Nonstatin Lipid-Lowering Agents

Opinion
Video

Dr Michos discusses safety and efficacy of available nonstatin therapies and emerging agents for treating hyperlipidemia.

Keith C. Ferdinand, MD, FACC, FAHA, FNLA: I think we can all agree that if a patient really cannot tolerate a statin, perhaps we can address their lipids using other nonstatin therapies. That leads me to you, Dr Michos. Can you give us a laundry list—it doesn’t have to be totally comprehensive—but [a list of] some of the newer agents that we have or alternative agents for statins in order to treat these patients who have elevated lipids?

Erin D. Michos, MD, MHS: Sure. First to mention [are] some of the older agents. I mean, there are still bile acid sequestrants. We don’t really use them very much because they’re not well tolerated and they can raise triglyceride levels, so they’re generally not recommended to patients with elevated triglyceride levels. [However], they can be used in pregnancy because they don’t have systemic absorption, although they’re usually not well tolerated in pregnancy. Then we have ezetimibe…[which] is a cholesterol intestinal inhibitor [that] can lower LDL [low-density lipoprotein] [by approximately] 18%. So, [it’s] kind of weak on its own, but [it’s] generally well tolerated and can be a useful tool when paired with other agents. It actually comes in some combinations with a statin, like rosuvastatin, as well as bempedoic acid, which I’ll talk about next. That is also in the guidelines to add next.

Bempedoic acid is an oral agent [that] inhibits ATP citrate lyase. It blocks this enzyme in the cholesterol synthesis pathway—the same pathway that statins inhibit, [but] it inhibits upstream of statins. By preventing cholesterol synthesis, this upregulates the LDL receptors on the surface of the liver to help clear all that LDL out of circulation. Bempedoic acid is a prodrug, so it has to be activated in the liver. It doesn’t have those muscle-associated symptoms that we see with statins. By itself, it can lower LDL [by approximately] 18% to 25%—a little bit on the higher end when it’s not used with a statin, more like 18% with a statin. But in combination with ezetimibe, you see [approximately] a 36% reduction in LDL. That’s getting into the range of a moderate-intensity statin, so that’s another option. We just had our recent CLEAR Outcomes trial [NCT02993406] published showing that it does reduce major adverse cardiovascular events, particularly in the primary prevention population subset of that trial. So, [this is] another useful tool [for patients who are] statin intolerant.

Now, thinking about our more potent agents, which sometimes we need to get to when patients are starting out with very elevated cholesterol—like our FH [familial hypercholesterolemia] population [and] our ASCVD [atherosclerotic cardiovascular disease] high-risk population—we have our PCSK9 inhibitors. Just as a reminder for our audience, PCSK9 is a protein that leads to the degradation of the LDL receptor. When you inhibit PCSK9, you also have more upregulation of LDL receptors to, again, clear LDL out of circulation. We have our monoclonal antibodies, evolocumab [and] alirocumab, that inhibit PCSK9. They lower LDL by [approximately] 60%—so very potent—and can be used on top of a statin. They also have some effect on lipoprotein [a]—[approximately] 25%—which seems to be also an important effect.

Then we have inclisiran, which is a small interfering RNA [molecule] that blocks the translation of the PCSK9 protein. This lowers LDL [by approximately] 50%. The nice thing about this is [that it’s] also given by injection. But after the baseline and 3-month dose, it’s only dosed every 6 months, so twice-a-year [dosing]. [That’s] only 1 more shot a year than your flu shot. For patients who have concerns [about] adherence or [who] don’t want to give themselves the injection, they could come into a clinic site and get that injection.

For our very high-risk homozygous FH patients, [who] are usually under the care of advanced lipid specialists, we do have things like evinacumab [and] lomitapide. [Those are] usually only prescribed by clinicians [who] are working in an advanced lipid clinic center. But the important thing is we have all these new tools now, so we just need to get patients to [the] goal.

Transcript Edited for Clarity

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