Sodium-Glucose Cotransporter-2 Inhibitor (SGLT2i) as a Primary Preventative Agent in the Healthy Individual: A Need of a Future Randomised Clinical Trial?

Abstract

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are a relatively novel class of drug for treating type 2 diabetes mellitus (T2DM) that inhibits glucose reabsorption in the renal proximal tubule to promote glycosuria and reduce blood glucose levels. SGLT2i has been clinically indicated for treating T2DM, with numerous recent publications focussing on both primary and secondary prevention of cardiovascular and renal events in Type 2 diabetic patients. The most recent clinical trials showed that SGLT2i have moderately significant beneficial effects on atherosclerotic major adverse cardiovascular events (MACE) in patients with histories of atherosclerotic cardiovascular disease. In this review and analysis, SGLT2i have however demonstrated clinically significant benefits in reducing hospitalisation for heart failure and worsening of chronic kidney disease (CKD) irrespective of pre-existing atherosclerotic cardiovascular disease or previous heart failure history. A meta-analysis suggests that all SGLT2 inhibitors demonstrated the therapeutic benefit on all-cause and cardiovascular mortality, as shown in EMPAREG OUTCOME study with a significant decrease in myocardial infarction, without increased stroke risk. All the above clinical trial recruited type 2 diabetic patients. This article aims to postulate and review the possible primary prevention role of SGLT2i in healthy individuals by reviewing the current literature and provide a prospective overview. The emphasis will include primary prevention of Type 2 Diabetes, Heart Failure, CKD, Hypertension, Obesity and Dyslipidaemia in healthy individuals, whom are defined as healthy, low or intermediate risks patients.

Hypothalamic Sex-Specific Metabolic Shift by Canagliflozin during Aging

“…In support, our current results highlight the effectiveness of Cana in the hypothalamus in mitigating age-related metabolic dysregulation in male mice. The early-onset and sustained improvements in metabolic parameters, including reduced body weight, fat mass, and enhanced glucose tolerance in aged UM-HET3 mice of both sexes, are consistent with the known mechanisms of action of Cana in improving peripheral insulin sensitivity and glucose metabolism (Sawada et al, 2017; Xu et al, 2021). The significant alterations in hypothalamic gene expression observed in Cana-treated males in both age groups, particularly related to insulin signaling and neuropeptides signaling, align with our observations that Cana significantly improved central insulin sensitivity in the hypothalamus of aged male but not female mice (Kullmann et al, 2021).…”

TorS ‐ Reframing a rational for type 2 diabetes treatment

“…However, the concerned cardio‐renal‐metabolic benefits of SGLT2i are reported now in non‐diabetic ASCVD/heart failure patients or non‐diabetic patients with chronic kidney disease, 106,107 implying that the concerned cardio‐renal outcomes are independent of the glucose‐lowering activity of SGLT2i. In line with that, SGLT2i are approved now for the treatment of heart failure and chronic kidney disease in non‐diabetic patients, and are considered as primary preventive agents in non‐diabetic individuals 108 . Similarly, growth suppression and apoptosis of cancer types by SGLT2i are reported in non‐diabetic normoglycemic normoinsulinemic patients and refer to cell types which lack SGLT2 cotransporters altogether 104 .…”

Recent Progress in the Diagnosis and Management of Type 2 Diabetes Mellitus in the Era of COVID-19 and Single Cell Multi-Omics Technologies

“…The first SGLT2i, dapagliflozin, was approved by the European Medicines Agency (EMA) in 2013, and the others are canagliflozin, empagliflozin, tofogliflozin, and ipragliflozin (approved in Japan and Russia) [ 89 ]. It has been significantly verified by clinical studies that SGLT2i reduce the risk of a series of cardiovascular or renal complications such as atherosclerotic CVD, myocardial infarction, and CKD [ 90 ]. T2DM-induced sterile inflammation, endothelial dysfunction, and oxidative stress lead to vascular injury.…”