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J Clin Hypertens (Greenwich). 2012; 14:422–428. ©2012 Wiley Periodicals, Inc.
The authors tested the hypothesis that an aggressive antihypertensive treatment is beneficial in protecting against target organ damage (TOD) in patients with type 2 diabetes/prediabetes. The authors enrolled 60 patients with uncontrolled hypertension and diabetes/prediabetes and performed clinic, home, and ambulatory blood pressure (BP) monitoring. Irbesartan, amlodipine, and indapamide were used according to a titration schedule from step 1 to 5 for target home BP level ≤125/75 mm Hg. The flow-mediated vasodilation (FMD), radial augmentation index (AI), pulse wave velocity (PWV), and urinary albumin excretion ratio (UACR), as a surrogate marker of TOD, were measured at baseline and 6 months. Compared with baseline, clinic, home, and ambulatory BP measures were significantly lower in the sixth month. FMD was increased significantly and AI, PWV, and UACR were reduced by the treatment. The extent of the changes in PWV and UACR were associated with the changes in all BP measures, but only the change in home morning BP was associated with the change in FMD. The change in AI was not associated with the change in BP levels, but was associated with the change in PWV. A very aggressive antihypertensive therapy guided by home morning BP was effective for surrogate end points in patients with diabetes/prediabetes.
To what extent blood pressure (BP) should be lowered in patients with type 2 diabetes is controversial. Most of the outcome trials of type 2 diabetes have shown that active treatment reduces cardiovascular outcomes.1–3 However, the achieved BP was not very low and higher than the level described in the hypertension4–6 and diabetes guidelines.7 Some studies have tested the effects of very low target levels of BP, such as 120/70 mm Hg in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study,8 128/75 mm Hg in the intensive group of the Appropriate Blood Pressure Control in Diabetes (ABCD) trial,9 and 133/73 mm Hg for the valsartan group in the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial.10 However, these studies did not provide any evidence of a reduction of cardiovascular events. In the post hoc analyses of the Irbesartan Diabetic Nephropathy Trial (IDNT)11 and the Perindopril Protection Against Recurrent Stroke Study (PROGRESS),12 the lower BP levels were associated with better cardiovascular outcomes, but the Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) trial,13 the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET),14 and the International Verapamil SR-Trandolapril Study (INVEST) trials15 showed no such benefits. With regard to target organ protection, tight control of BP <130 mm Hg was shown to be associated with better renal outcomes.16 Therefore, the effects of very aggressive antihypertensive treatments in type 2 diabetes are inconsistent and still uncertain for definitive recommendations on cardiovascular prognosis and target organ damage (TOD).
Out-of-office BP measures, such as home BP monitoring17–19 and ambulatory BP monitoring (ABPM),20–24 have been shown to be useful for the assessment of BP in type 2 diabetes. Because a substantial proportion of patients with diabetes show white-coat hypertension25 or masked hypertension,26–28 clinic BP-guided BP management may not always be sufficient for the management of hypertension in diabetic patients. In the Japanese hypertension guidelines, the BP goal at home was set to be <125/75 mm Hg. However, there have been few studies that investigated target home BP level <125/75 mm Hg as a guide of treatment in patients with diabetes. In the present study, we tested the hypothesis that a very aggressive antihypertensive treatment guided by home morning BP monitoring in patients with type 2 diabetes/prediabetes is effective in improving the measures of TOD.
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- Patients and Methods
One patient withdrew from the study at the second month, therefore a total of 59 patients completed the study. The baseline characteristics of patients are shown in Table I. The antihypertensive and antidiabetic drugs at baseline are shown in Table II. At the sixth month, the number of patients in each step were as follows: 2 in step 1, 8 in step 2, 18 in step 3, 13 in step 4, and 18 in step 5. With regard to home morning BP, 40.0% of patients achieved target SBP, 61.7% achieved target diastolic BP (DBP), and 30.0% achieved both the target SBP and DBP of <125/75 mm Hg. With regard to clinic BP, 61.7% achieved the target SBP, 78.3% the target DBP, and 53.3% both the target SBP and DBP of <130/80 mm Hg.
Table I. Baseline Characteristics of Patients
|Variables||Mean±SD or %|
|Patients, No.|| 59|
|Age, y|| 62.6±9.4|
|Male sex, No. (%)|| 31 (51.7)|
|Body mass index, kg/m2|| 26.2±4.3|
|History of angina, No. (%)|| 9 (15.0)|
|History of myocardial infarction, No. (%)|| 1 (1.7)|
|Stroke, No. (%)|| 0 (0)|
|History of peripheral artery disease, No. (%)|| 1.7|
|History of hypertension, y|| 7.5±7.8|
|Treatment of hypertension, y|| 5.0±6.0|
|Hyperlipidemia, No. (%)|| 32 (53.3)|
|Diabetes mellitus, No. (%)|| 45 (75.0)|
|History of diabetes mellitus, y|| 4.7±4.6|
|Treatment of diabetes, No. (%)|| 23 (38.3)|
|Glycated hemoglobin, %|| 6.4±0.6|
|Total cholesterol, mg/dL||200±30|
|HDL cholesterol, mg/dL|| 49±14|
|Serum creatinine, mg/dL|| 0.75±0.22|
|Estimated GFR, mL/min|| 89.2±28.3|
Table II. Drugs Used at Baseline
|Drugs at Baseline||No. (%)|
|Angiotensin receptor blockers||34 (56.7)|
|Calcium channel blockers||29 (48.3)|
|Angiotensin-converting enzyme inhibitors||4 (6.7)|
|Antiplatelet drugs||10 (16.7)|
|Antidiabetic medications||14 (23.3)|
| Biguanides||4 (6.7)|
| Sulfonylureas or meglitinides||12 (20.0)|
| Thiazolidinediones||2 (3.3)|
| Insulin||1 (1.7)|
The average BP levels at baseline and at 6 months are shown in Figure 1. Home morning SBP was lowered from 145±17 mm Hg to 128±11 mm Hg, and home morning DBP was lowered from 81±11 mm Hg to 73±9 mm Hg (both P<.001); home evening SBP was reduced from 133±17 mm Hg to 119±10 mm Hg, and home evening DBP was reduced from 73±10 mm Hg to 66±8 mm Hg (both P<.001). Clinic SBP was lowered from 147±18 mm Hg to 125±15 mm Hg (P<.001), but the clinic DBP was changed from 83±12 mm Hg to 80±54 mm Hg, which was not significant (P=.68). Average 24-hour SBP was lowered from 138±13 mm Hg to 125±11 mm Hg and average 24-hour DBP from 81±8 mm Hg to 73±6 mm Hg. Awake SBP changed from 142±13/83±10 mm Hg to 128±19/77±7 mm Hg (both P<.001); sleep SBP changed from 128±18/74±9 mm Hg to 113±13/66±7 mm Hg (both P<.001).
Figure 1. Differences in blood pressure from the baseline to 6 months. Clinic and home morning systolic blood pressure (SBP) (a). Clinic and home morning diastolic blood pressure (DBP) (a and b). Ambulatory SBP (c) and ambulatory DBP (d).
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As shown in Figure 2, by the aggressive lowering of home BP, FMD changed from 5.3%±2.1% to 5.9%±1.6% (P<.001) and AI (adjusted by heart rate 75 beats per minute) changed from 84%±10% to 78%±11% (P<.001). Similarly, PWV changed from 1635±252 cm/s to 1472±184 cm/s (P<.001) and log-UACR changed significantly by the treatment (P=.03).
Figure 2. Measures of target organ damage at baseline and 6 months. Changes in flow-mediated vasodilation (FMD) (a), changes in radial augmentation index (AI) adjusted by heart rate (HR) of 75 beats per minute (b), changes in pulse wave velocity (PWV) (c), and changes in urinary albumin excretion ratio (UACR) as the geometric mean (d).
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To look at the relationship between the BP-lowering effect of home SBP and the change in the measures of TOD, we ran Pearson’s correlation analyses as shown in Table III. The change in home morning SBP was inversely associated with the change in FMD; while the changes in clinic BP and ambulatory awake, sleep, and morning BP were not associated with the change in FMD. On the other hand, the change in home morning SBP was positively associated with the changes in PWV and log-UACR, and clinic and ambulatory BP measures showed similar correlations with the changes in PWV and log-UACR. The change in DBP showed similar but somewhat weaker correlations with the measures of TOD. However, none of the SBP measures were correlated with the changes in radial AI, but only clinic DBP was significantly correlated with AI. The change in central SBP was not correlated with the change in FMD, but was correlated with the change in PWV. Because central SBP is calculated from AI, the good correlation with AI should not be taken into account.
Table III. Correlations Between the Change in Blood Pressure and the Change in the Measures of Target Organ Damage
| ||FMD||P Value||Al||P Value||Log UACR||P Value||Rt baPWV||P Value||Lt baPWV||P Value|
|Home morning SBP||−0.32||.015||−0.09||.52||0.41||.001||0.29||.03||0.35||.007|
|Home evening SBP||−0.24||.07||−0.10||.48||0.29||.03||0.27||.04||0.36||.006|
|Home morning DBP||−0.12||.39||0.04||.79||0.36||.006||0.26||.054||0.28||.04|
|Home evening DBP||−0.17||.20||0.003||.98||0.14||.30||0.28||.03||0.35||.007|
Compared with baseline, laboratory data at the sixth month, such as serum creatinine, eGFR, potassium, HbA1c, and uric acid did not change significantly (data not shown).
There were 27 patients who reported adverse effects during the study period. In all of these cases, we made a careful assessment of whether the adverse effects were related to the study treatment, and concluded that 13 of 27 adverse effects could have been associated with this study. The details of these cases were as follows: 7 patients had dizziness/vertigo, 4 had peripheral edema, 1 had impotence, and 1 had erythema. Because these effects were transient and mild, all of these patients agreed to continue the study. Of note, the average BP values in the 7 patients during the period of dizziness/vertigo were 131±13 mm Hg/74±8 mm Hg for home morning BP, 122±9 mm Hg/65±8 mm Hg for evening BP, and 135±12 mm Hg/74±10 mm Hg for clinic BP, and these values were somewhat higher than those achieved for the overall patient group in this study.