PCSK9 in the Immunometabolism of Type 2 Diabetes

PCSK9 inhibition reduces cardiovascular events in patients with type 2 diabetes, while experimental studies implicate PCSK9 in immune activation, platelet function and organ-specific metabolism. Whether these mechanisms contribute clinically beyond atherogenic lipoprotein lowering remains uncertain. This critical narrative review integrates 108 appraised publications identified through structured searches and supplementary retrieval. Mechanistic evidence supports roles involving LDLR, CD36, intracellular cholesterol, mitochondrial stress and inflammatory signalling. The effects vary by cell type and compartment: local PCSK9 can promote injury in some models but preserve pancreatic, glomerular or cardiac function in others. Global knockout, tissue-specific deletion, extracellular antibodies and hepatic silencing consequently cannot be treated as equivalent interventions. Human biomarker and imaging studies provide translational signals, but generally cannot separate direct effects from concomitant lipoprotein changes. Randomised antibody trials establish cardiovascular efficacy and an overall reassuring glycaemic profile during follow-up, without demonstrating a clinically meaningful glucose-lowering effect. PCSK9 therefore has immunometabolic functions beyond plasma LDL regulation, but the available evidence does not isolate or quantify an additional clinical benefit independent of reductions in atherogenic lipoproteins. Tissue-specific mechanisms and causal mediation require further investigation before broader therapeutic claims are justified.