Aims This study aimed to investigate systematically (i) the appropriate dietary conditions to induce the features of the MetS in APOE*3Leiden.humanCholesteryl Ester Transfer Protein (E3L.CETP) mice and (ii) whether the response of this model to different antidiabetic and hypolipidemic drugs is similar as in humans. Methods Male obese, IR and dyslipidemic E3L.CETP mice were treated with antidiabetic drugs rosiglitazone, liraglutide or an experimental 11β‐hydroxysteroid‐dehydrogenase‐1 (HSD‐1) inhibitor, or with hypolipidemic drugs atorvastatin, fenofibrate or niacin for 4–6 weeks. The effects on bw, IR and plasma and liver lipids were assessed. Results Rosiglitazone, liraglutide and HSD‐1 inhibitor significantly decreased glucose and insulin levels or IR. Liraglutide and HSD‐1 inhibitor also decreased bw. Atorvastatin, fenofibrate and niacin improved the dyslipidemia and fenofibrate and niacin increased high‐density lipoprotein (HDL) cholesterol. In addition, hepatic triglycerides were significantly decreased by treatment with rosiglitazone and liraglutide, while hepatic cholesterol esters were significantly decreased by rosiglitazone and atorvastatin. Conclusions We conclude that the E3L.CETP mouse is a promising novel translational model to investigate the effects of new drugs, alone or in combination, that affect IR, diabetic dyslipidemia and non‐alcoholic fatty liver disease (NAFLD).