Statins aid manage cholesterol levels & reducing the risks linked with atherosclerotic cardiovascular disease; however, many patients cannot achieve their cholesterol goals or face adverse drug events. Read about the two new non-statin-approved cholesterol-lowering medicines over the past 2 years.

With the recent publication of the 2022 ACC Expert Consensus Decision Pathway on the Role of Nonstatin Therapies for LDL-Cholesterol Lowering, a crucial direction has been made available. In the last two years, the US Foods and Drug Administration (FDA) has authorised two new cholesterol-lowering medications. There has been little agreement or advice about their application.

The algorithms have been simplified for ease of use by clinicians in order to assist them in identifying patients who may require adjunctive non-statin medications, providing thresholds for consideration of those medications, and ranking those medications according to the strength of available evidence of efficacy and safety (as well as cost).

What are the new medications?

1. Bempedoic acid 

1. It is an oral medication, whereas inclisiran is administered subcutaneously.
2. Bempedoic acid reduces low-density lipoprotein (LDL) cholesterol by acting upstream from HMG-CoA reductase. Notably, in contrast to statins, it does not produce myalgia.
3. Alone, it reduces LDL cholesterol by around 25%; when combined with statins, it reduces LDL cholesterol by about 15% more than statins alone.
4. It is available in combination with ezetimibe 10 mg, and when coupled with a statin, LDL cholesterol is reduced by an extra 38%.
5. Many individuals on statin monotherapy do not achieve their LDL cholesterol objectives, and the combination of bempedoic acid and ezetimibe is an intriguing non-injectable alternative for many of these patients.

2. Inclisiran

1. The second new drug is inclisiran, a subcutaneous injection is given twice yearly in the office, following the first administration at baseline and again after three months.
2. Contrary to PCSK9 monoclonal antibodies (mAbs), which inhibit PCSK9 at the extracellular level, inclisiran inhibits PCSK9 synthesis at the intracellular level. However, they cannot be combined, since they operate via comparable routes.
3. Inclisiran reduces LDL cholesterol by around 50%, somewhat less than PCSK9 mAbs. The inclisiran RCT will not be available until 2024.

Where, therefore, do these new medications fall within the scope of treatment?

There are primarily two areas. One is for patients who do not fulfil their LDL cholesterol objectives on maximally tolerated statin treatment, after using medications that have shown an impact on endpoints in randomised controlled trials, such as ezetimibe and PCSK9 mAbs. The second option is for those who, often because of myalgia, cannot take statins.

Let's review the criteria for lowering LDL levels in various groups:

The first group comprises individuals with documented ASCVD who are at very high risk. A statin of high potency is indicated. Consider the addition of a non-statin medication — first ezetimibe or a PCSK9 mAb — if the LDL cholesterol level has not fallen by 50% or is not 55 mg/dL (in this group, the goal has been lowered from 70 to 55 mg/dL). If more lowering is required after their usage, try bempedoic acid. If adherence concerns or the inability to administer the injectable at home exist, Inclisiran may be substituted for a PCSK9 mAb.

Category 2 and category 3 have comparable recommendations. These are individuals with an LDL cholesterol level of more than 190 mg/dL and diabetics aged 40 to 75 years. Start with a medium- or high-intensity statin. Consider ezetimibe or a PCSK9 mAb if the patient does not get the desired results with the statin. Consider bempedoic acid or inclisiran if the target has not been reached.

For most of us, the biggest group is primary prevention for persons with an LDL cholesterol level between 70 and 189 mg/dL and a 10-year cardiac risk between 7.5% and 20%. Start with a moderate-intensity statin with a target of a 30%-49% LDL cholesterol reduction or an LDL cholesterol level of 100 mg/dL, and then titrate to a high-intensity statin if necessary.

Now this section is intriguing. The recommendations do not advocate non-statin medication for further LDL reduction in this group, even if the LDL cholesterol objective is not attained unless the 10-year cardiac risk is over 20%. Consider ezetimibe if, after intensive statin medication, the patient is not on target. Unless statins are intolerable, the use of newer medicines for further LDL reduction is not indicated for primary prevention at this time.

This takes us to the next group of patients: those who cannot tolerate statins. Consider two or three distinct statins. If the patient cannot tolerate them, bempedoic acid is an alternative. This group of patients may benefit from the combination of bempedoic acid and ezetimibe.

The implication of these recommendations is that since the new treatments lack RCT evidence on clinical effectiveness, they should be used only after those for which RCT data are available. This is crucial advice that provides clear direction for daily practice.

Disclaimer- The views and opinions expressed in this article are those of the author and do not necessarily reflect the official policy or position of M3 India.

About the author of this article: Dr Monish Raut is a practising super specialist from New Delhi.