Author + information
- Robert A. Vogel, MD⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Robert A. Vogel, Cardiology Section (111B), University of Colorado, 1055 Clermont Street, Denver, Colorado 80220
Statins have been approved for the treatment of dyslipidemia for 25 years. This class has demonstrated substantial and consistent reduction of cardiovascular events with an acceptable safety profile. Despite the widespread use of statins, patients continue to experience residual risk. To date, attempts to reduce that risk with additional lipid therapies have failed. Trials of niacin (AIM-HIGH [Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health] trial) and fenofibrate (ACCORD [Action to Control Cardiovascular Risk in Diabetes] trial) in subjects already on statins have recently shown no further risk reduction (1,2). Is statin therapy as good as it gets in treating dyslipidemia? If not, what will be the next lipid modifier with clinical benefit incremental to that of statins? The answer may lie in understanding how statins work. By inhibiting the rate-limiting step in hepatic cholesterol synthesis, statins decrease intracellular cholesterol, resulting in increased expression of hepatic low-density lipoprotein (LDL) receptors and increased hepatic clearance of circulating atherogenic particles including LDL. After delivering their cargo of atherogenic lipoproteins for intracellular degradation, most LDL receptors are recycled to the cell surface.
Less well recognized is that statins increase the expression of proprotein convertase subtilisin kexin 9 (PCSK9). PCSK9 promotes hepatic LDL receptor degradation, thereby reducing LDL receptor density and clearance of LDL particles. This negative feedback response attenuates statins' lipid effects. Conversely, blocking PCSK9 might be expected to increase the clearance of atherogenic lipoproteins and enhance the efficacy of statins. Thus, PCSK9 offers a novel approach to lipid management.
PCSK9's role in lipid metabolism was suggested by 3 observations. Abifadel et al. (3) first reported that a specific heterozygous PCSK9 missense mutation caused autosomal dominant hypercholesterolemia. Because loss of a single allele is usually functionally inconsequential, a gain-of-function mechanism was hypothesized. The second link was that PCSK9 messenger ribonucleic acid levels were found to be responsive to intracellular cholesterol (4). In the hepatocyte, PCSK9 undergoes obligatory autocatalytic cleavage, but its catalytic activity is independent of its affinity for the LDL receptor (5). This spatial and functional separation has important pharmacological implications. PCSK9 binds to the receptor and channels it internally toward the lysosomal compartment for degradation. In doing so, it inhibits the normal recycling of the LDL receptor back to the hepatic cell surface. A third and perhaps most important clue was that nonsense mutations in PCSK9 were associated with 15% to 30% reductions in LDL cholesterol, with significant reductions in cardiovascular risk (6). These experiments of nature provide plausibility to the hypothesis that pharmacologic interference with PCSK9 can provide clinical benefit.
In this issue of the Journal, McKenney et al. (7) report the results of a phase 2 trial of REGN727/SAR236553, a human monoclonal antibody to PCSK9 in subjects with LDL cholesterol ≥100 mg/dl on stable atorvastatin (10 to 40 mg) therapy. This trial randomized 183 subjects to 1 of 3 antibody doses or placebo administered subcutaneously every 2 weeks or higher doses every 4 weeks for a total treatment of 12 weeks. Both 2- and 4-week dosing resulted in 40% to 72% and 43% to 48% reductions in LDL cholesterol, respectively. Up to 9% increases in high-density lipoprotein (HDL) cholesterol, 19% decreases in triglycerides, and 29% decreases in lipoprotein(a) were observed. Mild injection-site reactions were the most common adverse events and 1 subject experienced leukocytoclastic vasculitis, which was successfully treated with drug discontinuation and steroid therapy.
This is a significant study, both because of the magnitude of LDL reduction achieved and the novel pathway (PCSK9 inhibition) utilized. Important questions remain. What is the extent of the unmet need for LDL reduction, not fulfilled by optimal statin therapy? The few patients who are truly statin intolerant might benefit from an alternative approach to LDL reduction. However, PCSK9 inhibition probably would be used as an adjunct to statin therapy. Maximum doses of effective statins reduce LDL cholesterol up to about 60%, resulting in average serum levels of 70 to 80 mg/dl. Existing statin studies suggest that cardiovascular risk continues to decrease with more intensive therapy, resulting in lower LDL cholesterol levels (8). Because maximal statin doses are infrequently prescribed, one might argue that there is a greater need for clinicians to use higher, evidence-based statin doses, especially for high-risk patients (9), than to seek add-on therapy. However, neither goal is mutually exclusive.
Is a combination of PCSK9 plus statin therapy safe? We do not know whether immune responses to fully humanized PCSK9 antibody will develop after prolonged treatment. The leukocytoclastic vasculitis observed in 1 subject may or may not have been a consequence of therapy, as this condition commonly occurs without drug initiation. Larger, phase 3 trials are certainly needed. Equally important, what are the consequences of very low LDL cholesterol that could be achieved with combination therapy? We currently have no clear safety concern for very low LDL cholesterol other than possibly an increase in hemorrhagic stroke (10). It has, however, taken 25 years of statin therapy to recognize their association with memory loss and new onset diabetes, recently acknowledged by the Food and Drug Administration (11).
Will patients be compliant with every 2- to 4-week administration of a subcutaneously administered drug, especially for an asymptomatic condition? About 50% of patients discontinue statin therapy within the first year. As mentioned previously, the affinity of PCSK9 for the LDL receptor is not dependent on its enzymatic activity, making oral administration of a small inhibitory molecule difficult. What orally administered drugs under investigation might supplant the need for PCSK9 inhibition? At present, anacetrapib, a cholesterol ester transfer protein inhibitor, has been shown to reduce LDL and increase HDL cholesterol by 40% and 138%, respectively (12). Even if its HDL effect has little clinical consequence, it may prove to be an effective LDL cholesterol–lowering agent.
What are the theoretical advantages and disadvantages of PCSK9 inhibition compared with statins? Statins have myriad pleiotropic effects, including reducing inflammation, coagulation, and oxidation, all important antiatherogenic factors (13). There is considerable debate about the extent to which these effects contribute to the efficacy of statins, but they probably play some role. PCSK9 inhibition probably will not share these effects. Conversely, maximally increasing LDL receptors may have synergistic advantages. By reversing statin-induced PCSK9 up-regulation, PCSK9 inhibition increases the statin's effectiveness on LDL cholesterol lowering. Moreover, LDL receptors contribute to the clearance of atherogenic lipoproteins other than LDL, such as intermediate-density lipoproteins and remnant particles, the latter via apolipoprotein E affinity. Increased intermediate-density lipoproteins and remnant particle clearance may have real therapeutic benefit beyond that provided by LDL reduction.
Brown and Goldstein won a Nobel Prize for their identification of the LDL receptor in 1985 while they were studying familial hypercholesterolemia. The therapeutic triumph of statins logically follows their pioneering efforts. So may PCSK9 inhibition (14).
Dr. Vogel has reported that he has no relationships relevant to the contents of this paper to disclose.
↵⁎ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
- American College of Cardiology Foundation
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