The Place and Value of Sodium-Glucose Cotransporter 2 Inhibitors in the Evolving Treatment Paradigm for Type 2 Diabetes Mellitus: A Narrative Review

Abstract

Over recent years, the expanding evidence base for sodium-glucose cotransporter-2 inhibitor (SGLT2i) therapies has revealed benefits beyond their glucose-lowering efficacy in the treatment of Type 2 diabetes mellitus (T2DM), resulting in their recognition as cardiorenal medicines. While SGLT2is continue to be recommended among the second-line therapies for the treatment of hyperglycaemia, their true value now extends to the prevention of debilitating and costly cardiovascular and renal events for high-risk individuals, with particular benefit shown in reducing major adverse cardiac events and heart failure (HF) and slowing the progression of chronic kidney disease. However, SGLT2i usage is still suboptimal among groups considered to be at greatest risk of cardiorenal complications. The ongoing coronavirus disease 2019 (COVID-19) pandemic has intensified financial pressures on healthcare systems, which may hamper further investment in newer effective medicines. Emerging evidence indicates that glycaemic control should be prioritised for people with T2DM in the era of COVID-19 and practical advice on the use of T2DM medications during periods of acute illness remains important, particularly for healthcare professionals working in primary care who face multiple competing priorities. This article provides the latest update from the Improving Diabetes Steering Committee, including perspectives on the value of SGLT2is as cost-effective therapies within the T2DM treatment paradigm, with particular focus on the latest published evidence relating to the prevention or slowing of cardiorenal complications. The implications for ongoing and future approaches to diabetes care are considered in the light of the continuing coronavirus pandemic, and relevant aspects of international treatment guidelines are highlighted with practical advice on the appropriate use of SGLT2is in commonly occurring T2DM clinical scenarios. The 'SGLT2i Prescribing Tool for T2DM Management', previously published by the Steering Committee, has been updated to reflect the latest evidence and is provided in the Supplementary Materials to help support clinicians delivering T2DM care.

Keywords: Cardiorenal protection; Cardiovascular disease; Cardiovascular risk; Chronic kidney disease; Diabetic kidney disease; Heart failure; Oral glucose-lowering medicines; Prescribing tools; SGLT2 inhibitors; Type 2 diabetes mellitus.

Fig. 1

An overview of key drivers of value relating to disease burden and pharmacological interventions [–79]. The value of a pharmacological intervention encompasses many different parameters relating to the direct cost of treatment, avoidance of resource- and time-consuming adverse events or disease-related complications, the impact on recipient QoL (as well as the burden of illness for family members and those who care for them) and the indirect implications of therapy on wider societal factors. HF Heart failure, ICER incremental cost-effectiveness ratio, QALY quality-adjusted life years, QoL quality of life, RCT randomised controlled trial, RRT renal replacement therapy

Fig. 2

Synopsis of the reciprocal effects of diabetes and COVID-19 [88]. The relationship between diabetes and COVID-19 is biunivocal. On one hand, people with diabetes have worse outcomes because of multiple associated conditions enhancing the risk. On the other hand, SARS-CoV-2, because of its tropism for the beta-cell, might cause new-onset diabetes or sustain hyperglycaemia at hospital admission. The impairment of beta-cell function along with the inflammatory cytokine storm and counter-regulatory hormonal responses can precipitate further acute metabolic complications (DKA or HHS). New-onset diabetes, hyperglycaemia at admission, and acute metabolic deterioration, in turn, can further worsen COVID-19 outcomes. DKA Diabetic ketoacidosis, HHS hyperglycaemic hyperosmolar syndrome, SARS-CoV-2 severe acute respiratory syndrome coronavirus 2. Reproduced with permission from Apicella et al. [88]

Fig. 3

A brief guide to SGLT2i prescribing in T2DM [–, –, –61, 94, 95, 100]. The traffic light system indicates the appropriate approach for people with T2DM in each situation: green indicates when SGLT2i therapy should be offered; amber situations are when SGLT2i therapy can be considered; and SGLT2i therapy should not be prescribed for people within the red category. The full SGLT2i Prescribing Tool is provided in the Electronic Supplementary Material section. BMI body mass index, CKD chronic kidney disease, CV cardiovascular, CVD cardiovascular diseases, DKD diabetic kidney disease, eGFR estimated glomerular filtration rate, GLP-1 RA glucagon-like peptide 1 receptor agonist, LADA latent autoimmune diabetes in adults, PAD peripheral arterial disease, SGLT2i sodium glucose cotransporter-2 inhibitor, SmPC summary of product characteristics, T2DM Type 2 diabetes mellitus, UTIs urinary tract infections

Fig. 4

Diagnostic monitoring for CKD/DKD in people with T2DM. a Algorithm for DKD testing, b frequency of monitoring per year by eGFR and adverse risk category for people with (or at risk of) CKD [43, 104, 105]. ABCD Association of British Clinical Diabetologists, AKI acute kidney injury, NICE National Institute for Health and Care Excellence, UACR urine albumin:creatinine ratio. Adapted from Winocour et al. [105] (https://diabetesonthenet.com/diabetes-primary-care/testing-for-kidney-disease-in-type-2-diabetes-consensus-statement-and-recommendations/)