Statins Remains Therapy of Choice for Most People at Risk for CVD

Despite concerns about the possible adverse effects that statins may in reducing levels of already low sex hormones, most people with type 2 diabetes are at risk for cardiovascular disease and so have more to gain from cholesterol-lowering therapy.

with Suma H. Konety, MD, and Elena A. Christofides, MD

The benefits of statin therapy in primary prevention of cardiovascular disease is undeniable. What is less clear is whether there might be a subpopulation of older adults for whom the endocrine and metabolic risks associated with statins, known as the ‘off-target effects’, might outweigh the benefits.

This treatment conundrum has grown following release of the 2018 American College of Cardiology/American Heart Association cholesterol guidelines, which substantially expanded the number of older individuals who are eligible for statin therapy.1

Low Sex Hormones Levels Raise Concerns about Statin Efficacy

According to the latest cholesterol management guidance,1 statins are recommended for adults ages 40 to 75 years without a history of cardiovascular disease (CVD) who have one or more risk factors (eg, dyslipidemia, diabetes, hypertension, history of cigarette smoking) and have a calculated 10-year risk of a CV event of > 10%, as well as patients with very elevated LDL-cholesterol levels (>190 mg/dL).

What is causing this added concern? Cholesterol is an important component in sex steroid synthesis, particularly as concerns testosterone production, and its inhibition in response to statin therapy potentially may impair gonadal steroidogenesis.2

To address this issue, a group of investigators analyzed data from the multi-ethnic study of atherosclerosis (MESA) study established to assess the effect of statins on sex hormone levels in six communities in the United States.3

MESA is a population-based trial following 6,814 adults, 45-84 years of age, who are Caucasian, African American, Hispanic, and Chinese living in the United States who had no signs of cardiovascular disease when they were originally recruited in 2000-2002.

Cardiovascular Risks Overrides Secondary Concerns in CVD Therapy

Among the participants, 6,171 had fasting blood samples drawn early in the morning to measurement of serum sex hormones at baseline, including dehydroepiandrosterone (DHEA),3 sex hormone binding globulin (SHBG), estradiol (E2), and/or total and bioavailable testosterone.

For this current analysis, women on hormone replacement therapy (n=1,021) were excluded, resulting in a total sample size of 1,987 women and 3,163 men. Of these, 345 women and 464 men were taking a statin (ie, atorvastatin, simvastatin, and pravastatin). The mean age of participants on statin therapy was 67 years; about one in four had been diagnosed with diabetes; 57% were male and 41% were Caucasian. Statin use was associated with lower levels of SHBG and dehydroepiandrosterone (DHEA) in both men and women, as well as lower total testosterone in men.3

There was no significant association between statin use and estrogen or bioavailable testosterone in women or men, and there was no statistical evidence that any of the statins were related to any of the sex hormones.

In an interview with EndocrineWeb, Suma H. Konety, MD, associate professor of medicine- cardiovascular division at the University of Minnesota in Minneapolis and a co-investigator for the NIH-funded MESA project, said: “Cholesterol is a required intermediate in sex steroid synthesis. This was the first study to shed light on the association between statin use and endogenous hormone levels. Most prior observational studies had heterogeneous results.”

Statins are associated with low SHBG levels, and low SHBG levels have been associated with an increased risk of type 2 diabetes (T2D). “These findings might offer a possible mechanistic pathway of how statins may be associated with an increased risk of T2D,” said Dr. Konety.

Does Low Estrogen, Low Testosterone Preclude Statins?

Elena A. Christofides, MD, director of endocrinology associates in Columbus, Ohio, said that she was not surprised by the outcomes, and was reassured that evidence demonstrating off-target effects of statins is now being investigated and discussed.

“Our patients are getting more savvy, doing their own research, and asking intelligent questions, and we need to be able to address their concerns,” Dr. Christofides told EndocrineWeb. She identified two examples of potential off-target effects:

“Women who go through menopause and are not taking hormone replacement therapy are at increased risk of cardiovascular disease as a result of their lower estrogen levels. Taking statins that lowers the levels of sex steroids further may potentially increase their risks of mental health and CVD consequences.

Similarly, while testosterone levels decline in both men and women with aging, lower testosterone levels, will of course, have a greater effect on men, so reducing serum cholesterol with statin therapy may adversely affect men with reduced testosterone levels in men.

Dr. Christofides said, the statins studied in this analysis are older medications, and there are now far more potent statins available that are more commonly prescribed. Similar research would be warranted to address possible off-target effects of these stronger medications. 

In acknowledging limits to the MESA findings, there is a need to delve deeper into possible ethnic differences, which ought to be investigated in light of the multi-ethnic and racially diverse study population, said Dr. Konety, and he hoped future analyses may be able to parse out the different effects of statins based on ethnicity.

“The population followed was older and the measurements were not on target,” said Dr. Christofides, explaining there was not breakout of testosterone ranges. She also wondered about whether the observed off-target effects are recoverable over time.

Does this study warrant changes to current clinical practice?

According to both Drs Konety and Christofides, absolutely not. They both agree that this study suggests statins may not be appropriate for every patient. “If statins are prescribed for primary prevention as per the current ACC/AHA guidelines, the evidence indicates benefits clearly outweigh the risks,” said Dr. Konety.

However, Dr. Christofides said, “we need to take into consideration whether off-target effects are of enough concern to warrant further discussion, and to better identify the group of patients for whom statin risks outweigh their benefits.”

“Statins are and should continue to be prescribed for primary prevention of cardiovascular disease according to the ACC/AHA guidelines; however, this study suggests that statin use may not be appropriate for everyone,” said Dr. Konety.

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