Degree of LDL Cholesterol-Lowering on High-Intensity Rosuvastatin Determines Clinical Impact

ORLANDO, FL—Greater percent reductions in LDL cholesterol are associated with bigger reductions in adverse cardiovascular outcomes among initially healthy men and women, a new analysis of the JUPITER trial suggests. The findings may help inform the ongoing debate over the merits of LDL goals versus cardiovascular risk reduction in primary prevention.

The data “provide general support for the concept of introducing percent reduction in LDL cholesterol into broader clinical practice, an approach consistent with that being advocated by current European, Canadian, and even US guidelines,” Paul Ridker, MD, MPH, of Brigham and Women’s Hospital (Boston, MA), said during a clinical trial update at the American Heart Association (AHA) 2015 Scientific Sessions.

“Further consideration of percent LDL reduction while on statin therapy might also provide a method to thoughtfully allocate PCSK9 inhibitors, should these agents prove effective for cardiovascular event reduction,” he continued. “This process, of course, will be assisted if the ongoing trials of PCSK9 inhibitors report results stratified by the percent reduction in LDL achieved by background statin therapy.”

Guidelines Vary

There has been controversy in recent years about the need for LDL cholesterol targets after American College of Cardiology (ACC)/AHA guidelines shifted away from a focus on fixed goals and toward an emphasis on reducing cardiovascular risk. But various guidelines remain relatively consistent when it comes to recommended percent reductions in LDL cholesterol, Ridker said.

European Society of Cardiology guidelines recommend fixed targets alone for low- and high-risk patients, but in high-risk patients advise a target of about 70 mg/dL or at least a 50% reduction when that target level cannot be reached. Guidance from the Canadian Cardiovascular Society recommends at least a 50% reduction for low-risk patients and a fixed target of 80 mg/dL or at least a 50% reduction in those at intermediate or high risk. And finally, the ACC/AHA recommendations call for moderate-intensity statin therapy (to give a 30% to 50% reduction in LDL cholesterol) in lower-risk patients and high-intensity therapy (to give at least a 50% reduction) in higher-risk patients.

To explore the relationship between percent reduction in LDL cholesterol and outcomes, Ridker and colleagues examined data from JUPITER, which included 17,802 initially healthy men and women randomized to rosuvastatin 20 mg (Crestor; AstraZeneca) or placebo and followed for up to 5 years. At baseline, mean values of LDL cholesterol, HDL cholesterol, and high-sensitivity C-reactive protein were 104 mg/dL, 50 mg/dL, and 4 mg/L, respectively.

Median percent reduction in LDL cholesterol with rosuvastatin was 50%, albeit with wide variability across the study population. A small proportion of patients had no reduction, roughly half had at least a 50% drop, and the rest had a smaller decline.

The rate of first-ever MI, stroke, hospitalization for unstable angina requiring coronary intervention, or cardiovascular death (primary endpoint) per 1,000 person-years was 11.2 with placebo, 9.2 for those with no reduction in LDL cholesterol (RR 0.86), 6.7 for those with a less than 50% reduction (RR 0.61), and 4.8 for those with at least a 50% reduction (RR 0.41; P < .00001 for trend). Similar trends were seen when looking at reductions in non-HDL cholesterol and apolipoprotein B.

The findings could have potential relevance as PCSK9 inhibitors emerge as a new class of lipid-lowering drugs, Ridker said, noting that patients with large reductions in LDL cholesterol on high-intensity statin therapy would derive the least theoretical benefit from the new agents and those with smaller or no reductions would possibly have the most to gain.

Focus on Both Risk, Benefit Important

In commentary following Ridker’s presentation, Michael J. Pencina, PhD, of Duke Clinical Research Institute (Durham, NC), said that there is a need to focus on both risk and benefit when talking about lowering lipid levels to reduce cardiovascular events. He noted that in the current US guidelines, there is an explicit emphasis on risk and only an implicit focus on benefit (risk reduction is expected as a result of treatment).

Although Ridker’s study highlights the variability in the percent reduction in LDL cholesterol with high-intensity statin therapy and its relationship with outcomes, Pencina said it does not inform whether the degree of LDL cholesterol-lowering could have been predicted from baseline values and whether risk reduction is more strongly related to percent reduction in LDL cholesterol or cardiovascular risk estimated using pooled cohort equations.

Also, the interplay between cardiovascular risk, baseline lipid level, and reduction in lipid level needs to be better understood, Pencina said.

“We agree that reduction in lipid level needs to be incorporated into assessment of benefit, [and] more work is needed to determine if there is a sufficiently simple way to incorporate this approach directly into the guidelines,” he said.

Source: 
Ridker PM, Mora S, Rose L, et al. Cholesterol treatment targets and clinical outcomes: a JUPITER trial update. Presented at: American Heart Association Scientific Sessions; November 10, 2015; Orlando, FL.

Disclosures:

• Ridker reports receiving research grants from the National Cancer Institute, the National Heart, Lung, and Blood Institute, and the NIH, being listed as a co-inventor on patents held by Brigham and Women’s Hospital related to use of inflammatory biomarkers in cardiovascular disease, and having relationships with Amgen, AstraZeneca, Boston Heart, Genzyme, Isis Pharmaceuticals, Novartis, and Pfizer.
• Pencina reports relationships with AstraZeneca, Bioventrix, Boehringer Ingelheim, Bristol-Myers Squibb, DC Devices, Merck, Neostem, Regeneron, Salix, Sanofi, and Theracos.