About 1 in 5 CAD patients who take statins do not achieve effective reductions in LDL cholesterol levels, thereby setting the stage for plaque progression, according to a meta-analysis published online February 26, 2015, ahead of print in Arteriosclerosis, Thrombosis, and Vascular Biology.

The study underscores the importance of monitoring LDL cholesterol levels after the start of statin therapy to ensure adequate response, say Stephen J. Nicholls, MBBS, PhD, of the University of Adelaide (Adelaide, Australia), and colleagues.

The investigators looked at pooled data from 7 prospective trials on 647 statin-naive patients who had established CAD and were started on rosuvastatin (46.9%), atorvastatin (31.2%), pravastatin (17.6%), or simvastatin (5.0%). All underwent IVUS imaging to determine plaque severity.

One-fifth of the patients were statin hyporesponders, defined as experiencing less than a 15% reduction in LDL cholesterol over follow-up; these subjects had similar baseline characteristics across the trials. Compared with responders, they were more likely to be younger, male, and obese and less likely to have a history of hypertension or dyslipidemia or to be treated with beta blockers at baseline.

Hyporesponders were more likely to be treated with atorvastatin and simvastatin and less likely to receive rosuvastatin. They also received smaller doses of atorvastatin and rosuvastatin but similar doses of pravastatin and simvastatin. There were no differences between responders and hyporesponders in the proportions receiving 40 mg atorvastatin, 20 mg rosuvastatin, 80 mg simvastatin, or 40 mg pravastatin. Use of other antiatherosclerotic medications at follow-up also was similar between the groups.  

Although at baseline the atheroma burden was similar between the groups, hyporesponders had smaller external elastic membrane (P = .005) and lumen volume (P = .03). These patients also exhibited less calcified disease, as evidenced by smaller percentage of IVUS images containing calcium (P = .04).

At baseline, risk factor control did not differ between the 2 groups, except for lower levels of LDL cholesterol and systolic blood pressure in hyporesponders.

Greater Progression to Atherosclerosis

Predictably, LDL cholesterol levels at follow-up were higher in hyporesponders than in responders (2.6 ± 0.6 vs 1.9 ± 0.6 mmol/L; P < .001). Interestingly, poor responders showed a 6.2% increase in LDL cholesterol at follow-up, which correlated with a higher triglyceride level (P < .001) and lower levels of HDL cholesterol (P = .004) and fasting glucose (P = .01).

Even after adjustment, hyporesponders showed greater progression in percent atheroma volume than responders despite being on the cholesterol-lowering medication. In addition, they were more likely to undergo substantial progression (> 5% relative increase) and less likely to demonstrate substantial regression (< 5% relative decrease). Although there was no difference in remodeling index, hyporesponders experienced a greater reduction in lumen volume (table 1).

The reasons for poor response to statins are not well understood, the authors say, though genetic variations affecting intestinal cholesterol absorption and/or production are a possibility. Poor adherence is an obvious potential explanation for “hyporesponse” to statins, they note, yet in the clinical trials in the current analysis the subjects were closely monitored and their compliance was greater than 90%.

The rapid disease progression seen in statin hyporesponders may be due not only to an increase in LDL cholesterol (6.2%) but to the diminution of statins’ pleiotropic effects, the investigators suggest. For example, the drugs have been shown to lower levels of the proinflammatory C-reactive protein (CRP), and hyporesponders tended to have a smaller reduction in CRP than responders (-16.7% vs -33.6%; P = .16).

“Ongoing clinical trials might elucidate an effective therapeutic strategy modulating inflammation associated with atherosclerosis,” Dr. Nicholls and colleagues say.

In addition, recent studies suggest that “the downregulation of cholesterol synthesis by statin therapy is compensated by a rise in intestinal cholesterol absorption,” they observe, and this statin-mediated effect might result in suboptimal lowering of LDL cholesterol levels in hyporesponders.

“Our current study underscores [the importance of] monitoring [LDL cholesterol] level after commencement of statin to ensure adequate response to statin therapy,” the authors conclude. “[It] also highlights clinical needs for emerging antiatherosclerotic therapies [that] modify additional targets in statin hyporesponders.”

In fact, recent data suggest the efficacy of alternative cholesterol-lowering agents such as ezetimibe (Zetia, Schering-Plough) and PCSK9 inhibitors. For example, results of the IMPROVE-IT trial, presented at the American Heart Association Scientific Sessions in November 2014, show that in ACS patients ezetimibe lowers LDL cholesterol more than simvastatin alone and reduces a composite of clinical events by 6.4%. And in the placebo-controlled DESCARTES trial, at 1 year the PCSK9 inhibitor evolocumab (Amgen) significantly reduced LDL cholesterol levels in hyperlipidemic patients over a range of risk.

Source:
Kataoka Y, St. John J, Wolski K, et al. Atheroma progression in hyporesponders to statin therapy. Arterioscler Thromb Vasc Biol. 2015;Epub ahead of print.

Disclosures:

• Dr. Nicholls reports receiving consulting fees, speaker’s honoraria, and research support from multiple pharmaceutical companies.

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