Empagliflozin-Metformin in Hypertension Therapy Synergistically Upregulate 3-Hydroxy-3-Methylglutaryl-Coenzyme A Synthase 2 and Acetyl-coenzyme A acyltransferase 1B

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 Further, our unpublished data indicates that βOHB upregulates 2 key lipid catabolic genes, 3-Hydroxy-3-Methylglutaryl-Coenzyme A Synthase 2 ( Hmgcs2 ) and acetyl-coenzyme A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 analysis. Renal gene expression of key lipid metabolism markers ( Hmgcs2 , Acaa1b ) were assessed via quantitative real-time PCR. Results: Compared to controls, rats treated with Empagliflozin + Metformin demonstrated the greatest reduction in systolic BP and diastolic BP (systolic: 168.7mmHg vs 217.9mmHg, diastolic: 122.2mmHg vs 162.5mmHg, p<0.0001), and was notably more effective than either treatment alone(p<0.0001). Given that the antihypertensive effects of these drugs have been associated with elevated βOHB levels, we assessed serum βOHB and found it to be highest in the combination group, suggesting synergistic ketosis (p<0.05). To explore the mechanism, we examined the key genes Hmgcs2and Acaa1b, which regulate lipid catabolism under ketogenic conditions. Both were significantly upregulated in the combination group ( Hmgcs2p<0.01, Acaa1b p<0.05). Interestingly, while Hmgcs2 upregulation was exclusive to the combination group, Acaa1b was also significantly increased in the Metformin group (p<0.01) highlighting Metformin’s distinct role in lipid oxidation. Conclusion: Our study identifies novel lipid catabolic pathways contributing to the antihypertensive effects of combined Empagliflozin and Metformin therapy. By synergistically increasing βOHB levels, this treatment enhances the transcription of key lipid-metabolizing genes, thereby promoting lipid utilization as an energy source. This shift reduces metabolic stress, contributing to a significant reduction in salt-sensitive hypertension. Our findings emphasize the clinical relevance of this synergistic approach, particularly for patients with both the conditions of hypertension and diabetes, offering a combined benefit of BP reduction and improved lipid metabolism. Bina Joe acknowledges funding support from the NIH (R01HL171401-01) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.