Accumulating data from several large, placebo-controlled studies suggests that sodium-glucose transporter 2 (SGLT-2) inhibitors and glucagon-like peptide 1 receptor (GLP-1) receptor agonists offer therapeutic benefits in the management of cardiovascular diseases, regardless of the patient’s diabetic status. In addition to their effects on glucose excretion, SGLT2 inhibitors have a positive impact on systemic metabolism. The aim of this study was to establish a non-invasive preclinical model of metabolic syndrome (MetS) to investigate the effects of novel antidiabetic therapies beyond glucose reduction, independent of obesity. Eighteen healthy adult Beagle dogs were fed an isocaloric Western diet (WD) for ten weeks. Biospecimens were collected at baseline (BAS1) and after ten weeks of WD feeding (BAS2) for measurement of blood pressure (BP), serum chemistry, lipoprotein profiling, fasting blood glucose, glucagon, insulin, NT-proBNP, BUN, creatinine, angiotensins, oxidative stress biomarkers, serum, urine and fecal metabolomics. Differences between BAS1 and BAS2 were analyzed using non-parametric Wilcoxon signed-rank testing with continuity correction. The isocaloric WD model induced significant variations in several markers of MetS, including elevated BP, increased glucose levels, and reduced HDL-cholesterol. It also caused an increase in circulating NT-proBNP levels, a decrease in serum bicarbonate levels, and significant changes in general metabolism, lipids, and biogenic amines. Short-term, isocaloric feeding with a WD in dogs replicates key biological features of MetS while also causing low-grade metabolic acidosis and elevating natriuretic peptides. These findings support the use of the WD canine model for studying the metabolic effects of new antidiabetic therapies independent of obesity.