Statins: A Critical Appraisal

Statins: A Critical Appraisal

You can find a number of well written books with articulate statistical analyses over the years questioning the results of statin therapy.   What is the true value and efficacy of statins (HMG-CoA reductase inhibitors) in treating and preventing heart disease?   The statistics can be overwhelming.   What is the real risk benefit ratio?

Lipids and the Emergence of Statin Therapy

Lipid research actually started sometime in the early 1920’s.   It gained more momentum in the 1950’s with John Gofman at the Laurence Radiation Lab in Berkeley.  Then the interest waned, so the field languished for another few decades. John Gofman turned his energies to examining and warning us of the dangers of constant low level radiation therapy

In the 1950’s and 1960’s the cholesterol theory was gaining more adherents. Anyone over 50-60 remembers well the exhortation to eat less fat. No eggs. Skimmed milk. Substitute margarine for butter. It was much healthier.   Cholesterol was bad. Turns out margarine is literally the bottom of the barrel stuff. Highly hydrogenated oils. Much less healthy. Personally, I never believed the cholesterol theory even in Medical School and was labeled a heretic. “Dummy, everyone believes the cholesterol story.”

One of the most erudite and gentlemanly Professors at UCSD Medical School was Dr. Daniel Steinberg, a prominent lipid researcher. He wrote a wonderful book The Cholesterol Wars which is one of the best historical accounts of the lipid research over the past 80 years.   He even admits “we almost lost the cholesterol debate if it had not been for the emergence of Statins.”

The Framingham Study was a large study begun about 45 years ago in a small town outside of Boston where a majority of the population has been studied annually. It is the best cross sectional study we have.

Interestingly, even the Framingham study proved that cholesterol is a bad predictor of heart disease.   50% of those who suffered heart attacks had totally “normal” cholesterol levels.  By the way, the term “normal” is a moving target and subject to standards committee declarations.   There is no “normal” cholesterol, only declared “acceptable levels.”   A GP, an internist or a cardiologist will have different and increasingly aggressive definitions of “normal.”

Association vs causality is an ancient debate which is not well settled. Aristotle proposed four postulates for causality. Many centuries later, David Hume, the great Scottish Enlightenment philosopher expounded about this in detail.

Cholesterol does not cause heart disease.

The Search for the Holy Grail: Ever More sub-fractions and biomarkers

Meanwhile, the field advanced from total cholesterol to more and more sub-fractions always looking for the holy grail.   The reductio ad absurdum. We started measuring HDL and LDL and then VLDL.   These are not cholesterol numbers as is so often believed. It is not “the bad cholesterol” or “the good cholesterol” but rather lipoprotein carriers.   LDL transports cholesterol to the heart in response to inflammation or injury.   HDL caries cholesterol away from the heart. Ergo, the HDL system is called the reverse transport system.   Think of it as a vacuum cleaner for the heart. The Normal LDL system carries cholesterol to the heart in response to injury. It is a normal adaptive response.

But something goes awry.   Cholesterol participates but does not initiate cardiovascular disease.   Cardiovascular disease is an inflammatory process.   There are many aspects or cause of inflammation.

So we began measuring finer fractions.   Lp(a) is a glycoprotein. Protein with sugar stuck on. It can be highly atherogenic (hardens the arteries).   It has never been popular.   LpPLA2 is another inflammatory factor possibly more accurate than LDL. It is a biomarker for the vascular inflammatory response.   CRP (c-reactive protein) is an inflammatory bio-marker. High elevations of CRP is very unhealthy.

Even Sydenham expostulated nearly 400 years ago:

“A man is as old as his arteries.”

Thomas Sydenham, MD, English Physician, 1624-1689

So why are you being constantly harangued about need to treat elevated cholesterol levels with Statins? That is Lipitor, Crestor, Zocor , Mevacor as common examples.

Data from Major Trials

Let’s look at the data.   This has been so confusing that even I have overwhelmed with the results after years and years of study. But upon reflection it is quite simple. All clinical trial numbers use relative statistics.   This is a common approach in clinical l trials — inflate (and conflate) the results.   This is the pernicious effect of Big Pharma. You need “validating” data to make the case to the FDA the physician and the patient.

Although this simple example always seem so fall flat, consider this. What is the reduction from 4% whole milk to 2% skimmed milk?   If I am an advertiser or researcher the answer is 50%! Sounds impressive and convincing — and significant.   But what is the absolute (real) reduction?   It’s …. 2%.   Not very impressive.

So consider these numbers from all the major cholesterol trials (a meta analysis) over the years that supports the assertion that Statins prevent heart disease:

Statins and Major Coronary Events

Statins Control Relative Absolute
events number events number  
WOSCOP 174 3302 5.27% 248 3293 7.53% 43% 2.26%
ADFCAPS 57 3304 1.73% 95 3301 2.88% 67% 1.15%
PROSPER 126 1585 7.95% 145 1654 8.77% 10% 0.82%
ALLHAT 380 5170 7.35% 421 5185 8.12% 10% 0.77%
ASCOT 163 5168 3.15% 249 5137 4.85% 54% 1.69%
CAREDS 43 1428 3.01% 65 1410 4.61% 53% 1.60%
MEGSA 23 3866 0.59% 43 3966 1.08% 82% 0.49%
TOTAL 966 23823 4.05% 1266 23946 5.29% 30% 1.23%

 

The 30% relative reduction is impressive and “statistically significant.” But the absolute difference is nearly zero.   No change.   It’s really that simple!

The difference between relative and absolute statistics changes the entire game.

What about the effect on cancer?

Statins and Cancer

Statins Control Relative Absolute
WOSCOP 44 3302 1.33% 49 3293 1.49% 12% 0.16%
ADFCAPS 252 3304 7.63% 259 3301 7.85% 3% 0.22%
ALLHAT 378 5170 7.31% 369 5185 7.12% -3% -0.19%
CARDS 20 1428 1.40% 30 1410 2.13% 52% 0.73%
MEGA 119 3866 3.08% 126 3966 3.18% 3% 0.10%
JUPITER 333 8901 3.74% 372 8901 4.18% 12% 0.44%
TOTAL 1146 25971 4.41% 1205 26056 4.62% 5% 0.21%

 

Absolute change nearly nil again.

And the effect on all cause mortality?

Statins and All Cause Mortality

Statins Control Relative Absolute
events number events number  
WOSCOP 106 3302 3.21% 135 3293 4.10% 28% 0.89%
ADFCAPS 80 3304 2.42% 77 3301 2.33% -4% -0.09%
PROSPER 163 1585 174 1654
ALLHAT 631 5170 12.21% 641 5185 12.36% 1% 0.16%
ASCOT 387 5168 449 5137  
CARDS 61 1428 4.27% 82 1410 5.82% 36% 1.54%
ASPEN 44 959 41 946  
MEGA 55 3866 1.42% 79 3966 1.99% 40% 0.57%
JUPITER 198 8901 2.22% 247 8901 2.77% 25% 0.55%
TOTAL 1725 33683 5.12% 1925 33793 5.70% 11% 0.58%

 

Same — nearly no change by absolute statistical analysis.

Now, does that mean there is no place for statins? Not exactly. These are all population-based studies and statistics.   They tell you nothing about any one particular individual.   You. What are the other possible risk factors? What is the chance statins will actually benefit you? The precise answer is: we don’t know. That is why there has been a profusion of ever more sophisticated tests over the years as mentioned above.

We are not focused on the essential benefit and mechanism of action of statins. They benefit you not by lowering LDL levels to 100, 80 or 60 (It gets more absorb each decade).   Statins are anti-inflammatory.   Remember, cardiovascular disease is an inflammatory process not a cholesterol problem.

Examination of Statin Risks

So what are the risks?   We began this discussion with risk-benefit. So far we see the benefit is questionable and unknown.

The risks are understated for reasons that are quite obvious.   This includes liver dysfunction with SGOT, SGPT and GGT enzyme rises, muscle aches and pains (fibromyalgias), memory loss or cognitive impairment, declines in CoQ10 and more recently a statistically significant increase in diabetes.

A decline in CoQ10 can actually precipitate heart failure in borderline cases as Dr. Steven Sinatra has warned over the years.   These “side effects” are always minimized. They are actually common and under reported.   Anyone taking a statin is cautioned to take at least 100-400 mg of CoQ10.     Anyone suffering any of these conditions does not experience these as “minor irritations.”

Nothing in medicine is 100%.   There are always side effects and consequence of any drug.   That is why we examine risk-benefit.   But the risk-benefit ratio seems much higher than stated. And the end points are irrationally monitored. It is not by lowering LDL.   It is inflammatory markers that should be followed.   That would be CRP, fibrinogen, LpPLA2, MPO, ESR just to name the most common tests available from any major lab.

Value of Imaging Studies

Finally, a word about imaging.   You can have “high statistical risk” profile without any disease.   Imaging modalities such as super-fast CT scans (HeartScan) and CIMT (carotid artery intimal media thickness ultrasound) are rapid approaches to identifying plaque development, the true harbinger of cardiovascular disease.

In the end, this is always a decision you make with your physician. What is the total picture? What are your perceived risks?   What did the imaging studies confirm? What is your fear factor of not doing anything?

Current Recommendations for Cardiovascular Health

I continue to recommend high dose fish oils (not caps); the high dose anti-oxidants Vitamin C, Vitamin E, and Alpha Lipoic Acid; Vitamin D3 and Vitamin K2; Ginkgo Biloba and Nattokinase (with professional guidance); low carbohydrate, high protein diet; moderate exercise (never stop moving); and loving caring relationships.   It was Dr. Dean Ornish who warned the greatest risk for cardio vascular disease is disconnectedness.

Now it’s up to you. Here are some references to bolster the case that Statins have questionable benefit.

Philip Lee Miller, MD

Los Gatos, CA

Sunday, June 14, 2015

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The Truth About Statins: Risks and Alternatives to Cholesterol-Lowering Drugs

Apr 24, 2012

by Barbara H. Roberts M.D.

The Dark Side of Statins: New Science That Shows How Drugs Like Lipitor May Do More Harm Than Good

Apr 9, 2014

by Mark Davis

The Great Cholesterol Myth: Why Lowering Your Cholesterol Won’t Prevent Heart Disease-and the Statin-Free Plan…

Nov 1, 2012

by Jonny Bowden and Stephen Sinatra

Statin Drugs Side Effects and the Misguided War on Cholesterol

May 21, 2008

by Duane Graveline

The Cholesterol Wars: The Skeptics vs the Preponderance of Evidence

Sep 24, 2007

by Daniel Steinberg

 

By M.D. Duane Graveline Lipitor: Thief of Memory, Statin Drugs and the Misguided War on Cholesterol (illustrated…

Jan 13, 2004

by M.D. Duane Graveline

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