Statins: The Good, the Bad, and the Unknown

Talking About Statins and Drug-Lifestyle Interaction

In July, Medscape posted "Growing Doubt on Statin Drugs: The Problem of Drug-Lifestyle Interaction," a perspective by cardiac electrophysiologist Dr John Mandrola about the value of statin medications in primary prevention for cardiovascular disease (CVD). The driver for his article was a recent experience in which he treated a patient's myalgia and arthralgia by discontinuing her statin. Dr Mandrola had no qualms about stopping the statin, citing a lack of data supporting a significant benefit for these drugs in primary prevention.

The commentary generated more than 600 responses from Medscape readers, a substantial majority of whom agreed with his viewpoint. This is a particularly interesting observation in light of the American College of Cardiology (ACC)/American Heart Association (AHA) "Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults," published in November 2013,^[1] which eliminated treating to target lipid-level goals based on patient risk for CVD and instead identified four subgroups of patients for whom high-, moderate-, or low-intensity statin therapy would be recommended.^[2,3]

The stakes are high. Estimates of the number of US adults who would be newly eligible for statin use under the new guideline range from 12.8 million^[4] to 45 million.^[5] Put another way, about 1 in 3 American adults overall, and perhaps as many as 1 billion worldwide, would be potential candidates for statin treatment.^[6] In an editorial in the Journal of the American Medical Association (JAMA), Dr John Ioannidis estimated that the total sales of statins may approach $1 trillion worldwide by 2020; the most commercially successful drug in history, atorvastatin (Lipitor®), had sales exceeding $120 billion between 1996 and 2011.^[6]

Comments from our readers about this contentious issue clustered in four major themes.

Statin Use in Women, the Elderly, and People Without CVD

The 2013 ACC/AHA guideline and two subsequent meta-analyses concluded that statins, as primary prevention, reduce overall and CV-related mortality and CV events in people at low risk for CVD.^[7] In light of this, a substantial number of readers were concerned that the ACC/AHA guideline would lead to indiscriminate use of statins as primary prevention in populations that might not substantially benefit from them. Readers who commented on this focused on women and the elderly (generally those in their 70s-90s).

Is it true that "no study has shown any benefit in women," as a family physician commented on Medscape? There has been substantial debate over this issue. In a letter to the editor published in American Family Physician in 2006, Michael Allen, MD, writing on behalf of the Canadian Academic Detailing Collaboration, noted that the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP-III) report published in 2002, until now the previous authoritative guideline on statin use as primary prevention, based their rationale for therapy in women on extrapolation of benefit in men.^[8] However, since then, other studies have shown a more conclusive benefit in women. In 2012, Kostis and colleagues^[9] published a meta-analysis of 18 randomized trials of 141,235 participants, 40,275 of whom were women, demonstrating a significant reduction in all-cause mortality and cardiovascular (CV) events in both men and women who were taking statins compared with those taking placebo or receiving usual care.

Another Medscape reader, a geriatrician, commented that he "did not find reliable data for the benefit of statin use in the elderly." As with women, recent research has shed new light on this growing population. A 2013 meta-analysis^[10] of eight randomized trials that included 24,674 patients aged 65 years or older without known CVD concluded that statins significantly reduced the risk for myocardial infarction and stroke compared with placebo. However, statins did not lower the risk for all-cause or CV-related mortality. A meta-analysis^[11] of randomized trials and observational cohort studies involving 13,622 elderly participants, over a quarter of whom were 80 years old or older, found insufficient data to make any recommendation regarding statin treatment in this population.

The new ACC/AHA guidelines^[1] describe four subgroups of patients in whom the benefits of statins outweigh the risks:

• Patients with clinically evident atherosclerotic CVD (ASCVD);

• Patients with primary low-density lipoprotein (LDL) cholesterol levels of 190 mg/dL or higher;

• Patients with type 1 or type 2 diabetes and an LDL cholesterol level of 70 mg/dL or higher in patients aged 40-75 years; and

• Patients with a 10-year risk of ASCVD of 7.5% or higher and an LDL cholesterol level of 70 mg/dL or higher, also in patients aged 40-75 years.

In addition to changes in the LDL thresholds used to determine eligibility for statin intervention, the new guideline changed the CV risk formula from the Framingham risk calculator used in the 2002 NCEP ATP-III report^[12] to a newer algorithm incorporating community-based pooled cohorts and development of the initial hard ASCVD event (defined as first occurrence of nonfatal myocardial infarction, coronary heart disease death, or fatal or nonfatal stroke).^[13]

Most of the increase in the number of American adults theoretically eligible for statins under the new guideline would be observed among those without CVD—the fourth subgroup— or about 10.4 million new people.^[4] To a lesser degree, the guidelines would potentially contribute to an increase in the number of eligible diabetic patients—the third subgroup—because the LDL threshold for statin eligibility was lowered from 100 to 70 mg/dL.

It is worth noting that the ACC/AHA guideline, like its predecessor, does acknowledge the limited data available in the elderly, specifically those older than 75 years old:

Few data were available for individuals >75 years of age. Additionally, in individuals 40 to 75 years of age with < 5% estimated 10-year ASCVD risk, the net benefit from statin therapy over a 10-year period may be small.^[1]

The guideline continues by stating that in patients in whom risk-based treatment decisions are uncertain despite quantitative risk assessment, shared decision-making is critical. As Dr Neil Stone, lead author of the new ACC/AHA guideline, told Medscape in an interview published on August 27, 2014, the discussion of CV risk is a four-step process that includes determination of a risk factor profile, discussion of optimal lifestyle choices, examination of benefits and risks associated with statins, and finally an "informed patient preference."

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Cite this: Gordon H. Sun. Statins: The Good, the Bad, and the Unknown - Medscape - Oct 10, 2014.