Empagliflozin in combination with trandolapril but not with triple therapy improves glucose and lipid metabolism in non-diabetic hypertensive model

Our previous study demonstrated antihypertensive, anti-inflammatory and metabolic effects of SGLT-2 inhibition in non-diabetic, Ren-2 transgenic hypertensive rats (TGR). The current study aimed to compare the combination of empagliflozin with angiotensin converting enzyme inhibition (trandolapril) versus triple therapy (hydralazine, hydrochlorothiazide, reserpine). Adult male hypertensive Ren-2 transgenic rats were pretreated with these drugs for four weeks. For the following two months, the rats were concomitantly given empagliflozin. Renal function and echocardiography were analyzed throughout the study. Oral glucose tolerance test, metabolic parameters, blood pressure and heart rate were evaluated at the end of the experiment. Additionally, blood pressure and heart rate were monitored by telemetry in trandolapril-treated TGRs. Empagliflozin reduced body weight gain more in trandolapril-treated animals than in rats on triple therapy, despite the latter having higher food consumption. Beneficial effects of empagliflozin in trandolapril-treated group included decreased epididymal fat mass, improved plasma glucose and insulin sensitivity and several metabolic parameters, such as non-fasting glucose, plasma insulin, plasma NEFA, and hepatic cholesterol. There was also reduced ectopic lipid accumulation in liver, kidneys, heart and skeletal muscles, and attenuated inflammation (leptin, MCP-1, TNFα) and steatotic gene markers. BP decreased slightly in trandolapril-treated group, with no effect on cardiac function, as evaluated by echocardiography. Renal function improved substantially with trandolapril treatment, with no additional effect from empagliflozin. In contrast, triple therapy combined with empagliflozin worsened most of the aforementioned effects. Our study´s results suggest that combining empagliflozin with ACE inhibition has beneficial effects, whereas combining empagliflozin with triple therapy has the opposite effect.