Dr. Briffa on statins and cholesterol reduction

Recent review on statins ignores body of evidence that suggests these drugs don’t work through cholesterol-reduction



http://www.drbriffa.com/blog/   November 15, 2010

Recent review on statins ignores body of evidence that suggests these drugs don’t work through cholesterol-reduction

Big cholesterol news emerged last week on the publication (much publicised) of a massive meta-analysis of statin treatment in those at relatively high risk of cardiovascular disease. The idea of this meta-analysis was to assess whether aggressive lowering of cholesterol (specifically LDL-cholesterol) brings additional benefits in terms of cardiovascular disease protection. The meta-analysis included results from a total of 26 trials (involving a total of about 170,000 individuals) [1].

What this meta-analysis found was that more intensive lowering of cholesterol was associated with a reduced risk of ‘vascular events’ such as heart attacks, fatal heart attacks and the most common form of stroke (ischaemic stroke). The authors state that for each 1.0 mmol/L (39 mg/dl) reduction in LDL-cholesterol, risk of vascular events was reduced by about a fifth. They go on to say “reduction of LDL cholesterol by 2-3 mmol/L would reduce risk by about 40-50 per cent.”

Perhaps not surprisingly, this meta-analysis is being used to ram home the conventional view that cholesterol causes cardiovascular disease, and that lower levels of LDL-cholesterol are better. However, there are a number of reasons why this study fails to tell the whole story about statins and cholesterol reduction.

Statin drugs have a number of different mechanisms which might allow them to reduce cardiovascular disease risk in a way which has nothing to do with cholesterol reduction. For example, statins have anti-inflammatory effects, which we would expect to lead to reduced risk of cardiovascular disease. Now, when we intensively lower cholesterol with these drugs, non-cholesterol-related effects (e.g. anti-inflammatory action) will generally be increased too. So, we cannot assume that any additional benefits from more intensive statin therapy have come from more intensive lowering of cholesterol.

In this meta-analysis, the results of a large number of studies was pooled. The problem is, these studies used a range of different drugs at different doses. Sometimes, the drugs were being tested against placebos, and sometimes they were being tested against other drugs. Rarely, two doses of the same drug were tested. Basically, the studies represent a huge hotchpotch of ‘methodologies’ and ‘variables’.

If you really want to take a scientific approach to assessing the role of cholesterol reduction on health, you would ‘control your variables’. This basically means changing only one thing. So, for instance, you could give two groups of people differing doses of the same statin. You could then see if the group on the higher dose had additional benefits, and also see if this appeared to be related to cholesterol reduction or something else. You’d be surprised how rarely such studies are done.

One example of such a study is the so-called TNT study [2]. Here, individuals with heart disease (very high risk of future vascular events) were given either 10 or 80 mg of atorvastatin for an average of about 5 years. The higher dose did lead to lower LDL levels and lower risk of death due to heart-related disease. The absolute reduce in risk was 0.5 per cent, by the way, so nothing to get too excited about. Plus, this study did not report on the non-cholesterol-related effects of the two different dosages, and so it’s impossible to gauge if the relative benefit of the higher dosage was down to LDL reduction and/or something else.

It should also be borne in mind, by the way, that the higher dose of statin in this study (eight times the lower dose, remember) did not lead to a reduction in overall risk of death. In other words, taking 8 times the dose of this drug for five years did not, overall, extend life by a single day, even in individuals at high risk of heart attacks and stroke.

The idea that the anti-inflammatory effects of statins (and not their cholesterol-reducing effects) may be at the heart of their benefits has been bolstered by work focusing on an inflammatory marker known as C-reactive protein (CRP). Statins are known to have the capacity to reduce CRP levels.

In one study [3] assessing the relationship between statin therapy and cholesterol and CRP levels, it was discovered that “Patients who have low CRP levels after statin therapy have better clinical outcomes than those with higher CRP levels, regardless of the resultant level of LDL cholesterol.” (emphasis mine).

In another study [4] published in the same edition of the journal, statin therapy and cardiovascular disease risk assessed using ultrasound scanning of the inside of the coronary arteries. It was found that “atherosclerosis regressed in the patients with the greatest reduction in CRP levels, but not in those with the greatest reduction in LDL cholesterol levels.”

In yet another study [5] it was found that when treating with statins, those with the highest levels of inflammatory markers at the start of the study derived the most benefit, irrespective of initial cholesterol
levels.

Evidence that statins don’t work through their cholesterol-reducing effect comes from other evidence, including the findings that:

•Statins substantially reduce the risk of stroke, despite the fact that raised cholesterol levels are a weak or non-existent risk factor for stroke [6,7].

•Statins are claimed to reduce CVD risk in individuals who have ‘normal’ or even ‘low’ cholesterol levels [8].

•More intensive cholesterol reduction does not necessarily lead to improved outcomes [9].

Despite what the authors of the recent Lancet review would have us believe, there is considerable evidence that statins primarily work through mechanism that are independent of their cholesterol-reducing effects.

Stepping aside from the science for a moment, let’s also perhaps inject some common sense. Let us not forget that cholesterol is a natural constituent of the body that is a major component in cell membranes, the brain, steroid hormones (including sex hormones) and vitamin D (which appears to have major disease-protective properties). It simply does not make sense to me that driving levels of this key substance to lower and lower levels if, in and of itself, beneficial to health. We would not make the case for driving levels of, say, sodium to lower and lower levels, would we? Or blood sugar levels?

All rationality and common sense seems to fly out of the window when certain doctors and scientists start talking about cholesterol. And when it comes to the science, it’s clear that many are ignorant of or choose to ignore the stacks of evidence that clearly contradict their stance.

References:

1. Cholesterol Treatment Trialists’ Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 9 November 2010 [epub ahead of print]

2. La Rosa JC, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352(14):1425-35

3. Ridker PM, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med 2005;352(1):20-8

4. Nissen SE, et al. Statin therapy, LDL cholesterol, C-reactive protein and coronary artery disease. N Engl J Med. 2005;352(1):29-38

5. Ridker PM, et al. Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events (CARE) Investigators. Circulation. 1998;98(9):839-44

6. Cholesterol, diastolic blood pressure, and stroke: 13,000 strokes in 450,000 people in 45 prospective cohorts. Prospective studies collaboration. Lancet 1995;346(8991-8992):1647-53.

7. Imamura T, et al. LDL cholesterol and the development of stroke subtypes and coronary heart disease in a general Japanese population: the Hisayama study. Stroke 2009;40(2):382-8

8. Ridker PM, et al, JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359(21):2195-2207

9. Kastelein JJ, et al, ENHANCE Investigators. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med 2008;358(14):1431-1443