12. SGLT-2 Inhibitor with Incretins

15. Add on to insulin EFFICACY AND TOLERABILITY OF GLP-1 RECEPTOR AGONISTS AND DPP-4 INHIBITORS AS ADDON THERAPY TO INSULIN Complementing Insulin Therapy to Achieve Glycemic Control Anthony H. Barnett Adv Ther (2013) 30:557–576 Glucagon-like peptide-1 and glucose-dependentinsulinotropic polypeptide (GIP) are incretinhormones that are secreted into the circulationby the intestine in response to nutrient intake.GLP-1 stimulates glucose-dependent insulinsecretion, inhibits glucagon secretion, delaysgastric emptying, increases feelings of satiety,and decreases food intake [82]. GLP-1 and GIPare rapidly degraded by the enzyme DPP-4,which exists as both a circulating and amembrane-bound form expressed in manytissues [82]. In individuals with T2DM, there isa decreased response of b-cells to GIP, whereasthe insulinotropic effect of GLP-1 is nearnormal [83]. Consequently, efforts have beendirected toward enhancing the effect of GLP-1by developing degradation-resistant GLP-1 receptor agonists and inhibitors of DPP-4.Of interest are the findings from some [84,85], but not all studies [86] that a-glucosidaseinhibitors may increase GLP-1 release in healthypeople as well as in patients with T2DMfollowing a mixed test meal. In addition,metformin has been shown to increase plasmalevels of GLP-1 after an oral glucose load inobese individuals without T2DM and inpatients with T2DM [87, 88]. The contributionof this effect to the antihyperglycemic efficacy of these drugs is not clear.