Epidemiology has repeatedly shown that elevated levels of cholesterol play a key role in the development of atherosclerotic disease. In particular, low density lipoprotein (LDL) cholesterol has been strongly associated with coronary heart disease (CHD) risk.1-5 Lowering LDL cholesterol reduces the incidence of atherosclerotic disease, irrespective of how the reduction is achieved. The efficacy of statins in this respect is well-known,6 but similar improvements in CHD events can also be seen if a LDL cholesterol reduction is provided by cholestyramine and even surgical bypass.7-9 The message is clear and has been proven - lowering LDL cholesterol improves cardiovascular (CV) outcomes, irrespective of the mode; however, there is a question over how much LDL cholesterol lowering is low enough and what supporting evidence there is for this.
Statins, LDL Cholesterol and CHD Risk Reduction
Studies of statin usage in both primary and secondary prevention settings have shown consistently that the risk of a CHD event is correlated closely with LDL cholesterol levels (see Figure 1).7-10 The results are impressive. The benefits of lowering LDL cholesterol levels extend to men and women with widely differing CV risk profiles and include reductions in CHD and total mortality as well as myocardial infarction (MI), revascularisation procedures, stroke and peripheral vascular disease (PVD).11
It is becoming increasingly evident that the more 'aggressive' the lipid lowering regimen, the greater the potential gain in terms of disease prevention. Some of the most compelling data comes from the recently published Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) study.12 A total of 654 patients with coronary disease and a baseline stenosis of at least 20% were randomised to receive treatment with a high dose of atorvastatin (80mg) or a moderate dose of pravastatin (40mg) over an 18-month period. Results demonstrated that coronary atherosclerosis (documented by intravascular ultrasound) was virtually arrested in the atorvastatin group, with patients experiencing mean on-treatment LDL cholesterol levels of 79mg/dL (2.1mmol/L), in effect a mean 46% reduction from baseline. In contrast to this, in the pravastatin group, where a 25% reduction from baseline led to mean LDL cholesterol levels of only 110mg/dL (2.9mmol/L), atherosclerosis continued to progress. Similar findings were reported by the Atorvastatin (80mg) compared with Simvastatin (40mg) on Atherosclerosis Progression (ASAP)13 and the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER; 80mg atorvastatin and 40mg pravastatin)14 studies. Both studies used ultrasound to determine carotid intima-media thickness as a measure of atherosclerotic progression. In line with REVERSAL, intensive lipid lowering strategies were seen to halt atherosclerosis, whereas moderate reductions in LDL cholesterol allowed for continued progression.
Benefits of aggressive lipid-lowering interventions have also been seen in patients experiencing an acute coronary syndrome (ACS) event. In the landmark Pravastatin or Atorvastatin Evaluation and Infection - Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) study, a total 4,162 patients hospitalised for an ACS event were randomised to receive standard (pravastatin 40mg) or intensive (atorvastatin 80mg) lipid-lowering therapy.15 After a mean 24 months of follow-up, the intensive therapy regimen resulted in median LDL cholesterol levels of 62mg/dL (1.6mmol/L), compared with 95mg/dL (2.5mmol/L) for standard therapy. This was accompanied by a lower risk of death from any cause or major cardiac events in the intensive therapy group, suggesting that aggressive lowering of LDL cholesterol provides additional clinical benefit over standard regimens in this patient population. The term 'aggressive' in this context relates not only to the magnitude of LDL reduction, but also to timing.
The results of the PROVE IT-TIMI 22 study are just in line with the 2001 NCEP ATP III recommendations stating that patients with ACS should receive lipid-lowering therapy on admission or within 24 hours.2 The time interval between the ACS event and enrollment in PROVE-IT was a maximum of 10 days. Intensive and fast lowering of LDL cholesterol, as has been seen with plasmapheresis, is accompanied by improved vasoreactivity within hours,16 a factor being of physiological relevance for an ACS event.
The recently published Treating to New Targets (TNT) study,17 which randomised 10,001 stable CHD patients to double-blind treatment, showed that mean LDL cholesterol levels were 77mg/dL (2mmol/L) with 80mg atorvastatin versus 101mg/dL (2.6mmol/L) with 10mg atorvastatin, after a median follow-up of 4.9 years. Patients treated with high-dose atorvastatin had 22% fewer CV events than those treated with the low dose.
How Much to Lower LDL Cholesterol
The realisation that extra low LDL cholesterol levels can pay dividends in terms of CHD prevention is changing the way CV medicine is practised. The ATP III of the NCEP recently revised its treatment guidelines to reflect the growing body of evidence that additional CV benefit can be obtained with aggressive lowering of LDL cholesterol. The updated guidelines take into consideration results from five recently-reported clinical trials of statin therapy,18 namely the Heart Protection Study (HPS),19 the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER)20, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial - Lipid-Lowering Trial (ALLHAT-LLT),21 the Anglo-Scandinavian Cardiac Outcomes Trial - Lipid-Lowering Arm (ASCOT-LLA)22 and the PROVE IT-TIMI 22 study.15 Embracing the findings from these trials, the ATP III now recommends that physicians consider lowering their LDL cholesterol treatment goals from less than 100mg/dL (2.6mmol/L) to less than 70mg/dL (1.8mmol/L) for certain patients at very high risk. These would be individuals with multiple major risk factors for CHD, diabetes plus CHD, severe and poorly controlled risk factors, multiple risk factors for metabolic syndrome and patients with ACS. The equivalent European guidelines suggest LDL cholesterol levels should be less than 115mg/dL (3mmol/L) in general and less than 100mg/dL (2.6mmol/L) for patients with established CV disease (CVD) and diabetes.23
At first glance, a target LDL cholesterol level of less than 70mg/dL (1.8mmol/L) may seem excessively low, but its validity can be supported by sound physiological rationale. LDL cholesterol levels of between 50mg/dL (1.3mmol/L) and 70mg/dL (1.8mmol/L) would be considered normal for native 'hunter-gatherers,' healthy human neonates, free-living primates and other wild animals, all of which do not develop atherosclerosis. These could be the levels for which humans are genetically adapted and the levels striven to be achieved.10
Randomised trial data have also suggested that atherosclerosis progression and CHD events are minimised when LDL cholesterol levels are lowered to less than 70mg/dL (1.8mmol/L) and that there are no major safety issues associated with reducing LDL cholesterol to these seemingly very low levels.10 Concerns have been raised in the past about a possible relationship with cerebral haemorrhage, but a causal link has not been established. The ATP III considers the possibility that side effects result from LDL cholesterol lowering per se to be 'remote'.18 Moreover, mammals do not have a dietary cholesterol requirement and are fully capable of synthesising sufficient sterol when placed on a cholesterol-free diet.
In Theory and In Practice
Despite the proven benefits of lipid lowering interventions, only a minority of patients achieve recommended treatment goals in clinical practice. This has implications, not only in terms of CVD prevention, but also for economics and the resulting increased burden on healthcare providers.
The European Action on Secondary Prevention by Intervention to Reduce Events (EUROASPIRE) I and II studies were among the first large-scale surveys to demonstrate disturbingly high lipid levels in CHD patients.24 Carried out in cardiology centres across Europe during 1995 to 1996 and 1999 to 2000, respectively, the studies showed clearly that, despite treatment, most individuals did not reach the total cholesterol treatment goal suggested by European guidelines23 of less than 5mmol/L (190mg/dL). The proportion of patients treated and controlled increased from 21% in EUROASPIRE I to 49% in EUROASPIRE II, in line with the growing trend for lipid lowering (i.e., statin) therapy, but the findings were nonetheless far from optimal.
Experience in the US also suggests that large proportions of patients have not been achieving NCEP target levels. The Lipid Treatment Assessment Project (L-TAP) sought to evaluate lipid levels in patients with dyslipidaemia who had been receiving the same lipid-lowering therapy for at least three months.25 A total of 4,888 patients were enrolled in a primary care setting during 1996 to 1997. Analysis subsequently demonstrated that, overall, only 38% of patients achieved or exceeded NCEP-specified LDL cholesterol target levels. Paradoxically, it was individuals at highest risk that had the lowest success rate - only 18% of patients with confirmed CHD achieved their LDL cholesterol treatment goal.
The Return on Expenditure Achieved for Lipid Therapy (REALITY) programme, a comprehensive primary-care-based retrospective study across nine European countries, also examined the use and effectiveness of lipid-lowering drugs in routine daily practice. Recently published results from the Spanish arm of the study for data collected between 1998 and 1999 showed that only 13% of patients achieved their LDL cholesterol goal (less than 100mg/dL; 2.6mmol/L) on initial treatment. An additional 13% attained goal after their treatment was changed (e.g., potency increased), but 74% were still inadequately controlled after three years of treatment and follow-up.26 It is striking that only 35% of patients in the Dutch arm of the study who did not achieve goal with initial therapy increased their potency level of lipid-lowering therapy.27
The 'real-world' effectiveness study of lipid-lowering agents carried out in an unselected cohort of CHD patients (n=605) in Germany from 1998 to 2002 is also of recent interest.28 Over a median follow-up of 3.6 years, the study showed that LDL cholesterol levels decreased by a median 42mg/dL (1.1mmol/L). The likelihood of LDL cholesterol falling below 100mg/dL (2.6mmol/L) was low (24%) and, consequently, the population-averaged post-treatment LDL cholesterol level remained relatively high (130mg/dL; 3.4mmol/L). The undertreatment of the population was related, at least in part, to underdosing of statins, with patients receiving lower than evidence-based doses of atorvastatin, pravastatin or simvastatin on 78% of treatment days. The consequences of under-treatment were stark. In theory, had LDL cholesterol levels been reduced to the recommended 99mg/dL (2.6mmol/L), an estimated 43% reduction in CHD events could have been gained. In practice, a reduction of only 18% was realised. These concerns were echoed by findings from the Swedish arm of the REALITY study, in which patients who reached treatment goals were 24% less likely to suffer a CV event compared with their undertreated counterparts.29
The Challenge of Achieving Treatment Goals
In spite of the increasing wide body of evidence for the benefit of reducing LDL cholesterol levels to less than 100mg/dL (2.6mmol/L), and even less than 70mg/dL (1.8mmol/L), many patients will not be able to achieve such low levels with currently available drugs. The reasons for this are many and varied. For example, initial doses of statins are often insufficient for patients to achieve their treatment goals. Upward dose titration can improve efficacy, but evidence suggests that doubling the initial dose provides only an additional 6% reduction in LDL cholesterol.30 In some cases, physicians and/or patients resist dose titration because of the fear of adverse events at higher doses. It has in fact been documented by an American College of Cardiology/American Heart Association/National Heart, Lung and BIood Institute Clinical Advisory Panel, which has stated that myopathy is more likely to occur at higher rather than lower doses of statins.11 In the publication arising from the PROVE IT-TIMI 22 study, the authors noted the occurrence of 'significantly more liver-related side effects' with high-dose atorvastatin than with standard-dose pravastatin.15 Similarly, although the A (Aggrastat) to Z (Zocor) trial showed that intensive and early initiation of lipid-lowering therapy was preferable to delayed, less intensive treatment in patients experiencing an ACS event, myopathy occurred in nine patients receiving simvastatin 80mg/day but in no patients treated with simvastatin 20 or 40mg/day.31
In other cases of patients not achieving their goal, it is often the reluctance of physicians to follow up and of patients to comply with a careful dose titration regimen. A number of factors are not in favour of physician or patient compliance at all. For example, several titration steps are often required, each being associated with only a small additional reduction in LDL cholesterol. Several potentially costly laboratory analyses may be involved, as well as considerable time (up to six weeks)2 before the efficacy of each statin dose and the need for further dose-titration can be fully assessed.
Recent estimates from the Analysis and Understanding of Diabetes and Dyslipidemia: Improving Treatment (AUDIT) study suggest poor patient compliance in general might be the underlying reason for patients not achieving goals in 46% of cases.32
From a mechanistic perspective, the pharmacological principle of focusing only on the statin-induced inhibition of hepatic LDL cholesterol synthesis may, in itself, be sub-optimal. More is to be gained from a treatment strategy that addresses the inhibition of cholesterol absorption as well as production. Ezetimibe/simvastatin, a dual inhibitor of cholesterol production and absorption, allows for such a treatment approach. Recent large-scale, randomised, controlled trials have shown that ezetimibe/ simvastatin produces greater reductions in LDL cholesterol than traditional statin therapy.33-38 More patients achieve their treatment goals, at lower doses of simvastatin and with fewer dose titrations than simvastatin alone. Moreover, patients treated with ezetimibe/simvastatin can see a marked reduction in their LDL cholesterol levels within only two weeks, which has clear benefits in terms of compliance. Improvements in efficacy are not at the expense of safety or tolerability - ezetimibe/ simvastatin has an adverse event profile similar to that of statin monotherapy. An active outcome programme for ezetimibe/simvastatin will confirm whether or not the enhanced LDL cholesterol lowering effects of treating two sources of cholesterol through dual inhibition translate into beneficial modifications of CV end-points. In the meantime, it would be pertinent to offer all appropriate patients with hyperlipidaemia the option of dual cholesterol inhibition with ezetimibe/simvastatin.
Conclusions
In summary, lowering LDL cholesterol levels has been repeatedly proven to improve CVD outcomes. Moreover, the greater the LDL cholesterol reduction, the more benefit there is to be gained. Treatment guidelines, such as those from the NCEP, are beginning to reflect the need to strive for much lower LDL cholesterol levels in clinical practice - as such, physicians who already find it difficult to treat and reach the goal will be faced with even greater challenges. Reductions in LDL cholesterol approaching 50% are needed to halt the progression of the atherosclerotic plaque.12 Ezetimibe/simvastatin can provide this level of reduction at the recommended starting dose, while traditional statin therapy typically cannot. Single inhibition statin monotherapy may no longer be optimal in this respect. Addressing two sources of cholesterol through dual inhibition with ezetimibe/simvastatin allows more patients to achieve their treatment goals33-38 and may therefore represent a more favourable approach to the management of LDL cholesterol.