Study population and methods
A population of 2018 patients diagnosed with type 2 diabetes mellitus who underwent consecutive evaluations, including blood pressure, urinalysis and determination of the serum creatinine levels in the Department of Diabetes, Metabolism and Kidney Disease of Edogawa Hospital, Tokyo, Japan between April 2008 and March 2011 was recruited for the study. Antihypertensive agents were essentially initiated when a systolic blood pressure (SBP) ≥ 130 mmHg and/or a diastolic blood pressure (DBP) ≥ 80 mmHg persisted after the lifestyle modification. The selection of antihypertensive agents was determined by each patient’s physician during the prospective observation period.
The blood pressure was measured twice with the subjects in the sitting position after a 5 minute rest. The lower value of the two measurements was used for the study. Hypertension was defined as a SBP ≥ 140 mmHg and/or a DBP ≥ 90 mmHg. The participants currently using antihypertensive medications were also classified as positive for hypertension. The target blood pressure is less than 130/80 mmHg according to the JNC7 [
6] and the guidelines proposed by the European Society of Hypertension and of the European Society of Cardiology [
8].
The patients were divided into four groups according to their blood pressure status. Categories 1, 2, 3 and 4 were defined to be the subjects showing 1) SBP < 130 mmHg and DBP < 80 mmHg, 2) SBP < 130 mmHg and DBP ≥ 80 mmHg, 3) SBP ≥ 130 mmHg and DBP < 80 mmHg, and 4) SBP ≥ 130 and DBP ≥ 80 mmHg, respectively. The doses and specific drug classes of antihypertensive agents for blood pressure control were dependent on the judgment of each patient’s physician.
The number of antihypertensive agents used was expressed as the sum of antihypertensive agents such as thiazide diuretics, loop diuretics, aldosterone antagonists, alpha blockers, beta blockers, calcium channel blockers (CCBs), ACEIs, ARBs, renin inhibitors, and centrally-acting adrenergic drugs being used.
The estimated glomerular filtration rate (eGFR) was calculated using the formula reported by Matsuo
et al.[
16]. This equation originated from the MDRD study group [
17] arranged for Japanese individuals, and it is recommended by the Japanese Society of Nephrology: eGFR (mL/min/1.73 m
2) = 194 × Scr
-1.094 × Age
-0.287 × 0.739 (if female).
The CKD stage was classified according to the eGFR and the urinary albumin excretion (UAE). The GFR stage was graded as: G1, eGFR ≥ 90 mL/min/1.73 m
2; G2, 90 mL/min/1.73 m
2 > eGFR ≥ 60 mL/min/1.73 m
2; G3a, 60 mL/min/1.73 m
2 > eGFR ≥ 45 mL/min/1.73 m
2; G3b, 45 mL/min/1.73 m
2 > eGFR ≥ 30 mL/min/1.73 m
2; G4, 30 mL/min/1.73 m
2 > eGFR ≥ 15 mL/min/1.73 m
2; and G5, 15 mL/min/1.73 m
2 > eGFR [
15]. The UAE is presented as the albumin-to-creatinine ratio (ACR; mg/g creatinine). The albuminuria stage was graded according to an analysis of a spot urine sample as: A1 (normoalbuminuria), ACR < 30 mg/g creatinine; A2 (microalbuminuria), 30 ≤ ACR < 300 mg/g creatinine; or A3 (macroalbuminuria), ACR ≥ 300 mg/g creatinine (or dipstick urinalysis revealing 2+, 3+ or 4+).
The HbA1c levels were determined by a high performance liquid chromatography method using an automated HLC-723 G7 analyzer (Tosoh Corporation, Tokyo, Japan) and calibrated by the Japan Diabetes Society (JDS) standard calibrators. The value for HbA1c (%) was estimated as a National Glycohemoglobin Standardization Program (NGSP) equivalent value (%) calculated by the formula: HbA1c = HbA1c (JDS) + 0.4, considering the relational expression of HbA1c (JDS) measured by the previous Japanese standard substance and the measurement methods and HbA1c (NGSP) [
18].
Statistical methods
All data are shown as the means ± SD. An analysis of variance (ANOVA) and the χ2 test were used for between-group comparisons of the continuous and categorical variables, respectively. A paired-t test was performed to determine the significance of the change in the number of antihypertensive agents. Differences of P < 0.05 (two-tailed) were considered to be statistically significant. The statistical software package JMP, version 8.0 (SAS Institute, Cary, NC, USA), was used to perform all of the analyses.