For the millions of people taking statins to control their cholesterol, the drugs can be life-saving. But concerns about the medications arose five years ago when a study linked them to a small increase in diabetes risk, putting a blemish on the drugs’ relatively clean safety record. Now, after further study, experts say the risk is limited to people who are already likely to develop diabetes, and even among these individuals, the heart-health benefits of statins outweigh the potential downsides.

A quarter of Americans aged 45 and older take Lipitor, Zocor, and other statins to lower high cholesterol levels, a major risk factor for heart attack and stroke. U.S. pharmacists doled out nearly 250 million scripts for the drugs in 2011, making statins the second most dispensed class of prescription medications, according to IMS Health, a healthcare technology and information company.

The drugs, first introduced in the 1980s, have revolutionized the treatment of cardiovascular disease. The death rate from heart disease plunged by nearly a third between 1999 and 2009 in the U.S., and many experts credit the widespread use of cholesterol-lowering statins as one of the reasons for the decline.

Still, the drugs haven’t been completely free of controversy. When a large 2008 trial of the drug Crestor (rosuvastatin) and subsequent analyses linked statins to a small increase in diabetes risk, the findings raised alarm among patients.

But more recent studies have fine-tuned researchers’ understanding of the relationship between statins and diabetes. The latest analyses clarify that the diabetes risk doesn’t apply to all statin takers, only those who are already on the verge of developing the disease. Even in these patients, the heart health protection offered by statins exceeds the hazards, according to most experts.

Statins: A Track Record of Success

Among people who have already had a heart attack or another cardiovascular event, the power of statins to save lives is indisputable. “The data are unequivocal,” said Vincent Bufalino, MD, a spokesperson for the American Heart Association and Senior Medical Director of Cardiology for Advocate Medical Group in Illinois. “The reduction in heart mortality is sizable.”

However, many people taking statins have no history of heart disease — they are prescribed the drugs as a line of defense against a first heart attack or stroke because they have elevated cholesterol, a family history, or other heart risk factors. The medical community has engaged in vigorous debate about whether statins produce a large enough benefit to justify prescribing them to millions more Americans as a preventive strategy, but the latest evidence has come out squarely in support of statins. A comprehensive Cochrane review, published this year, found that treating 1000 people without heart disease with statins for five years could prevent 18 heart attacks, strokes, or other major heart problems. This reduction is similar to the improvement seen with established measures for cardiovascular disease prevention, such as lowering blood pressure with medication.

“Most people believe statins are effective — the question is giving them to the right people,” said C. Michael Minder, MD, a cardiology research fellow at the Johns Hopkins Ciccarone Prevention Cardiology Center.

“There’s no question that certain patients are going to have side effects,” Dr. Minder said. The key, he said, is to identify those for whom the benefits outweigh the harms, which include a slightly higher risk of diabetes.

An analysis of 13 trials, published in the journal Lancet in 2010, found that individuals taking statins as a group were 9 percent more likely to develop diabetes. This risk translates to one additional case of diabetes for every 255 people taking statins over a four-year period — a small but meaningful increase. Other studies show statins slightly raise blood sugar levels, which likely accounts for the uptick in diabetes cases. High-dose statins hike the diabetes risk an additional 12 percent.

These findings prompted the U.S. Food and Drug Administration (FDA) last year to add a warning to all statin labels disclosing the risks for increased blood sugar and diabetes, but the agency stressed that the label change should not deter people from taking the medications.

And the latest research, published after the FDA issued the new safety warning, has further allayed concerns about statins and diabetes. Two analyses from large statin trials found that drugs increased diabetes rates exclusively in people who already had risk factors for the disease, such as above-normal fasting blood sugar or obesity, at the time they started taking the prescription.

In one of these studies, researchers from Brigham and Women’s Hospital and Harvard Medical School reanalyzed data from the 2008 JUPITER trial, the same study that first revealed a link between statins and diabetes. This follow-up analysis divided participants into two groups — a high-risk group that had at least one risk factor for type 2 diabetes and a low-risk group that had no diabetes risk factors. Individuals in the high-risk group who took a statin had a 28 percent increased risk of diabetes compared to those taking a placebo pill, but statin takers without any diabetes risk factors were no more likely to develop the disease than the placebo group. In fact, there were zero new cases of diabetes in the low-risk group. Further, in the group at high risk for diabetes, statins prevented 134 cardiovascular events or deaths for every 54 new cases of diabetes diagnosed.

“[Statins have] a slight effect on changing the progression of diabetes,” said Om Ganda, MD, Director of the Lipid Clinic at the Joslin Diabetes Center in Boston. “They don’t really cause diabetes in people who are at low risk to begin with.”

And even among people who have a higher chance of developing diabetes, the benefits of preventing severe, life-threatening heart problems and even death exceed the increased risk for diabetes, according to many experts. “You don’t want to introduce a new disease such as diabetes, but a lot of these people in the high-risk group will probably go on to develop diabetes anyways, and if you can prevent a heart attack or stroke or major operation, a lot of the patients at the end of the day will say that’s a reasonable tradeoff,” said Minder.

Statin Type May Impact Diabetes Risk

However, all statins aren’t created equal. A new analysis published online in April 2013 in the American Journal of Cardiology confirms previous findings that some statins may pose a higher diabetes risk than others. The study examined 17 past trials involving a total of five different statins and found that Crestor was associated with the greatest increase in diabetes cases relative to a placebo pill. Pravachol (pravastatin), a weaker statin in terms of its cholesterol-lowering abilities, was associated with the lowest rate of diabetes.

When treating people who have already had a heart attack or another cardiovascular problem, there is no doubt that doctors should prescribe a powerful statin to prevent a second event, said Eliano Navarese, MD, PhD, the new study’s lead author and a cardiologist. “But primary prevention [in people who do not have heart disease] is a gray zone where judgment should be based not only on the power to reduce cholesterol but also on awareness of avoiding diabetes in patients,” he said.

“There definitely seems to be a signal that more potent statins are associated with a higher risk of developing new-onset diabetes,” confirmed Minder.

“In my own practice, if I feel like a patient would benefit from a statin, but they have pre-existing diabetes or risk factors for developing diabetes, I’m more likely to reach for a drug that is less likely to worsen blood sugar, such as pravastatin,” he said. However, a stronger statin may be necessary if a patient’s cholesterol levels are well above the targeted range. “It’s a case-by-case basis,” said Minder. “If you’re not lowering their cholesterol you’re not doing them a service. You want to lower their cholesterol, but do it in the safest way possible.”

The people at risk for diabetes are often the very same individuals who are at risk for heart disease, said Dr. Ganda. “Preventing heart disease in people with diabetes is very important so one should not withhold the use of statins in people who are at risk for diabetes.”

Instead, Ganda said the best strategy for diabetes prevention is lifestyle change. Everyone with prediabetes, or elevated blood sugar levels, can benefit from losing weight, eating better, and exercising, but it’s even more important for those in this group who are starting on a statin. Dropping even 10 pounds may lower their risk of developing diabetes after they begin taking the medication, he said. And these same changes can also protect against heart attacks and strokes.

Dr. Bufalino agrees that adopting a healthy lifestyle is critical. When people who are at risk for diabetes begin taking a statin, it’s even more important for doctors to closely monitor these patients’ blood sugar levels, he added.

Physicians and their patients need to take many factors into consideration when choosing the best strategy for heart disease and diabetes prevention, said Ganda. “Every patient is different — individual treatment is very important.”