ISSN: 2451-0629
Archives of Medical Science - Atherosclerotic Diseases
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Official journal of the International Lipid Expert Panel (ILEP)
vol. 4
Letter to the Editor

Sodium glucose co-transporter 2 inhibitors mediated ketogenesis in patients with metabolic syndrome: clear benefit or anticipated fear?

Dimitrios Ioannis Patoulias

Arch Med Sci Atheroscler Dis 2019; 4: e13–e15
Online publish date: 2019/03/04
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Sodium glucose co-transporter-2 (SGLT-2 inhibitors) have gained significant ground in the field of therapeutics of type 2 diabetes mellitus (T2DM) [1]. Recently, Gonzalez-Ortiz et al. demonstrated that dapagliflozin, a sodium glucose co-transporter 2 (SGLT-2) inhibitor, is also effective in patients with metabolic syndrome (MetS), but without T2DM [2]. The researchers showed that dapagliflozin led to a significant improvement in the parameters of MetS, resulting in remission of MetS in 58.3% of all stratified participants [2]. This observation may reflect the multiple, pleiotropic effects of this novel drug class.
It is established that SGLT-2 inhibitors enhance ketogenesis via mediating the decrease in insulin secretion (due to glucosuria and subsequent decrease in blood glucose levels) and counter-regulatory increase in glucagon levels, while there is evidence of direct action of SGLT-2 inhibitors on pancreatic -cells [3]. Modest, but sustained ketone body reabsorption may also contribute to increased ketone body levels in subjects treated with SGLT-2 inhibitors. Ketogenesis is associated with a substantial increase in lipolysis rates, with shifting from glucose to free fatty acids as an energy substrate [3]. Gonzalez-Ortiz et al. demonstrated that dapagliflozin treatment in the corresponding arm resulted in a significant decrease in triglyceride levels and insulin secretion, which provides evidence on the background pathophysiologic mechanism [2].
The “hepatic fatty acid drainage hypothesis” and its implications in MetS have been formulated by Berge et al. [4]. Stimulation of ketogenesis and subsequent free fatty acid drainage from the liver can relieve fatty acid pressure on the adipose tissue and the skeletal muscle, improving insulin sensitivity and glucose uptake, along with a decrease in adipose tissue and ectopic fat accumulation [4]. Experimental data evince that impaired -oxidation is closely related to severe insulin resistance and vice versa [5], while ketogenesis arises as a crucial regulator of glucose metabolism and fatty liver disease [6].
Despite the fact that there are insufficient data concerning the implications of pharmacologically induced ketogenesis in MetS, previous data support the application of nutritional ketosis in patients with MetS [7]. Utilization of free fatty acids and generated ketones as an alternative fuel substrate results in significant improvement in the major components of...

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