SGLT-2 Inhibitors and Cardiovascular Protection: Lessons and Gaps in Understanding the Current Outcome Trials and Possible Benefits of Combining SGLT-2 Inhibitors With GLP-1 Agonists

Abstract

Landmark trials on diabetes control have shown variable results in terms of cardiovascular benefits, with the majority showing a favorable effect of glycemic control on microvascular and, more recently, macrovascular complications. However, some trials pointed out a CV hazard with tight diabetes mellitus (DM) control. Most of those trials were assessing the impact of glycemic control, more than evaluating the effect of a certain medication. In the last decade, food and drugs administration (FDA) has mandated that all new hypoglycemic agents run a CV outcome trial (CVOT) for safety in order to grant and sustain approval. The most stunning results came from relatively new agents in the field of diabetes management, sodium-glucose cotransporter-2 inhibitors (SGLT2i) and the glucagon-like peptide-1 agonists (GLP-1 agonists), details of these CVOTs will be addressed later in this document. SGLT2i effect on the cardiovascular system remains an area of extensive research. We aimed in this review to summarize what is the current evidence of cardiovascular protection upon using SGLT2i. Moreover, we wanted to raise a point that may be strongly adopted in the future, combining SGLT2i plus GLP-1 agonists, having a cardiovascular privilege in both molecules.

Effect of Sodium-Glucose Cotransporter-2 Inhibitors versus Dipeptidyl Peptidase 4 Inhibitors on Cardiovascular Function in Patients with Type 2 Diabetes Mellitus and Coronary Artery Disease

“…Previous trials can explain that there was no improvement in LVEF with SGLT2 inhibitors in our study. For HFrEF, changes in LVEF with SGLT2 inhibitors were more noticeable than with DPP4 inhibitors 13. NT-pro BNP level improved significantly in the SGLT2 inhibitor group, which affected cardiac function and ejection fraction, especially in the HFrEF group.…”

“…SGLT2 inhibitors decreased the risk of both HF hospitalization and mortality. These clinical trials showed that SGLT2 inhibitors have positive effects on patients with cardiovascular diseases 9,12,13. DPP4 inhibitors were determined not to be inferior, but saxagliptin was associated with significantly increased rate of HF hospitalization 10…”

“…Blockade of SGLT2 transporters induced urine with sodium and water secretion. Volume depletion caused by glycosuria and natriuresis resulted in decreased BP (systole, diastole) 13–15. The mechanism is not yet fully understood, but the neurohormonal system might be involved via natriuresis caused by SGLT2 transporters, which leads to altered body fluid volume status 14–16.…”

“…Although SGLT2 inhibitors were given to patients for a short amount of time, NT-pro BNP decreased more in the SGLT2 inhibitor group than in the DPP4 inhibitor group. Decreased NT-pro BNP indicates decreased cardiac wall stress13 and may indicate improved cardiac function in patients with CAD. However, LVEF was not different between the two groups.…”

Potential Therapeutic Effects of Sodium Glucose-linked Cotransporter 2 Inhibitors in Stroke

“…These benefits lead to cardiovascular protection through decreasing weight, lowering blood pressure, increasing the elasticity of the arteries and reducing its stiffness, lowering lipid production, decreasing systemic inflammation and the release of inflammatory biomarkers, increasing insulin production, decreasing insulin resistance, and decreasing uric acid levels. 16,17 Among studies reporting these benefits was a study conducted on apolipoprotein Eedeficient mice. These mice were fed a Western diet for 20 weeks and were treated with empagliflozin for 8 weeks.…”