Reply to letter to editor regarding the article, "Adenosine monophosphate-activated protein kinase-based classification of diabetes pharmacotherapy".

Sodium glucose co-transporter-2 inhibitors (SGLT2i) are the newest armamentarium in the management of the global type-2 diabetes pandemic.[1] Advantages of SGLT2i include their excellent glycemic efficacy, glycemic durability, significant blood pressure and weight reduction, lipid neutral, insulin resistance reduction, insulin-sparing effect, and an insulin independent mechanism of action.[2] Concerns associated with SGLT2i include mildly increased risk of lower urinary infection, euglycemic ketosis (especially in beta cell depleted state, elderly, sick patients, perioperative, and multiple comorbidities), and bone health impairment.[2]

The authors acknowledge the very relevant research letter highlighting the possible impact of SGLT inhibition on cardiovascular physiology at the cellular level through Adenosine monophosphate-activated protein kinase (AMPK) modulation. AMPK activation has been linked to SGLT-1 up-regulation. Similar data on SGLT-2 channel are lacking. However, as of today, conflicting data are available on the impact of SGLT-1 and cardiovascular pathophysiology (heart vs. brain). In studies on the autopsied human heart and murine perfused heart, SGLT-1 up-regulation at the level of myocardium was shown to provide protection against acute post-ischemia reperfusion injury by replenishing ATP stores in ischemic cardiac tissues through enhancing glucose availability resulting in reducing infarct size.[3] On the contrary, in mouse models of cerebral ischemia, middle cerebral artery occlusion was associated with increased cerebral SGLT-1 expression, AMPK activation (increased phosphorylated AMPK/AMPK ratio) leading to worsening of cerebral ischemic neuronal damage, with such changes being attenuated in cerebral SGLT-1 knockdown mice.[4]

This is important especially when SGLT2i as a class has been documented to have a beneficial impact on overall major adverse cardiac events outcomes in clinical trials, although with riders of increasing trend for cerebrovascular accidents with empagliflozin, and significantly increased risk for peripheral amputations with canagliflozin.[56] It should be highlighted that canagliflozin, but not dapagliflozin and empagliflozin has some SGLT-1 inhibition effect also. Hence AMPK activation may have a differential effect on different organ systems, and the complex interaction between AMPK and different SGLT channels need further evaluation. Further studies (both mechanistic and clinical) on SGLT-1 and SGLT-2 function in central nervous system and heart are needed to better characterize patients, who would derive maximum benefit from this class of molecule, with minimal potential side effects.

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