Empagliflozin-Metformin in Hypertension Therapy Synergistically Upregulate 3-Hydroxy-3-Methylglutaryl-Coenzyme A Synthase 2 and Acetyl-coenzyme A acyltransferase 1B
Abstract
Background: Combination therapy of Empagliflozin (a Sodium Glucose Transporter 2 Inhibitor) and Metformin (a biguanide) is known to lower Blood Pressure (BP) and is particularly suitable for type 2 diabetes mellitus patients with a high BP. Both drugs are known to enhance lipid catabolism, although the specific target genes involved remain unclear. Empagliflozin facilitates ketosis by increasing the levels of the ketone body β-hydroxybutyrate (βOHB), a metabolite previously reported by our laboratory to lower hypertension. Further, our unpublished data indicates that βOHB upregulates 2 key lipid catabolic genes, 3-Hydroxy-3-Methylglutaryl-Coenzyme A Synthase 2 ( Hmgcs2 ) and acetyl-coenzyme A acyltransferase 1B ( Acaa1b ) in the kidneys of Dahl S rats to mobilize lipids for energy metabolism. Given that Metformin also supports lipid catabolism, we hypothesize that combination therapy with Empagliflozin and Metformin synergistically upregulates Hmgcs2 and Acaa1b, contributing to the mitigation of hypertension. Methods: Male Dahl Salt-Sensitive (S) rats (n = 7/9 per group) were assigned to four groups: Control, Metformin, Empagliflozin, or a combination of Empagliflozin + Metformin. Treatment groups received (either 100 mg/L Empagliflozin, 1250 mg/L Metformin or both in drinking water) ad libitum for seven weeks. End point Blood pressure was measured continuously for 48 hours at four-hour intervals using radiotelemetry. Serum βOHB levels were quantified by colorimetric…
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