EBM Tools for Practice: From Atheroma to FOURIER: A Condensed History of Cholesterol Treatments

It was around 1900 when Rudolf Virchow noted that the artery walls of patients dying of occlusive vascular disease contained a yellowish fatty substance. The word chosen to describe this pathological condition was the Greek word for porridge, atheroma. This material later was identified to be cholesterol. At the time, a causal link between cholesterol levels and coronary artery disease (CAD) was not clear, because the plasma cholesterol levels of many patients with CAD did not differ significantly from that of the general population.¹

In the 1950s, the Framingham study began and prospectively studied many risk factors, including blood cholesterol levels and the risk of CAD. The outcome of this study revealed a strong correlation between elevated blood cholesterol levels and coronary heart disease (CHD) mortality.² Other studies supported this relationship and the lipid hypothesis was born.³ This theory proposes that elevated levels of total and low-density lipoprotein cholesterol (LDL-c) are causally related to CAD. The inverse – that lowering total and LDL cholesterol would reduce CAD risk – also would be expected to be true.

Prior to the 1980s, bile acid sequestrants, niacin and ileal bypass supported the lowering of cholesterol to reduce coronary heart disease in patients with CHD or at high risk of CHD. However, more efficacious agents to lower cholesterol did not come about until the 1980s. In that decade, the first of multiple statins was introduced into the clinical space with the approval of lovastatin. Health care professionals now had access to powerful medications that lowered circulating cholesterol levels through inhibition of the rate-limiting enzyme (HMG-CoA reductase) for production of cholesterol in the liver.⁴

The 1990s and 2000s ushered in large-scale outcome trials involving statins in both primary and secondary-prevention patient populations. These included the Scandinavian Simvastatin Survival Study (4S)⁵, the Heart Protection Study (HPS)⁶ and many others. These trials showed that treating patients with statins improved morbidity and mortality from cardiovascular (CV) causes.

More recently, the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) demonstrated that the addition of ezetimibe to simvastatin in patients presenting with acute coronary syndromes (ACS) and LDL-c < 125 mg/ dL benefited above and beyond that of the statin alone in reducing cholesterol levels and cardiovascular outcomes.⁷ The simvastatin plus ezetimibe arm reached an LDL-c average of approximately 54 mg/dL compared to the simvastatin-alone arm, in which patients achieved an average LDL-c of 69 mg/dL. These values represent well-treated patients in regard to cholesterol levels. This study affirmed the “lower is better” hypothesis and raised further questions, including whether lowering cholesterol even more would improve cardiovascular outcomes in high-risk patients.

In 2003, PCSK9 proteins were discovered and found to be integral in lipid metabolism.⁸ In populations of patients with loss-of-function PCSK9 mutations, LDL-c levels were, on average, 28% lower than those without the mutation and resulted in an 88% relative risk reduction of atherosclerotic CV events during 15 years of follow up. Conversely, gain-of-function mutations, which lead to higher LDL-c levels, were shown in populations to increase cardiovascular risk.⁹ Subsequent to these findings, the reduction of cholesterol via the mechanism of reducing the PCSK9 protein became an attractive therapeutic target.¹⁰ Scientists created fully human monoclonal antibodies in the past few years that prevented the PCSK9 protein from binding to the LDL receptor.¹¹ In 2015, the U.S. Food and Drug Administration (FDA) approved two monoclonal antibody PCSK9 inhibitors, alirocumab and evolocumab, on the basis of clinical trial evidence supporting their efficacy in LDL-c lowering and safety data. On average, these agents lower LDL-c from 50% to 60% when taken alone or in combination with a statin.¹²

The results of the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial were presented in March 2017. The study included >27,000 patients with known atherosclerotic death, myocardial infarction, stroke, hospitalization for unstable angina or coronary revascularization.13 Median baseline LDL-c dropped to 30 mg/dl in the active-treatment arm. This attained level of LDL-c is much lower than previous trials have been able to achieve.

All of the clinical data in totality would support that lowering of LDL-c levels improves morbidity and mortality in high risk patients and in those that already have established cardiovascular disease. We now have a variety of therapeutic choices – many with different mechanisms of action – to help patients achieve previously unattainable levels of low LDL-c.

Disclosure statement: Dr. Uusinarkaus has spoken for Merck, Regeneron, Sanofi, Amgen, Amarin and Kowa. He also has participated in advisory boards for Janssen and Novo Nordisk.