New AACE Lipid Guidelines Establish 'Extreme' CVD Risk Category

Miriam E Tucker

May 05, 2017

AUSTIN, Texas — In a departure from recommendations by cardiology societies, two endocrine groups have issued new lipid-management guidelines that bring back LDL-cholesterol "targets" and are the first ever to include a new "extreme-risk" category of patients, for whom an LDL-cholesterol level of less than 55 mg/dL is now advised.

These latest guidelines from the American Association of Clinical Endocrinologists (AACE) and the American College of Endocrinology (ACE) are published in the April issue of Endocrine Practice and were discussed on May 4 in a workshop here at the AACE 2017 Annual Scientific & Clinical Congress.

"All the emerging data are saying the same thing: The lower the LDL cholesterol the better, regardless of where your LDL is to begin with," one of the guideline authors, Paul S Jellinger, MD, professor of clinical medicine, University of Miami Miller School of Medicine, Florida, told Medscape Medical News in an interview.

That evidence, he said, led the AACE and ACE to differ from the controversial American Heart Association /American College of Cardiology guidelines of 2013 that removed LDL targets and instead recommended varying intensities of statin therapy to four groups of primary- and secondary-prevention patients.

In contrast, AACE/ACE now recommend LDL goals of < 55 mg/dL, < 70 mg/dL, < 100 mg/dL, and < 130 mg/dL for individuals at extreme, very high, high/moderate, and low risk for cardiovascular events, respectively.  

"Targets are very, very useful. They're strong incentives for both patients and physicians. We have HbA1c goals, we have blood-pressure goals. Why shouldn't we have LDL goals? There is strong evidence that the lower, the better," Dr Jellinger emphasized.

Indeed, he noted that AACE/ACE has, in fact, "never left" LDL targets, as they were a key feature of their prior guidance.

But ACC/AHA guideline coauthor Jennifer G Robinson, MD, professor in the departments of epidemiology and medicine and director, Prevention Intervention Center, the University of Iowa, Iowa City, defended the ACC/AHA approach.

"It is unfortunate that [AACE/ACE] continues to perpetuate LDL-cholesterol and other lipid goals. Low LDL levels may be better — but it matters how you get there and in whom. Using LDL thresholds and considering potential for net benefit are better approaches for personalizing cholesterol-lowering therapy," she told Medscape Medical News.

Targets for Five CVD Risk Categories

The AACE/ACE guidelines divide patients into five atherosclerotic cardiovascular disease (ASCVD) risk categories:

Extreme-risk goals: LDL < 55 mg/dL, non-HDL < 80 mg/dL, apolipoprotein B (apoB) < 70 mg/dL

  • Progressive atherosclerotic cardiovascular disease (ASCVD), including unstable angina, in patients after achieving an LDL-C <70 mg/dL.

  •  Established clinical cardiovascular disease in patients with diabetes, chronic kidney disease (CKD) stages 3/4, or heterozygous familial hypercholesterolemia (HeFH).

  • History of premature ASCVD (< 55 years of age in men, < 65 in women).

Very high-risk goals: LDL < 70 mg/dL, non-HDL < 80 mg/dL, apoB < 80 mg/dL

  • Established or recent hospitalization for acute coronary syndrome, coronary, carotid, or peripheral vascular disease, 10-year risk > 20%.

  • Diabetes or CKD stages 3/4 with one or more risk factors.

  • HeFH.

High-risk goals: LDL < 100 mg/dL, non-HDL < 130 mg/dL, apoB < 90 mg/dL

  • Two or more risk factors and 10-year risk 10% to 20%.

  • Diabetes or CKD stages 3/4 with no other risk factors.

Moderate risk: Same goals as high risk

  • Two or more risk factors and 10-year risk < 10%.

Low-risk goals: LDL < 130 mg/dL, non-HDL < 160 mg/dL, apoB not relevant)

  • 0 risk factors.

For calculating 10-year event risk levels, the AACE/ACE guidelines suggest using one of four established risk calculators: the Framingham Risk Assessment Tool; the Multi-Ethnic Study of Atherosclerosis (MESA) 10-year ASCVD Risk with Coronary Artery Calcification Calculator; the Reynolds Risk Score, which includes high-sensitivity CRP (hs-CRP) and family history of premature ASCVD; and for patients with type 2 diabetes, the United Kingdom Prospective Diabetes Study (UKPDS) risk engine.

FOURIER Was "a Home Run Hit Out of the Ballpark"

In a press briefing at the AACE meeting, Dr Jellinger and coauthor Yehuda Handelsman, MD, medical director and principal investigator, Metabolic Institute of America, Tarzana, California, reviewed some of the evidence they used to formulate these latest AACE/ACE recommendations, as well as newer data that they said support their target-based approach.

The 2014 Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) was the "icing on the cake" that clarified the benefits of extremely tight lipid control for individuals at very high or extreme risk, but there were several meta-analyses pointing in that direction prior to that study, Dr Jellinger said.

These included the 2010 Cholesterol Treatment Trialists' Collaboration and a 2014 meta-analysis of eight prospective randomized trials of statin therapy, both showing benefit for lowering LDL-cholesterol levels to 50 mg/dL or even lower.

And just recently, in March of this year, the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial showed that the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab (Repatha, Amgen) decreased major cardiovascular events — but not cardiovascular or all-cause deaths — when combined with statins, via lowering LDL cholesterol to a mean of 30 mg/dL.

FOURIER totally validated our guidelines in an important way.

"IMPROVE IT clearly nailed it and brought it home, and FOURIER totally validated our guidelines in an important way," Dr Jellinger commented to assembled journalists, adding that he sees FOURIER as "a home run hit out of the ballpark" but that the "grand slam" would come with longer-term data showing a mortality difference.

On the other hand, Dr Robinson asserted, "Although there is incremental further risk reduction from adding ezetimibe [Zetia, Merck] or a PCSK9 monoclonal antibody, no trial has compared titration with different LDL goals.

"Not only are LDL goals not evidence based as stated by this group, titration to goal fails to consider the potential for benefit to the individual patient," she asserted.

Worth the Cost?

The AACE/ACE document includes a discussion of cost-effectiveness of various lipid-lowering strategies.

In general, statins have been proven cost-effective in both secondary and primary prevention of ASCVD events in people at moderate to high risk or those with very elevated (≥ 190 mg/dL) LDL levels.

Ezetimibe coadministered with statin therapy in individuals unable to meet target LDL-C levels has not yet been evaluated for cost-effectiveness in the United States, although studies from Canada and the United Kingdom suggest that ezetimibe may prove cost-effective, particularly with use of generics.

Dr Handelsman noted that in the newly defined extreme-risk group, the chance of a CV event is 10% to 14% per year, climbing to 45% to 50% at 5 years.

Thus, he believes, in those patients the use of combination therapy in the extreme-risk group will likely prove particularly cost-effective. "Look at how much [the patients] cost. It's very expensive to save their lives and probably more expensive to keep them alive."

Dr Robinson sees it differently, however.

"Most patients will not achieve an LDL-C < 55 mg/dL from adding ezetimibe unless LDL-C is <65 mg/dL to start.…It would take more than 100 patients treated for 5 years to prevent one event. Adding a PCKS9 monoclonal antibody might prevent more events, but at no level of risk have these drugs shown to reach any level of cost-effectiveness at current pricing."   

Dr Jellinger is a speaker and/or advisory board member for Novo Nordisk, AstraZeneca, Amgen, Boehringer-Ingelheim, Merck, and Janssen. Dr Handelsman has received research grants from and is a consultant and/or speaker for Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer-Ingelheim, Grifolis, Hamni, Intarcia, Lexicon, Merck, Novo Nordisk, Sanofi, Takeda, Akcea, Amarin, diaDeux, Eisai, GlaxoSmithKline, LipoScience, Vivus, Sanofi, and Regeneron. Disclosures for the coauthors are listed in the paper. Dr Robinson's institution has received research grants from Amarin, Amgen, AstraZeneca, Eli Lilly, Esai, Esperion, GlaxoSmithKline, Merck, Pfizer, Regeneron/Sanofi, and Takeda. She is a consultant for Akcea/Ionis, Amgen, Dr Reddy, Eli Lilly, Esperion, Merck, Pfizer, and Regeneron/Sanofi.

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Endocr Pract. 2017;23:479-497. Article