Why carry out this study?
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Recently, several clinical trials have reported reduction in incidence of mineralocorticoid receptor blocker (MRB)-induced hyperkalemia when combined with sodium-glucose cotransporter 2 (SGLT2) inhibitors |
Esaxerenone, a nonsteroidal MRB, has favorable antihypertensive and renoprotective effects in hypertensive patients with diabetes mellitus (DM) but with an increased clinical risk of hyperkalemia, and should be administered with care in this population |
Evidence on the use of esaxerenone in combination with SGLT2 inhibitors has been reported from clinical trials but not from clinical practice. Thus, we investigated the efficacy and safety of esaxerenone combined with SGLT2 inhibitors in hypertensive patients with DM, possibly leading to a new treatment option for these patients |
What was learned from the study?
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Esaxerenone elicited significant antihypertensive and urinary albumin-to-creatinine ratio-lowering effects regardless of baseline creatinine-based estimated glomerular filtration rate, and its combination with SGLT2 inhibitors improved endpoints regarding serum potassium elevation against historical comparisons |
Combining esaxerenone and SGLT2 inhibitors did not interfere with either drug’s efficacy and may reduce the frequency of serum potassium elevations, suggesting they are a compatible combination |
Introduction
Methods
Study Design and Treatment
Patients
BP Measurements
Measurement of Other Outcomes
Efficacy Endpoints
Safety Endpoints
Statistical Analysis
Results
Patients
eGFR subcohorts | |||
---|---|---|---|
Total N = 93 | G1–G2 subcohort (≥ 60 mL/min/1.73 m2) n = 49 | G3 subcohort (30 to < 60 mL/min/1.73 m2) n = 44 | |
Sex, male | 64 (68.8) | 35 (71.4) | 29 (65.9) |
Age, years | 66.3 ± 9.9 | 62.2 ± 9.5 | 70.9 ± 8.3 |
Weight, kg | 74.4 ± 14.1 | 77.5 ± 15.1 | 70.9 ± 12.0 |
Body mass index, kg/m2 | 27.7 ± 4.1 | 28.4 ± 4.6 | 26.8 ± 3.3 |
Morning home SBP, mmHg | 136.4 ± 10.8 | 137.0 ± 9.8 | 135.6 ± 11.8 |
Morning home DBP, mmHg | 82.3 ± 9.6 | 85.5 ± 7.9 | 78.7 ± 10.1 |
Bedtime home SBP, mmHg | 131.9 ± 12.2 | 133.2 ± 11.5 | 130.3 ± 12.8 |
Bedtime home DBP, mmHg | 78.0 ± 11.1 | 81.8 ± 10.4 | 73.8 ± 10.3 |
Office SBP, mmHg | 136.5 ± 15.5 | 136.2 ± 16.5 | 136.8 ± 14.7 |
Office DBP, mmHg | 80.0 ± 10.4 | 81.9 ± 9.7 | 77.9 ± 10.8 |
UACR, mg/gCr | 145.3 ± 631.9 | 39.0 ± 62.4 | 263.6 ± 907.1 |
< 30 | 58 (62.4) | 34 (69.4) | 24 (54.5) |
30 to < 300 | 28 (30.1) | 14 (28.6) | 14 (31.8) |
≥ 300 | 7 (7.5) | 1 (2.0) | 6 (13.6) |
eGFR, mL/min/1.73 m2 | 66.8 ± 20.6 | 81.1 ± 17.9 | 50.8 ± 7.7 |
Serum potassium, mEq/L | 4.2 ± 0.4 | 4.3 ± 0.4 | 4.2 ± 0.4 |
HbA1c, % | 6.8 ± 0.7 | 6.8 ± 0.6 | 6.8 ± 0.8 |
Duration of hypertension, years | N = 70 10.2 ± 7.5 | n = 41 8.6 ± 6.0 | n = 29 12.4 ± 8.9 |
Duration of T2DM, years | N = 79 8.6 ± 6.5 | n = 45 7.5 ± 5.0 | n = 34 10.1 ± 7.9 |
Other complications | 89 (95.7) | 48 (98.0) | 41 (93.2) |
Diabetic retinopathya | 11 (11.8) | 7 (14.3) | 4 (9.1) |
Dyslipidemia | 79 (84.9) | 42 (85.7) | 37 (84.1) |
Hyperuricemia | 27 (29.0) | 11 (22.4) | 16 (36.4) |
Heart failure | 20 (21.5) | 10 (20.4) | 10 (22.7) |
Basal antihypertensive agents | |||
One RAS inhibitor | 31 (33.3) | 20 (40.8) | 11 (25.0) |
One CCB | 18 (19.4) | 9 (18.4) | 9 (20.5) |
One RAS inhibitor + one CCB | 44 (47.3) | 20 (40.8) | 24 (54.5) |
Oral hypoglycemic drugs | |||
One SGLT2 inhibitor | 31 (33.3) | 15 (30.6) | 16 (36.4) |
One SGLT2 inhibitor + one other oral hypoglycemic drug | 29 (31.2) | 18 (36.7) | 11 (25.0) |
One SGLT2 inhibitor + two other oral hypoglycemic drugs | 33 (35.5) | 16 (32.7) | 17 (38.6) |
Other hypoglycemic drugs than SGLT2 inhibitor | |||
Biguanides | 26 (28.0) | 14 (28.6) | 12 (27.3) |
Thiazolidinediones | 4 (4.3) | 0 (0.0) | 4 (9.1) |
Sulfonylureas | 6 (6.5) | 3 (6.1) | 3 (6.8) |
Rapid-acting insulin secretagogues | 5 (5.4) | 2 (4.1) | 3 (6.8) |
DPP4 inhibitor | 53 (57.0) | 30 (61.2) | 23 (52.3) |
Alpha-glucosidase inhibitor | 1 (1.1) | 1 (2.0) | 0 (0.0) |
Insulin preparation | 0 (0.0) | 0 (0.0) | 0 (0.0) |
GLP1 agonist | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Dose of esaxerenone at the end of treatment (last dose) | |||
1.25 mg | 22 (23.7) | 1 (2.0) | 21 (47.7) |
2.5 mg | 45 (48.4) | 31 (63.3) | 14 (31.8) |
5 mg | 26 (28.0) | 17 (34.7) | 9 (20.5) |
BP-Lowering Effects of Esaxerenone
Effects of Esaxerenone on the UACR
Effects of Esaxerenone on Biomarkers
Safety
eGFR subcohorts | |||
---|---|---|---|
Total N = 93 | G1–G2 subcohort (≥ 60 mL/min/1.73 m2) n = 49 | G3 subcohort (30 to < 60 mL/min/1.73 m2) n = 44 | |
Any TEAEs | 42 (45.2) | 22 (44.9) | 20 (45.5) |
Drug-related TEAEs | 12 (12.9) | 6 (12.2) | 6 (13.6) |
Serious TEAEs | 2 (2.2) | 1 (2.0)a | 1 (2.3)b |
Drug-related serious TEAEs | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Discontinued study treatment due to TEAEs | 6 (6.5) | 2 (4.1) | 4 (9.1) |
Discontinued study treatment due to drug-related TEAEs | 6 (6.5) | 2 (4.1) | 4 (9.1) |
Death | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Frequent TEAEs occurring in ≥ 2 patients | |||
Dizziness | 7 (7.5) | 2 (4.1) | 5 (11.4) |
Back pain | 6 (6.5) | 4 (8.2) | 2 (4.5) |
Pyrexia | 6 (6.5) | 3 (6.1) | 3 (6.8) |
Nasopharyngitis | 4 (4.3) | 3 (6.1) | 1 (2.3) |
Headache | 3 (3.2) | 2 (4.1) | 1 (2.3) |
Tooth decay | 3 (3.2) | 0 (0.0) | 3 (6.8) |
Blood potassium increased | 2 (2.2) | 0 (0.0) | 2 (4.5) |
Hyperkalemiac | 1 (1.1) | 1 (2.0) | 0 (0.0) |