Diabetes is associated with significantly increased morbidity and mortality from atherosclerotic vascular disease. Type 2 diabetes is frequently part of the metabolic syndrome and a lipid profile characterized by elevated plasma triglycerides (TG’s) and low HDL cholesterol is common. Statins lower LDL cholesterol (LDL-C) by inhibiting cholesterol synthesis in the hepatocyte, causing increased expression of surface LDL receptors and enhanced LDL clearance from plasma. The use of statins to reduce cardiovascular risk has been extensively studied in people with diabetes and risk reductions of 20-40% have been achieved. Therefore, lowering LDL-C with statin therapy remains the primary lipid related approach to reducing cardiovascular (CV) risk in diabetic patients. Guidelines around the world are in agreement that the higher a person’s CV risk, the more intensive should be the LDL lowering therapy. For the highest risk category, an LDL-C of <1.8mmol/L is recommended. This is not always achievable with statins alone, and frequently combination therapy, such as the cholesterol absorption inhibitor ezetimibe, is required. Statins are generally well tolerated but side effects can occur, most commonly myalgia, requiring a reduced dose of statin and making achievement of targets more difficult.
Proprotein convertase subtilisin/ kexin type 9 (PCSK9) is a phosphoprotein, synthesized in the liver, that can bind to the LDL receptor. It is subsequently endocytosed and the LDL receptor-PCSK9 complex then undergoes intracellular degradation, preventing the LDL receptor being recycled to the cell surface. This leads to a decreased number of LDL receptors on the surface of cells. Individuals with loss of function mutations for PCSK9 have reduced LDL levels and markedly reduced CV risk. Conversely, gain of function mutations produce high LDL levels and a clinical picture resembling familial hypercholesterolaemia. Statins increase the concentration of PCSK9 by 14–47% in a dose depended manner, a phenomenon that potentially reduces efficacy. Inhibiting PCSK9 has the potential to reduce LDL-C and to enhance the efficacy of statin therapy.
The most advanced approach to PCSK9 inhibition is the use of monoclonal antibodies and three alirocumab, evolocumab and bococizumab, are well advanced in phase 3 studies. These agents are administered by subcutaneous injection at 2–4 weekly intervals, and as monotherapy reduce LDL-C by 50-60%. More impressive is the combination with a statin: when added to maximal statin therapy, additional LDL-C reductions of up to 70% have been observed.
Data in people with diabetes is limited, but in a study of over 100 subjects, 86% of whom were taking statins, treatment with evolocumab achieved a 47% reduction in LDL-C. There were minimal changes in other lipids and no adverse effect on glycaemic control. Large end-point studies containing substantial numbers of diabetic subjects are ongoing.
LDL-C remains an important therapeutic target in people with diabetes. Statins are the mainstay of treatment, but may be incompletely effective or not tolerated in many patients. The PCSK-9 inhibitors provide a potentially useful therapy to further reduce CV risk in diabetes.