The role of SGLT2 inhibitors beyond glucose-lowering to cardio-renal protection

J Karalliedde

doi:10.15829/1560-4071-2021-4323

Abstract

People with type 2 diabetes mellitus (T2DM) are at high risk of developing cardiovascular disease (CVD) and kidney disease. This enhanced cardio-renal risk persists despite improvements in care and treatments over the last 20 years. Intensive glucose control alone does not substantially reduce the risk of CVD and end stage kidney disease (ESKD). However, in 2015 the landmark EMPA-REG trial demonstrated for the first time the benefits of Empagliflozin a sodium-glucose co-transporter 2 (SGLT2) inhibitor on CVD events and mortality in people with T2DM. Since this trial several other SGLT2 Inhibitors including Dapagliflozin and Canagliflozin have demonstrated CVD benefits. SGLT2 inhibitors have also demonstrated significant reductions in the risk of hospitalization for heart failure (HHF) and ESKD. As a consequence of this growing evidence, there has been a shift in the focus of care in T2DM from glucose management to preservation of organ function. SGLT2 inhibitors have emerged as key treatment to reduce CVD, HHF and prevent progression of kidney disease. The benefits for reducing HHF and preventing ESKD have been observed in people with and without T2DM in large randomised controlled clinical trials. In T2DM the positive effects of SGLT2 inhibitors occur early and are independent of their glucose lowering effects. It is vital that all clinicians recognise the remarkable benefits of SGLT2 inhibitors and use this important class of drugs promptly and early to prevent CVD, HHF and ESKD.

Highlights

The importance of the kidney to the pathophysiology of type 2 diabetes mellitus (T2DM) has been appreciated for many decades [1]
The DAPA-HF trial in 4744 patients with New York Heart Association Class 2, 3 or 4 HF and an ejection fraction 40% or less demonstrated a beneficial effect for dapaglif lozin compared with placebo (26% relative risk reduction) on the primary outcome of a composite of worsening of HF or cardiovascular death (hazard ratio (HR) 0.74, 95% confidence interval (CI) 0.65-0.85)
A meta-analysis of these two trials comprising 8474 participants demonstrated that sodium glucose cotransporter 2 (SGLT2) inhibitors were associated with a 30% reduction in all-cause death (HR 0.87, 95% CI 0.77-0.98), 14% reduction in cardiovascular death (HR 0.86, 95% CI 0.76-0.98) and a 25% reduction

Summary

Introduction

The importance of the kidney to the pathophysiology of type 2 diabetes mellitus (T2DM) has been appreciated for many decades [1]. Blood pressure reduction In clinical trials and real-world studies there are consistent sustained reductions in both systolic (~5 mm Hg) and diastolic (~2 mm Hg) blood pressure with all SGLT2 inhibitors These effects are likely to be related to the coupling of glucose and sodium reabsorption in the proximal tubule. SGLT2 inhibition leads to both an osmotic diuresis and mild natriuresis and a corresponding reduction in extracellular fluid and plasma volume [4, 5] Of importance these blood pressure lowering effects are observed in people without T2DM [4]. Similar results were observed in people with T2DM and longer duration of diabetes in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial which suggesting that glucose control did not have a beneficial impact on CVD and that intensive glucose lowering may be associated with harm [9].

Primary endpoint

Rare Common Uncommon Common

Enhancing cardiac energy e ciency Reducing Hypoxia

Conclusions