Ischaemic cardiomyopathy (ICM) is the most common cause of heart failure (HF) and often coexists with diabetes mellitus (DM). Yet, their combined effects are seldom investigated and are poorly understood. We performed multi-omic analyses of end-stage ICM with DM (ICM-DM), ICM-No DM, non-ischaemic cardiomyopathy with DM (NICM-DM), and NICM-No DM against healthy age-matched donors (AMD). Tissue was sourced from pre-mortem human left ventricular myocardium. Though fatty acid oxidation proteins were down-regulated in ICM-DM relative to AMD and other HF conditions, the unique ICM-DM down-regulation of acylcarnitines, perilipin, and ketone body, amino acid, and glucose metabolising proteins indicated lipid metabolism may not be entirely impaired. Oxidative phosphorylation appeared exacerbated in ICM-DM, consistent with purportedly increased oxidative stress. Extracellular matrix proteins were up-regulated principally in ICM-DM despite the absence of scar tissue. These findings indicate DM confounds the pathological phenotype in HF, and the need for a paradigm shift regarding lipid metabolism.