Managing hyperlipidemia is a mainstay of cardiovascular risk reduction. The 2013 ACC/AHA guidelines no longer target specific low-density lipoprotein (LDL)-cholesterol levels, but recommend lipid-lowering therapies of varying intensity based on the predicted risk of cardiovascular events . Adoption of the new guidelines would result in millions more Americans receiving high-potency statins; it is therefore important to investigate potential dangers associated with aggressive therapy and the long-term implications for patients.
Many studies have shown that strict adherence to lipid-lowering medications improves outcomes for patients who are at risk for or have had cardiovascular events [2-5]. The Adult Treatment Panel III guidelines (2002), still used by many physicians, recommended intensive therapy for those in the “very high risk” category: those with known coronary artery disease plus diabetes, tobacco use, or the metabolic syndrome. The current guidelines now recommend high-dose statins (atorvastatin 40-80 or rosuvastatin 20-40 mg daily) for those with clinical evidence of atherosclerotic cardiovascular disease (ASCVD), LDL >190 mg/dL, or a 10-year ASCVD risk of greater than 7.5%. The recommendations make 12.8 million new patients, many in perfect health, candidates for statin therapy .
Eliminating treat-to-target therapy lessens the role for combination therapy with other cholesterol-lowering medications (colesevelam, ezetimibe, fenofibrate, niacin) to reach a certain goal. Despite previous guidelines suggesting addition of these medications, evidence has shown that using them to further decrease non-HDL cholesterol does not further reduce the risk of ASCVD [7,8]. Furthermore, many studies have shown that there is an increased risk of adverse effects when statins are combined with other drugs, particularly with gemfibrozil [9,10].
The incidence of adverse side effects with intensive lipid-lowering therapy is low. The most common side effect associated with statins is myalgia, and this effect does not appear to be dose-dependent. A 2006 retrospective analysis of over 14,000 patients found no difference in the incidence of myalgia between patients taking atorvastatin 80 mg daily (intensive dose) compared to 10 mg (low dose); furthermore, no cases of rhabdomyolysis were reported .
Another side effect associated with statins is hepatic dysfunction. A 2007 review showed a dose-dependent increased risk of elevated liver enzymes with increasing statin doses . The elevation is usually benign and returns to baseline with a change in therapy; the risk of progression to liver failure is extremely low .
More recently, statin therapy has been associated with a slight (9%) dose-dependent increased incidence of diabetes mellitus in patients with pre-existing risk factors [14,15].
Options for patients who experience adverse side effects include either brief cessation of treatment, decreasing dosing frequency, or switching to a different statin. Recent n-of-1 trials identified cases of statin-related myalgia and elevated liver enzymes and found that, following a 3-week washout interval, the symptoms were not significantly different between those restarted on the same statin and those on placebo . Hydrophilic statins with a better side effect profile, such as rosuvastatin, may be attempted in patients not tolerating other therapy [17,18].
There are concerns that if a physician does not target high-dose statin therapy to a goal LDL, the value may become dangerously low. There have been several case studies suggesting a link between low cholesterol levels and violent or suicidal behavior; however, no causative mechanism has been implicated [19-22]. There have also been trials showing an increased risk of hemorrhagic stroke with lower levels of LDL [23-25]. The SPARCL trial found no association between LDL level and hemorrhagic stroke risk in patients with recent stroke and no known coronary heart disease, but instead found an increased incidence of hemorrhagic stroke in patients receiving 80 mg of atorvastatin .
With the new guidelines, an aggressively treated high-risk patient could potentially attain LDL levels below 40 mg/dL. To evaluate potential risks, one study compared patients following an acute coronary event treated to an LDL goal of 80-100 mg/dL to those treated to a more aggressive goal as low as <40 mg/dL. The authors found no adverse effects with lower levels, but found fewer major cardiac events in those with LDL levels below 60 mg/dL compared to higher target levels of LDL . A more recent study of over 6000 patients with LDL levels below 60 mg/dL on statin therapy found no increased risk of malignancy, hepatic dysfunction, or rhabdomyolysis, as well as a 35% reduction in mortality compared to patients not started on statin therapy .
Due to the low risk of adverse outcomes, the guidelines recommend starting statin therapy on otherwise healthy adult patients with 10-year ASCVD risk of >7.5% to lower the risk of eventual ASCVD. The JUPITER trial showed that healthy adults with LDL levels <130 mg/dL and high-sensitivity C-reactive protein (CRP) levels >2 mg/l treated with rosuvastatin to achieve LDL levels <50 mg/dL had a lower risk of ASCVD without an increase in reported adverse events when compared to adults with LDL target levels below 130 mg/dL . AFCAPS/TexCAPS, a 1998 primary prevention trial of over 6000 patients, reported that adults with an average LDL level (221 mg/dL) started on lovastatin therapy had a significantly reduced incidence of a first major acute coronary event with no difference in side effects from those not started on statin therapy . The beneficial effect of early treatment has not yet been conclusively demonstrated. More research needs to be done to make physicians feel more comfortable with early treatment.
While there are other lipid parameters available to monitor the progression of atherosclerosis (see Dr. Weintraub’s commentary below), LDL levels should still be closely monitored to evaluate efficacy of therapy and encourage patient participation. A very low LDL concentration, and the means of achieving it, has shown to be safe and effective. Future research should focus on long-term outcomes of aggressive therapy in low-risk populations to examine potential extrapolation to an even broader population. Many practitioners have joked that statins should be added to the water supply, like fluoride for teeth. Are they truly that far off?
Commentary by Dr. Howard Weintraub
There has been a clear evolution in the strategies for lipid lowering and the tools we have to achieve the desired levels of LDL. Dr. Scott Grundy published his views on the topic in a widely cited work in 2004. As noted in this review there have been several papers that have identified lower LDL levels being associated with a reduction in cardiovascular events. Older studies were able to compare active lipid lowering versus placebo. Contemporary studies compared different statins and end- treatment LDL in the setting of gradually improving background care (such as ACE inhibitors, angiotensin receptor blockers, antiplatelet agents, beta-blockers, etc.). Supporters of a more aggressive strategy have been not been disappointed with the results. We have also been able to appreciate the importance of addressing the contribution of additional risk factors for atherosclerosis such as hypertension, obesity, smoking, age, inactivity, metabolic syndrome, and diabetes .
What has emerged from the trials is support for related lipid endpoints (such as apolipoprotein B and the number of LDL particles)  and inflammatory markers (such as high-sensitivity C-reactive protein)  and noninvasive plaque imaging. In many cases these can augment the risk that has been documented in patients with metabolic syndrome and diabetes. The studies have identified a large number of patients who may have been inaccurately felt to be at low risk and are subsequently identified to potentially profit from lower LDL levels. In addition, the perception that HDL is a routinely beneficial biomarker and one that should be targeted with specific therapy has been challenged by several large trials. This is due to our understanding that HDL functions as a “garbage truck” that facilitates the transfer of LDL from cholesterol-laden macrophages that are resident in plaque, to the liver where disposal occurs. However, these studies have questioned the wisdom of adding fibrates or niacin to statin therapy [8, 34]. An explanation for this dilemma has been offered in a recent publication in JACC showing that while niacin raised HDL-C it did not improve reverse cholesterol transport .
Hence, as stated in this very good review, we are left with the promise of improved outcomes when levels of atherogenic lipoproteins are aggressively lowered. But it would appear there are a wide variety of patients (other than those post-MI) who may derive great benefit from lowering LDL to very low levels, in addition to attention to the other contributors to “residual risk.”
Molly Anderson is a 4th year medical student at NYU School of Medince
Peer reviewed by Howard Weintraub, MD, Cardio Medicine, NYU Langone Medical Center
Image courtesy of Wikimedia Commons
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