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 Yale-New Haven Hospital, New Haven, Connecticut, USA HealthLINK: Women's Health

January 30, 2002

News this month
Simvastatin plus niacin lower heart attack risk

Two widely prescribed cholesterol-lowering drugs—simvastatin (Zocor) and niacin—can slow, and in some cases, slightly reverse the narrowing of coronary arteries, according to a study published in The New England Journal of Medicine. On its own, simvastatin reduces bad cholesterol, or LDL, while niacin is known to boost good cholesterol, or HDL. The study results show that when simvastatin and niacin are combined, heart disease can be slowed, and in some cases reversed.

When simvastatin and niacin are combined, heart disease can be slowed, and in some cases reversed.

Much of current cholesterol treatment is directed toward lowering high levels of LDL, but studies have shown that raising HDL may have an equal impact on reducing the risk of heart attack or other cardiac events. About 40 percent of those with heart disease have low HDL levels.

Cholesterol study
In the study, lead author B. Greg Brown, MD, professor of medicine at the University of Washington School of Medicine, and his colleagues placed 160 heart patients—87 percent of whom were men with an average age of 53 years old—who had low HDL (under 35 in men and 40 in women) and normal LDL levels into one of four groups:

  • One group received simvastatin and niacin, which is vitamin B3.
  • Another group was placed on 800 international units of vitamin E, 1,000 milligrams of vitamin C, 25 mg of beta-carotene and 100 micrograms of selenium. Antioxidants, especially vitamin E, have been found to inhibit LDL cholesterol. Studies are mixed on whether they reduce heart disease.
  • A third group was placed on both the drugs and the antioxidants.
  • A fourth received placebos.

All were given dietary counseling and participated in a cardiac rehabilitation program.

At the start of the study and after three years, all participants were given angiograms, which measured the plaque buildup on the artery walls. Too much plaque can close up an artery, stop blood flow and lead to a heart attack.

Plaque decreased by 0.4% among those on simvastatin and niacin.

Results look promising
The angiograms showed that for those on placebo, plaque increased 3.9 percent over three years. By comparison, plaque decreased by 0.4 percent among those on simvastatin and niacin. Those on antioxidants showed a 1.8 percent increase in plaque buildup and those on both the drugs and antioxidants showed a 0.7 percent increase.

Positive impact on “cardiac events”
Results were similarly impressive when looking at heart attacks or other “cardiac events.” There were 12 cardiac events among those on placebo, including one death; 11 among those on antioxidants; six among those on both drugs and antioxidants, including one death; and only one among those on the simvastatin and niacin.

Each drug alone has been shown to reduce heart attacks and other events by 30 to 40 percent, but the two medicines together nearly doubled this positive effect.

Among those on simvastatin and niacin, LDL levels fell 42 percent; triglycerides fell 36 percent, and HDL2, the most protective form of HDL, according to Brown, rose 65 percent. These changes are significantly greater than previous studies have indicated from either drug used alone.

“…if you want to raise HDL with therapy, you should probably not be using antioxidants.”
- B. Greg Brown, M.D.

Antioxidants
“Our interpretation is that if you want to raise HDL with therapy, you should probably not be using antioxidants,” Brown said. On the other hand, using a statin drug and niacin together is “probably underprescribed,” he said. Although the study used only simvastatin, Dr. Brown says the results of a combination probably would be similar if one of the other statin drugs was used.

Patients treated only with the vitamin combination did better than the placebo group but worse than the group that received only simvastatin and niacin. And a fourth group that received the vitamins plus the two drugs had worse results than those who received the two drugs alone, suggesting that antioxidants may blunt the benefits of statins and niacin.

Antioxidant vitamins (in this case, Vitamins E, C, beta carotene and selenium) are thought to reduce a process called oxidation that makes LDL cholesterol more likely to collect and form plaque inside artery walls. Some recent studies, however, have questioned whether these vitamins really slow down oxidation. Antioxidants are “not proven to be of any value. In fact, they interfere,” said Dr. Brown.



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Leonard Grauer, M.D. portrait

Combination drug therapy shows promise but needs study

Although the beneficial effect of using a combination of simvastatin and niacin is not surprising to most doctors, the degree of improvement demonstrated in this very small study is striking. Combination therapy reduced the three-year risk of having a cardiovascular event (heart attack, stroke, angioplasty, coronary bypass operation or a cardiac death) to only one in 33 patients versus eight of 34 patients in the placebo-treated group.

“The degree of improvement demonstrated in this very small study is striking.”

Statin drugs
In general, statin drugs lower the level of low-density lipoprotein (LDL) cholesterol, and they slightly raise levels of high-density lipoprotein (HDL) cholesterol. This statin class of drugs has proven to be very effective in lowering cholesterol and cardiac event rates in many large studies. What was unusual in this small, combination drug study was the low dose—13 milligrams—of simvastatin. In previous studies, 20 to 40 milligrams was used.

Niacin
Conversely, the dose of niacin, which is usually considered a second-line drug that works primarily by raising HDL cholesterol, was very high compared to the dose that most patients can tolerate. Many people have difficulty taking these high doses of niacin because of the common side effect of flushing. In this study, the dose was 2,400 milligrams, which is much higher than many people would be able to handle comfortably.

“In this study, the dose [of niacin]…is much higher than many people would be able to handle comfortably.”

Niacin has been available for many decades. It tends to raise the HDL or “good” cholesterol. Other than flushing, it has very few common side effects. Some new slow-release formulations of niacin are now available that may make larger doses easier to tolerate. Also, if it is taken at night and with food, and if the dose is gradually increased, it may produce less flushing.

Like the statin drugs, about 1 percent of the people who take niacin may experience some reversible liver abnormalities. Niacin also tends to raise blood sugar levels slightly.

Need additional studies
This study indicated combination therapy had a favorable effect on cholesterol levels and resulted in slight improvements in arterial narrowing. The greatest benefit was clearly the markedly reduced risk of cardiovascular events for participants who took both niacin and simvastatin. Twenty-four percent of those on placebo had a cardiac event, such as a heart attack, compared to 3 percent of those taking the combination of niacin and simvastatin.

The study, however, involved a very small group of patients; additional studies involving many more patients are clearly needed. Remember, most of the statin studies have included between 3,000 and 6,000 patients. This one began with only 160 patients and ended with 146, spread across four treatment categories.

Most participants were relatively young men. All had premature heart disease, low HDL cholesterol levels and mildly elevated LDL cholesterol. They were followed over a three-year period.

Before there are major changes in treatment approaches, much larger studies are needed to confirm the findings reported here. Also, we do not yet have a head-to-head comparison of a low dose of a statin combined with a high dose of niacin, as used in this study, to treatment with just a high dose of a statin. Which would be better?

Antioxidants not showing promise
This study also included a small sample of patients taking antioxidants, including vitamin E, C, beta-carotene and selenium. These patients showed no benefit from antioxidant therapy, and those participants who took the antioxidants in addition to niacin and simvastatin did not fare as well as those taking niacin and simvastatin alone. Again, the study was too small to draw any conclusions, but there is no evidence to suggest taking vitamins offers any benefit to those with heart disease.

Cholesterol management
One interesting sidelight is that those on placebo experienced some improvements in cholesterol levels. They began with average LDL levels of 127 and reduced them to 116 with no drug therapy. Probably the dietary counseling and exercise programs that were used for all patients regardless of their drug treatment group were beneficial.

The Framingham Heart Study, the landmark study, begun in 1948, which has taught us much of what we know about heart disease and its risk factors, indicates the single most valuable number to look at in regard to cholesterol is the ratio of total cholesterol to HDL. If that ratio is under three, an individual has a very low risk of developing heart disease. Patients in this study began with a ratio of 6.5. After simvastatin/niacin treatment, that ratio improved to 3.5. The placebo-treated group's ratio improved slightly from 6.2 to 5.2, probably because of a better diet and regular exercise.

One wonders if outcomes of the simvastatin/niacin group would have been even better if a higher dose of simvastatin had been used to further lower LDL levels, thereby lowering total cholesterol levels and thus improving the total cholesterol-to-HDL ratio even more.

Controlling cardiac risk factors
Better control of cardiac risk factors has yielded major benefits. Years ago, it was not uncommon to see relatively young people in their 50s and 60s suffering from very severe heart attacks. With the discovery of new drugs, better modification of risk factors, improved methods of early detection and newer treatments (such as coronary angioplasty and coronary bypass operations), we seldom see severe heart attacks in individuals in their 50s and 60s. Better prevention and better treatments result in improved outcomes.

I doubt whether this small pilot study will dramatically change how physicians treat their patients; however, it should serve as the foundation for future larger and more comprehensive studies that will provide us with more information about how best to manage cholesterol and reduce the risk of cardiovascular disease.

Dr. Grauer, whose office is in New Haven, is the founding member of The Cardiology Group, P.C. He is a cardiologist at the Yale-New Haven Heart Center and Yale-New Haven Hospital, as well as an associate clinical professor of cardiology at the Yale University School of Medicine.

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