Treatment with SGLT2 Inhibitor Empagliflozin Modulates Renal Sympathetic Nerve Activity in Diabetic Rabbits

In patients with type 2 diabetes, antihyperglycemic treatment with the sodium‐glucose cotransporter 2 (SGLT2) inhibitor empagliflozin is associated with a reduction in cardiovascular mortality of 38% (EMPA‐REG OUTCOME trial). In individuals with poorly controlled type 2 diabetes, sympathetic nervous system (SNS) activation is associated with poor cardiovascular outcomes. We explored the notion that the mechanisms underlying the cardiovascular benefits of empagliflozin treatment may involve an action on the SNS. Diabetes was induced by a single dose of alloxan in New Zealand White rabbits. We determined the changes in blood pressure (BP), heart rate (HR) and renal sympathetic nerve activity (RSNA) as well as baroreflex responses to changes in BP and norepinephrine spillover in conscious rabbits. The effects of one‐week treatment with empagliflozin were compared to those of another blood glucose‐lowering treatment insulin, the proximally‐acting natriuretic acetazolamide, the ACE inhibitor perindopril, vehicle treatment and to an untreated diabetic group. Diabetic rabbits (n=39) were treated with daily insulin to maintain a stable elevation in blood glucose (20.5±0.4mM vs 6.5±0.4mM in controls) over 4 weeks. Diabetes was associated with 9% greater BP than in non‐diabetic rabbits (P=0.02) but no difference in RSNA or HR. One‐week treatment with empagliflozin lowered blood glucose by 43% (without insulin), and there was a 49% increase in water intake. There was no difference in BP, HR or RSNA between empagliflozin‐treated and untreated diabetic rabbits or those treated with acetazolamide. However, insulin lowered blood glucose similarly to empagliflozin (32%) and increased HR (+10%) while perindopril lowered BP (−9%). There was marked augmentation (+69%) of the maximum RSNA response to baroreceptor unloading in diabetic rabbits compared to non‐diabetic (P<0.01). Empagliflozin attenuated the baroreflex by 34% and acetazolamide had a similar blunting effect (−29%, both P<0.05). Empagliflozin also attenuated the HR baroreflex (−8%) but insulin and perindopril had no effect on either baroreflex. Diabetes did not alter BP or HR variability but empagliflozin and acetazolamide treatment increased mid frequency HR power. Norepinephrine spillover to plasma was similar in diabetic and non‐diabetic rabbits but was elevated after both empagliflozin (+147%) and acetazolamide (+134%, P<0.05). In conclusion, empagliflozin effectively normalized the maximal RSNA response to acute BP lowering without altering resting hemodynamic or sympathetic activity in conscious diabetic rabbits. The similarity of these effects with those of acetazolamide suggests that the mechanism underlying the cardiovascular benefits of empagliflozin is linked to its natriuretic action. Support or Funding Information This work was supported by Boehringer Ingelheim.