It is well-recognized that atherosclerotic diseases are common in patients with type 2 diabetes mellitus. Hypertension is not only an independent risk factor for atherosclerosis, but is also common in the type 2 diabetic patients [1,2]. Furthermore, hypertension is a risk factor for the onset and progression of diabetic microand macrovascular complications, as well as hyperglycemia [3,4]. The risk for cardiovascular events synergistically increases in patients with both diabetes mellitus and hypertension [5]. Although the target blood pressure is recommended to be less than 130/80 mmHg in order to prevent diabetic vascular events [6,7], hypertension is often resistant to treatment in patients with type 2 diabetes mellitus [8,9]. It is difficult to control blood pressure using single agents, and combination therapy is needed in many diabetic patients with hypertension [9,10]. When examining patients with hypertension resistant to antihypertensive agents, it is important to re-evaluate the various causes such as lifestyle, body weight, smoking habit and excessive alcohol consumption, in addition to re-considering the medication. These are also risk factors for cardiovascular diseases, as well as hypertension and diabetes [6,7], therefore, it is possible that subjects requiring the combination therapy with antihypertensive agents may also have advanced atherosclerosis. Although the associations of cardiovascular events with the level of blood pressure achieved by medication or with the type of antihypertensive agents used have been reported previously [3,6,7,11-13], the relationship between atherosclerosis and the number of antihypertensive drugs required in the clinical setting has not yet been investigated. It is possible that hypertensive subjects requiring more antihypertensive agents show progressive vascular damage independent of the control of blood pressure.

In the present cross-sectional study, the associations between the number of antihypertensive agents being used by patients with type 2 diabetes mellitus and 1) the grade of atherosclerosis according to non-invasive surrogate markers for atherosclerosis and 2) the other risk factors for atherosclerosis were investigated. We consider that these results indicate the necessity of a more aggressive approach for the diabetic patients requiring intensive therapy for hypertension independently from the blood pressure control.

A population of 2107 patients diagnosed with type 2 diabetes mellitus who underwent consecutive treatments in the Department of Diabetes, Metabolism and Kidney Disease of Edogawa Hospital, Tokyo, Japan between April 2008 and March 2011, were screened for this study. For diagnosis of chronic kidney disease (CKD), 89 patients without urinalysis findings were excluded from the study. Because it is considered that a certain amount of time is required to adjust the dosage of antihypertensive agents, 653 subjects who were treated for less than 12 months were excluded from the study. Also excluded were 6 subjects whose blood pressure data were absent from their medical records following 12 months of treatment in our department. Finally, the associations between the number of antihypertensive agents being used and the clinical characteristics of the patients were evaluated in 1359 subjects who were treated for more than 12 months in the present cross-sectional study.

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 diagnosis of hypertension for this cross-sectional study was performed according to the medical records at the final visit to our hospital. The target blood pressure was 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 [7]. The selection of antihypertensive agents was determined by each patient’s physician during the treatment period.

The patients were divided into two categories according to their blood pressure status. Categories 1 and 2 were defined to include the subjects showing 1) SBP <130 mmHg and DBP <80 mmHg and 2) SBP ≥130 mmHg or DBP ≥80 mmHg, respectively.

The number of antihypertensive agents was expressed as the sum of the antihypertensive agents, such as thiazide diuretics, loop diuretics, aldosterone antagonists, alpha blockers, beta blockers, calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), renin inhibitors, and centrally-acting adrenergic drugs that were being used.

The obese individuals were defined as those having a body mass index ≥25.0 kg/m².

The serum total cholesterol, LDL-cholesterol, HDLcholesterol and uric acid concentrations were measured with a TBA-200 FR NEO device using the Determiner L TC II, Determiner L LDL-C, Determiner L HDL-C and Determiner L UA instruments (Kyowa Medex Co., Ltd., Tokyo, Japan). Hyperlipidemia was defined by serum concentrations of total cholesterol ≥5.7 mmol/L, a LDLcholesterol level ≥3.6 mmol/L, or as patients who were already undergoing treatment with lipid-lowering agents. The triglyceride concentrations were not investigated in this study because fasting blood samples could not always be obtained for measurements. Hyperuricemia was defined by serum uric acid levels >416 μmol/L or as patients using allopurinol according to the guidelines proposed by the Japanese Society of Gout and Nucleic Acid Metabolism [14].

Anemia was defined as a hemoglobin level <135 g/L in men and 120 g/L in women according to the guidelines of the European Renal Association-European Dialysis and Transplantation Association [15] and the National Kidney Foundation [16].

The estimated glomerular filtration rate (eGFR) was calculated using the formula reported by Matsuo, et al. [17] This equation originated from the MDRD study group [18] arranged for Japanese individuals, and it is recommended by the Japanese Society of Nephrology: eGFR (mL/min/1.73m²) = 194 × Scr^−1.094 × Age^−0.287 × 0.739 (if female).

CKD was defined as a decreased eGFR (<60 mL/min/ 1.73 m²) and/or a urinary albumin-to-creatinine ratio (ACR) >30 mg/g creatinine [18,19].

The HbA1c levels were determined by a high performance liquid chromatography method using an automated HLC-723G7 analyzer (Tosoh Corporation, Tokyo, Japan) and calibrated by the Japan Diabetes Society (JDS) standard calibrators.

The ankle-brachial pressure index (ABI) and brachialankle pulse wave velocity (baPWV), as indicators of atherosclerosis, were measured using a Form PWV/ABI, BP-203PRE II instrument (Omron Colin Co., Ltd, Bunkyo, Tokyo, Japan). The intima-media thickness (IMT) of the carotid artery was measured via ultrasonographic examinations by skilled laboratory technicians using an Aplio XV ultrasound machine (Toshiba Medical Systems Corp., Ohtawara, Tochigi, Japan) as described previously [20].

Table 1 shows the clinical characteristics of the study patients. The mean observation period in the study subjects was 27 ± 10 months. Their mean blood pressure