LDL Management​

  • LDL─The Principal Cause of Heart Disease 
     

    • Evidence from controlled clinical trials has corroborated a causal role for LDL-C in atherogenesis. Lowering of LDL-C levels is associated with reduced risk of cardiovascular disease (CVD) mortality and morbidity rates that is directly proportional to the magnitude of LDL-C reduction.

    • Epidemiological and interventional studies show that a 50 mg/dL decrease in LDL-C results in 32% reduction in heart attack and  20% reduction in stroke whereas a 10 mm Hg decrease in systolic blood pressure results in 22% reduction in MACE (major acute coronary events) and 41% reduction in stroke.

    • Studies of individuals with genetically low LDL-C levels (PCSK9 gene loss of function) have shown that  a lifelong 1% reduction in LDL-C confers a 3% reduction in CVD ─ far greater than 1% reduction observed in randomized clinical trials that usually lasts only 5 years.

    • The optimum LDL-C level is currently standardized at 40 mg/dL.4 Grundy et al4 have demonstrated a log-linear relationship between increased serum LDL-C levels and increased relative risk for CAD. The data plotted in this way suggest that for every 1 mg/dL increase in LDL-C, the relative risk increases by 1%. Thus, an individual with an LDL-C of 70 mg/dL has a 30% higher risk than one with an LDL-C of 40 mg/dL.

    • Intense LDL-C lowering yields superior benefits than moderate lowering; the absolute benefit is related to the person’s’ baseline absolute risk and the degree of LDL-C lowering but not the initial LDL-C level.

    • In the JUPITER Study of adults with LDL-C <130 mg/dl, those who were randomized to rosuvastain had a 45 % reduction in heart attack and other CVD outcomes. Strikingly, those who achieved an LDL-C <50 mg/dl had a 65% reduction in CVD outcome compared to just 24% among those who did not achieve LDL-C <50 mg/dl.  Conversely those who had LDL-C >70 mg/dl had no benefit (possibly due to not taking the statin as directed). It is worth noting that most of these subjects were at low-risk of CAD and had low LDL-C of 108 mg/dl).

    • It is worth highlighting that those achieving LDL-C <50 mg/dl had no increase in side effects compared to those who had LDL-C >50 mg/dl. Thus, greater reduction in LDL-C  and CVD risk  can be achieved  without a systematic increase in adverse events.

    • The Cholesterol Treatment Trialists’ (CTT) Collaborators have showed that more-intensive therapy produces further reductions in each category of major CVD events (coronary death, heart attack, coronary angioplasty/stent/bypass, and ischemic stroke). The reductions in risk per mmol/L (40 mg/dl) reduction in LDL cholesterol were similar, irrespective of the baseline concentration of LDL cholesterol, even in patients with baseline LDL cholesterol less than 75mg/dl.

    • In sharp contrast, earlier lowering of LDL-C confers greater benefits as shown in Figure 083.8 For instance a 40mg decrease in LDL-c reduce CVD risk by 54% at age 35 compared to only 20% at age 65.

    • These results do not imply that an LDL-cholesterol concentration of less than 75mg/dl should be achieved in every low-risk person but the treatment should not be denied in high risk individuals such as those with heart disease, stroke, diabetes and metabolic syndrome.7

    • LDL-C lowering reduces CVD risk in women, elderly, people with chronic kidney disease and different levels of CVD risk (Framingham Risk Score). 

    • The JUPITER Trial demonstrated that, in primary prevention rosuvastatin reduced CVD events in women with a relative risk reduction similar to that in men, a finding supported by meta-analysis of primary prevention.

    • An 80 mg/dL reduction in LDL-C and/or non-HDL-C confers a 60-80% reduction in CVD after 5 years of treatment (1:1 relationship).

    • Earlier guidelines developed by the U.S. National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) have evolved to include LDL-C < 100 mg/dL as the optimal goal for primary prevention in persons with multiple CHD risk factors and LDL-C < 70 mg/dL as an optional goal for very high risk patients.4 The latter is also considered a reasonable target for high risk patients with CVD. Similar guidelines have also been adopted in Europe and Canada.

    • Pharmaco-economic analyses have suggested that higher LDL-C lowering efficacy statins are more cost-effective than lower efficacy statins in terms of LDL-C reduction and goal attainment, quality-adjusted life years (QALY) and projected CVD risk reduction.15, 16 Conversely, switching to a low potency statin results in increased LDL-C levels and lower goal attainment.

    • Although LDL-C goal attainment rates have overall improved during the past decade, only about one-third of high-risk patients with CVD attain levels of LDL-C < 70 mg/dL.17, 18  Given the well-established association between LDL-C lowering and CVD risk reduction, more intensive statin therapy with high potency statins (such as atorvastatin or rosuvastain in high doses) is necessary to achieve the specific targets.  It is possible that some patients who do not attain LDL-C goals are unwilling to take or intolerant of high dose statin therapy or physicians may be reluctant to use high-dose statins.

    • In a recent analysis of a managed care database in the U.S. (n = 284,915), the proportion of high risk patients with CVD treated with lipid-lowering therapy (LLT) (including statins, niacin, fibrates, bile acid sequestrants, ezetimibe/simvastatin, and ezetimibe,)  increased steadily from 59% to 71% from January 2004 to August 2008.

    • Combinations therapy (with niacin, fibrates, ezetemibe or resin) may help to limit the need for higher statin doses in those patients requiring more intensive LDL-C reductions (e.g. > 50%) and provide greater drug adherence as well.18 While the lipid-lowering efficacies of these combination therapies are known, randomized clinical trials assessing the effects of these therapies on CVD outcomes are still awaited.

    • Much of the progress in reducing CVD and mortality, is largely attributed to improved cholesterol management, especially the use of higher efficacy LDL-C lowering agents.

    • Although statins have become the mainstay of lowering LDL-C, weight reduction of 10 kg can decrease LDL-C by  8mg/dl and dietary modification can reduce LDL-C by 40  mg/dl.