Circulation Reports ORIGINAL ARTICLE Circ Rep 2019; 1: 405 – 413 doi: 10.1253/circrep.CR-19-0070 Heart Failure Comparison of Canagliflozin, Dapagliflozin and Empagliflozin Added to Heart Failure Treatment in Decompensated Heart Failure Patients With Type 2 Diabetes Mellitus Masaki Nakagaito, MD; Shuji Joho, MD; Ryuichi Ushijima, MD; Makiko Nakamura, MD; Koichiro Kinugawa, MD Background: Three sodium-glucose cotransporter-2 inhibitors (SGLT2i), canagliflozin, dapagliflozin and empagliflozin, successfully reduced hospitalization for heart failure (HF) in patients with type 2 diabetes mellitus (T2DM). It remains unclear, however, whether the efficacy of the 3 SGLT2i for HF in T2DM patients is similar. Methods and Results: Eighty-one T2DM patients hospitalized due to decompensated HF were enrolled. After treatment for HF, one of the 3 SGLT2i was non-randomly used, and clinical parameters for HF and T2DM were followed for 7 days. The attending physician was allowed to adjust the dose of furosemide. No differences were observed between the 3 groups in the increase of glycosuria, or in the decreases of body weight and blood pressure 7 days after SGLT2i (interaction P>0.05). Urine volume was similarly increased on day 1, and returned to the baseline on day 7 in each group. Decrease in B-type natriuretic peptide and increase in plasma renin activity were significant in each group. Plasma aldosterone concentration, however, was significantly increased in the empagliflozin and canagliflozin groups (P<0.01, respectively), but not in the dapagliflozin group. Additionally, plasma noradrenaline was significantly increased in the empagliflozin group (P<0.01), but not in the canagliflozin and dapagliflozin groups. Conclusions: The neurohumoral responses to the 3 SGLT2i are different under similar volume correction in HF patients with T2DM. Key Words: Diabetes mellitus; Heart failure; SGLT2 inhibitor ype 2 diabetes mellitus (T2DM) is closely associated beneficial effect as a class effect on HF condition.13,14 It with the onset and progression of cardiovascular remains unclear, however, whether the 3 SGLT2i are T disease and heart failure (HF).1,2 Pharmacological similarly effective for HF itself in patients with T2DM. and non-pharmacological treatments that improve the As a preliminary step in the observation of the long-term outcome for HF have been established, but T2DM as a effectiveness of SGLT2i, it is necessary to confirm the comorbidity further worsens the prognosis in patients with efficacy and safety in the short term. Therefore, the goal of HF.3–5 Thus, intensive treatment for T2DM is considered this study was to compare the short-term efficacy and safety to be beneficial for prevention of cardiovascular morbidity. of the 3 SGLT2i, canagliflozin, dapagliflozin and empa- Contrary to expectation, however, intensive treatment for gliflozin in acute decompensated HF patients with T2DM. T2DM including insulin, thiazolidine and dipeptidylpep- tidase-4 inhibitors failed to improve the onset of cardio- Methods vascular events.6–9 Sodium glucose co-transporter-2 inhibitors (SGLT2i) Subjects reduce hyperglycemia by decreasing renal glucose reabsorp- This was a single-center, non-randomized, open-label study. tion, thereby increasing urinary glucose excretion. To date, This study involved 81 patients who were hospitalized due several large placebo-controlled cardiovascular outcome to decompensated HF complicated with T2DM at Toyama trials using 3 SGLT2i (canagliflozin, dapagliflozin and University Hospital. The inclusion criteria were as follows: empagliflozin) have demonstrated significant reductions (1) chronic HF with guideline-directed medical therapy in mortality and HF hospitalization in patients with including angiotensin-converting enzyme inhibitors (ACEI) T2DM.10–12 Given that SGLT2i could reduce blood pressure or angiotensin II receptor blockers (ARB), β-blockers and and body weight in addition to the original action of diuretics; (2) glycated hemoglobin (HbA1c) before study improving glycemic control, the 3 SGLT2i might exert a intervention ≥6.1% in patients with T2DM; (3) age ≥20 Received August 5, 2019; revised manuscript received August 20, 2019; accepted August 21, 2019; J-STAGE Advance Publication released online September 27, 2019 Time for primary review: 1 day Second Department of Internal Medicine, University of Toyama, Toyama, Japan K.K. is a member of Circulation Reports’ Editorial Team. Mailing address: Shuji Joho, MD, Second Department of Internal Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. E-mail: [email protected] ISSN-2434-0790 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected] Circulation Reports Vol.1, October 2019 406 NAKAGAITO M et al. Figure 1. Study design. HF, heart failure Table 1. Patient Demographic and Disease Characteristics Total Canagliflozin Dapagliflozin Empagliflozin P-value (n=81) (n=34) (n=24) (n=23) Age (years) 72.6±13.2 74.2±10.7 71.6±15.6 71.4±14.1 0.810 Male 50 (62) 24 (71) 12 (50) 14 (61) 0.282 Body weight (kg) 59.1±14.8 58.7±14.4 61.4±14.0 57.4±16.5 0.702 BMI (kg/m2) 23.3±4.3 22.9±4.0 24.8±4.3 22.5±4.7 0.092 HbA1c (%) 7.3±1.2 7.1±1.0 7.4±1.3 7.5±1.5 0.629 FBG (mg/dL) 134±55 133±53 144±64 124±49 0.501 LVEF (%) 43±18 44±19 44±17 41±18 0.811 IHD 34 (42) 15 (44) 9 (38) 10 (44) 0.868 DCM 11 (14) 5 (15) 5 (21) 1 (4) 0.249 VHD 11 (14) 6 (18) 2 (8) 3 (13) 0.592 HF treatment period (days)† 8.8±6.2 7.6±5.7 8.3±5.3 11.2±7.4 0.101 HF treatment β-blockers 71 (88) 31 (91) 19 (79) 21 (91) 0.321 ACEI/ARB 70 (86) 25 (74) 24 (100) 21 (91) 0.011 Loop diuretics 56 (69) 24 (71) 17 (71) 15 (65) 0.891 MRA 56 (69) 21 (62) 18 (75) 17 (74) 0.473 Thiazides 3 (4) 2 (6) 1 (4) 0 (0) 0.509 Tolvaptan 20 (25) 8 (24) 6 (25) 6 (26) 0.975 Anti-diabetic agents Sulfonylureas 7 (9) 2 (6) 4 (17) 1 (4) 0.244 DPP-4i 45 (56) 19 (56) 16 (67) 10 (44) 0.278 Biguanides 10 (12) 4 (12) 4 (17) 2 (9) 0.702 Insulin 10 (12) 4 (12) 3 (13) 3 (13) 0.989 Data given as mean ± SD or n (%). †Time from hospitalization to the day before starting SGLT2i (baseline). ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers; BMI, body mass index; DCM, dilated cardiomyopathy; DPP-4i, dipeptidyl peptidase-4 inhibitor; FBG, fasting blood glucose; HbA1c, glycated hemoglobin; IHD, ischemic heart disease; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; SGLT2i, sodium glucose co-transporter-2 inhibitor; VHD, valvular heart disease. years at the time of obtaining consent; (4) oral meal intake; use of i.v. vasodilators or inotropes during the preceding and (5) consent given, with sufficient understanding of the 24 h. Exclusion criteria were as follows: (1) previous use documents. Before enrollment, patients were also required of SGLT2i; (2) severe infection, scheduled surgery, or to be hemodynamically stable, which was defined as (1) recent serious trauma; (3) serious renal failure (estimated systolic blood pressure (SBP) ≥90 mmHg before the study; glomerular filtration rate <20 mL/min/1.73 m2); (4) preg- (2) no cardiogenic shock; (3) no dehydration; and (4) no nancy or breastfeeding in the study period; (5) urinary tract Circulation Reports Vol.1, October 2019 Comparison of 3 SGLT2i in Acute HF With DM 407 Table 2. Change in Clinical Parameters After 7 Days of SGLT2i Treatment (n=81) Baseline Day 7 P-value Vital signs SBP (mmHg) 112±14 108±15 0.004 DBP (mmHg) 64±11 61±10 0.057 Heart rate (beats/min) 73±13 70±12 0.003 Body weight (kg) 59.1±14.8 57.7±14.7 <0.001 Blood parameters Hemoglobin (g/dL) 12.6±2.4 13.0±2.3 <0.001 Hematocrit (%) 38.0±6.6 38.9±6.6 0.001 Serum albumin (g/dL) 3.3±0.4 3.6±0.4 <0.001 Total bilirubin (mg/dL) 0.7±0.4 0.8±1.3 0.397 Serum sodium (mEq/L) 138±3 137±3 <0.001 Serum potassium (mEq/L) 4.3±0.5 4.5±0.5 0.002 Serum creatinine (mg/dL) 1.07±0.40 1.20±0.49 <0.001 eGFR (mL/min/1.73 m2) 55.6±24.2 49.9±22.4 <0.001 Serum insulin (μU/mL) 11.0±13.1 8.2±5.3 0.048 Plasma BNP (pg/mL) 324±280 228±242 <0.001 Plasma NT-proBNP (pg/mL) 2,778±3,456 2,339±3,505 <0.001 Plasma renin activity (ng/mL/h) 7.5±9.5 13.5±14.5 <0.001 Plasma aldosterone (pmol/L) 121±81 172±129 <0.001 Plasma noradrenaline (pg/mL) 371±206 426±243 0.016 24-h urine test Urine volume (mL/24 h) 1,270±604 1,330±461 0.358 Urine glucose (g/24 h) 2.6±9.4 25.5±25.9 <0.001 Loop diuretics dose (mg/day) 22±21 20±21 <0.001 Data given as mean ± SD. BNP, b-type natriuretic peptide; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; NT-proBNP, N-terminal pro-b-type natriuretic peptide; SBP, systolic blood pressure; SGLT2i, sodium glucose co-transporter-2 inhibitor. or genital infection; (6) history of hypersensitivity to the Urine glucose was measured using 24-h urine. Treatment study drugs; (7) severe ketosis, diabetic coma or precoma; for HF was not changed throughout the study period, and (8) otherwise considered unsuitable by the attending except for minimal loop diuretic dose adjustment at the physician.