origins of type 2 diabetes medications

The origins of diabetes medications provide an intriguing catalogue of clinical serendipity and scientiﬁc design. Use of insulin (beyond 1922) gave recognition to insulin resistance and the categorisation of type 2 diabetes (T2DM). The ﬁrst sulphonylurea (carbutamide, 1956) emerged from its use as an antibacterial sulphonamide prone to cause hypoglycaemia, and biguanides were ﬁrst used to treat diabetes in 1957 despite their glucose-lowering properties having been known since the 1920s. Alpha-glucosidase inhibitors arose from a screening programme for amylase inhibitors by Bayer in the 1970s and acarbose was introduced in 1990. The ﬁrst thiazolidinedione (ciglitazone; not developed) was identiﬁed in a screening programme for triglyceride-lowering compounds by Takeda in the late 1970s and gave rise to pioglitazone (approved 1999), although ﬁrst to market was troglitazone (from Warner Lambert 1997, withdrawn 2000). Exendin, an analogue of the incretin hormone glucagon-like peptide-1 (GLP-1), was identiﬁed in 1992 in the saliva of a lizard (Heloderma suspectum), and took until 2005 to be marketed as exenatide. To promote the efﬁcacy of endogenous GLP-1, its rapid inactivation by the enzyme dipeptidylpeptidase-4 (DPP4) was blocked by clever molecular design of the ﬁrst DPP4 inhibitors (vildagliptin and sitagliptin, approved in 2006). SGLT2 inhibitors are based on phlorizin, identiﬁed in apple tree bark (1835) and modiﬁed (2000) to avoid intestinal degradation: further modiﬁcations to increase selectivity against SGLT2 gave dapagliﬂozin and canagliﬂozin - approved 2012 and 2013, respectively, in Europe.