Effects of the dual sodium–glucose linked transporter inhibitor, licogliflozin vs placebo or empagliflozin in patients with type 2 diabetes and heart failure

Abstract

Explore the efficacy, safety and tolerability of the dual sodium-glucose cotransporter (SGLT) 1 and 2 inhibitor, licogliflozin in patients with type-2 diabetes mellitus (T2DM) and heart failure.Methods: This multicentre, parallel-group phase IIA study randomized 125 patients with T2DM and heart failure (New York Heart Association II-IV; plasma N-terminal pro b-type natriuretic peptide [NT-proBNP] >300 pg/mL) to licogliflozin (2.5 mg, 10 mg, 50 mg) taken at bedtime, empagliflozin (25 mg) or placebo (44 patients completed the study). The primary endpoint was change from baseline in NT-proBNP after 12 weeks. Secondary endpoints included change from baseline in glycated haemoglobin, fasting plasma glucose, weight, blood pressure, fasting lipid profile, high-sensitivity c-reactive protein, and safety and tolerability.Results: Licogliflozin 10 mg for 12 weeks significantly reduced NT-proBNP vs placebo (Geometric mean ratio 0.56 [95% confidence interval: 0.33, 0.95], P = .033). A trend was observed with 50 mg licogliflozin (0.64 [95% confidence interval: 0.40, 1.03], P = .064), with no difference between licogliflozin and empagliflozin. The largest numerical decreases in glycated haemoglobin were with licogliflozin 50 mg (−0.58 ± 0.34%) and empagliflozin (−0.44 ± 1.18%) vs placebo (−0.04 ± 0.91%). The reduction in body weight was similar with licogliflozin 50 mg (−2.15 ± 2.40 kg) and empagliflozin (−2.25 ± 1.89 kg). A numerical reduction in systolic blood pressure was seen with licogliflozin 50 mg (−9.54 ± 16.88 mmHg) and empagliflozin (−6.98 ± 15.03 mmHg) vs placebo (−2.85 ± 11.97 mmHg). Adverse events (AEs) were mild, including hypotension (6.5%), hypoglycaemia (8.1%) and inadequate diabetes control (1.6%). The incidence of diarrhoea (4.9%) was lower than previously reported. Conclusion:The reduction in NT-proBNP with licogliflozin suggests a potential benefit of SGLT1 and 2 inhibition in patients with T2DM and heart failure.

Effect of sodium–glucose cotransporter 2 inhibitors on cardiac structure and function in type 2 diabetes mellitus patients with or without chronic heart failure: a meta-analysis

“…A total of 21 RCTs [ 10 , 24 , 25 , 29 – 31 , 33 , 39 – 52 ] were recognized eligible in this meta-analysis, including 3 in crossover design [ 41 , 44 , 50 ]. A total of 10,978 participants were enrolled, including 6236 in the SGLT2i group and 4821 in the control group.…”

“…The mean follow-up period ranged from 14 days to one year, including three studies [ 41 , 50 , 51 ] less than 3 months. Participants with T2DM that were mostly in stage A–B HF were enrolled in 10 studies [ 24 , 25 , 39 , 40 , 44 , 46 , 48 , 49 , 51 , 52 ], and patients with T2DM and stage C HF were enrolled in 11 studies [ 10 , 29 – 31 , 33 , 41 – 43 , 45 , 47 , 50 ]. LVMI, LVEDVI, LVESVI, LAVI, LVEF, GLS, the E/e’ ratio, plasma NT-proBNP level, and the KCCQ score were reported in 6 [ 24 , 25 , 29 , 44 , 45 , 52 ], 3 [ 25 , 29 , 30 ], 3 [ 25 , 29 , 30 ], 4 [ 25 , 29 , 45 , 52 ], 9 [ 24 , 25 , 29 – 31 , 39 , 40 , 44 , 45 ], 4 [ 24 , 39 , 44 , 51 ], 8 [ 24 , 25 , 30 , 31 , 44 , 45 , 49 , 52 ], 11 [ 10 , 24 , 25 , 31 , 41 , 44 – 46 , 48 – 50 ] and 3 [ 10 ...…”

“…Cardiac structure and function were evaluated by magnetic resonance imaging in 4 studies [ 24 , 25 , 29 , 51 ], echocardiography in 8 studies [ 24 , 30 , 31 , 39 , 44 , 45 , 49 , 52 ], and impedance cardiography in 1 study [ 40 ]. The treatment for the control group was placebo in 15 studies [ 10 , 24 , 25 , 29 , 33 , 40 – 44 , 46 , 47 , 50 – 52 ], and conventional treatment or other antidiabetic drugs in 6 studies [ 30 , 31 , 39 , 45 , 48 , 49 ]. Baseline characteristics of the eligible studies were presented in Table 1 .…”

“…The impacts on LVEF [ 25 , 26 ], global longitudinal strain (GLS) [ 24 , 27 ], and diastolic function [ 25 , 28 ] were also inconsistent in different studies. Similarly, in patients with T2DM and HF, the effects of SGLT2i on left ventricular hypertrophy [ 27 , 29 ], cardiac function [ 27 , 30 , 31 ], and neurohormonal parameters [ 32 , 33 ] were inconsistent. Whether such diversity was due to insufficient sample size or heterogeneity among studies remains to be explored.…”

Dual SGLT-1 and SGLT-2 inhibition improves left atrial dysfunction in HFpEF

“…SGLT inhibitors were designed to block the eponymous transporter in the proximal (SGLT-2) and distal (SGLT-1) tubule, which is responsible for the reabsorption of glucose filtered by the kidney glomerulus [ 7 ]. However, there is a growing body of evidence, that SGLT inhibition exerts its cardiovascular benefits beyond glycemic control, especially in patients with diabetes and heart failure [ 8 ]. Various sites-of-action (and an interplay thereof) have been suggested, e.g.…”