Thursday, April 03, 2008

Lowering "bad" cholesterol does not help

Below is a popular summary of some recent research, followed by a paragraph from the Editorial in the prestigious medical journal concerned (NEJM). The brainiacs found a combination of existing drugs that lowered cholesterol by 27% but the outcome for the patients was unaltered. The original journal abstract can be read here. The results will be no surprise to those who are not of the cholesterol religion

A heavily promoted heart drug endorsed by the National Institute for Health and Clinical Excellence (NICE) may be worthless, according to a newly published trial. Ezetimibe (Ezetrol) was recommended by NICE last year for patients with inherited high cholesterol, to be used in conjunction with a statin drug such as simvastatin. But results published in the New England Journal of Medicine and presented yesterday at the American College of Cardiology annual scientific session in Chicago show that it may add nothing to the effectiveness of the statin.

The trial is highly controversial, with claims that it was deliberately suppressed by the drug's manufacturers and released only in response to congressional pressures. The data were made public in January by Merck and Schering-Plough, which makes the drug, but this is the first formal publication. Ezetrol is hugely successful. It is advertised heavily in America, where its sales exceed $5 billion. In the United Kingdom in 2006 - before the NICE endorsement - more than a million prescriptions for Exetrol were written out, worth more than œ40 million. The trial does not show that Ezetrol is damaging, and confirms that it reduces "bad" LDL cholesterol. The assumption was that it would add to the benefits already proven for simvastatin, producing a double-drug with even better lifesaving effects.

The new trial was designed to compare the effects of simvastatin alone with simvastatin plus Ezetrol in slowing the progression of coronary artery disease in patients with familial hyper-cholesterolaemia - a condition in which a tendency to high cholesterol levels is inherited. This was done by measuring the degree of blockage of the arteries in more than 600 patients given either plain simvastatin, or simvastatin plus Ezetrol, for two years. The result was that adding Ezetrol did nothing to slow the progress of the disease. Plaque build-up on the artery walls was the same in patients who took the combination as it was in those who took simvastatin alone.

Earlier studies have shown that plaque build-up is a good proxy for death rates. The more plaque, the more deaths. So most cardiologists will conclude that prescribing Ezetrol is unlikely to prolong the lives of their patients. Other trials are in progress that will measure actual outcomes, such as deaths or heart attacks, but they are not likely to be published before 2011. Until then, says an editorial in the New England Journal of Medicine, it seems prudent to encourage patients whose cholesterol levels remain high despite an optimal dose of statins "to redouble their efforts at dietary control and regular exercise". Other drugs such as niacin, fibrates and resins should be considered if diet, exercise and a statin have failed.

The results throw the whole science of cholesterol reduction into question. [Again] Until now the greater the reduction, the better. But the trial has shown that it is possible to reduce bad cholesterol significantly and yet come out no better, and maybe worse. That is a shock.

In the US the waters have been muddied by claims that Merck and Schering-Plough completed the trial two years ago but did not publish the results until a congressional inquiry was launched. The trial was completed in April 2006, but both companies say it is time-consuming to analyse scans taken of carotid arteries and they only knew of the results early in January. Executives have denied selling shares in the companies before the trial was made public. Peter Kim, president of Merck Research Laboratories, said: "We stand behind ezetimibe and our science, which has brought these cholesterol-lowering medications to millions of patients around the world." A spokesman for NICE said that it would be looking at the results of the study.


Excerpt from the NEJM editorial

"The ENHANCE trial was conducted in patients with familial hypercholesterolemia, a condition characterized by high levels of LDL cholesterol. Patients were randomly assigned to receive either simvastatin alone or a combination of simvastatin plus ezetimibe. Combination therapy resulted in LDL cholesterol levels that were 27% lower than those achieved with monotherapy, and C-reactive protein levels were also significantly lower with combination therapy. Unexpectedly, however, the trial showed that despite increased lowering of LDL cholesterol in the group that received ezetimibe, the rate of progression of atherosclerotic disease, as measured by intima–media thickness, was the same in the two study groups. It is this paradox, which is at odds with our traditional understanding of the relationship between LDL cholesterol and atherosclerosis, that has puzzled investigators and clinicians alike. The paradox and other important questions that are raised by the trial, including the rationale for the use of carotid intima–media thickness as a surrogate end point, are discussed in detail by Brown and Taylor in an accompanying editorial."

Fasting could help fight cancer

Worth a try

A pilot study is about to start on cancer patients to see if fasting can make chemotherapy more effective, and with fewer side effects such as deafness and hair loss. Making chemotherapy more selective has been a research goal of cancer scientists for decades. Doctors could control the spread of cancers much better, and even cure some, if chemotherapy was not so toxic to the rest of the body

But now an alternative way to improve the treatment has been found, not by targetting chemotherapy at cancer cells with a "magic bullet" but by making normal cells tougher, providing a "magic shield", either by fasting or by drugs to mimic the effects of fasting. Fasting for as little as 48 hours protects healthy cells against chemotherapy, according to a study by a team led by Dr Valter Longo at the University of Southern California, which is preparing to test the method on a small group of bladder cancer patients. The pilot clinical study is planned at the university's Norris Cancer Centre within six months.

Mice given a high dose of chemotherapy after fasting continued to thrive, reports the team, which includes Lizzia Raffaghello at Gaslini Children's Hospital in Genoa, Italy. The same dose killed half the normally fed mice and caused lasting weight and energy loss in the survivors. Test tube experiments confirmed normal human cells were two to five times more resistant than cancer cells to chemotherapy after a short period of starvation. In yeast, the difference was up to 1000 fold. "If we get to just a 10-20 fold differential toxicity with human metastatic (spreading) cancers, all of a sudden it's a completely different game against cancer," Dr Longo says. "My hope is that many places around the world will carefully design small clinical trials on starvation and protection against chemotherapy."

He adds that the effects of starvation can also be mimicked by a drug and this approach will also be tested. "We have identified a drug target and drug as well as a modified diet that appear to work almost as well as starvation. Naturally this is the best way to go because a period of starvation longer than 48 hours may be required but would not be possible (in humans) to obtain the same remarkable effects observed in mice" says Dr Longo.

" This is a very important paper. It defines a novel concept in cancer biology," comments cancer researcher Prof Pinchas Cohen, University of California, Los Angeles, UCLA. "In theory, it opens up new treatment approaches that will allow higher doses of chemotherapy. It's a direction that's worth pursuing in clinical trials in humans."

Dr Felipe Sierra, director of the Biology of Aging Program at the National Institute on Ageing, adds, "This is not just one more anti- cancer treatment that attacks the cancer cells. To me, that's an important conceptual difference." The team stresses that fasting is not the same as malnourishment, when inadequate nutrients are taken in, and can easily be tolerated given progress in cancer care. "We have passed the stage where patients arrive at the clinic in an emaciated state. Not eating for two days is not the end of the world," Dr Sierra says. "This could have applicability in maybe a majority of patients," adds David Quinn, of USC Norris Hospital and Clinics, who is preparing the trial with Dr Longo.

The initial trial will study if a 48 hour starvation is sufficient to generate protection, without the risk of making the patient too weak and even more sensitive to chemotherapy. The finding chimes with a range of work on the anti ageing effects of calorie restriction. Dr Longo had been introduced to this idea 15 years ago by the late Roy Walford of UCLA, who showed that a nutritious diet that is low in calories can make a range of species live longer. Dr Longo's team later demonstrated that the anti-aging effect of calorie restriction is caused in part by the ability of cells to become resistant to stress.

The calorie restriction/starvation based method is effective not only because it protects cells but because of Dr Longo's discovery that the same genes that decrease this stress resistance are the ones involved in cancer. "By definition, cancer cells do not require growth factors for growth and do not respond well to anti-growth orders," he says. "Thus, starvation provides an order to all cells to go into a "anti-chemotherapy protected mode" but the only cells that do not respond are cancer cells."


1 comment:

Anonymous said...

"Combination therapy resulted in LDL cholesterol levels that were 27% lower than those achieved with monotherapy. Unexpectedly, however, the trial showed that despite increased lowering of LDL cholesterol in the group that received ezetimibe, the rate of progression of atherosclerotic disease, as measured by intima–media thickness, was the same in the two study groups."

The best (cheap and readily available) blood test predictor of heart disease is the simple ratio: total triglycerides divided by HDL (3X being the grey area, lower being better, mine being exactly 1.0). Nowhere does LDL levels enter into heart disease prediction. It's all ratios, not absolute levels of one thing, be it cholesterol, LDL, HDL, triglycerides, etc.

If they lowered LDL ("bad cholesterol"), what happened to HDL ("good cholesterol") or triglycerides (fatty acid fuel for cells)? Namely, what happened to the relevant ratio of triglycerides/HDL?

HDL is "high density" BECAUSE it it full of triglycerides (fatty oils), but as it courses its way through the body, being a TRANSPORT VEHICLE for both cholesterol and triglycerides, as it empties its treasure of fatty oil, naturally *becomes* LDL. Why? It's just a shell. It practically doesn't exist unless you fill it with oil to give it "high density." An analogy may be had: take a piece of slightly stale bread and dip it in olive oil. It gets really soft, right? Heavier even. More dense.

So perhaps a drug that INTERFERES with the EXTREMELY finely balanced blood system (clotting should only happen for tissue injury not within healthy vessels but this system has many hundred variables!!!) basically, in layman's terms, just "screws everything up."