Since the release of the Adult Treatment Panel III (ATP III) cholesterol guidelines in 2002,¹ the medical community has been eagerly waiting for a new document that summarizes all the dense basic science and clinical research data in the field of lipids over the past decade. We were anticipating recommendations on how to improve residual risk assessment using more inclusive measures of atherogenic cholesterol such as non- high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein B (apoB), high sensitivity C-reactive protein (hsCRP) and Coronary Artery Calcium. We were also waiting for a new well-validated method of estimating cardiovascular risk and a better understanding of when to add non-statin lipid lowering medications. However, the new guideline ² has proposed a major shift in treating cholesterol and has become one of the more controversial guidelines ever released. So, were the new guidelines worth the wait?

Why it Was Worth the Wait

Following the recommendations of the Institute of Medicine,³ the task force synthesized its recommendations on statin therapy exclusively from well-designed randomized controlled trials (RCTs) and meta-analyses; an idealistic novel approach making the guidelines one of the strongest evidence-based documents ever released. They acknowledged the absence of clinical trial data that support treatment to specific low-density lipoprotein cholesterol (LDL-C) and non-HDL-C goals and instead identified four major populations that benefit from statins as follows:

1. Patients with clinical atherosclerotic cardiovascular disease (ASCVD)
2. Patients with LDL-C ≥ 190 mg/dL
3. Patients with diabetes mellitus, age 40-75, with LDL-C 70-189 mg/dL
4. Patients without diabetes mellitus, age 40-75 with LDL-C 70-189 mg/dL and a 10-year ASCVD risk ≥ 7.5% per the new risk calculator

Another major step forward in the new guideline is the inclusion of stroke as an outcome in the new ASCVD risk calculator, a controversial subject since most studies do not differentiate between embolic or atherosclerotic stroke. In contrast to ATP III guidelines that recommended an LDL-C target < 100 mg/dL in diabetic patients, the new guideline endorses the use of moderate to high intensity statins in all diabetic patients between 40-75 years of age with LDL-C 70-189 mg/dL. The new guideline also acknowledges that adherence to a healthy diet and lifestyle is the keystone of cardiovascular health. Finally, they encourage physicians to engage with their patients in a healthy discussion about the risks and benefits of statin therapy before initiating treatment. In summary, the task force has succeeded in consolidating the crème de la crème of data into simplified guidelines that can be easily followed by all medical professionals and treat the patient not the number.

Why it Was Not Worth the Wait

Eliminating treatment targets: A paradigm shift
The new guideline has caused much controversy by changing the fundamentals of cholesterol treatment from an approach that treats to specific LDL-C and non-HDL-C targets to one that treats specific patient populations regardless of their lipid profile. It encourages repeating a lipid panel 4-12 weeks after the initiation of statin therapy to assess patient compliance rather than the efficacy of statin therapy. It presumes that high-intensity statin therapy reduces LDL-C by ≥ 50% while moderate-intensity reduces it by 30% to < 50%. However, this reduction is not a universal finding in all studies because multiple factors are involved in determining each individual's response to statin therapy.

For example, in ASTEROID (A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden),⁴ secondary prevention patients on high-intensity rosuvastatin therapy of 40 mg daily had a mean LDL-C reduction of 53% only; thus, approximately half of the patients did not meet the definition of high-intensity statin therapy in the new guideline. The casual role of LDL-C in the pathophysiology of ASCVD and the totality of evidence from RCTs and other studies point towards one core concept; the lower the LDL-C, the less the ASCVD risk. As pointed out by Raymond et al,⁵ there is a reproducible relationship between the LDL-C level achieved and the absolute risk in primary and secondary prevention populations (Slide 1). Therefore, we believe that having LDL-C or non-HDL-C treatment targets is crucial in assessing and treating residual risk at follow up after initiating statin therapy.

Limited role for non-statin lipid lowering medications
The new guideline makes it clear that statins are a must, but fails to acknowledge what to do when statins are not enough or when patients are intolerant to statins. It does not strongly recommend the use of non-statin lipid lowering medications because of the lack of definitive data that proves its efficacy. A recent systematic review showed that the combination of a lower dose statin and another lipid-lowering medication is more effective at lowering LDL-C than a high dose statin alone.⁶ There is no doubt about the efficacy of high-intensity statins as first-line therapy in high-risk patient; however, the role of non-statin medications in reducing residual risk and in patients with statin intolerance is minimized in the new guidelines. Non-statin lipid lowering medications are very effective at lowering LDL-C and most experts would add one or more when the LDL-C level remains elevated or when patients have recurrent ASCVD despite high dose statin therapy.

The new 10-year ASCVD risk calculator
Perhaps the most controversial aspect of the new guideline is the new risk calculator. The same guideline that eliminates treatment goals due to the lack of RCT data to support it, recommends using a calculator that was neither extensively validated in primary prevention populations nor released early for public commentary and expert opinion. It was derived from five population-based cohorts of African Americans and non-Hispanic whites and relies heavily on age and sex to determine ASCVD risk while ignoring other important factors such as family history.²

Soon after the release of the new guideline, Drs. Ridker and Cook showed that when the new calculator was applied to more recent cohorts such as the Women's Health Study, Physician's Health Study and Women's Health Initiative, it overestimated the 10-year ASCVD risk by 75% to 150% making approximately 30 million more Americans eligible for statin treatment.⁷

A recent study in a Swiss population showed the new risk calculator doubled the prevalence of high-risk individuals compared to the European Society of Cardiology SCORE equation.⁸ It led to a 30-fold increase in the number of high-risk individuals amongst those 50-60 years old and a total extra cost of treatment of 333.7 million Euros per year. Moreover, the new calculator makes virtually all African American men older than 62 years old with no other risk factors candidates for at least a moderate intensity statin (Slide 2). Given its inconsistent performance in different populations, we would have expected extensive validation of the efficacy of this calculator in large prospective studies before its release.

Primary prevention and the unfortunate young
The new guideline recommendations for using statins in primary prevention are limited to patients 40-75 years old unless their LDL-C is ≥ 190 mg/dL. However, the process of atherosclerosis starts at very young age and therefore failure to start lipid-lowering medications in the younger dyslipidemic population is a failure of primary prevention (Slide 3). Despite the absence of RCTs that address statin therapy in the young age group, a moderate or high dose statin may be considered in certain high-risk individuals.

What happened to hypertriglyceridemia?
Hypertriglyceridemia is a marker of dyslipidemia. In the current era of diabetes, obesity and metabolic syndrome epidemics, we have witnessed increasing prevalence of elevated triglyceride-rich remnant lipoproteins, characteristic of insulin resistance. These include very-low density lipoproteins, intermediate-density lipoproteins, and chylomicron remnant particles that may be more atherogenic than LDL-C.⁹ Therefore, hypertriglyceridemia may be a potential indication to assess residual risk by measuring more inclusive measures of atherogenic cholesterol such as non-HDL-C or apoB and possibly initiate statins.

Conclusions

The new guideline document, with all its pros and cons, represents a colossal shift in cholesterol treatment. In the midst of all this controversy, we believe we can find common ground where we all can agree on certain core concepts. We can all agree that treatment with a moderate to high-intensity statin is a must for all patients within the four major groups identified by the guideline. We can also agree that LDL-C and non-HDL-C treatment targets are crucial for residual risk assessment and treatment. Non-statin lipid lowering medications may be beneficial for reducing residual risk and for statin intolerant patients. The new calculator should be validated extensively in more cohorts and needs to include other factors such as family history. Physicians and patients must engage in a healthy dialogue about the benefits and risks of treatment with statins as well as non-statins. In conclusion, we should always remember that patients are unique and guidelines are only a tool for direction not for dictating clinical practice.

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References

1. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002;106:3143–3421.
2. 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. [Epub Ahead of Print].
3. Graham R, Mancher M, Wolman DM, Greenfield S, SteinberE, eds; Institute of Medicine. Clinical Practice Guidelines We Can Trust. Washington, DC; Nat Acad Proc 2011:253.
4. Nissen SE, Nicholls SJ, Sipahi I, et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA 2006;295:1556–1565.
5. Raymond C, Cho L, Rocco M, Hazen SL. New cholesterol guidelines: worth the wait? Cleve Clin J Med 2014;81:11–19.
6. Gudzune KA, Monroe AK, Sharma R, Ranasinghe PD, Chelladurai Y, Robinson KA. Effectiveness of Combination Therapy With Statin and Another Lipid-Modifying Agent Compared With Intensified Statin Monotherapy: A Systematic Review. Ann Intern Med 2014. [Epub ahead of print]
7. Ridker PM, Cook NR. Statins: new American guidelines for prevention of cardiovascular disease. Lancet 2013;382:1762–1765.
8. Vaucher J, Marques-Vidal P, Preisig M, Waeber G, Vollenweider P. Population and economic impact of the 2013 ACC/AHA guidelines compared with European guidelines to prevent cardiovascular disease. Eur Heart J 2014. [Epub ahead of print]
9. Varbo A, Benn M, Tybjærg-Hansen A, Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol 2013;61:427–436.

Keywords: Cholesterol, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Risk Reduction Behavior

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