Adding thiazide to a rennin-angiotensin blocker regimen to improve left ventricular relaxation in diabetes and nondiabetes patients with hypertension

Takeshi Takami,¹ Hiroshi Ito,² Katsuhisa Ishii,³ Kenei Shimada,⁴ Katsuomi Iwakura,⁵ Hiroyuki Watanabe,⁶ Shota Fukuda,⁷ Junichi Yoshikawa<sup>8

1</sup>Department of Internal Medicine, Clinic Jingumae, Kashihara, Japan; ²Department of Cardiovascular Medicine, Okayama University, Graduate School of Medicine, Okayama, Japan; ³Department of Cardiology, Kansai Electric Power Hospital, Osaka, Japan; ⁴Department of Internal Medicine and Cardiology, Osaka City University of Medicine, Osaka, Japan; ⁵Cardiovascular Center, Sakurabashi Watanabe Hospital, Osaka, Japan; ⁶Department of Cardiology, Sakakibara Heart Institute, Tokyo, Japan; ⁷Department of Medicine, Osaka Ekisaikai Hospital, Osaka, Japan; ⁸Nishinomiya Watanabe Cardiovascular Center, Nishinomiya, Japan

Abstract: The urinary albumin to creatinine ratio (UACR) is an independent predictor of outcomes in patients with diastolic dysfunction. Thus, we investigated the relationship between diastolic dysfunction, UACR, and diabetes mellitus (DM) in the EDEN study. We investigated the effect of switching from an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) to a combination of losartan and hydrochlorothiazide on left ventricular (LV) relaxation in patients with hypertension and diastolic dysfunction. We enrolled 106 patients with and 265 patients without DM. All patients had diastolic dysfunction and had not achieved their treatment goals with an ACEi or ARB. The measurements of e′ velocity and E/e′ ratio was performed with echocardiography as markers of LV diastolic function. We switched the ACEi or ARB to losartan/hydrochlorothiazide and followed these patients for 24 weeks. UACR was decreased in patients with DM (123.4 ± 288.4 to 66.5 ± 169.2 mg/g creatinine; P = 0.0024), but not in patients without DM (51.2 ± 181.8 to 39.2 ± 247.9 mg/g creatinine; P = 0.1051). Among DM patients, there was a significant relationship between changes in UACR and changes in e′ velocity (r = –0.144; P = 0.0257) and between changes in estimated glomerular filtration rate and changes in the E/e′ ratio (r = –0.130; P = 0.0436). Among patients without DM, there was a significant relationship between changes in high-sensitivity C-reactive protein (hs-CRP) and changes in E/e′ (r = 0.205; P = 0.0010). Multivariate analysis demonstrated changes in hemoglobin A_1c levels as one of the determinants of change of e′ and E/e′ in patients with DM, whereas hs-CRP was the determinant of change of e′ among patients without DM. These data suggest that improvement in LV diastolic function is associated with an improvement of DM and a concomitant reduction in UACR among DM patients, and with a reduction of hs-CRP in patients without DM when thiazide is added to a renin–angiotensin blocker treatment regimen.

Keywords: diastolic dysfunction, diabetes, urinary albumin to creatinine ratio, losartan, HCTZ