The debut of the proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors evolocumab (Repatha, Amgen) and alirocumab (Praluent, Sanofi-Regeneron) in mid-2015 has completely changed the landscape of primary and secondary prevention of coronary heart disease (CHD). If ever there were a “Cinderella” story in science, it would be this one which embodies a true “bench to bedside” tale. The drug target for inhibition of PCSK9 was discovered with the identification of both gain of function (GOF) and loss of function (LOF) mutations in this enzyme. The GOF mutation resulted in heterozygous familial hypercholesterolemia (HeFH) and high levels of CHD while LOF mutations resulted in a significantly lower LDL-cholesterol and risk of CHD.
Here is a typical patient with FH you might see in clinical practice (case adapted from Yuan et al1): A 34-year-old man of Irish ancestry was referred for dyslipidemia management. He had been in good general health until the age of 29 years, when routine blood tests returned a plasma total cholesterol (TC) result of 387 mg/dL and an LDL-C concentration of 309 mg/dL. His family history included premature CAD: his father and 2 paternal uncles each had elevated plasma levels of LDL-C and died of MI before 50 years of age.