Role of cholesterol in prevention and mortality benefit of statins
debated in media

January 30, 2008

Michael O'Riordan
New York, NY - There is no shortage of cholesterol news to begin the new
year, especially with questions deriving from the Effect of Combination
Ezetimibe and High-Dose Simvastatin vs Simvastatin Alone on the
Atherosclerotic Process in Patients with Heterozygous Familial
Hypercholesterolemia (ENHANCE) trial. Now, an editorial published over
the weekend in the New York Times questions the cholesterol hypothesis,
specifically that current medical practice is focusing inappropriately
on LDL cholesterol rather than on the lipoproteins that carry the "bad"
cholesterol. [1]
The opinion piece, titled "What's cholesterol got to do with it?" by
Gary Taubes, author of Good Calories, Bad Calories: Challenging the
Conventional Wisdom on Diet, Weight Control, and Disease, zeroes in on
the Vytorin (ezetimibe/simvastatin, Merck/Schering-Plough
Pharmaceuticals) storm, using the current controversy as a launching pad
to question the clinical importance of lowering LDL cholesterol.

"The idea that cholesterol plays a key role in heart disease is so
tightly woven into modern medical thinking that it is no longer
considered open to question," writes Taubes. "This is the message that
emerged all too clearly from the recent news that the drug Vytorin had
fared no better in clinical trials than the statin therapy it was meant
to supplant."
In light of these findings from the ENHANCE trial, many cardiologists,
writes Taubes, said that "the result implied nothing about their
assumption that LDL cholesterol is dangerous, only about whether it is
always medically effective to lower it.

"But this interpretation is based on a long-standing conceptual error
embedded in the very language we use to discuss heart disease," he
writes. "It confuses the cholesterol carried in the bloodstream with the
particles, known as lipoproteins, that shuttle that cholesterol around.
There is little doubt that certain of these lipoproteins pose dangers,
but whether cholesterol itself is a critical factor is a question that
the Vytorin trial has most definitely raised. It's a question that needs
to be acknowledged and addressed if we're going to make any more headway
in preventing heart disease."

Losing sight of abnormal lipoproteins
In his article, Taubes provides a brief history, noting that in the
1950s researchers suspected that lipoproteins, carriers of cholesterol,
might play a bigger role in cardiovascular disease. However, measuring
these lipoproteins was difficult and expensive, while cholesterol
testing was relatively easy to order up for any doctor.
By the 1960s, scientists were able to measure the cholesterol inside the
different types of lipoproteins‹high-density, low-density, and
very-low-density lipoproteins. Studies later showed that cholesterol in
LDL was a marginal risk factor, leading to the concept that LDL carries
bad cholesterol and HDL carries good cholesterol. HDL and LDL later
became "good" and "bad" cholesterol, losing sight of the idea that the
causal agent in cardiovascular disease might be abnormal lipoproteins,
writes Taubes.
The results with statin drugs, which lower LDL cholesterol and prevent
MI, have led many to believe that lowering LDL prevents heart disease.
However, statins have other pleiotropic effects, including lowering the
number of low-density and very-low-density lipoproteins in the blood,
including the smallest, densest, and most noxious form of LDL, writes
Taubes. Moreover, the ENHANCE study with Vytorin, as well as data on
estrogen therapy and torcetrapib, all of which lower LDL cholesterol,
have failed to show a benefit, he writes.
"If the evidence continues to challenge the role of cholesterol, then
rethink it, without preconceptions, and consider what these other
pathways in cardiovascular disease are implying about cause and
prevention," writes Taubes. "A different hypothesis may turn out to fit
the facts better and one day help prevent considerably more deaths."

Lifesaving role of statins called into question
Will taking a statin make you live longer? That's the question put forth
by another article in the New York Times [2]. In the fallout from the
ENHANCE trial, the paper notes that statins are excellent for reducing
LDL-cholesterol levels and reducing the risk of heart attack, but for
many users statins do not prolong life.

Middle-aged men with cardiovascular disease do derive significant
benefit from statins, science reporter Tara Parker-Pope writes, but many
statin users don't have heart disease, just elevated LDL-cholesterol
levels. "For healthy men, for women with or without heart disease, and
for people over 70, there is little evidence, if any, that taking a
statin will make a meaningful difference in how long they live," writes
Pope.

Dr Harlan Krumholz (Yale University School of Medicine, New Haven, CT)
agreed. "I do think that we do not disclose often enough to patients
where there is uncertainty," he told heartwire. "Statins are remarkable
drugs that have been shown to reduce risk in many populations and to be
particularly useful in high-risk populations. The magnitude of benefit
is smaller in lower-risk populations even if the relative risk is the
same, making it harder to show benefit and translating into more people
that need to be treated to produce a benefit."
Pope notes that the PROSPER study, published in the Lancet in 2002 and
reported by heartwire, found the drugs did not reduce mortality in
patients 70 years of age and older.
"In the oldest populations I have the greatest degree of uncertainty,"
agreed Krumholz. "I believe our best approach is to engage in shared
decision making, where the uncertainty is disclosed and the
recommendation is based on what evidence is available and the
preferences, values, and goals of the patients. There is still much to
learn."
One recent meta-analysis, also reported by heartwire, showed that
statins did translate into a 22% lower mortality risk for high-risk
patients 65 years of age and older who had a prior MI or established
cardiovascular disease. The number needed to treat (NNT) to save one
life in this analysis was 28, reported lead investigator Dr Jonathan
Afilalo (McGill University, Montreal, QC). "If a patient has had a heart
attack, they generally should be on a statin," he told the Times.
Pope also writes that treatment with a statin does not improve quality
of life and that the drugs do cause side effects, such as muscle pain.
To heartwire, Krumholz said there are many patient groups that remain
understudied, such as minorities, women, the elderly, and those with
renal dysfunction. While the results from trials are extrapolated to
these populations, where is less certainty, the mainstream opinion is
that statins are effective.
"The open debate is good, but we need to be sure that patients
understand the balance of benefits and risks with any medications, and
it would seem a shame if the recent publicity led high-risk patients to
discontinue statins because they incorrectly believe them to be
ineffective."

Debating whether or not lowering LDL cholesterol is enough
With questions surrounding the mortality benefits of statins and the
importance of lowering LDL cholesterol being asked in the media, some
high-profile cardiologists also get in on the act in the January 29,
2008 issue of Circulation, with Drs H Robert Superko (St Joseph's
Translational Research Institute, Atlanta, GA) and Spencer King III
(Emory University School of Medicine, Atlanta, GA) [3] debating the
effectiveness of lowering LDL to reduce cardiovascular risk and
suggesting that new strategies are necessary. Taking an opposing stand
is Dr Scott Grundy (University of Texas Southwestern Medical Center,
Dallas), who argues for the promise of LDL-lowering therapy in primary
and secondary prevention [4].
According to Superko and King, a danger for the future health of
patients lies in assumptions that cholesterol reduction alone can stem
the tide of coronary heart disease. They argue that "this is not enough"
and state that the "well-meaning focus on LDL-cholesterol reduction has
deflected interest in other therapeutic aspects of lipoprotein treatment
that provide equal or greater benefit."
They also point to the many clinical trials with monotherapy showing a
consistent 25% reduction in cardiovascular events. This relative risk
reduction, they suggest, obscures the fact that 25% is simply
insufficient.
To support their argument, Superko and King point to the PROVE-IT trial,
a comparison of high-dose atorvastatin vs pravastatin 40 mg, suggesting
that while the relative 16% reduction in clinical events is laudable,
22.4% of patients treated with atorvastatin 80 mg still experienced a
clinical event. These events occurred despite LDL cholesterol being
lowered to 62 mg/dL. The NNT also remains too high in monotherapy
trials, write Superko and King, but combining LDL lowering with
therapies to raise HDL cholesterol could reduce the NNT. In addition, as
has been shown in different trials, combining LDL-lowering with
HDL-raising therapy can actually regress atherosclerosis, whereas
monotherapy with LDL-lowering drugs alone can't.
According to Grundy, however, whether raising HDL by pharmacological
intervention will reduce cardiovascular risk remains to be proven,
noting that the science in this area is still "in the arena of
speculation."
He writes that LDL is a cause of atherosclerotic cardiovascular disease
and that lowering it will reduce the risk, as has been shown by the past
20 years of research. Intensive LDL-lowering therapy, even in the
presence of atherosclerosis, can reduce the risk of clinical events 40%
to 50%, and not 25% as suggested by Superko and King, although he
concedes there is still a residual risk of 50% to 60%. Reducing
cigarette smoking and understanding the contribution of metabolic
syndrome to clinical events as well as various arterial wall factors can
help reduce this residual risk, writes Grundy.

Grundy has been an investigator on a grant from Merck and has been a
consultant to Pfizer, Merck/Schering-Plough, and AstraZeneca. Superko
reports a research grant from Agilent Technologies and has served on the
speakers' bureau for KOS Pharmaceuticals.

Sources

  1. Taubes G. What's cholesterol got to do with it? New York Times.
January 27, 2008. Available at www.nytimes.com
  2.
  3. Parker-Pope T. Great drug, but does it prolong life? New York
Times. January 29, 2008. Available at www.nytimes.com
  4.
  5. Superko RH, King SB. Lipid management to reduce cardiovascular
risk: a new strategy is required. Circulation 2008; 117:560-568.
  6.
  7. Grundy SM. Promise of low-density lipoprotein-lowering therapy for
primary and secondary prevention. Circulation 2008; 117:569-573.
  8.

Related links

  €  Questioning the importance of LDL cholesterol: The ENHANCE fallout
  €  [HeartWire > Cardiometabolic risk; Jan 22, 2008]
  €  ENHANCE saga continues: Experts dispute ezetimibe's future and
³weight² of imaging studies
  €  [HeartWire > Cardiometabolic risk; Jan 16, 2008]
  €  ENHANCE results yield disappointment for ezetimibe
  €  [HeartWire > Cardiometabolic risk; Jan 14, 2008]
  €  IDEAL: Intensive lipid lowering after acute MI did not reduce the
risk of major coronary events
  €  [HeartWire > Cardiometabolic risk; Nov 15, 2005]
  €  TNT: Intensive lipid lowering in stable CHD patients reduces the
risk of major cardiovascular events
  €  [HeartWire > Cardiometabolic risk; Mar 08, 2005]
  €  Experts react to the new NCEP ATP III guidelines: Many anticipate
further changes down the road
  €  [HeartWire > Atherosclerosis; Jul 16, 2004]
  €  PROVE-IT: Atorvastatin 80 mg reduces major CV events by 16%
compared with pravastatin 40 mg in ACS patients
  €  [HeartWire > Atherosclerosis; Mar 08, 2004]