, respiratory disease, or suicide. The advantage of using large-scale trials to demonstrate negatives of statin therapy was seen in trials of the 80-mg dose of simvastatin. Whereas 40 mg of simvastatin appeared safe in the HPS, two clinical trials using an 80-mg dose of simvastatin showed an excess of myopathy incidence compared with placebo.
| STUDY | POPULATION | STATIN AND DOSE USED (N) | LDL-C REDUCTION | EFFICACY AGAINST CHD | EFFICACY AGAINST STROKE |
|---|---|---|---|---|---|
| HPS | Age 40-80 y with coronary disease, other occlusive disease, diabetes | Simvastatin 40 mg/day (10,269) vs. placebo (10,267) | 37% | Significant reductions in total mortality, fatal and nonfatal MI, revascularization | Yes |
| PROSPER | Age 70-82 y with history of, or risk factors for, vascular disease | Pravastatin 40 mg/day (2891) vs. placebo (2913); mean follow-up, 3.2 y | 3% | No reduction in total mortality, but significant reduction in fatal and nonfatal CHD | No, although a decrease in TIA (low rate of stroke in placebo group) |
| PROVE-IT–TIMI 22 | 4162 subjects with ACS; mean age, 58 y | Atorvastatin 80 mg (2099) vs. pravastatin 40 mg (2063); mean follow-up, 2.0 y | 10% with pravastatin, 42% with atorvastatin | Greater reduction in combined endpoint with atorvastatin than with pravastatin | No |
| CARE | 4159 subjects post MI; mean age, 59 y | Pravastatin 40 mg vs. placebo; mean follow-up, 5 y | 28% | Significant reduction of primary endpoint | Yes |
| LIPID | 9014 subjects aged 31-75 y with MI and ACS | Pravastatin 40 mg/day (4512) vs. placebo (4502); mean follow-up, 5 y | 25% | Significant reduction of primary endpoint | Yes |
| TNT | 10,001 subjects age 35-75 y with stable CHD | Atoravastatin 10 mg/day (5006) vs. 80 mg/day (4995); follow-up, 4.9 y | 80 mg/day: 77 mg/dL 10 mg/day; 101 mg/dL Further reduction: 23% Further LDL-c reduction: 22% | Significant reduction in primary endpoint; significant improvement in fatal and nonfatal MI and major coronary events, but no improvement in mortality | Yes |
| IDEAL | 8888 subjects < 80 y with prior MI | Simvastatin 20 mg/day (4449) vs. atorvastatin 80 mg/day (4439) | Simvastatin: 104 mg/dL Atorvastatin: 81 mg/dL (22%) | No significant lowering of primary combined endpoint of coronary death, confirmed nonfatal MI, or cardiac arrest with resuscitation; no significant decrease in any coronary event | No |
| PRIMARY PREVENTION CLINICAL TRIALS | POPULATION | STATIN DOSAGE | LDL-C REDUCTION | EFFECTIVE AGAINST CHD | EFFECTIVE AGAINST STROKE |
|---|---|---|---|---|---|
| AFCAPS/TEXCAPS | 5608 men aged 45-73 y and 997 women aged 55-73 y with lipid entry criteria (low HDL-c required) | Lovastatin 20 mg and 40 mg/day (3304) vs. placebo (3301) | 25% | Yes | NR |
| WOSCOPS | High-risk men aged 45-64 y without prior MI, followed up for 4.9 y | Pravastatin 40 mg/day (3302) vs. placebo (3293) | 26% | Yes | No |
| ASCOT-LLA | 10,305 hypertensive patients aged 40-79 y with at least three other cardiovascular risk factors; followed up for 3.3 y before study was halted by the DSMB | Atorvastatin 10 mg/day (5168) vs. placebo (5137) | 29% | Yes | Yes |
| ALLHAT-LLA | 10,355 subjects aged ≥55 y who met lipid criteria, monitored for up to 8 y | Pravastatin 40 mg/day | 16.7% (related to drop-ins in placebo group plus drop-outs in treatment groups) | No; 18% difference in LDL-c between groups because of high crossover and dropout rates | No |
| JUPITER | 17,802 apparently healthy men and women with LDL-c <130 mg/dL and hs-CRP 2.0 or higher | Rosuvastatin 20 mg (8901) vs. placebo (8901) | 50% | Yes | Yes |
| CARDS | 2838 men and women with type 2 diabetes and ≥1 other risk factor | Atorvastatin 10 mg/day | 40% | Yes | Yes |
The mechanism for this may be due to a polymorphism in one of the several hepatic membrane transporters. For example, a common single-nucleotide variation in the SLCO1B1 gene that encodes organic anion transporter polypeptide (OATP) 1B1 decreases the transporting activity of OATP1B1 and results in elevated statin concentrations, especially of simvastatin acid. In the Study of the Effectiveness of Additional Reductions in Cholesterol (SEARCH), a genome association study, the risk for myopathy in those assigned to simvastatin was increased by a factor of 4.5 per copy of a common SLCO1B1 variant found to be present in 15% of the population who developed myopathy during the trial.
Numerous primary and secondary prevention trials of statin therapy led to the prospective meta-analysis of data from 90,056 subjects in 14 randomized trials of statins. Known as the Cholesterol Treatment Trialists’ (CTT) collaboration, the LDL-c reductions owing to statin therapy at 1 year ranged from 14 mg/dL to 69 mg/dL with a mean of 42 mg/dL. After 5 years, a highly significant reduction in all-cause mortality was observed, as was a significant 19% reduction in coronary mortality ( Figure 24-2 ). Nonsignificant rate reductions were also seen in noncoronary vascular mortality and nonvascular mortality. Statin therapy substantially reduced MI and CHD death and coronary revascularization by about 25%, and the rates for fatal or nonfatal stroke were reduced by 17% on average. The proportional reduction in major vascular events differed significantly ( P < .0001) according to the absolute reduction in LDL-c achieved, but it remained similar throughout the range of LDL-c studied. These benefits were significant within the first year but were greater in subsequent years. Moreover, statin therapy was demonstrated to be safe with no increase in cancer risk. Taken as a whole, this large dataset suggested that the promise of prolonged statin treatment with substantial LDL-c reductions in those at risk over a wide range of LDL-c was clinically meaningful. A follow-up report from the CTT was a meta-analysis of data from 170,000 participants in 26 randomized trials that included trials with high-dose versus low-dose statin therapy; it indicated that further reduction in LDL-c can be shown to produce further reductions in cardiovascular (CV) outcomes such as MI, revascularization, and ischemic stroke. Across all 26 trials, which included primary and secondary prevention, all-cause mortality was reduced by 10% per 1.0 mmol/L (38.8 mg/dL) LDL-c reduction. This was due primarily to effects on CHD, but with no significant effects on stroke. These data support the use of a maximally tolerated safe dose of a statin to lower LDL-c in those at increased CV risk.
