Blood Pressure Reduction: An Added Benefit of Sodium–Glucose Cotransporter 2 Inhibitors in Patients With Type 2 Diabetes

Sodium–glucose cotransporter 2 (SGLT2) inhibitors are a newly approved class of glucose-lowering medications with a novel mechanism of action. These agents increase glycosuria, which leads to improved glucose control. They also produce an osmotic diuresis that, in part, contributes to blood pressure reduction and calorie loss secondary to glycosuria leading to weight loss (1,2). A recent review of SGLT2 inhibitors focuses on the blood pressure–lowering effects of the two approved glucoselowering agents, dapagliflozin and canagliflozin (3). While not approved as antihypertensive agents, they may potentially aid in lowering blood pressure in patients with diabetes. A review of studies in both hypertensive and normotensive patients with type 2 diabetes demonstrates a 4–10 mmHg reduction of systolic blood pressure (3). In this issue of Diabetes Care, Tikkanen et al. (4) investigate the effectiveness and safety of the newest agent in this class, empagliflozin, on blood pressure using 24-h ambulatory blood pressure monitoring. This study randomized over 800 subjects with type 2 diabetes, mean age of 60 years, and good kidney function (i.e., a mean estimated glomerular filtration rate [eGFR] of 84 mL/min/1.73 m). These subjects either were normotensive (,140/90 mmHg) or had stage 1 hypertension ($140/90 , 160/99 mmHg). They were randomized to either empagliflozin 10 mg daily, empagliflozin 25 mg daily, or placebo. The primary end point was the change in HbA1c over the 12-week study. The coprimary end point was change in mean 24-h systolic blood pressure for which the study was 90% powered to see a 4 mmHg difference from placebo. The authors demonstrated a significant reduction in 24-h systolic and diastolic blood pressures, 4/2 mmHg lower than placebo at the 25 mg dose of empagliflozin. The use of 24-h ambulatory blood pressure monitoring in the study by Tikkanen et al. is important and distinctive as it is the gold standard for assessing blood pressure (5). Moreover, it is the largest study to date to assess blood pressure lowering during both day and night with the use of SGLT2 inhibitors. Ambulatory blood pressure is recommended in the U.K. for evaluating all new patients with hypertension by the National Institute for Health and Care Excellence guidelines (5). Given the hypothesis of the study and its specific aim, it would have been more compelling if it stratified patients by level of eGFR (i.e., .45, ,60, and .60 mL/min/1.73 m) to assess the spectrum of blood pressure lowering across stages of kidney disease as was done with canagliflozin (6). This would have required substantially more subjects, however. Additionally, the study could have been powered for a blood pressure end point; however, this class of drugs is not approved as a blood pressure–lowering agent. The exact mechanism of blood pressure lowering with these agents is not completely understood; however, proposed mechanisms are listed in Table 1. Blood pressure reduction by these agents is assumed to be related to its osmotic diuretic effect, although they have very slight natriuretic effects much less than low-dose thiazide diuretics. It is curious that if osmotic diuresis was the sole mechanism, then the antihypertensive effect would wane as kidney function decreases; however, this is not the case (3). Similar levels of blood pressure reduction are seen in people with eGFR of 45 mL/min/1.73 m as those with 85 mL/min/1.73 m. Also, there is no