SGLT2 Inhibitors - The New Standard of Care for Cardiovascular, Renal and Metabolic Protection in Type 2 Diabetes: A Narrative Review

Abstract

A substantial evidence base supports the use of sodium-glucose cotransporter-2 inhibitors (SGLT2is) in the treatment of type 2 diabetes mellitus (T2DM). This class of medicines has demonstrated important benefits that extend beyond glucose-lowering efficacy to protective mechanisms capable of slowing or preventing the onset of long-term cardiovascular, renal and metabolic (CVRM) complications, making their use highly applicable for organ protection and the maintenance of long-term health outcomes. SGLT2is have shown cost-effectiveness in T2DM management and economic savings over other glucose-lowering therapies due to reduced incidence of cardiovascular and renal events. National and international guidelines advocate SGLT2i use early in the T2DM management pathway, based upon a plethora of supporting data from large-scale cardiovascular outcome trials, renal outcomes trials and real-world studies. While most people with T2DM would benefit from CVRM protection through SGLT2i use, prescribing hesitancy remains, potentially due to confusion concerning their place in the complex therapeutic paradigm, variation in licensed indications or safety perceptions/misunderstandings associated with historical data that have since been superseded by robust clinical evidence and long-term pharmacovigilance reporting. This latest narrative review developed by the Improving Diabetes Steering Committee (IDSC) outlines the place of SGLT2is within current evidence-informed guidelines, examines their potential as the standard of care for the majority of newly diagnosed people with T2DM and sets into context the perceived risks and proven advantages of SGLT2is in terms of sustained health outcomes. The authors discuss the cost-effectiveness case for SGLT2is and provide user-friendly tools to support healthcare professionals in the correct application of these medicines in T2DM management. The previously published IDSC SGLT2i Prescribing Tool for T2DM Management has undergone updates and reformatting and is now available as a Decision Tool in an interactive pdf format as well as an abbreviated printable A4 poster/wall chart.

Keywords: Cardiovascular, renal and metabolic protection; Oral glucose-lowering medicines; SGLT2is; Sodium-glucose cotransporter-2 inhibitors; Standard of care; Type 2 diabetes mellitus.

Fig. 1

Change in risk of adverse events with SGLT2is for people with T2DM [36]. Adapted from Nuffield Department of Population Health Renal Studies Group, SGLT2 inhibitor Meta-Analysis Cardio-Renal Trialists’ Consortium. Impact of diabetes on the effects of sodium glucose co-transporter-2 inhibitors on kidney outcomes: collaborative meta-analysis of large placebo-controlled trials. Lancet. 2022;400:1788–801 [36]. The figure shows the specific absolute effects on adverse events associated with SGLT2i use in people with T2DM, based on large-scale randomised trials. The absolute effects were estimated by applying the specific relative risk of an event in the active treatment arm to the average event rate in the placebo arms (first event only). Negative numbers indicate events avoided by SGLT2 inhibition per 1000 patient-years. Mean eGFR values are given for combined trial populations. ASCVD atherosclerotic cardiovascular disease, CKD chronic kidney disease, CV cardiovascular, eGFR estimated glomerular filtration rate, LLA lower limb amputation, SGLT2i sodium glucose co-transporter-2 inhibitor, T2DM type 2 diabetes mellitus

Fig. 2

Schematic representation of the relative risk and benefit profile for SGLT2i therapies based upon RCT and real-world data [–, , , , –31, 41, 49, 51, 56, 81, 82]. CKD chronic kidney disease, CV cardiovascular, CVD cardiovascular disease, DKA diabetic ketoacidosis, DKD diabetic kidney disease, ESKD end-stage kidney disease, LLAs lower limb amputations, RCT randomised controlled trial

Fig. 3

SGLT2i decision tool—abbreviated summary [, , , , , , , , , , , , –, –, , , –, , , , –129]. The full SGLT2i Decision Tool can be viewed and downloaded in an interactive pdf format from the supplementary materials associated with this narrative review paper. ASCVD atherosclerotic cardiovascular disease, BMI body mass index, CKD chronic kidney disease, CVD cardiovascular disease, DKD diabetic kidney disease, eGFR estimated glomerular filtration rate, GLP-1 RA glucagon-like peptide-1 receptor agonist, HbA1c glycated haemoglobin A1c, LADA latent autoimmune diabetes in adult, PAD peripheral arterial disease, PEI pancreatic exocrine insufficiency, QRISK cardiovascular risk score, SGLT2i sodium glucose cotransporter-2 inhibitor, SmPC summary of product characteristics, T2DM type 2 diabetes mellitus, UACR urine albumin-to-creatinine ratio, UTIs urinary tract infections