Statins have been the go-to-medication to treat individuals with familial hypercholesterolemia (FH) and other forms of high cholesterol since the 1980s. And while statins remain the first class of medication used for FH, other classes of cholesterol lowering medications including PCSK9 inhibitors, are now recognized as important in managing FH.
There are two types of PCSK9 inhibitors approved by the Food and Drug Administration (FDA) monoclonal antibodies in 2015, and small interfering RNA in 2021. Although both are PCSK9 inhibitors, they have different mechanisms of action and we discuss them separately.
There are currently two monoclonal antibodies against PCSK9 available today in the United States:
- Alirocumab (Praluent)
- Evolocumab (Repatha)
Alirocumab and evolocumab are injectable drugs that target proprotein convertase subtilisin kexin 9 (also known as PCSK9), a protein that interferes with the clearance of blood cholesterol.
These drugs work by disabling the PCSK9 protein in the blood, which allows LDL-cholesterol (bad cholesterol) to be removed from the blood by the normal liver clearance processes.
Alirocumab and evolocumab, alone or in combination with other LDL lowering drugs, have been demonstrated to be highly effective at lowering LDL and in reducing cardiovascular events such as heart attack and stroke. Studies have shown that these drugs reduce LDL- cholesterol by 40 to 65 percent beyond the effect of other lipid lowering drugs. For individuals with FH, this is an important breakthrough, as early and regular treatment can reduce the risk of stroke and heart attacks significantly.
When Are PCSK9 inhibitors Recommended for Familial Hypercholesterolemia?
Doctors will typically prescribe statins, cholesterol absorption inhibitors or bile acid sequestrants first. If these therapies alone, or in combination with each other, don’t lower cholesterol enough, PCSK9 inhibitors may be prescribed.
- PCSK9 inhibitors are approved for use, in addition to diet either alone or in combination with other LDL lowering therapies, in adult patients with primary hyperlipidemia including heterozygous familial hypercholesterolemia (HeFH). These PCSK9 inhibitors are also approved for people with clinical atherosclerotic cardiovascular disease (ASCVD), such as heart attacks or strokes, who require additional lowering of LDL cholesterol. Finally, both alirocumab and evolocumab are approved for use by patients with homozygous familial hypercholesterolemia (HoFH), a rare and severe form of FH.
These monoclonal antibodies are self-injected as a subcutaneously every 2 to 4 weeks.
Small interfering RNA (siRNA):
There is one approved siRNA which prevents the production of PCSK9 in the cell:
- Inclisiran (Leqvio)
While inclisiran is also a PCSK9 inhibitor, its mechanism of action is entirely different than the monoclonal antibodies discussed above. Inclisiran works inside our cells to prevent the production of PCSK9 protein. With less PCSK9 protein around our cells are better able to remove LDL from the blood.
Inclisiran was approved in late 2021. When added to maximally tolerated statin therapy inclisiran lowered LDL by an additional 48-52%. Currently inclisiran is approved in individuals with heterozygous FH (HeFH) and for people with ASCVD who after diet and maximally statin still require further LDL reduction. If ongoing studies document a reduction in heart attacks and strokes, the groups of people for which inclisiran is approved will broaden.
Incisiran is given as an injection in the health care providers (HCP) office. It is given at baseline, again 3 months later and then every 6 months always in the HCP’s office.