The 2023 Cholesterol Guidelines
A few days ago, the long-anticipated 2018 AHA/ACC Cholesterol Clinical Practice Guidelines were released at the American Heart Association Scientific Sessions 2018 in Chicago.
The update from 2013 was viewed favorably in the cardiology community, as it reflected a large body of evidence that has accumulated since, specifically the recommendations for targeting LDL< 70 mg/dL in secondary prevention and using non-statin lipid-lowering medications (ezetimibe and PCSK9 inhibitors) with proven incremental reduction in cardiovascular events. In primary prevention, the recommendations for the use of coronary calcium score to decide on statin therapy in intermediate risk patients and the use of several ASCVD risk enhancers in borderline risk patients also reflected a decade of accumulating evidence.
In fact, many cardiologists feel that the new 2018 guidelines finally reflect what they already practice or would like to practice. I definitely feel this way, but are guidelines always meant to come that late after the evidence? Also, should guidelines be static documents at specific time intervals? When writing guidelines that will be used by millions around the globe, it is crucial to strike the right balance in being timely in providing guidance for clinicians but also cautious in not providing premature recommendations based on low levels of evidence, which could result in harm. This is not an easy job and the authors of the current guidelines successfully achieved this balance, in my opinion.
At Scientific Sessions 2018 where the new guidelines were released and made headlines in the morning, new science was being presented in the afternoon showing that these guidelines might already be outdated! The REDUCE-IT trial, which showed that icosapent ethyl 4g/day reduced major adverse cardiovascular events by 25%, was only one example.
I could not but reflect: What will be in the next cholesterol guidelines? How outdated will our current guidelines be if we wait another five years? And if new treatments will target triglycerides and inflammation, should we even change the name to “Atherosclerosis Management Guidelines”?
Here are my predictions for the next set of guidelines:
- The LDL target cutoffs will be shifted downwards by 20-30mg/dL. In the highest risk patients we will be talking about LDL targets of <50mg/dL for secondary prevention and <70mg/dL for primary prevention. There is accumulating evidence that “lower is better” and that very low LDL (~20mg/dL) is safe, so as we become comfortable with targeting <70mg/dL in the coming few years, it would be reasonable to move the needle even lower.
- Polygenic Risk Scores (PRS) will be used to risk-stratify patients <40 years of age and target a fraction of the population with high polygenic risk score who would benefit from statin therapy despite their LDL not being >160mg/dL. The predictive ability of the polygenic risk score for CAD is already established and retrospective data show that statin therapy can attenuate the risk of CAD in those with highest polygenic risk score. Establishing the value of implementing PRS in clinical practice will require prospective randomized trials, and we are likely to see that in the near future.
- New non-statin therapies to target ASCVD will emerge and have a major role in treatment. Icosapent Ethyl is leading the way, but other triglyceride lowering agents are also promising, specifically inhibitors of Angiopoietin-like 3 (ANGPTL3) and Apolipoprotein C-3 (APOC3). Antisense oligonucleotide inhibitors of apolipoprotein(a) successfully reduced Lp(a) levels in a Phase 2 trial presented at this year’s scientific sessions. Future phase 3 trials will test whether lowering Lp(a) will reduce CV events. If proven, we might see more emphasis on Lp(a) screening and treatment cut-offs in the next guidelines. Finally and most importantly, the role of heightened inflammation in ASCVD risk is clear. While low-dose methotrexate did not reduce ASCVD outcomes in the CIRT trial, targeted anti-cytokine therapy with canakinumab did improve outcomes in the patients selected for high hsCRP in the CANTOS trial. The next guidelines will likely recommend routine hsCRP screening in secondary prevention to identify patients with residual inflammatory risk (high hsCRP, low LDL) who could benefit from anti-cytokine therapy.
- And then there’s the atherosclerosis vaccine! A “Cutting Edge in Cardiovascular Science” presentation at Scientific Sessions 2018 by Dr. Klaus Ley highlighted that this is possible in mice. Will it be possible to safely manipulate the adaptive immune system in humans to create an atherosclerosis vaccine? The answer is probably yes, but it would be wishful thinking to hope for it in the next guidelines.
Those are my predictions. What are yours?