Obesity, Type 2 Diabetes (T2D) and related metabolic disorders afflict hundreds of millions worldwide. State of the art treatments include analogues of the endogenous gut peptide hormones called ‘incretins’. The two principal peptides that form this class, Glucagon-like Peptide 1 (GLP-1) and Glucose-dependent Insulinotropic Peptide (GIP) stimulate their cognate receptors (GLP-1R and GIPR) in different tissues with the primary function of maintaining glucose homeostasis in addition to having neuro- and cardioprotective effects. These peptides however suffer from poor metabolic stability and are rapidly degraded by the ubiquitous serine protease, dipeptidyl peptidase IV (DPP-4). We describe here the design and development of potent small molecule compounds that are able to repair the truncated hormone and then withstand further hydrolysis. Activity can be restored to within a few fold of the native hormone with no further loss in potency due to enzyme catalyzed hydrolysis. These compounds offer possible orally bioavailable therapeutic relief.