theheart.org's statin safety survey draws mixed response

March 14, 2012

Montreal, QC - Nearly two-thirds of respondents to a recent theheart.org poll are "somewhat concerned" or "very concerned" about an increased risk of diabetes in patients treated with a statin. And yet the concern does not appear to be derived from what they are seeing in clinical practice, with 686 respondents (87%) stating they have "never" or only "infrequently" observed increases in blood glucose/HbA1c levels in patients. In contrast, just 107 of the 793 individuals say they have observed increases in blood glucose/HbA1c levels.

The survey, intended to assess physicians' concerns about the risk of diabetes in patients treated with statin therapy as well as the potential for cognitive changes in statin-treated patients, is in response to recent labeling changes approved by the Food and Drug Administration (FDA). Taking a statin, according to a label change for the entire drug class, can raise blood sugar and HbA1c levels. The labeling changes also include new information on the potential for usually minor and reversible cognitive side effects.

The change, however, has generated no shortage of debate in theheart.org forum and has befuddled some cardiologists, who think the warning will turn some patients, as well as cardiologists, off the lipid-lowering medications. Of those polled, just 107 of the 793 individuals "often" observe increases in blood glucose/HbA1c levels.

"Statins are among the most studied medications in cardiology, with scores of randomized trials showing morbidity and mortality benefits in diverse populations," commented Dr Ralph Althouse (Swedish Heart and Vascular Institute, Everett, WA). "These benefits clearly outweigh the potential problems of a small increase in glycosylated hemoglobin or a possible ill-defined effect on cognition from case reports rather than randomized trials. These irresponsible statements from FDA will sow panic among patients as well as doctors. If it results in them stopping a proven safe and effective medication studied in randomized trials in hundreds of thousands of patients, it makes a mockery of evidence-based medicine."

Dr Staffan Lindeberg (Lund University, Sweden) expressed the views of many in theheart.org poll when he stated: "Blood sugar is a surrogate variable. Premature death and cardiovascular end points are not."

Dr George Honos (Centre Hospitalier de l'Université de Montréal, QC) agreed, saying the benefits of statin therapy are proven beyond doubt and there is little concern about diabetes or cognitive declines. "These drugs are in large part responsible for the excellent prognosis enjoyed by my cardiac patients who remain asymptomatic for many years with just a yearly visit to my office for renewal of their prescription," he wrote. "I have never encountered a new case of diabetes or cognitive impairment attributable to a statin drug."

Also commenting on the issue, Dr Andrey Espinoza (Hunterdon Cardiovascular Associates, Flemington, NJ) argues that there is a risk/benefit trade-off with any pharmaceutical agent. However, he is not so sure that the increased risk of diabetes is related to the drug, but rather related to inactivity.

"I would still contend that most patients who develop diabetes do so because of dietary and inactivity issues more so than iatrogenic issues," writes Espinoza. "I don't see or treat normal [body-mass-index] BMI patients with diabetes. Almost every diabetic I have ever treated is either overweight or morbidly obese. [In] understanding and appreciating potential for adverse drug effects, I still think our focus should place more of an emphasis on nutrition and exercise. These are two of the most effective tools to combat just about every medical affliction that ails our society."

On the other hand . . .

Despite many clinicians expressing their belief in the value of the drugs in treatment of high-risk patients with cardiovascular disease risk factors or overt cardiovascular disease, a few doctors reiterated the adage "that what the mind doesn't know, the eyes do not see."

To heartwire, Dr Eric Topol (Scripps Clinic, La Jolla, CA) noted that "captopril cough" did not emerge until it was first reported in a case series in the Lancet, and this eventually led to the widespread acceptance of cough as a common side effect of ACE inhibitors. Like the captopril cough, many statin trials were not specifically looking for an increased risk of diabetes mellitus but "backed into the problem." Moreover, the increased risk of diabetes observed in trials became evident only in the past four or five years, having surfaced in studies testing potent statins such as atorvastatin, rosuvastatin (Crestor, AstraZeneca), and high-dose simvastatin. Moreover, with an incidence that ranges between one case of diabetes mellitus in every 150 to 200 treated patients, it would take a large number of patients to observe the off-target effect.

"If physicians start looking for it, they'll see the trade-off of intensive statin dosing: nice LDL levels vs glucose dysregulation in patients without any history of coronary, cerebrovascular, or peripheral disease," commented Topol.

Dr Colin Rose (McGill University, Montreal, QC), like others, said he is very concerned about the potential risks of statin therapy, especially in patients without cardiovascular disease.

"Statins are a moral hazard," Rose commented. "Many patients and even some cardiologists believe that as long as one's 'cholesterol' is low while taking a statin, one can eat anything in unlimited quantities. The vast majority of 'high-risk' primary-prevention patients are obese, and they become even more obese when prescribed a statin and increase their risk of becoming diabetic. So I never prescribe statins in primary prevention."

Likewise Dr Radoslaw Lenarczyk (Silesian Center for Heart Disease, Zabrze, Poland) observed: "I think these findings need to be verified urgently because the problem seems to be serious and can involve many thousands of patients worldwide. If these findings are true, our current practice concerning statin use (especially in older women with risk factors but no overt cardiovascular disease) has to be revisited."

In contrast, Dr Richard Howard (Medcenter One Healthcare System, Bismarck, ND), who said he is "somewhat concerned" about the increased risk of diabetes, believes there might be other mitigating factors.

"I have seen patients with increasing HbA1c who were also taking statins, but usually it is because they are gaining weight and are noncompliant with their diabetes care," said Howard. "I have also noted patients develop cognitive decline over time. They have small-vessel vascular disease and dementia, and they also take a statin for their vascular disease. Did this cause their cognitive decline? Remember the saying, 'post hoc ergo propter hoc'? To my knowledge these associations have never been proven in an RCT [randomized controlled trial], and this just gives patients another excuse to refuse to take an important and potentially lifesaving medication."

Cognitive changes with statin therapy

The role of statins in cognitive decline is even murkier, especially given that much of the evidence is anecdotal. Media reports, including a 2010 story in the Wall Street Journal , have quoted physicians saying that their patients have lost the ability to concentrate or recall words. Others have told heart wire that they had patients who do not believe they are "as sharp" as they were prior to starting statin therapy.

In theheart.org poll, 423 respondents (53%) said they were "somewhat concerned" or "very concerned" about memory loss or cognitive declines in their patients. Despite the concerns, 65% of respondents said they have "never" observed changes in cognitive function in their patients, while 28% reported seeing such changes "infrequently." Only 55 respondents (7%) stated they see changes in cognitive function "often."

One neurologist who responded to the poll, Dr Walter Carlini (Providence Medical Group, Medford, OR), said that he has treated patients with statin-related adverse events. Another physician stated he noticed some cognitive decline in himself when his dose of rosuvastatin was doubled, while yet one more stated that since these data have been published he stopped taking a statin for primary prophylaxis. On the whole, however, these opinions were in the minority, and most of those polled felt that further evidence is needed to firmly establish a link between cognitive decline and statin use, especially given the drug's long track record of safety.

"In terms of cognitive decline, certainly more studies will be needed to objectively define the amount before we can make certain judgments," commented Dr Michael Gillette (Malcolm Randall VA Medical Center, Gainesville, FL), adding that he does "not anticipate significant changes to my current practice."

FDA draws fire

Dr Elena Citkowitz (Yale University School of Medicine, New Haven, CT) is concerned about the message the label change sends to physicians and how this might affect future reporting of adverse events. "The FDA warnings about the cognitive side effects of statins are based on anecdotal reports and, as the FDA states, have not been demonstrated in RCTs," she commented in the survey. "An increase in reports about memory loss, etc, will probably be seen because such symptoms have in a sense been validated by the FDA warning. A formal warning when no objective evidence exists creates a troublesome precedent."

Dr Sherif Labib (Lahey Clinic, Burlington, MA) added that case reports are the weakest form of evidence to establish a causal relationship.

"While [the FDA] correctly point out the softness of the evidence in their letter, cognitive dysfunction or perceived cognitive dysfunction is not an uncommon complaint in the age group that uses statins, with or without its actual use," Labib observed. "The mere possibility of decline in brain function can provoke a negative visceral reaction that may reduce patient compliance among patients who may stand to benefit the most from statin use."

Dr Thomas Nielsen (Southview Medical Group, Birmingham, AL) had similar concerns, stating in the poll that he was worried patients will want to stop their statin because the local paper is reporting the drugs cause "fuzzy thinking."

"The true fuzzy thinking around here is at the FDA," he writes.

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