Gaseous Surface of Jupiter: Many cardiologists are hailing the massive JUPITER trial as a breakthrough, claiming that statin therapy could reduce cardiovascular risk even in patients with normal LDL. The challenge in interpreting the study lies in distinguishing the solid scientific core from the vaporous hype surrounding it. Photo courtesy Hubble Space Telescope/European Space Agency/NASA.

The JUPITER trial, presented last month at the American Heart Association’s annual meeting, may very well be the cardiovascular story of the year. It suggests that rosuvastatin can reduce cardiovascular events and deaths even in seemingly healthy people with normal LDL cholesterol levels.

That is certainly welcome news for statin advocates, who are still smarting from the controversy surrounding Vytorin earlier this year.

Like its namesake planet, JUPITER (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin) is massive, and exerts strong gravitational pull. It is one of the largest prospective primary prevention trials ever undertaken, and for that reason, it warrants serious attention. But as with its namesake, it will take considerable analysis to differentiate the solid scientific matter from the large volume of swirling gas.

Hearts Inflamed

The study, presented at AHA by principal investigator Paul Ridker, MD, of Brigham & Women’s Hospital, Boston, and published that same week in the New England Journal of Medicine, involved 17,802 “apparently healthy” men and women from 26 countries, with normal LDL (under 130 mg/dL) but elevated CRP (>2.0 mg/L). They were randomly assigned to treatment with rosuvastatin (Crestor), 20 mg per day, or placebo.

JUPITER, sponsored by AstraZeneca, the maker of rosuvastatin, was originally intended to run for 4 years, but it was stopped earlier this year after just 1.9 years of follow-up, when interim analysis showed a significant 44% reduction in the composite endpoint of death, heart attack, and cardiac event requiring revascularization therapy.

Among other apparent benefits, the rosuvastatin patients showed a 55% reduced risk of non-fatal MI, and a 48% reduced risk of non-fatal stroke. The investigators deemed it unethical to continue a placebo arm in light of these findings, and opted to close the study.

In his presentation at AHA, Dr. Ridker noted that rosuvastatin lowered LDL by 50% in the treated patients compared with those on placebo, and also reduced CRP by 37%. This, he said, translated into a 20% reduction in all-cause mortality. Dr. Ridker pointed out that all racial and ethnic subpopulations appeared to benefit from rosuvastatin.

The trial definitely underscores the importance of the inflammatory process in CVD, and throws light on a statin’s ability to attenuate that inflammation. Among the major take-home points is that there is plenty of room for prevention, even if LDL values are normal, and especially if CRP is high.

A Slam-Dunk … Or Is It?

On face value, JUPITER scores a slam-dunk for rosuvastatin, and by extension, for statins in general—a blockbuster drug category that has faced considerable bad press in recent years, as well as attrition as “first generation” statins go off patent. The study certainly points to a shiny new indication for rosuvastatin—elevated CRP in healthy people with normal lipids. It is also likely to be a boon for CRP testing.

Many cardiovascular experts are hailing the findings as a major breakthrough; some are calling for a revision of national therapeutic guidelines, and much wider use of statins, even in people who seem to be healthy and at relatively low risk. The potential, they say, is to avert thousands of unfortunate sudden deaths like newsman Tim Russert’s.

Others urge caution. Before we start putting statins in baby formula and public water supplies, we need to look more closely at the data, and tease out the less obvious risks and costs of broader statin use.

In his “Topolog” post on www.theheart.org immediately following presentation of the JUPITER data, Eric Topol, MD, Dean of the Scripps School of Medicine, La Jolla, said the study truly deserves landmark status as one of a very few large-scale primary prevention trials. But he intimated that rosuvastatin might not be quite the life-saver that JUPITER’s investigators and statin advocates would like it to be.

And if it is, it’s likely to be an expensive one.

He points out that the “apparently healthy people” in the trial were actually not so healthy: many were overweight, and 40% had metabolic syndrome at baseline; about 15% were current smokers; 10% had marked family histories of coronary heart disease. Further, baseline CRPs averaged around 4, which is definitely on the high side. In short, many JUPITER subjects were, “at significantly elevated risk,” Dr. Topol said.

Further, while rosuvastatin conferred a 20% relative risk reduction for all-cause death, and a relative reduction of composite endpoints approaching 50%, the absolute risk reductions were small. The percentage of rosuvastatin patients who died from CV events, or who had a non-fatal MI, stroke, revascularization procedure, or hospitalization for unstable angina was 1.6%, versus 2.8% in the placebo arm, an absolute risk reduction of 1.2%. CVD-related deaths, MI, and stroke went from 1.8% in the placebo group to 0.9% in the rosuvastatin group, a risk reduction of 0.9%—a benefit, to be sure, but a pretty modest one.

Based on these figures, Dr. Topol estimated that, “Only 1 person [would be] helped out of 120 treated for a 2 year period.”

Given the drug’s cost (roughly $3.65 per pill), writing prescriptions for all of the estimated 7.4 million Americans fitting the JUPITER patient profile would add roughly $9 billion to the nation’s annual health care tab. The hope is that such an intervention would prevent about 44,000 CV events and more than 18,000 deaths per year, according to a financial analysis by Drs. James Stein and Jon Keevil, of the University of Wisconsin, Madison.

Enter Achilles …

More worrisome was the fact that roughly one in 200 rosuvastatin patients developed diabetes before the study was halted, a far greater incidence than in the placebo group. This was “a statistically significant difference, and something that just popped up,” said Dr. Topol. A statin-associated increase in diabetes has never been seen in any prior statin trials. “There’s a trade-off; reducing death and heart attacks but inducing diabetes risk.”

Diabetes notwithstanding, the JUPITER investigators gave rosuvastatin a clean bill of health, noting no difference in incidence of serious adverse effects between the rosuvastatin and placebo groups.

But many holistically minded physicians have reservations about the safety conclusions. They are concerned about long-term adverse effects like myopathy—especially cardiomyopathy—secondary to statin-induced co-enzyme Q10 depletion, as well as liver damage and cognitive dysfunction, none of which were evaluated in JUPITER.

“Statins interfere with the biosynthesis of CoQ10, and without CoQ10 there is reduced contractile strength of cardiac muscle. The news of wide ranging benefits of statins will be a watershed for an increasing epidemic of cardiomyopathy in the near future,” predicted Roby Mitchell, MD, of the Tahoma Clinic, Renton, WA, immediately following release of the JUPITER data.

Trading MI for CHF?

Dr. Mitchell pointed to a study by researchers at Drexel University, showing a 131% increase in the number of people over age 65 hospitalized for congestive heart failure (CHF) from the years 1980 to 2006. That number went from 348,866 people hospitalized in 1980 to 807,082 in 2006. The trend was particularly strong among women.

Coincidentally—or not—this study was presented at the AHA meeting on the same day as the JUPITER trial. The lead author, John Erwin, III, MD, did not identify statins as the driver of the increased CHF rates, but this period of acceleration in CHF hospitalizations clearly overlaps the era of widespread statin use, which certainly raises a question.

Dr. Erwin’s analysis, “intimates that the increase in incidence of cardiomyopathy is due to longevity made possible by statin drugs, as if cardiomyopathy is a part of the natural aging process,” Dr. Mitchell told Holistic Primary Care. “It is not.”

Richard Ash, MD, director of the Ash Center for Comprehensive Medicine, in New York City, said one of his biggest concerns about statins is their adverse long-term effect on the liver. “Liver function can be affected by statins, even though blood tests are normal. You have to lose about 80% of liver function before traditional blood tests even begin to elevate. So the tests are not really good for early detection of problems, and they can actually be misleading if one does not truly understand what is being measured.”

Over So Soon?

Some observers question whether rosuvastatin’s adverse effect profile would be so squeaky clean if the trial had continued to its original 4-year duration. In his post to a forum on www.theheart.org, cardiologist Sanjay Kaul, MD, of Cedars Sinai Medical Center, Los Angeles questioned the wisdom of stopping JUPITER so early, given that “we have no idea about the long-term safety of very low LDL levels as achieved in this trial.”

Dana Ullman, MPH, founder of Homeopathic Education Services, Berkeley, CA, and an outspoken advocate for natural alternatives to drug therapies, believes there may have been other motives behind the decision to stop the trial mid-stream, beyond the stated concern for the welfare of placebo-treated patients.

“Drug companies love to stop studies early because there are considerably more side effects the longer the studies go. The side effects from statins can be very serious, including a higher incidence of diabetes, crippling muscle problems, kidney disease, and malignant heart rhythms. Stopping this study early conveniently reduces the evidence for evaluating these side effects,” Mr. Ullman told Holistic Primary Care.

Dr. Ross G. Walker, a cardiologist in Sydney, NSW, Australia, echoed these concerns, urging clinicians to keep in mind the gulf that often exists between clinical studies and real world practice.

“In clinical trials, the adverse event rates always appear to be very low, and typically rather close to placebo. In the real world these adverse events are much higher. I have been practicing cardiology for over twenty years, and I can assure you that a significant number of patients taking statins over a long period will experience either some subtle issue or at times a serious problem that significantly affects the quality of their lives,” Dr. Walker told Holistic Primary Care.

He said muscle weakness, myalgias, liver abnormalities, and neuropsychiatric problems are the most common. More worrisome, though, is the fact that, “I am now seeing a number of my patients who have been taking statins long-term, developing cancers unusual for their age group or demographic. This has never been confirmed in carefully designed clinical trials but there has never been a clinical trial of statin therapy beyond ten years, which is when I’m seeing these events occurring.”

There was no increased risk of cancer associated with rosuvastatin in the JUPITER trial. But with only 1.9 years of follow-up, it is not sufficient grounds to dismiss the possibility.

Fare Thee Well, LDL?

Some clinicians believe that while JUPITER validates rosuvastatin as a tool for reducing CVD events, it also challenges the almost ironclad belief that LDL is the key risk factor in CVD. This idea has guided clinical practice for the better part of the last 20 years.

James Ehrlich, MD, a pioneer in early CVD screening, and Chief Medical Officer of Atherotech, the company that brought the VAP (Vertical Auto Profile) lipid test to market, said the JUPITER study, “confirms something we have known for years—that the level of LDL cholesterol is not strongly associated with risk. Most people who have heart attacks have unremarkable LDL levels.”

He said Atherotech will be running VAP tests, which give detailed analyses of a broad spectrum of lipid subfractions, on blood samples from JUPITER study subjects. “It is very likely that the high-risk people, those with metabolic syndrome, will have a high level of Apo B and non-HDL. So it is wrong to consider these people to have a normal cholesterol profile, simply because their LDLs were under 130. LDL is not a good marker for risk.”

The inflammatory component of CVD is very important to consider. But as with the lipid component, it is essential to avoid building practice guidelines around overly simplistic models, said Dr. Ehrlich.

Proceed With Caution

“My concern is that most doctors will take a simplistic approach and automatically put people on statins if their CRP is high. CRP can be high for any number of inflammatory reasons. To commit someone to long-term statin therapy based upon a nonspecific marker is absurd,” he told Holistic Primary Care.

Instead, high CRP should prompt a physician to investigate further to see if the patient truly is at high CVD risk. “Get an advanced lipid test or perform a heart scan or carotid intimal medial thickness test or get a specific marker for risk like Lp-PLA2. It is a call for more information, not an invitation to take an automaton-like approach to prescribing lifelong statins.”

Dr. Walker said statins do have a place in CVD risk management, but physicians need to use them very judiciously. “My concern is that we really do not know the long term (greater than 10–15 year) effect of regularly swallowing these powerful metabolic regulators. Cholesterol is an essential component of the cell membrane and an obligate precursor for bile acid, steroid hormone and vitamin D synthesis.”

He believes statins should be used only in patients who’ve had a prior atherosclerotic vascular event, in any vascular bed, those who have Framingham (or equivalent) 10-year risk greater than 20%, or those whose coronary calcium scores are greater than the 75th percentile for age and sex. “If you do not fit one of the above criteria (regardless of your cholesterol level or hsCRP), there is not one shred of evidence that statin therapy will improve your mortality rates over a prolonged period of time.”

The JUPITER data will likely encourage wider use of rosuvastatin. But Dr. Walker emphasized that a combination of achieving ideal body weight, eating good quality natural food and less of it, having 2–3 hours of exercise (at least) per week, having no addictions (i.e., cigarette smoking, excessive alcohol or illegal drugs) and regularly partaking of happiness—the best medicine on the planet—will reduce your risk for all diseases by 70%, with no potential side effects.