What medication is used for mixed hyperlipidemia?

Statin drugs are very effective in reducing levels of low-density lipoprotein (LDL) cholesterol, one of the causal agents in the development of atherosclerotic disease. Statins lower cholesterol by inhibition of HMG-CoA reductase, the rate-limiting step in the synthesis of cholesterol. Nevertheless, there are patients who have a suboptimal response to statin therapy or cannot tolerate effective doses, and the efficacy of statins in lowering LDL cholesterol is variable. Additionally, many patients suffer recurrent cardiovascular events because of residual risk despite statin use. There is a compelling need to identify agents that specifically target LDL cholesterol via other mechanisms as well as work with statins to more effectively lower LDL cholesterol.

One approach has been to target biochemical pathways that impact LDL receptor availability. The human monoclonal antibodies evolocumab and alirocumab work by inhibiting the action of proprotein convertase subtilisin-kexin type 9 (PCSK-9). PCSK-9 is a protein that binds to LDL cholesterol when it binds to hepatic LDL receptors.

Together, this complex of PCSK-9 and LDL cholesterol are taken into the hepatocyte attached to the LDL receptor. The presence of this protein with the LDL receptor + LDL cholesterol marks the receptor for degradation, and receptor degradation leads to increased circulating LDL levels as the LDL receptor is not recycled back to the hepatocyte surface where it will continue to bring LDL cholesterol into the liver and out of plasma.

It is also worth noting that the administration of statins upregulates synthesis of the PCSK-9 protein, as a counter-regulatory reaction to statin inhibition of cholesterol biosynthesis. The Nobel Prize-winning work of Brown and Goldstein postulated the potential for a counter-regulatory mechanism tied to intracellular cholesterol levels. This mechanism was discovered to be mediated by the PCSK-9 protein, which is believed to limit the efficacy of statin agents in the treatment of hypercholesterolemia and is a counter-regulatory pathway to balance the LDL cholesterol-lowering efficacy of statins.

Hobbs and co-workers discovered families with lower natural cholesterol levels and very low rates of coronary artery disease. Genetic analysis localized this trait to the gene encoding for PCSK-9 protein, thus sparking a decade-long effort to develop a new set of drugs to lower cholesterol. Loss of function of PCSK-9 protein, either through a genetic trait or by blocking the protein with a monoclonal antibody such as evolocumab and alirocumab dramatically reduces LDL cholesterol levels when given with or independent of statins.

More recently, a small interfering RNA (siRNA) molecule was designed that harnesses the body's natural method of blocking RNA transcription of the mRNA for PCSK-9. Inclisiran, now undergoing Food and Drug Administration review, uses the RNA silencing mechanism (RISC) in liver cells to block the production of PCSK-9. Inclisiran has been engineered to only be taken up by hepatocytes and has been shown in Phase 2 trials to reduce LDL cholesterol when given with a statin or independent of a statin. The agent is administered on average every six months as a subcutaneous injection.

Two large, Phase III trials were reported at the 2019 American Heart Association Scientific Sessions in Philadelphia. Mayo Clinic has played a pivotal role in the Phase II and Phase III development of inclisiran for LDL-C lowering through the work of R. Scott Wright, M.D., cardiologist at Mayo Clinic in Rochester, Minnesota. Dr. Wright led the Phase III ORION-10 trial, which examined the efficacy of inclisiran versus placebo in a large cohort of patients with atherosclerotic cardiovascular disease (ASCVD) who were already on statins or other lipid-lowering therapy.

In ORION-10, 1,561 patients with ASCVD were randomized to placebo (n = 780) or inclisiran (n = 781) for approximately 18 months. Inclisiran or placebo was administered on days 1 and 90, then every six months thereafter. To be included, the patients had to have documented ASCVD, elevated LDL cholesterol (> 70 mg/dL), and be on maximally tolerated statin therapy or other LDL cholesterol-lowering oral therapy (10% of patients in the study were also taking ezetimibe). The median LDL cholesterol was 105 mg/dL in both groups. At the termination of the trial, there was a 58% reduction in LDL cholesterol in the treated group compared with the placebo group on day 510 and a sustained 56% reduction over days 90 through 540, both p < 0.001. There was no evidence of any difference in liver, muscle or hematological side effects between placebo and inclisiran. The ORION-10 trial was not powered to detect changes in clinical event rates.

Although the effect on LDL cholesterol by both the monoclonals and inclisiran has been quite dramatic, questions remain, such as how the drugs affect levels of high-density lipoproteins, lipoprotein(a) and triglycerides. The use of the PCSK-9 monoclonal antibodies has been lower than expected, largely due to pricing issues and possibly due to the need for 26 injections annually. It is not yet known whether the treatment effect translates into a reduced incidence of coronary disease or reduced mortality.

It is important to note that nearly all of the reduction in ASCVD mortality to date in clinical outcome trials largely depends on the degree of reduction in LDL cholesterol. Inclisiran is being specifically tested for its effect on cardiovascular outcomes in the 15,000 patient ORION-4 trial.

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