PCSK9 inhibitors--past, present and future

Lowering low-density lipoprotein cholesterol (LDL-C) reduces cardiovascular disease (CVD) morbidity and mortality. Statins are the treatment of choice for lowering LDL-C but a considerable number of patients treated with statins are unable to achieve LDL-C target values and many are statin-intolerant. New LDL-C-lowering drugs--antibodies to PCSK9 (alirocumab, evolocumab and bococizumab)--have been developed and are being tested in large clinical trials. They further reduce LDL-C above maximally tolerated statin therapy by up to > 70%; they also reduce Lp(a), non-HDL-C, apolipoprotein-B, and modestly increase HDL-C. These drugs are well tolerated and even patients who achieved very low LDL-C ≤ 0.65 mmol/l (∼ 25 mg/dl) did not have any significant adverse effects. Treatment with PCSK9 inhibitors resulted in LDL-C target values in 70-90% of patients according to the guidelines. However, although PCSK9 inhibitors seem to be the most promising emerging therapeutic option for LDL-C lowering today, outcome data with endpoints on their effects are still lacking. Another important open question is their long-term safety. Their use in statin-intolerant patients also raises questions, as the criteria for statin-intolerance are neither clear nor generally accepted. The presumed high cost of PCSK9 inhibitors might be an obstacle for their broader use.