Mechanism of the blood pressure-lowering effect of sodium-glucose cotransporter 2 inhibitors in obese patients with type 2 diabetes

Abstract

BackgroundSodium-glucose cotransporter 2 (SGLT2) inhibitors are reported to have BP-lowering effect in addition to blood glucose-lowering effect, however, its mechanism is still unknown. This study aimed to investigate the mechanism of blood pressure (BP) lowering effects of SGLT2 inhibitors using 24-h urinary collection in obese type 2 diabetes patients.MethodsTwenty patients with type 2 diabetes (age 48.2 ± 10.7 years, BMI 33.0 ± 4.9 kg/m2) were enrolled. Urine volume, 24-h urinary glucose and sodium excretion, and BP at baseline and 2 weeks and 6 months after administration were measured. Body weight, glycosylated hemoglobin, and BP were evaluated before and 1, 3, and 6 months after SGLT2 inhibitor administration. We evaluated the changes in urine volume and urinary excretion of glucose and sodium as well as correlations among urine volume and urinary sodium glucose excretion at 2 weeks and 6 months after administration of the SGLT2 inhibitors. Furthermore, we investigated the correlations between changes in BP and urinary excretion of sodium and glucose at the same time.ResultsTwo weeks after administration, systolic BP (SBP) significantly decreased (128.5 ± 11.0 to 123.2 ± 9.8 mmHg, P = 0.0314), but diastolic BP (DBP) did not (74.4 ± 10.4 to 73.4 ± 8.5 mmHg, P = 0.5821). The decreased SBP significantly correlated with increased urinary glucose excretion (R = −0.62, P = 0.0073), but not increased urinary sodium excretion. At 6 months, SBP (118.6 ± 11.0 mmHg, P = 0.0041) and DBP (68.4 mmHg, P = 0.0363) significantly decreased. The decreased SBP significantly correlated with increased urinary sodium excretion (R = −0.60, P = 0.0014), but not increased urinary glucose excretion.ConclusionsSGLT2 inhibitors significantly decreased SBP after 1 month and DBP after 6 months in obese patients with type 2 diabetes. The main mechanism of the BP-lowering effect may be plasma volume reduction by osmotic diuresis at 2 weeks and by natriuresis at 6 months after SGLT2 inhibitor administration.

Role of the sodium‐hydrogen exchanger in mediating the renal effects of drugs commonly used in the treatment of type 2 diabetes

“…As with incretin‐based drugs, SGLT2 inhibitors (empagliflozin, dapagliflozin and canagliflozin) promote natriuresis, which is accompanied by a decrease in both blood pressure and body weight . The weight reduction is related, in part, to volume depletion and is not solely the result of loss of calories in the urine . In addition, SGLT2 inhibitors ameliorate albuminuria and reduce both glomerular hyperfiltration and the development of renal disease in experimental diabetes .…”

“…What can account for the striking natriuretic effects of SGLT2 inhibitors in the proximal tubule? Although often, and mistakenly, regarded purely as glycosuric agents, SGLT2 inhibitors increase in both glucose and sodium excretion in the urine . This finding is consistent with the natriuresis seen in patients with familial renal glycosuria who have mutations in the SGLT2 coding gene .…”

“…In early work, the effects of SGLT2 inhibitors on the proximal tubule were ascribed entirely to their actions to block the cotransporter; that is, the natriuretic effect was viewed as being co‐dependent on the increase in glucose excretion. However, in patients treated with SGLT2 inhibitors, there is little relationship between the magnitude of glucose and sodium excretion in the urine . Furthermore, experimentally, selective loss of SGLT2 gene function does not lead to the volume depletion that is characteristically seen with pharmacological SGLT2 inhibition .…”

Contrasting effects on the risk of macrovascular and microvascular events of antihyperglycemic drugs that enhance sodium excretion and lower blood pressure

“…Long-acting glucagon-like peptide-1 (GLP-1) receptor agonists (e.g. empagliflozin, dapagliflozin and canagliflozin) block the reabsorption of both glucose and sodium in the proximal tubule [3]. Drugs that inhibit dipeptidyl peptidase-4 (DPP-4; e.g.…”

“…liraglutide, semaglutide and exenatide) produce prolonged stimulation of the GLP-1 receptor [1]. All three classes of drugs exert natriuretic effects that contribute to their ability to lower blood pressure [3][4][5]. sitagliptin, saxagliptin and alogliptin) enhance the actions of endogenous GLP-1, but may also augment the effects of non-GLP-1 peptides that are normally degraded by DPP-4 [2].…”