Treatment Targets: The Increasing Care Gap

In patients at risk for a CV event, there may be no incremental reduction in LDL-C achievable with current therapy that does not lead to an incremental further reduction in risk. Several major studies have associated more intensive versus less intensive LDL-C lowering with increased protection against CV events including PROVE-IT,(1) TNT,(2) SEARCH,(3) and IDEAL.(4) These and other trials have also provided reassurance that low levels of LDL-C are safe. In the TNT trial, which provided an impressive demonstration of the principle that lower is better in patients with established CV disease, there appeared to be a continuous proportional relationship between lower LDL-C and lower rates of events across every stratification up to and including <1.03 mmoL, which was the lowest stratification evaluated.(5) Although only 11% of the study population achieved LDL-C levels this low, and the relative risk reduction over the next stratum, those with a level between 1.03 and 1.55 mmol/L, did not reach statistical significance, the slope of the correlation between LDL-C and risk remained consistent. There was no evidence of any increase in adverse events that correlated with LDL-C reductions. In the Cholesterol Treatment Trialists meta-analysis of 14 cholesterol-lowering therapy trials in 18,686 patients with diabetes, there was a significant 21% proportional reduction in major vascular events per mmol/L reduction.(6) Data such as these have been included in the recently revised Canadian Cardiovascular Society (CCS) guidelines, which have set aggressive targets for patients with established CV disease as well as for those at moderate risk of experiencing their first CV event.(7) The LDL-C target, which should be pursued in all high risk patients, is ≤2.0 mmol/L or a 50% reduction in LDL-C from baseline. The same target is appropriate in intermediate risk patients if the baseline LDL-C is ≥3.5 mmol/L. If the LDL-C is lower in the intermediate-risk group, the same LDL-C targets should be considered if ApoB is ≥1.2 g/L or if non-LDL-C is ≥4.3 mmol/L. The trigger for lipid-lowering treatment in low risk patients is an LDL-C ≥5.0 mmol/L except in individuals with familial hypercholesterolemia who should be treated at any LDL-C level. The evidence to support lipid lowering even in low-risk patients includes a meta-analysis conducted by the Cholesterol Treatment Trialists.(8)In data pooled from 27 trials with statins, this analysis stratified patients by 5-year major cardiovascular event risk. A significant risk reduction was observed for all groups, including those with less than a 10% estimated 5-year risk for an event. In the JUPITER trial which recruited otherwise healthy patients with an elevated C-reactive protein (CRP) level, a marker of elevated CV risk, highly significant CV risk reduction accompanied median LDL-C reductions even though patients were required to have LDL-C <3.35 mmol/L at entry (Table 1) (9). Although statins have proven instrumental in establishing the value of intensive lipid lowering, and are the preferred therapeutic modality, the cardiovascular benefits appear to be related to the magnitude of LDL-C reduction and may be independent of which treatment strategy is used to reach the target. In the Cholesterol Treatment Trialists analysis, for example, the correlations between LDL-C lowering and CV risk reduction were consistent without regard to treatment arm. Despite the fact that the vast majority of prospective data linking LDL-C reductions to protection from CV risk was performed with a statin therapy, other sets of data, including epidemiologic studies,(10) suggest that low LDL-C provides CV protection no matter how it is achieved. For this reason, most guidelines, including those issued by the CCS, recommend targets independent of therapeutic strategy, while emphasizing that statins are the preferred initial treatment in light of the accumulated evidence.  While lifestyle modifications, such as low cholesterol diet or greater exercise, may exert cardioprotective effects independent of lipid lowering, pharmacologic options, including bile acid sequestrants, cholesterol absorption inhibitors, and fibrates are also recommended in order to reach targets not achieved on statins and lifestyle modifications alone. These alternatives are essential substitutes in those who do not tolerate statins.

Barriers to Reaching Treatment Targets

In surveys to determine the proportion of patients on lipid lowering therapies who are reaching LDL-C goals, the targets of therapy are increasingly stringent according to risk which explains the higher rate of high-risk patients relative to low-risk patients not reaching treatment goals. For example, in an international survey of nine countries that included Canada, 86% of low risk, 74% of moderate risk, and 67% of high risk patients were at goals defined by cholesterol management guidelines.(11) With an overall 67.3% of treated patients at goal, Canada was below the median 73% success rate, ranking fifth against a high of 83.5% in Korea and a low of 47.4% in Spain (Fig. 1). However, the authors noted that overall control rates had climbed steeply, despite more rigorous goals, since a similar survey published in 2000.(12)

The reasons for lower success rates in patients at greater risk cannot be wholly attributed to more stringent goals. In Canada, the LDL-C target is the same in those with high and moderate risk. For many patients whose high risk is defined by Framingham Risk Score (>20% estimated 10-year risk defines high risk), the elevated baseline LDL-C levels are more difficult to bring to the target range with standard doses of statin monotherapy. Although the LDL-C lowering effect per milligram of any specific statin varies, all agents in this class provide their greatest lipid lowering effect at the lowest recommended dose (Fig. 2).(13) Higher doses provide relatively modest further reductions in LDL-C, averaging 5% to 7% each time the dose is doubled. For high risk patients with a high baseline level, large doses of statins may still be insufficient to bring LDL-C to goal. Even if statin doses can be raised high enough to reach LDL-C treatment goals, several obstacles remain. Several initiatives, including one in Canada,(14) have been developed to identify patients who required higher starting doses in order to accelerate the titration process. Another is that the risk of adverse events increases with intensive-dose therapy.(15)  While it is estimated that 10% to 15% of patients on chronic statin therapy experience some form of muscle-related symptoms,(16) The U.S. Food and Drug Administration (FDA) has required labeling for some statins that includes a black-box warning about the potential for severe myopathies at the highest doses. In the effort to avoid these adverse events, many physicians may be unwilling to titrate statins beyond moderate dose levels even when patients remain short of goals. Intolerance to statins is typically described in relative terms. Absolute contraindications, such as hepatotoxicity and rhabdomyolysis are rare.(17) The prevalence of myalgias in routine use of statins is difficult to estimate. In patient surveys and post-marketing studies, rates of myopathies are lower than in clinical trials.(18) This suggests many such complaints captured when patients are asked about specific side effects are not significant in daily practice. However, even subtle side effects may influence adherence rates. Defined as taking >80% of medication, adherence rates at one year were approximately 50% in one Canadian study.(19)Not surprisingly, poor adherence is associated with an increased risk of CV events.(20) Again, as side effects are dose-related, the higher doses needed to reach treatment targets may limit adherence and the advantage of seeking recommended goals.

Strategies to Reach LDL Targets

Bringing LDL levels to target is essentially never an isolated goal in patients at risk for CV events. Statins are the first-line pharmacologic therapy for individuals with elevated LDL-C, but these agents are not the first step in treatment. Although clinicians may give limited attention to lifestyle modifications because of the difficulty involved in enlisting patients to make these changes, regular exercise and a healthy diet can have an important favorable impact on a host of CV risk factors(21) at the same time that produce improvements in LDL-C as well as other lipid subfractions.(22) It is essential that lifestyle changes be emphasized and pursued even if a well-tolerated regimen of a statin monotherapy is effective at bringing patients to the LDL-C target. Statins are identified in the CCS guidelines as first-line therapy for the treatment of elevated LDL-C due to their efficacy, their tolerability, and their proven ability to reduce CV events in large trials. However, in those not able to reach treatment goals with lifestyle changes and a well-tolerated dose of statin monotherapy, the treatment goals should still be pursued with adjunctive pharmacotherapies. The alternatives with the greatest impact on LDL-C are the cholesterol absorption inhibitor ezetimibe and bile acid sequestrants. When added to a statin, both types of agents provide a further LDL reduction ranging from 10% to 20%. In a placebo-controlled trial, bile acid sequestrants were the first to associate a reduction in LDL-C with a reduction in CV risk.(23) Comparable data are not available for ezetimibe. Both drugs are well tolerated. Bile acid sequestrants are associated with constipation. However, this risk is lower with second generation colesevelam relative to the first generation agents cholestyramine and colestipol (Fig. 3). (24) Statins have been instrumental in defining the goals of LDL-C lowering, but it is important to recognize that they are not the only avenue for achieving these goals. In the CCS guidelines, as in other major guidelines, reaching the target is considered essential for providing optimal protection against CV events. The tight correlation between LDL-C and risk of events provides the rationale for pushing through to the treatment goal even if multiple therapies are needed.

Conclusion

Despite the efficacy of statins for lowering LDL-C, there is a significant and persistent care gap in reducing the risk of CV events through the treatment of dyslipidemias. In those intolerant to statins or who do not reach goals on statins alone, other methods of reducing LDL should be pursued. While other dyslipidemias and other CV risk factors should be addressed aggressively, the overwhelming evidence that link LDL-C targets to a reduction in CV risk justifies particular urgency for considering treatments beyond statins when statins alone are not enough to bring the patient to goal.

References

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