A Comprehensive Analysis of SGLT2-inhibition in Type 2 Diabetes and Heart Failure

Abstract

Type 2 diabetes mellitus (T2DM) and heart failure (HF) are diseases that commonly co-exist and have been shown to increase mortality. There is a variety of treatment options available to treat T2DM, however in the context of HF, many have been shown to not have any beneficial effects on reducing morbidity or mortality, while some are demonstrably harmful. The sodium-glucose linked co-transporter type 2 (SGLT2)-inhibitor class of drug was developed as a novel anti-diabetic agent that acts independent of the insulin-incretin pathway to lower blood sugar. Part of the off-target effects that have been seen with this drug class include weight loss, blood pressure reduction and diuresis – all of which are key in reducing cardiovascular risk, particularly in HF. An unexpected but consistent finding in large cardiovascular outcome trials (which are now mandatory for all new anti-diabetic agents) across the entire SGLT2-inihbitor class was that of improved HF outcomes. The mechanism of this effect was poorly characterised and required further exploration. The Research into the Effect of SGLT2-inhibiton on Left Ventricular Remodelling in Patients with Heart Failure and Diabetes Mellitus (REFORM) trial, addresses the literature gap in this area, and is the first to study the effects of SGLT2-inhibition specifically in the HF population. It showed no difference between groups in the primary endpoints of left ventricular (LV) end diastolic volume or LV end systolic volume; +4.15 ml; 95%CI: -18.52 to 26.83; p=0.714 and +0.96 ml; 95%CI: -17.07 to 19.00; p=0.915 respectively. Patients on dapagliflozin had weight reduction; -1.97kg; 95%CI: -3.99 to 0.05; p=0.056 lower diastolic blood pressure; -6.58mmHg; 95%CI: -11.93 to-1.23; p=0.017 higher haemoglobin; +1.16 g/dL; 95%CI: 0.60 to 1.74; p<0.001 and increased serum beta-hydroxybutyrate; +0.04 mmol/L; 95%CI: 0.001 to 0.08; p=0.045. They were also more likely to stop or reduce their dose of loop diuretics; 50.0% vs 8.7%; p=0.005. Further exploratory analysis revealed that dapagliflozin may improve measures of LV remodelling in patients with baseline LV ejection fraction of 45% or more. We have demonstrated, for the first time, that the effects of dapagliflozin seen previously in the T2DM population remains consistent in the HF population with T2DM. We have also have generated new avenues of research to improve our understanding of this drug class and its potential future use.

Date of Award	2019
Original language	English
Awarding Institution	University of Dundee
Sponsors	European Foundation for the Study of Diabetes
Supervisor	Chim Lang (Supervisor) & Allan Struthers (Supervisor)