Gliflozins in hypertension: basic mechanisms and clinical insights

Abstract

Sodium-glucose cotransport (SGLT) inhibitors, or gliflozins, initially developed for managing type 2 diabetes mellitus, have emerged as promising therapeutic agents for hypertension, offering both cardiovascular and renal protection. Recently, a dual SGLT1/SGLT2 inhibitor was approved for the treatment of heart failure (HF), including preserved and reduced ejection fraction. Clinical trials consistently demonstrate the ability of gliflozins to lower blood pressure (BP) and reduce cardiovascular events, particularly in patients with comorbid conditions such as chronic kidney disease and HF. However, these trials typically include hypertension as a comorbidity rather than as the primary condition, and data specific to patients with hypertension and without diabetes mellitus remain limited. This review highlights recent clinical and basic mechanistic insights into the antihypertensive effects of gliflozins. We discuss their influence on BP regulation, including modulation of renal sodium handling, the renin-angiotensin-aldosterone system, and vascular function. In addition, gliflozins exhibit significant anti-inflammatory and antifibrotic properties, reducing the risk of organ damage associated with chronic hypertension. Their metabolic benefits extend beyond glucose control, contributing to weight loss, and reduced uric acid levels, collectively supporting better cardiovascular outcomes. Accordingly, we also provide a brief overview of these metabolic effects. As ongoing research continues to explore the broader therapeutic applications of gliflozins, these agents may become integral to the management of hypertension, particularly in patients with complex cardiovascular and renal conditions.

Keywords: SGLT1/SGLT2; blood pressure control; gliflozins; hypertension; sodium-glucose cotransporter.

Figure 1.. Blood pressure-dependent and independent effects of gliflozins in hypertension.

Figure 2.. Reabsorption of glucose and sodium in the proximal tubule.

The schematic of the nephron, including the S1, S2, and S3 proximal tubule segments, is shown on the left. The expanded image illustrates glucose and sodium transport in the S1/S2 and S3 segments, respectively.

Figure 3.

The chemical structures of empagliflozin (Jardiance^®, A), dapagliflozin (Farxiga^®, B), canagliflozin (Invokana^®, C), and Sotagliflozin (Inpefa^® / Zynquista^®, D).