#361 Advanced Lipidology

October 24, 2022 | By Chris Chiu

Video

Lipids Update 2022: Cardiovascular Risk Reduction and New Medications on the Horizon with Erin Michos, MD

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.

Unfortunately, this episode will not be available for CME. You can claim free CME for other episodes at curbsiders.vcuhealth.org!

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Credits

• Producer and written by: Christopher Chiu MD, FACP, FAAP
• Show Notes: James Antaki MD
• Infographic: Edison Jyang
• Cover Art: Kate Grant MBChB, DipGUMed
• Hosts: Matthew Watto MD, FACP; Paul Williams MD, FACP   
• Associate Editor: Leah Witt MD
• Showrunner: Matthew Watto MD, FACP
• Technical Production: PodPaste
• Guest: Erin Michos MD, MHS

Sponsor: Birch Living

Birch is giving $400 off all mattresses and 2 free eco-rest pillows at BirchLiving.com/curb. 

CME Partner: VCU Health CE

Show Segments

• Intro, Getting to know Dr. Erin Michos, Pick of the Week
• Patient Case, Digging into ASCVD Risk 
• Coronary artery calcium scoring – why it’s important
• What are “Risk Enhancing Factors”?
• Biomarker testing, what is the significance of Lip a and how can we use it to drive management?
• Introduction to PCSK9 inhibitors
• More than just statins – other LDL-lowering medications
• siRNAs, ASOs – Pelacarsen and more
• Apollo Trial regarding Pelacarsen
• Importance of Family History
• What to do if maxed out on a statin or statin intolerance – Ezetimibe, PCSK9 inhibitors, MAB therapies, and more
• Bempedoic Acid discussion
• Medication side effects
• Homozygous FH – approach to treatment, ANGPTL3 inhibitors
• Triglycerides discussion, icosapent ethyl, the REDUCE-IT trial
• Wrap-up and Take home points, Outtro

Advanced Lipidology Pearls

1. Lifestyle changes remain the cornerstone of cardiovascular disease prevention and should never be neglected in our conversations with patients. “Primordial prevention” is key! We should start as early as possible in preventing ASCVD risk. A patient’s risk from plaque burden is not only due to the magnitude of LDL elevation but duration of exposure 
2. Risk-enhancers (e.g. family history, chronic inflammatory disorders, pregnancy-related adverse outcomes) should  guide management for patients who are in the borderline and intermediate ASCVD risk groups
3.  Coronary Artery Calcium Scoring can be a very useful tool to provide more data in assisting with shared decision making, ESPECIALLY in patients who are very reluctant to start a statin. Don’t underestimate the power of a CAC score of zero.
4. Biomarkers can be useful to help drive management – particularly Lp(a) for further risk-stratification. Dr. Michos’s expert opinion is to check Lp(a) levels in ALL patients at least once, particularly in those with strong family history and those with a premature history of CAD
5.  Antisense oligonucleotides (ASOs), such as Pelacarsen, and siRNAs, such as Olpasiran, are ground-breaking new medications that can be useful when managing patients with elevated Lp(a) levels and refractory hypercholesterolemia
6. Encourage combination therapy in very high-risk patients early! Medications such as ezetimibe and PCSK9 inhibitors (evolocumab, inclisiran) can be very useful additions for patients who are maxed out on statin therapy with refractory hypercholesterolemia.
7. For statin-intolerant patients, remember to always start low and go slow before transitioning to other medications. 
8. Novel therapies such as bempedoic acid are promising alternatives as lipid-lowering agents with few side effects and positive outcomes.
9. Homozygous familial hyperlipidemia (FH) can be difficult to treat – ANGPTL3 inhibitors are becoming a mainstay of treatment for those with homozygous FH due to favorable reduction in LDL
10.  Icosapent Ethyl, omega 3 oils should be considered as an important treatment option for patients with persistent hypertriglyceridemia

Advanced Studies in Lipidology

What exactly is ASCVD? – Refresher

Atherosclerotic Cardiovascular Disease

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

ASCVD Risk Calculator 

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.

2018 Update

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).

Primary Prevention – Refresher

The Foundation Remains the Same: Lifestyle 

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)

Risk Categories and Recommendations – Refresher

Since the 2018 update, we have 4 ASCVD risk categories. These are according to the patient’s 10-year ASCVD risk: 

• Low: < 5%
• Borderline: 5- <7.5%
• Intermediate: 7.5- <20%
• High: > 20%

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).

Other Groups

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). 

Risk Enhancing Factors – Refresher

What are these risk-enhancing factors specifically? (Grundy 2018) Include but not limited to the following –

• Family history of premature ASCVD (male < 55 years or female < 65 years) 
• Primary hypercholesterolemia with LDL 160-189 mg/dL
• Chronic kidney disease
• Chronic inflammatory disorders (e.g. lupus, RA, HIV) 
• Pregnancy-associated complications with higher ASCVD risk (e.g. gestational diabetes, pre-eclampsia) 
• High-risk ethnicities
• Non-fasting triglycerides > 175 mg/dL on at least 3 separate occasions
•  Biomarkers: high-sensitivity CRP > 2 mg/dL, Lp(a) > 50 mg/dL, apoB > 130 mg/dL 
• ABI < 0.9

Coronary Artery Calcium Scoring 

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): 

1. Patients who are hesitant to be on medications/statins
2. Patients who are reluctant to increase the dose of statins/medications due to adverse effects (myopathies, etc.)
3. Older patients with questionable benefit of starting a statin late in life (due to limited projected time-to-benefit)
4. Patients age 40-55 who fall into the “borderline” ASCVD category and have other co-morbidities that increase risk (can simply be considered another risk-enhancing factor)

Biomarkers

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.

New Medications on the Horizon

siRNAs, ASOs – Pelacarsen, Olpasiran, and More

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.

Ezetimibe and the PCSK9 Inhibitors – Refresher

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).

The New Kid on the Block – Bempedoic Acid

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.

FH and ANGPTL3 Inhibitors

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.

Hypertriglyceridemia and Icosapent Ethyl

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! 

Take Home Points and Future Directions

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:

• Lifestyle changes remain the cornerstone and foundation of cardiovascular prevention, and should never be neglected!
• Use risk enhancers to guide management for patients who are in borderline ASCVD risk groups. Coronary Artery Calcium (CAC) scoring is a very useful tool that can be used as a tiebreaker to start statins. Don’t underestimate the power of a CAC of zero!
• The earlier the better! Recognize high-risk patients and start them on combination therapy early. Then titrate up as able – all the medications we’ve discussed are excellent options as combination therapy depending on the clinical situation
• Biomarkers are useful to help drive management. Dr. Michos recommends checking an Lp(a) at least once in ALL patients – especially those with premature ASCVD and significant family history

Links

• Curbsiders Addiction Medicine Series: http://thecurbsiders.com/addiction 

For more reading:

• Gaine, S. P., Quispe, R., Patel, J., & Michos, E. D. (2022). New Strategies for Lowering Low-Density Lipoprotein Cholesterol for Cardiovascular Disease Prevention. Current Cardiovascular Risk Reports, 1-10. (PubMed)
• Quispe, R., Sweeney, T., Varma, B., Agarwala, A., & Michos, E. D. (2022). Recent Updates in Hypertriglyceridemia Management for Cardiovascular Disease Prevention. Current atherosclerosis reports, 1-12. (PubMed)

Goal

Listeners will develop novel approaches to the prevention and management of hypercholesterolemia and ASCVD with the emergence of new treatment strategies,  medications, and therapies.

Learning objectives

After listening to this episode listeners will…  

1. Define the different risk categories in primary prevention assessment of patients with hyperlipidemia and recognize what are potential risk enhancers.
2. Develop an approach to manage patients with risk enhancers including elevated Lp(a).
3. Recognize what new therapies are available or likely soon to be available for LDL lowering, Lp(a) lowering and Triglyceride lowering as well as treatment of homozygous familial hypercholesterolemia.

Disclosures

Dr. Erin Michos reports several relevant financial disclosures. 

• Advisor – Astra Zeneca
• Advisor – Bayer
• Advisor – Boehringer Ingelheim
• Advisor – Esperion
• Advisor – Novartis
• Advisor – Novo Nordisk
• Advisor – Pfizer

The Curbsiders report no relevant financial disclosures. 

Citation

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.