AbstractAimTo study the effects of the sodium‐glucose co‐transporter‐2 (SGLT2) inhibitor empagliflozin, the angiotensin receptor blocker (ARB) losartan, and their combination on blood pressure, while studying the mechanisms potentially involved.MethodsA total of 24 people with type 2 diabetes (T2D) (age: 66 ± 6 years; body mass index: 31.0 ± 3 kg/m²; estimated glomerular filtration rate: 90 ml/min/1.73m²) received a 1‐week treatment with empagliflozin 10 mg once daily, losartan 50 mg once daily, their combination, and placebo, in a randomized double‐blind crossover design, with 4‐week washout periods in between. Blood pressure, arterial stiffness, autonomic nervous system activity and plasma volume, extracellular fluid and serum albumin were assessed.ResultsVersus placebo (139 mmHg), empagliflozin reduced systolic blood pressure (SBP) by 8 mmHg (P = .001), losartan by 12 mmHg (P = .001) and empagliflozin + losartan by 15 mmHg (P < .001). Combination therapy had a larger SBP‐lowering effect versus empagliflozin monotherapy (‐7 [95% CI ‐12; ‐2] mmHg) and numerically larger effects versus losartan monotherapy (‐3 [‐8; 2] mmHg). Empagliflozin reduced sympathetic nervous system (SNS) activity, arterial stiffness and extracellular fluid, while increasing serum albumin. Losartan reduced SNS activity and arterial stiffness. Combination therapy induced volume contraction variables, together with a reduction in SNS activity and arterial stiffness.ConclusionIn people with T2D, SGLT2 inhibition in combination with an ARB had a larger blood pressure‐lowering effect versus placebo than either of the drugs alone. Our data further suggest that the mechanisms underlying these blood pressure reductions at least partially differ between these agents.