Drilling Down on the Cholesterol Treatment Guidelines

Francisco Lopez Jimenez, MD; Thomas G. Allison, PhD; Randal J. Thomas, MD; Vinaya Simha, MBBS, MD


April 30, 2014

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A Roundtable Review of the Cholesterol Guidelines

Francisco Lopez Jimenez, MD: Greetings. I am Dr Francisco Lopez Jimenez, director of the preventive cardiology program at the Mayo Clinic. Today we will be convening a roundtable review on the 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines on the treatment of blood cholesterol.[1]

I am joined by my colleagues, Dr Thomas Allison, Dr Randal Thomas, and Dr Vinaya Simha. They are consultants at Mayo Clinic from cardiology and endocrinology. Welcome, everybody.

I will start with Dr Thomas. Would you mind giving us a summary of the guidelines and the major strengths?

Randal Thomas, MD: The new blood cholesterol guidelines from the ACC/AHA attempted to take the evidence from randomized controlled trials to make things simpler for clinicians to manage cholesterol. They grouped people according to risk and then recommended medications, statins, in particular, according to the risks of certain groups. One group, for example, is patients who already have atherosclerotic cardiovascular disease. A second group is those who have an elevated low-density-lipoprotein [LDL] cholesterol level (>190 mg/dL). Another group is those who have diabetes, and whether they are at low or high risk, depends on a risk calculation. The final group is perhaps the most controversial, and that is patients who have a 10-year risk for an atherosclerotic cardiovascular disease event of at least 7.5%, using a new risk calculator known as the "pooled cohort calculator."

The idea is to use the evidence base from randomized controlled trials to direct our use of the statin medications, recommending either moderate- or high-dose statins, depending on which of these subgroups people fall into.

Dr Jimenez: Dr Allison, what do you think about the recommendation to treat patients at high risk for cardiovascular disease regardless of the cholesterol level—whether it is 80 mg/dL, 90 mg/dL, 120 mg/dL, or 140 mg/dL—where the risk is the most important factor?

Should Risk Trump Cholesterol Level?

Thomas Allison, PhD: That has some limitations. Although the guidelines were very definitive about being evidence-based, none of the clinical trials that I am aware of used the Framingham Risk Score to recruit patients, none published the Framingham Risk Scores, and none analyzed their final results by Framingham Risk Score, and yet, that is the basis of the guideline. It is just an interesting point—I'm not trying to be critical.

Back to your question, the data are very limited. Only the JUPITER study[2] had significant numbers of patients with an LDL cholesterol at baseline below 130 mg/dL, and all of the patients in that study had other risk factors. Everyone had elevated C-reactive protein levels, and many patients had hypertension, insulin resistance, or obesity. The principal analysis was not performed on the basis of LDL-cholesterol levels, although a subsequent paper looked at that to some degree.[3]

My feeling is that young patients with high lipid levels whose risk scores are in the 7.5% range or above (or even slightly below) would benefit from statin therapy because they have lipid abnormalities and they have many years in which to develop cardiovascular disease.

At the other end of the spectrum, older patients with normal lipid levels who by age 60 to 65 have not developed cardiovascular disease are very unlikely to benefit during their lifetime from statin therapy when their LDL-cholesterol level is already <100 mg/dL.

Dr Jimenez: Dr Simha, the other side of the coin, which is the younger individual who has a high cholesterol level—not high enough to qualify for therapy, but still high enough to worry the patient and the provider? The guidelines are not very clear on what to do in the younger individual. For example, would you treat a 38-year-old man with an LDL-cholesterol level of 170 mg/dL with a family history of premature coronary disease?

The Younger Patient: Statin Off the Bat?

Vinaya Simha, MBBS, MD: Probably not right off the bat, but in this person who is 38 years old, has a high cholesterol level and a bad family history, after a reasonable period of lifestyle intervention, if his LDL cholesterol still remains higher than 160 mg/dL, I would strongly consider pharmacotherapy for him. We don't have randomized controlled trial data to show a benefit in this age group; nonetheless, we have enough data from other lines of evidence to support the benefit of lowering the LDL burden over an extended period of time, and that would be very beneficial.

What is the downside of treating such patients? After all, patients like this are least likely to have side effects from statin therapy, and for low- to moderate-intensity generic statin therapy, cost isn't a big issue.

My bias would be to treat him. The only reservation that I would have is the patient's values. Some patients would probably feel very reassured to be on statin therapy, but others feel burdened by the label of having a disease that needs lifelong pharmacotherapy. I would discuss these issues with him, but my bias would be to encourage him to pursue statin pharmacotherapy.

Dr Jimenez: That highlights the importance of recognizing that younger individuals will rarely have a high 10-year risk because they are young. But the 30-year predictor might give us a better estimation of the long-term probability to develop the disease, and that might help the patient and the provider to share the decision about what to do.

Dr Allison: That is a very good point. The guidelines stress the primacy of lifestyle modification as the first line of risk reduction. However, the guideline is not precise about how long we should wait with lifestyle and whether we are allowed to recalibrate the risk score on the basis of lifestyle modification results. In a patient who has an 8% to 9% risk when we first see him, and then he quits smoking, that risk is going to drop dramatically. Even if smoking isn't involved, if his blood pressure is improved or he loses weight, he might fall below the 7.5% level of risk at a subsequent evaluation. It is inherent, but not spelled out exactly, that you should reassess the risk, particularly in these younger patients, at least a second time before you launch therapy.

Give Lifestyle a Chance, But How Long?

Dr Jimenez: That takes me to the next question for Dr Thomas. For how long is it reasonable to wait in a patient who is labeled as high risk and has an elevated LDL cholesterol and an elevated 10-year risk? How long is it reasonable to recommend lifestyle changes and retest, before we prescribe medications? Should we just do both at once and then reassess the need for the statin later on?

Dr Thomas: That is a good question, and I agree with Tom and Vinaya, that it is a matter of discussing with a patient and deciding what is best in each individual case. I would say that the higher risk the patient, the more likely it is that we would start both therapies.

If a patient is at a borderline 10-year risk (between 7.5% and 10%), I would wait three to six months to see whether with lifestyle changes, the patient can get his or her 10-year risk to below 7.5%.

On the other hand, if the patient has known cardiovascular disease and is at high risk, I would start statin therapy at the same time that we initiate lifestyle therapy.

Dr Allison: Vinaya brought up the important point that in the younger patient, and with statins at lower doses, this is a very safe, very well-tolerated therapy. A few people need to be backed off because of side effects, but it isn't a huge burden.

Dr Jimenez: We may also want to identify the real potential to reduce the risk, because in some patients (maybe the very high-risk patients), even after modifying some factors, they will still be at high risk.

Dr Allison: Yes.

Dr Thomas: Although the risk appears to be low in that group of individuals, we don't have good 30-year data to see how safe statins are for that length of time. We assume that they are safe. We have had good results clinically, as well as in research studies for relatively long periods of time, but we still don't know. My bias would still be that if we can help people control their risk without medication, that is the way we should proceed and use the medications as needed.

The Diabetes Cohort

Dr Jimenez: Let me move to a different area, which is diabetes. The guidelines recommend statin treatment for every patient with diabetes, either type 1 or 2, older than 40 years. Dr Simha, what is your take on that? Would you treat every patient with diabetes with statins?

Dr Simha: No, I wouldn't. But before finding fault with the new guidelines about such sweeping recommendations, I would like to commend them for at least not labeling diabetes as a cardiovascular risk equivalent, as many of the earlier guidelines did. That was a gross mischaracterization, and it is very good that the new guidelines have more restrictions on who should be treated.

I don't think that someone who is 45 years of age, diagnosed with type 2 diabetes six months ago, with no other risk factors and a non–high-density-lipoprotein [HDL] cholesterol of 110 mg/dL needs statin therapy, at least on the basis of available evidence. We have very little evidence in terms of primary prevention in people with diabetes about who would benefit, especially in those who would have a lower LDL-cholesterol level. The only large-scale primary-prevention trial in diabetes was the CARDS trial,[4] and the mean LDL cholesterol in that group was 120 mg/dL.

For the guidelines to say that all people with diabetes and cholesterol levels between 70 mg/dL and 100 mg/dL should receive a statin, we don’t have any data to show that. I feel that most of these patients will probably benefit from statin therapy, but we clearly don't have that evidence.

Dr Jimenez: I was doing the calculation the other day, and it is possible for a patient with diabetes to have an estimated 10-year risk below 5%, and therefore, according to one of the main recommendations of the guidelines, that patient will not benefit from statin treatment. The other thing to consider is the risk, potential or real, to cause diabetes with statin therapy. Whether statins impair the control of diabetes is yet to be determined but is something else to consider.

Dr Simha: We have very few data to suggest that statins impede the control of diabetes. Most of the new-onset diabetes seems to occur primarily in people with impaired fasting glucose or a family history of diabetes, so I am not worried too much about the effects of statins on glycemic control. You bring up a very good point that the pooled-cohort risk equation already has diabetes incorporated. We could base our decision to start statin therapy on the estimated risk alone, so as long as the estimated risk is less than 5% (or whatever we decide on), and if the non-HDL cholesterol is, for example, below 130 mg/dL, then I don't think the patient will benefit from statin therapy.

The Cholesterol RCT Wish List

Dr Jimenez: We would like to finish with a general question for everybody. If you have to pick one randomized trial that is highly needed, what would you want?

Dr Thomas: I would probably go back to the question we were discussing. For people who are at a borderline level of risk, if we go with lifestyle therapy first rather than statin therapy, which approach would be better? That would be interesting to see.

Dr Jimenez: Good. Something else?

Dr Allison: A trial in the lower-risk patients with better lipid levels, but that is a very expensive and long-term trial. It may not be feasible to do it, and like exercise trials or smoking trials, we may be forced to use epidemiological or observational data for it.

Dr Jimenez: I'm sure that many experts in the field will want to see a clinical trial comparing the old approach of targeting a specific number vs giving a dose or intensity according to risk.

Thank you, everybody, for your participation. Thank you for your attention, and we hope you continue to follow our roundtable review series at theheart.org on Medscape.


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