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Current Controversies in Lipid-lowering Therapy

Neil Stone, MD, Professor of Medicine, Northwestern University

Dr. Stone was a member of the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP I and ATP III).

Yes, the NCEP/ATP III guidelines are aggressive enough. The intensity of low-density lipoprotein (LDL) reduction should be based on the absolute risk; the ATP III calculator is an easy method to determine absolute coronary risk.

Beyond coronary risk, ATP III does consider the metabolic syndrome. ATP III, based on the results of the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT), Incremental Decrease in Events through Aggressive Lipid Lowering (IDEAL), and Treating to New Targets (TNT) trials, recommends that a reasonable therapeutic option is an LDL <70 mg/dL. This option is particularly important in patients with cardiovascular disease (CVD) and acute coronary syndrome, multiple metabolic risk factors, or severe risk factors.

Is it worth the incremental cost of potential side effects to achieve an LDL-cholesterol level of 68 mg/dL?

• We don’t know this yet. Statins appear to be remarkably well tolerated in clinical trials; the problem is that the clinical trials may not represent the patients seen in clinical practice. By definition, trials exclude patients with elevated liver enzymes, impaired kidney function, or compliance problems, and people who abuse alcohol. When a frail elderly woman on 12 medications enters the cardiac care unit, the clinician must exercise caution before prescribing a high-dose statin.
• Many people with diabetes are on multiple medications, have coronary heart disease (CHD), and do not have an LDL <70 mg/dL or non-high-density lipoprotein (HDL) <100 mg/dL despite lipid-lowering therapy. How low can we go when we consider the cost and safety aspects in people with diabetes?
• Although lower LDL levels correlate with better outcomes in secondary prevention trials, you should not always attempt further lowering of LDL. Physician judgment is paramount.
• Attention must be given to the total way we reduce risk. Making LDL lowering optional—as ATP III has done—seems reasonable, and without denying that if LDL can be lowered safely and easily that would be a good thing.

Advanced Lipoprotein Analysis: Clinically Useful?

Richard L. Dunbar, MD, Penn Cardiac Care at Penn Presbyterian Medical Center, University of Pennsylvania, Philadelphia

The traditional lipid panel is crude. Although LDL is the most important lipoprotein, many clinicians estimate the level of LDL instead of measuring it.

Limitations to estimating LDL:

• The calculation is prone to underestimate LDL in people who have not fasted for 12 hours, patients with triglycerides (TGs) >200 mg/dL, people with diabetes or liver diseases, and women taking hormone-replacement therapy.
• Moreover, a study at the University of Pennsylvania showed a significant degree of error in estimated vs measured LDL levels in patients with the metabolic syndrome compared with patients without the metabolic syndrome.

Direct measures of LDL are not accurate in all patients. Patients with TGs >500 mg/dL had normal, or even below-average, LDL apolipoprotein B (apo B) levels. In contrast, patients with elevated apo B levels had TG levels between 200 and 400 mg/dL. Thus, new choices beyond the traditional lipid panel are important.

The most important advanced lipid test is the cholesterol content of non-HDL cholesterol. Measuring apo B gives complimentary information, ie, the number of atherogenic particles. Nuclear magnetic resonance also gives information about particle number.

Clinical pearls:

• We expect too much from estimations of LDL. As an alternative, non-HDL cholesterol is a very practical, advanced lipid test.
• Measuring particle number is a close second—it is now both achievable and helpful.

The Safety of Statins

Beatrice A. Golomb, MD, PhD, Assistant Professor of Medicine, University of California–San Diego

Are we conditioned to think of cholesterol as a nefarious substance that courses through our blood for the sole purpose of congealing in our arteries and causing CVD? In addition to cholesterol, other products in the mevalonate pathway have pivotally important functions. What are the beneficial verus harmful effects of statins?

The statin trade-off:

• Statins increase nitric oxide in the endothelium, which reduces eROS. These antioxidant effects of statins are associated with many of the statins’ benefits, including plaque stability and endothelial function. These benefits, which are important for increasing flow in patients for whom flow is compromised, are most likely to be expressed in patients with pre-existing impairments in flow, ie, patients with CVD.
• However, statins also have pro-oxidant effects. For example, statins produce dose-dependent reductions in coenzyme Q10, which leads to increased mitochondrial eROS, the major source of eROS production. In addition, reductions in coenzyme Q10 lead to impaired cell energy production, particularly in people with preexisting mitochondrial vulnerability (the elderly). Subjects expressing muscle adverse effects on statins have had increases in oxidation stress markers in their blood.

Are the benefits of statins greater in patients with higher CHD risk?

• When the major statin clinical trials are ranked on the basis of heart-disease risk in the enrolled population, the risk ratio for total mortality—an endpoint that takes into account harms and benefits—starts out highly favorable in high cardiac risk groups. But as the cardiac risk of the enrolled patient population is successively lower, the overall mortality benefit first attenuates and then becomes neutral. In the United States there have been no statin trials in bona fide low-risk populations.

Statin therapy and women

• Women have lower risk of heart disease compared with men even when enrolled in the same clinical trial. For this and perhaps other reasons, women have not expressed the same benefits in overall mortality that men have, even in studies with high-risk patients. The risk ratios have been neutral or slightly unfavorable in women. Dr. Golomb noted that she and her group have attempted to perform a meta-analysis and have requested data on total mortality for women in the statin and placebo groups from the major statin trials, but they were denied access to these data.

Is statin therapy safe in people who have mitochondrial vulnerability?

• Mitochondrial deficits are only clinically expressed when there is a large fraction of cell loss or cell-function loss, on the order of perhaps 50% or greater. This means that, even in patients for whom clinical recovery is complete, there remains the possibility that physiological recovery is incomplete.
• In double-blind crossover biopsy studies, mitochondrial abnormalities that are found in association with the development of muscle symptoms are not completely reversible. Similar findings are seen with other physiological markers, such as respiratory exchange ratios.
• Approximately 50% of rhabdomyolysis patients report persistent clinical effects with statin therapy. Patients with muscle adverse effects without rhabdomyolysis who report complete recovery have faster times to re-onset of muscle symptoms when they are rechallenged with statins compared with time to the first onset of adverse muscle effects. This is consistent with persistent subclinical (physiological) impairment.

On average, middle-aged men at high risk for CVD have net benefit to mortality and morbidity. However, middle-aged men at high risk for heart disease who express adverse drug reactions have an unknown risk-benefit profile. In this latter group, the risk is increased and the benefits may be lower. That is, statins may be increasing oxidative stress markers. The persistent adverse events associated with statins are a special concern for the elderly, for women, and for lower-risk men for whom existing randomized-controlled-trial evidence has not clearly supported benefits exceeding harms.

There are several reasons why adverse events are seen in clinical practice and not in clinical trials:

• Good mitochondrial function is associated with good energy and these are the people who enter clinical trials.
• More importantly, compliance run-in protocols bias study-participant pools in favor of those who do not have adverse reactions on statin therapy.
• Mitochondrial dysfunction accrues over time. Many patients will tolerate statins for over 1 year, and then in year 2 or year 3 may develop myopathy conditions that result in their discontinuation of therapy. The duration of clinical trials may not be long enough to capture these types of patients.

Are there long-term adverse effects from statin therapy?

• The two most commonly reported harms are muscle adverse effects and cognitive impairment. There is debate as to whether or not the cognitive impairment fully resolves following discontinuation of statin therapy.

Pleiotropic Effects of Statins

Julian Halcox, MD, The Heart Hospital, London

Statins have pleiotropic effects that are relevant to atherogenesis. Many of these effects are mediated by inhibition of isoprenoids, which serve as lipid attachments for intracellular signaling molecules. (See Liao JK. Am J Cardiol. 2005.)

These cholesterol-independent effects include

• Improved endothelial function
• Enhanced stability of atherosclerotic plaques
• Decreased oxidative stress and inflammation
• Inhibition of the thrombogenic response

Data indicate that there are biological effects occurring that are clinically detectable long before changes in cholesterol and inflammation are detected. C-reactive protein is just as important a predictor of future risk in acute coronary-syndrome patients as LDL cholesterol. (See Ridker. N Engl J Med. 2005.)

Is managing LDL-cholesterol sufficient?

• Data from a meta-regression analysis indicate that residual risk is an important issue. Post-myocardial infarction patients were projected to experience a 93% reduction in the of CHD death from a pharmacologic approach and a 97% reduction in the risk of CHD death with the addition of lifestyle changes. (See Robinson.JACC. 2005.) Thus, it is important to manage the whole global risk profile of the patient. Physicians need to look beyond LDL-cholesterol and employ aggressive lifestyle measures with or without drug therapy.