Chapter I: The Body of Evidence with SGLT-2 inhibitors in cardio-renal risk reduction
SGLT-2 Inhibitors in Cardio-Renal Risk Reduction: An Overview
T2DM is associated with multiple comorbidities, including cardiovascular disease (CVD), hypertension, obesity, dyslipidemia and chronic kidney disease (CKD), which increase its morbidity and mortality and complicate treatment decisions (Baptist 2018).
Death from CV disease (CVD) is 70% higher in adults with diabetes compared to those without diabetes, and patients with diabetes have a decreased life expectancy, mostly due to premature CV death (CDC 2020). Over the past two decades, the prevalence of T2DM has significantly increased, and the excess risk of cardiovascular disease, cardiovascular death, and diabetic kidney disease (DKD) have remained unchanged or increased in T2DM patients compared to those without diabetes (Das 2018; Saran 2017).
Although the association between T2DM, CVD, and DKD remain complex, there is a dire need for comprehensive strategies to reduce their risks in patients with T2DM. In recent years, several antiglycemic agents have shown that they not only improve glycemic parameters, but also reduce the risk of cardiovascular events and improve renal outcomes as demonstrated in multiple cardiovascular outcome trials (CVOT). These trials, originally designed to demonstrate CV safety, have provided valuable practice-changing insights that have shifted the focus of T2DM care beyond glucose control into more comprehensive risk management and prevention (Das 2020).
As a result, a growing body of evidence is accumulating on the ability of newer antihyperglycemic agents to improve cardiorenal events in T2DM patients. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors have been extensively studied in several CVOT and real-world studies and have been shown to reduce heart failure hospitalizations and improve renal outcomes in these patients (Das 2018). More recently, these agents have been shown to improve cardiovascular outcomes even in patients without type 2 diabetes, and there is extensive discussion about their utility in patients with HF or chronic kidney disease regardless of the presence or absence of diabetes (Cherney 2019; McMurray 2019; McMurray 2020).
A brief history of SGLT-2 Inhibitors
The story of SGLT-2 inhibitors starts back in 1835, with phlorizin, which is a chemical that was isolated from the bark of the apple tree. It was noted that this compound increased urinary glucose extraction, and ultimately, many decades later, the mechanism by which that occurred was discovered, which was the reduction of reabsorption of glucose (Ehrenkranz 205). Subsequently, again, about four decades later, it was found that it blocked the increase in post-prandial blood sugar after ingestion of sugar by rats. Then, ultimately, analogs of this compound were developed, and the first SGLT-2 inhibitor was tested in humans in 2003, then ultimately approved in 2012 (Zelniker 2018).
