Ready to take the next step in management of your patient with hyperlipidemia? Dr. Erin Michos (@erinmichos) returns to give us a lesson in Advanced Lipidology. She updates us on what new medications we can use for those difficult to treat lipids and what medications are on the horizon.
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Atherosclerotic cardiovascular disease (ASCVD) is the buildup of cholesterol/plaque in arteries, or atherosclerosis, and can lead to acute coronary syndrome (ACS), peripheral arterial disease (PAD), myocardial infarction (MI) or stroke/cerebrovascular accident (CVA). When referring to the commonly utilized ASCVD risk calculator, we are looking at the risk for both fatal and non-fatal MI and stroke
The ASCVD risk calculator is just one of several cardiovascular disease risk calculators, however this one is supported in several studies and based primarily on guidelines from 2013 (Goff 2013). It is a peer-reviewed calculator that uses pooled cohort equations from several massive studies by the NHLBI to estimate 10-year primary risk of ASCVD among patients with pre-existing cardiovascular disease between the ages of 40 and 79. The calculator utilizes race, sex, and co-morbidities (e.g. diabetes, hypertension, and hyperlipidemia) to estimate risk.
The 2013 recommendations encouraged use of the calculator to guide ASCVD treatment for patients at risk. By 2018, however, providers recognized that the calculator does not necessarily utilize or include important risk enhancing factors, as described by Dr. Michos. These factors may place patients at higher risk, in order to drive the decision-making process when it comes to prescribing lipid-lowering medications. The 2018 update is, therefore, just another aspect of a large evolution within medicine over the past decade to drive decision-making based on patient-centered, individualized care. With the update, the decision to start statins for patients is more personalized and less concrete (Grundy 2018). As years have passed, more information regarding those who are “borderline” or “intermediate” risk has emerged, making the decision to start lipid-lowering medications less black and white. Even since the 2018 update, providers have shifted their practice even more to include risk enhancing factors in the decision-making process. For example, the Coronary Artery Calcium (CAC) score has come about as a significant new modality that drives management of ASCVD (more below).
As per Dr. Michos, “primordial” prevention, or the emphasis on lifestyle intervention, should be prioritized first above anything else when it comes to ASCVD management. We should stress this education with patients as early as possible. She specifically notes that it’s not necessarily the magnitude of LDL burden but the duration of exposure that really determines ASCVD risk. There is no such thing as too much education regarding diet and exercise! These lifestyle factors are the absolute key to preventing ASCVD, and should be the cornerstone of patient discussion, whether on medications or not.
Diet alone has the potential to decrease LDL by 30-40 mg/dL! We should highlight the importance of having a diet rich in fruits, vegetables, and lean meats and sparse in saturated fats and red meats (Grundy 2018). It is essential that patients strive for moderate aerobic exercise at least 4 times per week for 30 minutes at a time (expert opinion). CDC recommends adults need 150 minutes of moderate-intensity physical activity and 2 days of muscle strengthening activity, according to the current Physical Activity Guidelines for Americans (CDC Website)
Since the 2018 update, we have 4 ASCVD risk categories. These are according to the patient’s 10-year ASCVD risk:
We should use risk-enhancers and CAC (as below) to help guide management for patients who are in the borderline and intermediate ASCVD risk groups.
For patients in the “intermediate” risk category, it is typically recommended to start a moderate-intensity statin based on discussion with the patient and particularly with the presence of risk-enhancing factors (class I recommendation).
For patients in the “borderline” risk category, consider a moderate-intensity statin based on patient discussion and the presence of risk-enhancing factors (class IIb recommendation).
Patients with diabetes mellitus and age between 40 and 75 years should be prescribed a moderate-intensity statin (class I recommendation) or a high-intensity statin (class IIa recommendation) regardless of cholesterol/LDL levels and ASCVD risk.
Patients with LDL > 190 mg/dL should be prescribed a high-intensity statin regardless of ASCVD risk (class I recommendation).
What are these risk-enhancing factors specifically? (Grundy 2018) Include but not limited to the following –
Per Dr. Michos, Coronary Artery Calcium (CAC) scoring is a valuable modality to risk-stratify patients, particularly for those in the borderline and intermediate risk categories. It is both a sensitive and specific marker to corroborate risk for certain patients that may be hesitant to start a statin. Not only does it help justify the decision to start a statin/other lipid-lowering medication, it may also be a significant driver to defer medications if negative (powerful negative predictive value when CAC is zero). According to the MESA study (Bertoni 2016), patients with diabetes and a CAC score of zero had similar outcomes as patients without diabetes.
Guidelines recognize certain patient demographics that CAC primarily targets (Grundy 2018):
Biomarkers can be very useful to help drive management of patients – particularly patients who may have refractory hypercholesterolemia. Dr. Michos’s expert opinion is to check Lp(a) levels in ALL patients at least once – but it is particularly important to check levels in those with a strong family history of hypercholesterolemia as well as in those with a premature history of CAD. Because Lp(a) levels are strongly dependent on genetic inheritance, it is important to take a detailed family history for patients who are high-risk. Several targeted therapies are emerging for the management of elevated Lp(a) levels, including Pelacarsen (more below)!
For patients who have refractory ASCVD, you can consider checking apolipoprotein B (apoB) levels as well (expert opinion) in order to further characterize the etiology of their disease.
Antisense oligonucleotide (ASO) and small interfering ribonucleic acid (siRNA) agents both target biomarkers like lp(a) in the liver. The agent that is farthest along in trials, Pelacarsen (ASO targeting lp(a)), has been shown to reduce lp(a) levels by more than 80% in the phase III HORIZON Trial (Yeang 2022). Olpasiran (siRNA) also targets lp(a) and is not far behind Pelacarsen. Top results from the Ocean 2 (O’Donoghue, 2022) study demonstrated that Olpasiran decreased lp(a) levels by more than 90%. Both of these medications are once a month subQ injections that are not yet available but will likely be excellent, easy-to-use additions for very high-risk patients – particularly those that have elevated lp(a) levels (expert opinion). Pelacarsen and Olpasiran are just a few of several siRNA and ASO agents that target high-risk biomarkers currently in development (not FDA approved) and undergoing trials.
What are good medications to add to statins for further lipid-lower management, particularly for those who are maxed out on statins with continually elevated LDL or for those who are intolerant to high statin doses? For a few years now, several providers have looked to ezetimibe and Proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) inhibitors (e.g. monoclonal antibodies such as evolocumab) as the next best options. The PCSK9 protein regulates circulating LDL-C levels by inhibiting the action on recycling of the LDL receptor on hepatocytes. Suppression of PCSK9 causes hepatocytes to more efficiently clear circulating LDL-C from the plasma. As per Dr. Michos, it is important to move early with combination therapy. The IMPROVE-IT and ODYSSEY trials demonstrated the benefits of ezetimibe and PCSK9 inhibitors, respectively. Adding ezetimibe to a moderate-intensity statin reduced ASCVD risk considerably, as shown in the IMPROVE-IT trial (Cannon 2015). The ODYSSEY trial demonstrated that the addition of a PCSK9 inhibitor such as alirocumab yielded an additional 62% reduction in LDL when combined with high intensity statins, particularly in patients with FH or known coronary disease (Robinson 2015).
Much like the MABs that target PCSK9, Inclisiran has emerged as a medication that has shown much promise with regards to combination therapy. It is an siRNA that targets PCSK9. Similarly to evolocumab, it is typically reserved for patients with FH or for those who are known to be at very high risk for ASCVD. ORION is a phase 3 trial that has demonstrated the efficacy of adding Inclisiran for patients with elevated LDL despite receiving maximum statin therapy (Ray 2020). Studies have demonstrated that Ezetimibe and the PCSK9 inhibitors are intended to be co-administered with statins, as opposed to monotherapies, or as substitutions for statins (expert opinion).
Bempedoic Acid is an oral drug that inhibits the synthesis of cholesterol – in the same pathway as statins. More specifically, it inhibits the enzyme ACL citrate lyase in the liver. The CLEAR Harmony (Ray 2019) and CLEAR Wisdom (Goldberg 2019) trials demonstrated that the addition of Bempedoic Acid to statin therapy lowered LDL levels by approximately 18%. The CLEAR Serenity (Laufs 2019) trial demonstrated LDL reduction of 21% in patients who are unable to tolerate statins.
One of the primary advantages of Bempedoic Acid is that it is only activated in the liver and has thus not been shown to have the same statin-associated muscle symptoms. Additionally, it does not increase the risk of diabetes like statins. Notably, it is actually associated with a lower risk of diabetes. An oral combination agent of Ezetimibe and Bempedoic Acid has demonstrated a reduction of up to 30% in LDL levels – reaching levels similar to that of moderate-intensity statins!
Like any pharmacologic agent, Bempedoic acid does have its drawbacks – it has been reported to increase uric acid levels and potentially precipitate gout flares for those with a history of gout. Tendon rupture has also been recognized as a rare adverse effect. Overall, however, the safety of the drug is not in question and is promising in the fact that it does not take effect in muscle and thus does not cause the dreaded myopathies that are associated with statins.
Inhibition of angiopoietin-like protein 3 (ANGPTL3) is being studied as potential therapy for individuals with familial hypercholesterolemia. ANGPTL3 is involved with the regulation of lipoprotein lipase (LPL). Inhibition of ANGPTL3 and therefore higher activity of LPL results in LDL reduction. Reduction in LDL levels with these medications works independently of LDL receptors – thus, ANGPTL3 inhibitors are helpful in those with FH as these patients typically have very low to absent LDL receptor levels. Vupanorsen (Antisense oligonucleotide targeting ANGPTL3) was shown to significantly reduce LDL levels and triglycerides by up to 40-60%. Nevertheless, it has been associated with increased fatty liver and elevated LFTs for which the program for that particular agent has recently been discontinued. It did, however, open the door for other investigational therapies specifically targeting ANGPTL3.
It is important to recognize that, even in isolated or residual hypertriglyceridemia, lifestyle changes and statins remain the cornerstone of treatment for first-line therapy. Nonetheless, new medications are emerging. Icosapent ethyl is a purified eicosapentaenoic acid ethyl ester of which the mechanism is not fully understood although several complex cellular effects have been proposed. Per Dr. Michos, its benefit does not necessarily arise from simply lowering triglyceride levels, but actually from its anti-inflammatory or anti-thrombotic effects. The REDUCE-IT trial tested patients with a history of CAD, diabetes, or other risk factors already on a statin with refractory hypertriglyceridemia (135-499 mg/dL) and assessed cardiovascular outcomes after the addition of icosapent ethyl (Bhatt 2019). Icosapent ethyl, when combined with statin therapy, was found to reduce adverse cardiovascular events by up to 25%! It has been FDA approved since 2019.
A side note for everyone: icosapent ethyl and fish oil are NOT the same! Many over the counter fish oil supplements have been found to have some extra ingredients that would not be conducive to cardiovascular health, like hidden saturated fats!
This is a very exciting field with a lot more to look forward to! The medications we’ve discussed – ezetimibe, PCSK9 inhibitors, Pelacarsen, Bempedoic Acid, Icosapent ethyl and more – have laid the groundwork for hundreds of future studies and for the emergence of new medications that will be invaluable to cholesterol management in the future. Don’t forget:
For more reading:
Listeners will develop novel approaches to the prevention and management of hypercholesterolemia and ASCVD with the emergence of new treatment strategies, medications, and therapies.
After listening to this episode listeners will…
Dr. Erin Michos reports several relevant financial disclosures.
The Curbsiders report no relevant financial disclosures.
Chiu CJ, Antaki J, Michos E, Williams PN, Watto MF. “Advanced Lipidology – Lipids Update 2022: Cardiovascular Risk Reduction and New Medications on the Horizon with Erin Michos, MD”. The Curbsiders Internal Medicine Podcast. http://thecurbsiders.com/episode-list Final publishing date, 2022.
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