Adding Non-Statin Leads to Even Lower LDL

Addiction MedicineAdding other drugs to lower-intensity statin therapy can lower LDL cholesterol as well as or better than higher-intensity statin therapy, but the effects on long-term outcomes remain uncertain, a systematic review showed.

A low-intensity statin plus a bile acid sequestrant reduced LDL cholesterol levels by 0% to 14% more than moderate-intensity statin monotherapy in high-risk patients with hyperlipidemia, according toKimberly Gudzune, MD, MPH, of Johns Hopkins University School of Medicine, and colleagues.

And compared with high-intensity statin therapy, a moderate-intensity statin plus ezetimibe (Zetia) dropped LDL cholesterol levels up to 15% more in patients with established atherosclerotic cardiovascular disease and up to 21% more in patients with diabetes, the researchers reported online in Annals of Internal Medicine.

Research was lacking into whether those additional reductions resulted in any change in clinical outcomes over the long term or came at the cost of additional adverse events, however.

So even though adding a bile acid sequestrant or ezetimibe to lower-intensity statin therapy could be an alternative to higher-intensity statin monotherapy in patients who can’t tolerate or don’t respond to the higher doses, “clinicians should use these strategies with caution and counsel their patients, given the lack of evidence regarding atherosclerotic cardiovascular disease risk reduction benefits and limited data on adverse events,” Gudzune and colleagues wrote.

Donald Lloyd-Jones, MD, of the Northwestern University Feinberg School of Medicine in Chicago, said the study “reaffirms exactly what we said in the prevention guidelines.”

He was referring to the four guidelines for the prevention of atherosclerotic cardiovascular disease released by the American College of Cardiology and the American Heart Association last November, including one dealing with cholesterol lowering. In it, statins were placed as the treatments of choice based on the strength of the evidence supporting their use — and showing improvements in long-term clinical outcomes — and the weakness of the evidence for other lipid-lowering therapies.

Acknowledging that not all patients tolerate or respond to high-intensity statin therapy, however, Lloyd-Jones and the other guideline authors noted that combinations of lower-dose statins and nonstatin medications may be considered on a case-by-case basis, with certain caveats.

“If you think it’s reasonable to reduce LDL further over and above the maximum tolerated dose of statin, then there are combinations that will reduce LDL further,” Lloyd-Jones said. “But you have to understand that we either have evidence that that does not reduce events further or we’re uncertain. And therefore you have to consider the potential benefits, the potential harms, and use your clinical judgment.”

To assess the relative risks and benefits of combinations of lower-dose statins and various nonstatin therapies, Gudzune and colleagues reviewed data from 36 randomized trials that included adults at high risk for atherosclerotic cardiovascular disease, which included those with an LDL cholesterol level of 190 mg/dL or higher, pre-existing cardiovascular disease, or diabetes. Most of the studies included men in their 50s or 60s.

Although some benefit was found for combinations that included a bile acid sequestrant or ezetimibe, there was not enough evidence to judge the effects of combinations with fibrates, niacin, or omega-3 fatty acids. The evidence also was insufficient to compare long-term clinical outcomes between any of the treatment regimens included in the review.

“This is a nice paper, but I suspect that many clinicians and certainly those with a high interest in lipid treatment already know that lower-dose statin, when combined with a second lipid agent (most know this best with ezetimibe), produced at least similar, but probably slightly better, lipid values (especially LDL cholesterol) compared with lower-dose statins alone,” Carl “Chip” Lavie, MD, of John Ochsner Heart and Vascular Institute in New Orleans, told MedPage Today.

The researchers acknowledged that their analysis was limited by the quality of the included studies: many had a short duration of treatment, high attrition rates, and a lack of blinding. Also, none of the trials included patients with statin intolerance, who might have the most to gain from a lower-intensity statin combination therapy.

The study was funded under a contract from the Agency for Healthcare Research and Quality (AHRQ).

Gudzune reported potential conflicts of interest with the AHRQ and Johns Hopkins Adjusted Clinical Groups Software. Her co-authors reported relationships with AHRQ and Pri-Med CME.

From the American Heart Association:

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