This article is more than 5 years old. Information may no longer be current.
2 decades of pharmacological prevention
Click Here to Manage Email Alerts
Editor’s Note: Cardiology Today is celebrating its 20th anniversary in 2017. We are reaching out to experts in cardiology for their take on changes in CV medicine since the publication launched in 1997. For this article, Michael H. Davidson, MD, professor and director of the Lipid Clinic at University of Chicago Medicine, and a member of the Cardiology Today Editorial Board, focuses on advances in pharmacological prevention of heart disease.
In 1950, Konrad Bloch, a refugee from Nazi Germany, elucidated the cholesterol synthetic pathway. Thirty-seven years later, lovastatin, the first inhibitor of HMG-CoA reductase — the principal rate-limiting enzyme for cholesterol synthesis — was approved by the FDA for clinical use. This class of drugs, statins, has revolutionized the pharmacological prevention of CVD.
Lovastatin (Mevacor, Merck) was followed by the regulatory approval of several other statins and ushered in the “statin era.” The most important breakthrough came 7 years later in 1994, with the presentation of the Scandinavian Simvastatin Survival Study (4S) Trial, which demonstrated that simvastatin (Zocor, Merck) decreased MI, CV death and total mortality.
For the past 20 years, multiple trials have confirmed that statins reduce major adverse CV events across the spectrum of high-risk patients and higher-dose statins are more effective than lower-dose statins. In fact, the statins were so universally successful in reducing major adverse CV events in trials that in the view of many experts, the “LDL hypothesis,” which attributes the clinical benefit to LDL reduction, was transformed into the “statin hypothesis,” culminating in the 2013 American College of Cardiology/American Heart Association Guidelines that recommended a maximally tolerated dose of statins for four high-risk populations (atherosclerotic CVD, diabetes, LDL > 190 mg/dL and 10-year risk > 7.5%) and no longer advocated an LDL therapeutic goal.
For more than a decade following the PROVE-IT-TIMI 22, TNT and IDEAL trials, the “lower the better” LDL was the mantra for reducing CV risk, but more recent trials called into question the clinical value of nonstatin therapies for lowering LDL. The first kink in the armor for the LDL hypothesis was the ENHANCE trial, which failed to show that ezetimibe (Zetia, Merck), a cholesterol absorption inhibitor, added to a statin reduced atherosclerotic progression as determined by an ultrasound measurement of carotid intimal media thickness.
Although a controversial trial, this study challenged the prevailing view that all therapeutic approaches that lower LDL should improve CV outcomes. Other large CV outcomes trials with nonstatins, such as ACCORD with fenofibrate and AIM-HIGH and HPS2-THRIVE with niacin, failed to demonstrate a reduction in residual risk in combination with statin therapy. These series of combination trials that failed to show an added benefit to statin monotherapy led directly to the evidence-based recommendations of 2013 AHA/ACC cholesterol guidelines that nullified the previous guidelines that promoted LDL goal achievement.
However, the tide has now turned back to resurrecting the LDL hypothesis based on very recent evidence. Genomic studies have ascertained that multiple polymorphisms that alter LDL levels are associated with greater than expected reductions (or increases if the mutation causes higher LDL levels) in CV events, linking LDL as a causal factor for CHD. In addition, IMPROVE-IT in 2015 and FOURIER in 2017 proved that lowering LDL with two nonstatins, ezetimibe and the anti-PCSK9 monoclonal antibody evolocumab (Repatha, Amgen), respectively, results in a decrease in major adverse CV events with the benefits comparable to statins when the magnitude and length of LDL lowering are adjusted (ie, on the same line for absolute reduction in events for absolute decrease in LDL as seen in the Cholesterol Treatment Trials, which determined this linear relationship in a combined analysis of all the major statins’ CV outcome trials).
In light of this new evidence that has validated the LDL hypothesis, the debate has now shifted to cost-effectiveness and how best to maximize patient outcomes with existing therapies. The past 20 years have been instrumental in setting the stage for an upcoming era in which CVD will be eliminated with the implementation of lifestyle and pharmacological therapies if initiated early and appropriately to reduce high levels of atherogenic lipoproteins that are the root cause of the leading cause of death in the United States.
References:
ACCORD Study Group. N Engl J Med. 2010;doi:10.1056/NEJMoa1001282.
AIM-HIGH Investigators. N Engl J Med. 2011;doi:10.1056/NEJMoa1107579.
Cannon CP, et al. N Engl J Med. 2004;doi:10.1056/NEJMoa040583.
Cannon CP, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1410849.
Goff DC, et al. Circulation. 2013;doi:10.1161/01.cir.0000437741.48606.98.
Goff DC, et al. J Am Coll Cardiol. 2013;doi:10.1016/j.jacc.2013.11.005.
HPS2-THRIVE Collaborative Group. N Engl J Med. 2014;doi:10.1056/NEJMoa1300955.
Kastelein JP, et al. N Engl J Med. 2008;doi:10.1056/NJEMoa0800742.
LaRosa JC, et al. N Engl J Med. 2005;doi:10.1056/NEJMoa050461.
Pedersen TR, et al. JAMA. 2005;doi:10.1001/jama.294.19.2437.
Sabatine MS, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1615664.
Scandinavian Simvastatin Study Group. Lancet. 1994;doi:10.1016/S0140-6736(94)90566-5.
Stone NJ, et al. Circulation. 2013;doi:10.1161/01.cir.0000437738.63853.7a.
Stone NJ, et al. J Am Coll Cardiol. 2013;doi:10.1016/j.jacc.2013.11.002.
Disclosure: Davidson reports consulting for Amgen, Merck, Regeneron and Sanofi.