PCSK9 in the Immunometabolism of Type 2 Diabetes

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition reduces cardiovascular events in 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 an original corpus of 108 appraised publications, with targeted additions during revision. It evaluates whether findings from different compartments and experimental perturbations can be transferred to particular treatments and clinical outcomes. Mechanistic evidence implicates receptor trafficking, intracellular cholesterol, mitochondrial stress and inflammatory signalling. Effects vary by cell type and compartment: local PCSK9 promotes injury in some models but preserves pancreatic, glomerular or cardiac function in others. Global knockout, tissue-specific deletion, extracellular antibodies and hepatic silencing are therefore distinct exposures. Human biomarker and imaging studies provide translational signals but generally cannot isolate direct effects from concomitant lipoprotein changes. Randomised antibody trials establish cardiovascular efficacy and an overall reassuring glycaemic profile, without demonstrating clinically meaningful glucose lowering. PCSK9 has broader immunometabolic functions, but the available evidence does not quantify an additional clinical benefit independent of atherogenic lipoprotein lowering. Tissue-specific mechanisms and causal mediation require further investigation.