Peter P. Toth, M.D., Ph.D., et al. Nucleic Acid Delivery for Endothelial Dysfunction in Cardiovascular Diseases. Methodist DeBakey Cardiovascular Journal. 2019;15(1):1-92.
The discovery of statins (3-hydroxy-3-methylglutaryl CoA reductase inhibitors) is a consequence of the highly targeted, arduous search for naturally occurring compounds that inhibit cholesterol biosynthesis. An enormous amount of basic scientific, genetic, and clinical research substantiated the role of lipoprotein-derived cholesterol in atherogenesis. Quantifying the impact of lipid lowering on cardiovascular event rates became an issue of utmost urgency. Although a variety of nonstatin drugs had been tested in clinical trials, they found limited utility in the clinical setting due to lack of mortality reduction or tolerability issues. As multiple prospective randomized statin trials began publishing their results, it became clear that reducing atherogenic lipoprotein burden with these drugs was highly efficacious, safe, and generally well tolerated. Statins have been shown to reduce risk for nonfatal MI, ischemic stroke, need for revascularization, and cardiovascular and all-cause mortality. They have also been shown to stabilize and even regress established atherosclerotic plaque. For the first 2 decades of their use, statin dosing was largely determined by risk-stratified low-density lipoprotein cholesterol (LDL-C) goals. More recently, there has been a transition away from LDL-C goal attainment with a focus more on cardiovascular risk and percent LDL-C reduction. Unfortunately, long-term adherence rates with statin therapy remain low and, even when used, they tend to be underdosed.Keywords
3-hydroxy-3-methylglutaryl-coenzyme A reductase, atherosclerosis, cardiovascular events, low-density lipoprotein cholesterol, lovastatin, mevastatin
Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of morbidity and mortality in developed nations, and its incidence continues to rise. Atherogenesis generally begins at an early age and is reversible if intercepted while plaque is not yet fibrotic or calcified. It is now highly established that apoprotein B100-containing lipoproteins, particularly low-density lipoprotein cholesterol (LDL-C), are a primary driver of atherogenesis.1 The use of lipid-lowering medications to reduce atherogenic lipoprotein burden in serum slows the rate of atherosclerosis disease progression and can even reverse disease if treated aggressively.2 This manuscript provides a historical perspective on statin development, summarizes major prospective randomized trials that established their efficacy, and reviews some extant issues regarding their use that need further investigation.
SOME HISTORICAL PERSPECTIVE
Investigations performed by Anitschkow in 1913 demonstrated a direct causal relationship between cholesterol and the development of aortic atherosclerotic plaques.3 In the early 1960s, the Seven Countries Study and Framingham Study both showed a strong association between serum cholesterol levels and risk for myocardial infarction (MI) and death.4,5 Using preparative ultracentrifugation, Gofman and coworkers demonstrated that elevated levels of low-density lipoprotein cholesterol (LDL-C) were frequently observed in patients who sustained acute cardiovascular (CV) events.6 Working in Beirut, Lebanon, Khachaturian identified a dose-response relationship between elevations in LDL-C and risk for MI in patients afflicted with the heterozygous and homozygous forms of familial hypercholesterolemia (FH).7 Goldstein and Brown subsequently elucidated the molecular basis of FH, which they attributed to either reduced hepatocyte cell surface expression of the LDL receptor (LDL-R) or near-complete lack of expression of this receptor in the settings of heterozygous and homozygous FH, respectively.8,9 Considerable additional clinical and basic scientific investigation supported the conclusion that LDL-C is an important causal agent in atherogenesis.
It was correctly reasoned that if LDL-C plays a critical role in the etiology of atherosclerotic disease, then therapeutic effort should be made to reduce its levels in serum and thus decrease the risk of developing ASCVD. In the World Health Organization Primary Prevention Trial, the fibric acid derivative clofibrate lowered serum total cholesterol (TC) by 9%. Clofibrate treatment significantly reduced the risk for nonfatal MI by 25%, had no effect on fatal MI, but increased all-cause mortality.10 The Coronary Drug Project, which evaluated the long-term safety and efficacy of five lipid-influencing drugs, demonstrated an increased risk of adverse events with estrogen and thyroid hormone supplementation, a reduced risk of nonfatal MI with nicotinic acid, and no benefit from clofibrate.11 However, it took 15 years of follow-up to demonstrate a mortality benefit with nicotinic acid, and the resultant dermal flushing made it difficult to tolerate.12 In the Lipid Research Clinics Coronary Primary Prevention trial (LRCPPT) that evaluated the efficacy of cholestyramine therapy, a bile acid-binding resin, cholestyramine reduced TC and LDL-C by 13.4% and 20.3%, respectively.13 After 7.4 years of follow-up, CV mortality and nonfatal MI were significantly reduced by 24% and 19%, respectively; however, all-cause mortality did not differ between the treatment arms. The latter finding coupled with tolerability issues of cholestyramine made for limited adoption of this therapy. However, LRCPPT demonstrated proof of concept; namely, that therapeutic reduction of TC and LDL-C impacts the risk for CV events.
Given the prevalence of dyslipidemia, there was clear urgency in developing new compounds that could substantially reduce the burden of atherogenic lipoprotein in a safe, tolerable, and substantial manner.
DEVELOPMENT OF THE STATINS
Cholesterol is synthesized from acetyl coenzyme A (acetyl CoA) in a 30-step pathway. The rate-limiting step for cholesterol biosynthesis is regulated by 3-hydroxy-3-methylglutaryl CoA reductase (HMG-CoA reductase), which catalyzes the reduction of HMG to mevalonate. Akira Endo hypothesized that some organisms likely produce naturally occurring HMG-CoA reductase inhibitors as a defense mechanism against infection from microbes that require cholesterol or other steroids for their survival.14 It stood to reason that such molecules might function as a highly effective means of lowering serum cholesterol because they would inhibit its production. The search for a natural HMG-CoA reductase inhibitor required the screening of more than 6,000 microbial species.15 Mevastatin was isolated from the blue-green mold Penicillium citrinum; it had significant structural similarity to HMG-CoA and was a competitive inhibitor of HMG-CoA reductase, with an association constant 10,000-fold higher than HMG-CoA.16
In cell culture and in some animal species (i.e., dogs17 and monkeys18), mevastatin proved to be a highly effective inhibitor of cholesterol biosynthesis and reduced serum cholesterol. The stage was set to test the efficacy of mevastatin in a small group of humans. The first patient to receive mevastatin was afflicted with homozygous FH and had a baseline LDL-C of 1,000 mg/dL.19 Mevastatin reduced her LDL-C by 300 mg/dL, and within 5 months there was evidence that her tendinous xanthomas were regressing. Subsequently, patients with heterozygous FH were treated with mevastatin, and once again LDL-C decreased by approximately 30%.19 At about this time, investigators at Merck isolated lovastatin from Aspergillus terreus and it, too, induced significant reductions in TC and LDL-C.20 Brown and Goldstein later showed that, in addition to inhibiting HMG-CoA reductase, lovastatin also upregulated LDL-R along the hepatocyte surface via activation of sterol regulatory element binding proteins that increased nuclear expression of LDL-R as intracellular cholesterol levels decreased.9 Hence, statin therapy also promoted increased clearance of LDL particles as part of their mechanism of action.
Progress was rapid. Multiple other statins were developed, including simvastatin, pravastatin, atorvastatin, fluvastatin, cerivastatin, and pitavastatin. Of these, only cerivastatin was found to have an unacceptable adverse event profile and was removed from global markets due to excess risk of rhabdomyolysis, particularly when combined with gemfibrozil.21
STATIN OUTCOMES TRIALS
The Scandinavian Simvastatin Survival Study (4S) was the first prospective randomized outcomes trial with a statin, and the results were remarkable.22 All patients enrolled in 4S had established coronary artery disease (CAD). After 5.4 yrs of follow-up and a 25% decrease in TC and 35% decrease in LDL-C, the following outcomes were significantly reduced: all-cause mortality (30%), risk of a major coronary event (34%), CV mortality (35%), stroke (30%), and coronary interventions (37%). Secondary prevention studies with pravastatin were also positive.23,24 Primary prevention trials with pravastatin and lovastatin showed a substantial reduction in risk for first-time CV events.25-27 Atorvastatin therapy was associated with significant reductions in risk for CV events in patients with diabetes mellitus or hypertension.28,29 The Heart Protection Study demonstrated benefit irrespective of baseline LDL-C.30 The Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE-IT) and Treating to New Targets (TNT) studies both suggested that when it comes to LDL-C levels, lower is better.31,32 Among patients with elevated C-reactive protein and an LDL-C < 130 mg/dL, the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) study found that rosuvastatin significantly reduced both CV and all-cause mortality as well as a wide variety of CV end points.33
In response to the findings of these and other studies (summarized in Table 1), the National Cholesterol Education Program Adult Treatment Panels recommended risk-stratified LDL-C goals for patients in both the primary and secondary prevention settings.34,35 Thus, it was recommended that LDL-C be reduced more aggressively as risk for CV events increased, and that the highest-risk patients achieve LDL-C < 70 mg/dL.36 This approach was replaced in 2014 by a new guideline that emphasizes statin dose/intensity and percent LDL-C reduction as a function of risk for CV events.37 Guidelines from around the world continue to emphasize LDL-C reduction to modulate risk for future CV events, and statin therapy continues to be the standard of care for dyslipidemia management. Guidelines agree that all patients with established ASCVD should be on a statin irrespective of baseline TC or LDL-C.
EXTANT ISSUES WITH STATIN THERAPY
Long-term adherence to statin therapy is poor, even among patients in the secondary prevention setting. Statin discontinuation after 6 months is still in the 50% range,38,39 a shocking statistic given their risk-to-benefit ratio and the range of CV events they reduce. Unsurprisingly, statin discontinuation is associated with an increase in risk for CV events.40,41 Negative press associated with statin therapy correlates with risk for statin discontinuation and CV events. It is crucial that patients understand why they are prescribed statins and the implications of premature discontinuation.
Muscle-Related Side Effects
Myalgia is the leading reason for statin discontinuation, and patients frequently stop therapy without informing their physicians.42 Statin-related muscle pain is attributable to a highly heterogeneous group of etiologies,43 and progress in this area has been slow. Patients frequently mistake arthralgias for myalgias. Certainly, the incidence of muscle-related adverse events is higher in clinical practice than what has been observed in clinical trials, largely because patients with a history of myalgia were excluded from participating.44 We need more objective serum skeletal muscle markers that can help to discriminate true statin intolerance from more nonspecific causes of myalgia.
Serum Transaminase Elevations
It was thought until recently that statins had some degree of hepatic toxicity. The risk of liver failure on a statin is essentially identical to the background rate in the population not treated with statins. There are certainly patients who experience an idiosyncratic rise in serum transaminase levels in response to statins, but this is mainly due to a drug interaction or underlying hepatic steatosis, which can be associated with oscillations in serum transaminase levels secondary to changes in intrahepatic inflammatory tone. The U.S. Food and Drug Administration no longer recommends routine measurement of serum transaminases because of low diagnostic yield.45
Reluctance to Titrate Statins
Despite the fact that new guidelines emphasize statin dose and potency, there continues to be reluctance to titrate statins out of safety concerns.46 Side-effect profiles are slightly impacted as statin dosages are increased. However, the benefits far outweigh the risks. There also continues to be lingering fear that we are driving LDL-C levels “too low.” LDL particles are an end product of lipoprotein metabolism and, to a large degree, represent spent, garbage lipid. There is really not much one does with LDL particles. However, they are clearly toxic to arterial walls. Genome-wide association studies and Mendelian inheritance studies uniformly agree that any genetic polymorphism that confers a lower LDL-C is atheroprotective, and the opposite is also true: Any polymorphism that increases LDL-C also increases risk for ASCVD.47 Based on recent randomized studies, not only is it true that “lower is better” but “lowest is best.” In both the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT)48 and Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trials,49 the subgroups with the lowest attained LDL-C had the lowest event rates, with no increased risk for adverse events.
There are bloggers and talk show guests insisting that statins cause cognitive impairment. To date, no such relationship has been identified.50,51 Neither the Heart Protection Study52 nor the Pravastatin in Elderly Individuals at Risk of Vascular Disease (PROSPER) trial,53 which used validated cognitive batteries in older patients, were able to detect a statin-induced reduction in cognitive capacity. More recently, the Evaluating PCSK9 Binding Antibody Influence on Cognitive Health in High Cardiovascular Risk Subjects (EBBINGHAUS) study failed to demonstrate any adverse effect on cognition when combining evolocumab and statin therapy, even at very low levels of attained LDL-C.54
Statins and Diabetes Mellitus
The JUPITER trial investigators reported an increase in risk for diabetes mellitus (DM) with rosuvastatin therapy. However, rosuvastatin accelerated time to new-onset DM compared to placebo by an average of only 5.4 weeks.55 A subsequent meta-analysis suggested that 1,000 patients have to be treated annually with low-dose statin therapy to induce one new case of DM; with moderate- to high-dose statin therapy, one person will develop DM for every 500 treated per year.56 Hence, the risk is relatively low. Moreover, it has been shown that the patients who develop DM on statin therapy are already prediabetic: The greater their number of risk factors for metabolic syndrome, the higher their risk for DM.57 This must be actively contextualized for patients. Moreover, it should also be made clear that diabetic patients derive as much benefit from statin therapy as do nondiabetics.
Atherosclerosis is an inflammatory disease. High-sensitivity C-reactive protein (hs-CRP) levels in serum correlate with risk for cardiovascular events. The Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) demonstrated that the antagonism of interleukin-1B with a monoclonal antibody reduced both hs-CRP and risk for CV events independent of changes in lipoprotein cholesterol levels.58 Post hoc analyses of multiple statin trials have shown that the dual targets of LDL-C < 70 mg/dL and CRP < 1.0 provide the highest levels of risk reduction.59,60 It is time to assess whether or not hs-CRP should be a target of statin therapy.
- Statins represent a vital therapy for patients with dyslipidemia and for attenuating cardiovascular (CV) risk in both primary and secondary prevention.
- The discovery of statins was not happenstance; it was the product of targeted investigation to find naturally occurring compounds that inhibit the rate-limiting step of cholesterol biosynthesis.
- Dyslipidemia and atherosclerotic cardiovascular disease are widely prevalent throughout the world. Despite the fact that statins reduce CV events and mortality, these agents are underutilized and frequently underdosed.
- Statins have been shown to be safe and efficacious over 4 decades of intensive investigation. The role of low-density lipoprotein cholesterol (LDL-C) in atherogenesis is among the most intensively studied issues in all of medicine.
- Patients need to be actively educated about the risks of statin therapy, but these risks should be very carefully contextualized. For instance, risk of new-onset diabetes is low, and we no longer believe there is a threshold of LDL-C below which risk for adverse events increases.
- Statin discontinuation rates remain unacceptably high. This is an urgent issue that must be addressed at both an individual patient and societal level.
Dr. Toth conducts research on behalf of Amarin, Amgen, and Kowa and is a consultant for Amarin, Amgen, Kowa, Merck, Novo-Nordisk, Theravance, Regeneron, and Sanofi. Dr. Banach is a consultant for Abbott/Mylan, Abbott Vascular, Actavis, Akcea, Amgen, Biofarm, Daiichi Sankyo, Esperion, Krka Pharma, Eli Lilly, MSD, Resverlogix, Sanofi-Aventis, and Valeant and conducts research on behalf of Sanofi and Valeant.
Cholesterol: Can’t Live With It, Can’t Live Without It
Pownall HJ, Gotto AM Jr. Cholesterol: Can’t Live With It, Can’t Live Without It. Methodist DeBakey Cardiovasc J. 2019;15(1):9-15.
How Much Do Lipid Guidelines Help the Clinician? Reading Between the (Guide)lines
Orringer C. How Much Do Lipid Guidelines Help the Clinician? Reading Between the (Guide)lines. Methodist DeBakey Cardiovasc J. 2019;15(1):16-22.