Hi there,

Currently, SGLT2 inhibitors are the newer kids on the platform for treating diabetes which acts by inhibiting renal glucose absorption an insulin independent mechanism and it has been approved in Europe and Canada as a add on therapy with other antidiabetics such as sulfonylurease and metformin analogues. despite of the above mentioned benificial effects they do increase glucagon secretion.

While DPP-4 inhibitors inhibit DPP-4 activity in peripheral plasma, which prevents the inactivation of the incretin hormone glucagon-like peptide (GLP)-1 in the peripheral circulation. This in turn increases circulating intact GLP-1, which results in stimulated insulin secretion and inhibited glucagon secretion, causing increased glucose utilization and diminished hepatic glucose production, which ultimately causes reduced HbA1c levels.

In my opinion they can be combined together for achieving a synergestic effect.

Very interesting question Subhro.. Theoretically you are right.. Cardiovascular benefits of Sglt2 inhibitors are disproportionate the amount of glucose reduction. It can also cause hyperglucagonemia. One less common but important side effect of Sglt2 inhibitor is euglycemic ketoacidosis which is often difficult to diagnose. Mechanism of this ketoacidosis is hyperglucagonemia, noninsulin dependence glucose clearance and hypovolumia. So drugs which decreases glucogon level like DPP4 inhibitor combination with Sglt2inhibitor will probably have benifits in avoiding this complication and better control of diabetes. Recently one article have been published in Nature regarding Sglt2inhibitor and hyperglucagonemia. Thanks..

there is been several publications where glucagon rise with the use of Dapagliflozin has been demonstrated. This is likely significant in patient's that are insulinopenic as a contributor towards euglycemic ketoacidosis. when combining with a DPP 4 inhibitor, you will get some suppression of glucagon-probably more glucagon suppression than true meaningful insulin secretion-however, the suppression of glucagon, as one would expect, would not be as significant as if he were to be using it in combination with a GLP-1 receptor agonist. That being said, the combination of the SGL T2 inhibitor with a GLP-1 receptor agonist (Liraglutide at this time, since Semaglutide was not an event driven trial)seems to be the best of all worlds in terms of reducing overall cardiovascular risk! However, there is no data that I am aware of looking at additional risk reduction if both of these classes are used in combination versus each one individually.