By Molly Anderson
Peer Reviewed
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 [1]. 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 [6].
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 [11].
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 [12]. The elevation is usually benign and returns to baseline with a change in therapy; the risk of progression to liver failure is extremely low [13].
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 [16]. 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 [26].
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 [27]. 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 [28].
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 [29]. 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 [30]. 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 [31].
What has emerged from the trials is support for related lipid endpoints (such as apolipoprotein B and the number of LDL particles) [32] and inflammatory markers (such as high-sensitivity C-reactive protein) [33] 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 [35].
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
References
1. Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013 Nov 7. pii: S0735-1097(13)06028-2. doi: 10.1016/j.jacc.2013.11.002. [Epub ahead of print] http://content.onlinejacc.org/article.aspx?articleid=1770217
2. LaRosa JC, Grundy SM, Waters DD, et al; Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352(14):1425-1435. http://www.nejm.org/doi/full/10.1056/NEJMoa050461
3. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes; Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators. N Engl J Med. 2004;350(15):1495-1504.
4. Mills EJ, O’Regan C, Eyawo O, et al. Intensive statin therapy compared with moderate dosing for prevention of cardiovascular events: a meta-analysis of >40 000 patients. Eur Heart J. 2011;32(11):1409-1415.
5. Cholesterol Treatment Trialists’ (CTT) Collaborators, Mihaylova B, Emberson J, Blackwell J, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012;380(9841):581-590.
6. Pencina MJ, Navar-Boggan AM, D’Agostino RB Sr, et al. Application of new cholesterol guidelines to a population-based sample. N Engl J Med. 2014;370:1422-1431.http://www.ncbi.nlm.nih.gov/m/pubmed/24645848/
7. Guyton JR, Slee AE, Anderson T, et al. Relationship of lipoproteins to cardiovascular events: the AIM-HIGH Trial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes). J Am Coll Cardiol. 2013;62(17):1580-1584. http://www.ncbi.nlm.nih.gov/pubmed/23916935
8. The AIM HIGH Investigators, Boden WE, Probstfield JL, Anderson T, et al. Niacin in patients with low HDL cholesterol receiving intensive statin therapy. N Engl J Med. 2011;365(24):2255-2267.
9. Chatzizisis YS, Koskinas KC, Misirli G, Vaklavas C, Hatzitolios A, Giannoglou GD. Risk factors and drug interactions predisposing to statin-induced myopathy: implications for risk assessment, prevention and treatment. Drug Saf. 2010;33(3):171-187.
10. Bottorff MB. Statin safety and drug interactions: clinical implications. Am J Cardiol. 2006;97(8A):27C-31C.
11. Newman C, Tsai J, Szarek M, Luo D, Gibson E. Comparative safety of atorvastatin 80 mg versus 10 mg derived from analysis of 49 completed trials in 14,236 patients. Am J Cardiol. 2006;97(1):61-67. http://www.ncbi.nlm.nih.gov/pubmed/16377285
12. Alsheikh-Ali AA, Maddukuri PV, Han H, Karas RH. Effect of the magnitude of lipid lowering on risk of elevated liver enzymes, rhabdomyolysis, and cancer: insights from large randomized statin trials. J Am Coll Cardiol. 2007;50(5):409-418.
13. Younoszai Z, Li Z, Stepanova M, Erario M, Cable R, Younossi ZM. Statin use is not associated with liver related mortality. Ann Hepatol. 2013;13(1):84-90. http://www.ncbi.nlm.nih.gov/pubmed/?term=Younoszai+Z%2C+Li+Z%2C+Stepanova+M%2C+Erario+M%2C+Cable+R%2C+Younossi+ZM.+Statin+use+is+not+associated+with+liver+related+mortality
14. Ridker PM, Pradhan A, MacFadyen JG, Libby P, Glynn RJ. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet. 2012;380(9841):565-571.
15. Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010;375(9716):735-742. http://www.ncbi.nlm.nih.gov/pubmed/20167359
16. Joy TR, Monjed A, Zou GY, Hegele RA, McDonald CG, Mahon JL. N-of-1 (single-patient) trials for statin-related myalgia. Ann Intern Med. 2014;160(5):301-310.
17. Hansen KE, Hildebrand JP, Ferguson EE, Stein JH. Outcomes in 45 patients with statin-associated myopathy. Arch Intern Med. 2005;165(22):2671-2676.
18. Glueck CJ, Aregawi D, Agloria M, et al. Rosuvastatin 5 and 10 mg/d: a pilot study of the effects in hypercholesterolemic adults unable to tolerate other statins and reach LDL cholesterol goals with nonstatin lipid-lowering therapies. Clin Ther. 2006;28(6):933-942.
19. Asellus P, Nordstrom P, Jokinen J. Cholesterol and CSF 5-HIAA in attempted suicide. J Affect Disord. 2010;125(1-3):388-392.
20. Golomb BA. Cholesterol and violence: is there a connection? Ann Intern Med. 1998;128(6):478-487.
21. Vartiainen E, Puska P, Pekkanen J, Tuomilehto J, Lonnqvist J, Ehnholm C. Serum cholesterol concentration and mortality from accidents, suicide, and other violent causes. BMJ. 1994;309(6952):445-447.
22. Golomb BA, Kane T, Dimsdale JE. Severe irritability associated with statin cholesterol-lowering drugs. QJM. 2004;97(4):229-235. http://www.ncbi.nlm.nih.gov/pubmed/15028853
23. Ebrahim S, Sung J, Song YM, Ferrer RL, Lawlor DA, Davey Smith G. Serum cholesterol, haemorrhagic stroke, ischaemic stroke, and myocardial infarction: Korean national health system prospective cohort study. BMJ. 2006;333(7557):22.
24. Iso H, Jacobs DR Jr., Wentworth D, Neaton JD, Cohen JD. Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the multiple risk factor intervention trial. N Engl J Med. 1989;320(14):904-910.
25. Yano K, Reed DM, MacLean CJ. Serum cholesterol and hemorrhagic stroke in the Honolulu Heart Program. Stroke. 1989;20(11):1460-1465.
26. Amarenco P, Bogousslavsky J, Callahan A 3rd, et al; Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355(6):549–559.
27. Wiviott SD, Cannon CP, Morrow DA, Ray KK, Pfeffer MA, Braunwald E, PROVE IT-TIMI 22 Investigators. Can low-density lipoprotein be too low? The safety and efficacy of achieving very low low-density lipoprotein with intensive statin therapy: a PROVE IT-TIMI 22 substudy. J Am Coll Cardiol. 2005;46(8):1411-1416.
28. Leeper NJ, Ardehali R, DeGoma EM, Heidenreich PA. Statin use in patients with extremely low low-density lipoprotein levels is associated with improved survival. Circulation. 2007;116(6):613-618. http://www.ncbi.nlm.nih.gov/pubmed/17664373
29. Hsia J, MacFadyen JG, Monyak J, Ridker PM. Cardiovascular event reduction and adverse events among subjects attaining low-density lipoprotein cholesterol <50 mg/dl with rosuvastatin: The JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin). J Am Coll Cardiol. 2011;57(16):1666-1675.
30. Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998;279(20):1615-1622. http://www.ncbi.nlm.nih.gov/pubmed/9613910
31. Mora S, Wenger NK, Demicco DA, et al. Determinants of residual risk in secondary prevention patients treated with high- versus low-dose statin therapy: the Treating to New Targets (TNT) study. Circulation. 2012;125(16):1979-1987.
32. El Harchaoui KE, van der Steeg WA, Stroes ES, et al. Value of low-density lipoprotein particle number and size as predictors of coronary artery disease in apparently healthy men and women: . The EPIC-Norfolk Prospective Population Study. J Am Coll Cardiol. 2007;49(5):547-553.
33. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein: the JUPITER Trial. N Engl J Med. 2008:359(21):2195-2207.
34. The ACCORD Study Group, Ginsberg HN, Elam MB, Lovato LC, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362(17):1563-1574.
35. Khera AV, Patel PJ, Reilly MP, Rader DJ. The addition of niacin to statin therapy improves high-density lipoprotein cholesterol levels but not metrics of functionality. J Am Coll Cardiol. 2013;62(20):1909-1910.