Prevalence of resistant hypertension and associated factors in Japanese subjects with type 2 diabetes

Accepted Manuscript Title: Prevalence of resistant hypertension and associated factors in Japanese subjects with type 2 diabetes Author: H. Yokoyama S. Araki S. Watanabe J. Honjo S. Okizaki D. Yamada R. Shudo H. Shimizu H. Sone M. Haneda PII: DOI: Reference:

S0168-8227(15)00364-2 http://dx.doi.org/doi:10.1016/j.diabres.2015.08.007 DIAB 6457

To appear in:

Diabetes Research and Clinical Practice

Received date: Revised date: Accepted date:

2-3-2015 4-8-2015 18-8-2015

Please cite this article as: H. Yokoyama, S. Araki, S. Watanabe, J. Honjo, S. Okizaki, D. Yamada, R. Shudo, H. Shimizu, H. Sone, M. Haneda, Prevalence of resistant hypertension and associated factors in Japanese subjects with type 2 diabetes, Diabetes Research and Clinical Practice (2015), http://dx.doi.org/10.1016/j.diabres.2015.08.007 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Highlights

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The prevalence of treatment resistant hypertension is unclear in diabetes. This was estimated by mean values of office blood pressure over one year. It was evaluated with a high achievement of BP goals and adequate adherence. It was associated with cardiovascular risks and familial predisposition to hypertension. Treatment resistant hypertension is common and important in diabetes.

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Japanese subjects with type 2 diabetes

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Prevalence of resistant hypertension and associated factors in

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H YOKOYAMA (1), S ARAKI (2), S WATANABE (1), J HONJO (1, 3), S OKIZAKI (1, 4), D YAMADA (1), R SHUDO (1), H SHIMIZU (1), H SONE (1, 5), M HANEDA (3)

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(1) Jiyugaoka Medical Clinic, Internal Medicine, Obihiro, Japan, (2) Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan (3) Department of Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan (4) Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Sagamihara, Japan (5) Department of Internal Medicine, Niigata University Faculty of Medicine, Niigata, Japan

Running title:Rresistant hypertension in type 2 diabetes Address correspondence and reprint requests to: Hiroki Yokoyama, Jiyugaoka Medical Clinic, Internal Medicine, West 6, South 6-4-3, Obihiro 080-0016, Japan TEL +81-155-20-5011 FAX +81-155-20-5015 E-mail [email protected] Abstract 248 words Text 3722 words Tables 3, Figure 1 Supplemental Table 2

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ABSTRACT

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Objective: The prevalence of treatment resistant hypertension (RH) depends on methods used for blood pressure (BP) measurements, goals of BP, and therapeutic efforts in terms of medication and adherence. We focused on diabetic subjects and explored the prevalence of RH in primary care practice.

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Methods: In 1,737 subjects with type 2 diabetes who continued regular visits, office BP was evaluated by multiple measurements over one year. RH was defined as using more than four antihypertensive drugs or failure to achieve the goal with three antihypertensive drugs from different classes. The RH prevalence was investigated with BP goals <130/80 and 140/90 mmHg. Results: The percentage of subjects who achieved BP goals <130/80 and 140/90 were

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70.5% and 93.8% with adherence to medication ≥ 95%, and the corresponding prevalence rates of RH in treated subjects were 28.4% and 21.8%, respectively. Factors independently associated with RH were age (odds ratio 1.02 [95% CI 1.01–1.04]), body mass index (1.10 [1.06–1.13]), variability in systolic BP (1.06 [1.02–1.09]), triglycerides (2.86 [1.34–6.11]), macroalbuminuria (3.33 [2.03–5.48]), estimated glomerular filtration rate (0.98 [0.97–0.99]), retinopathy (1.91 [1.39–2.61]), and family history of hypertension (1.85 [1.23–2.21]). Worsening albuminuria and glomerular filtration rate enhanced the prevalence of RH in a graded manner. Conclusion: Careful estimation of office BP values over one year with a high achievement of BP goals and adequate adherence revealed that the prevalence of RH in type 2 diabetes is high. RH was characterized by accumulation of cardiovascular genetic and environmental risks. Key Words: type 2 diabetes mellitus, resistant hypertension, prevalence, risk factors, therapeutics

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Abbreviations T2DM, type 2 diabetes mellitus ESRD, end-stage renal disease BP, blood pressure NHANES, national health and nutrition examination survey RH, resistant hypertension GFR, glomerular filtration rate JSH, Japanese Society for Hypertension JNC, Joint National Committee JDS, Japan Diabetes Society HbA1c, glycosylated hemoglobin A1C

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HDL, high density lipoprotein BMI, body mass index RASI, renin angiotensin system inhibitor Cr, creatinine ACR, urinary albumin-to-creatinine ratio LDL, Low density lipoprotein CVD, cardiovascular disease CAD, coronary artery disease RIACE, the renal insufficiency and cardiovascular events study

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Introduction Arterial hypertension complicated with type 2 diabetes (T2DM) confers an enhanced risk of developing albuminuria, renal function loss, end-stage renal disease (ESRD), cardiovascular disease and premature death [1-4]. These facts prompted us to emphasize the importance of maintaining blood pressure (BP) control according to the guideline for T2DM. However, a recent report from NHANES (national health and nutrition examination survey) indicated that in subjects with diabetes, 37.3% achieved BP <130/85 mmHg and 54.6% achieved BP <140/90 mmHg in 2005-2008 [5]. This means that BP management in subjects with T2DM may be inadequate in primary clinical practice. Thus, the assessment as to why it is difficult to achieve the recommended BP levels is an important issue on the improvement of BP management in subjects with T2DM. One of the plausible reasons may be an existence of treatment-resistant hypertension (RH). RH is defined as having uncontrolled hypertension on over three antihypertensive drugs from different classes, one of which should ideally a diuretic, or controlled on over four antihypertensive drugs [6, 7]. The prevalence of RH is estimated ranging widely from 10% to 30% of treated hypertensive patients [8-12]. This could be due to the difference of study designs, i.e., epidemiological studies or clinical trials, and of study protocols regarding the use of antihypertensive drugs. In addition, subjects with RH are recently reported to be at a higher risk for cardiovascular events than those with non-RH [13], indicating that RH is clinically of importance to prevent cardiovascular events. In particular, RH in subjects with T2DM may be important because T2DM itself is a potentially higher risk for renal and cardiovascular diseases and subjects with T2DM need empirically the larger number of antihypertensive drugs to achieve the target levels of BP than non-diabetic population [14]. However, RH in this population has been poorly investigated and characterized. In addition, it remains unclear in subjects with T2DM as to how increased albuminuria and reduced glomerular filtration rate (GFR) are linked to RH although renal dysfunction is known to be associated with RH [10, 15]. Familial predisposition to hypertension in T2DM was reportedly a risk factor not only for systemic blood pressure elevation, but also for progression of renal dysfunction [16-18]. However, attempts to explore potential genetic contributions to RH are rare while gene-environmental interactions may be associated with RH leading to ESRD and cardiovascular disease in T2DM [19]. Thus, a greater understanding of the prevalence and clinical features associated with RH is important to improve the prognosis of subjects with T2DM in primary clinical practice. The aim of this study was to investigate the prevalence of RH and associated 6

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factors while elucidating the clinical manifestations according to hypertension status in T2DM in a primary care setting with a large-number of subjects with careful monitoring and treatment of BP. Since the target BP for T2DM remains controversial, i.e., <130/80 mmHg by the Japanese Society for Hypertension (JSH) [20] but <140/90 mmHg by the 8th Joint National Committee (JNC) [21], this study employed the two BP goals to

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facilitate comparisons across studies.

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Methods Study population This cross-sectional study was performed with the aim of identifying clinical characteristics of subjects with T2DM according to the achievement of blood pressure goals and use of antihypertensive drugs in primary care practice as well as to explore the prevalence of RH and associated factors. T2DM was diagnosed according to the Japan Diabetes Society (JDS) criteria. Among all consecutive subjects with T2DM who regularly visited the outpatient clinic of Jiyugaoka Internal Medicine from June 2012 to May 2013, only subjects who had already been treated for diabetes and its complications for more than a year were included. These subjects have received education about diet, exercise and medications for the adequate controls of blood glucose, BP and lipids according to the guideline recommended by JDS over more than a year prior to the study entry. Subjects with secondary hypertension were excluded on the basis of interview and clinical manifestations. Subjects on dialysis were excluded. Among a total of 1,894 subjects who fulfilled the above criteria, those who did not keep an appointment or take drugs for more than a month were excluded (n=157), leaving 1,737 subjects for this study. The participants attended the clinic every 1-2 months by appointment and continuously received appropriate diabetes care and education, which was intended to maintain glycosylated hemoglobin A1c (HbA1C) values <7.0% (53

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mmol/mol), BP <130/80 mmHg, serum concentrations of total cholesterol <5.2 mmol/L (200 mg/dL), triglycerides <1.7 mmol/L (150 mg/dL), high density lipoprotein (HDL)

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cholesterol ≥1.0 mmol/L (40 mg/dL), and body mass index (BMI) 20–24 kg/m2, as recommended by the JDS guidelines. According to the JDS guideline, antihypertensive drugs used were initially a renin-angiotensin system inhibitor (RASI) followed by addition of a calcium channel blocker, β blocker, or diuretics. In cases that showed side effects such as electrolyte abnormalities, hypotension, and/or other abnormalities, these were discontinued at the discretion of one of the regularly attending six physicians in accordance with the guideline. For such subjects other classes were considered. Because the study entry was mostly after a few years of treatment when BP control and blood glucose control were stabilized, there were few changes in antihypertensive drugs during the 1-year study period. The dose of each antihypertensive drug was at least the standard dose, and the full dose was used in cases in whom BP control was inadequate despite the concomitant use of other classes. The study was approved by the local ethical committee and was carried out in accordance with the Helsinki Declaration II. Measurements BP was measured with an appropriately sized cuff in the sitting position after resting for 8 Page 7 of 31

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more than 5 minutes using an automated standardized BP device. BP was measured twice and the average was used. So as to minimize bias due to different values from visit-to-visit and seasonal changes, and to express as near-to-real office BP levels as possible, office BP measurements were obtained over a 1-year period between June 2012 and May 2013, with a mean of 8 (range 6-12) visits, and the average level was used in the analysis. For each subject intrapersonal mean and SDs of all recorded measurements of systolic BP were calculated, and the visit-to visit variability in serially measured systolic BP was defined as follows: coefficient of variation = SD / mean

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systolic BP ×100. Use of antihypertensive drugs was noted from the last visit during the study period. Non-fasting blood samples were drawn three times in the 1-year period and analyzed to measure serum creatinine and lipids, and the average levels were used in the analysis. HbA1C was measured at each visit by high performance liquid chromatography, which has been certified by the American National Glycohemoglobin Standardization Program. Serum and urinary concentrations of creatinine (Cr) were measured by an enzymatic method with an isotope-dilution mass spectrometry traceable calibrator (N-assay L Creatinine Kit, Nittoubo Medical Co., Tokyo, Japan). Urinary albumin was measured three times a year using random urine samples by a turbidimetric immunoassay. The urinary albumin excretion rate was measured using the albumin-to-creatinine ratio (ACR). Normoalbuminuria, microalbuminuria, and macroalbuminuria were defined as an ACR <3.0 mg/g Cr, ACR ≥3.0 and <30.0 mg/g Cr, and ACR ≥300 mg/g Cr, respectively, in at least two of three samples. The GFR was estimated using the following equation recently generated by The Japanese Society of

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Nephrology: GFR (ml/min/1.73m2) = 194×Scr-1.094×Age-0.287×0.739 (if female) [22]. This equation was confirmed to be reasonably accurate in estimating GFR for the Japanese population by overcoming the underestimation of GFR at high values up to 110 ml/min/1.73 m2 [22]. Low density lipoprotein (LDL) cholesterol was calculated by Friedewald’s foumulae. Previous major acute cardiovascular disease (CVD) events were classified as coronary artery disease (CAD) or ischemic stroke by including coronary, cerebrovascular and carotid revascularization. Diabetic retinopathy was diagnosed after pupillary dilation by ophthalmologists. Family history of hypertension, defined as the presence of hypertension in first-degree relatives, was obtained through a face-to-face interview. At every visit, subjects were asked about the number of antihypertensive tablets that were left, and the rate of taking prescribed antihypertensive tablets in the study-year was calculated. Subjects have to pay 30% for the drugs, and they cannot purchase drugs by themselves without visiting a clinic and obtaining a prescription in 9 Page 8 of 31

Japan, and drugs are prescribed for 1-2 months at each visit.

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Classification of hypertension status It has been judged important in terms of a strategy to improve BP control to classify and characterize subjects by hypertension status such as treated controlled, treatment resistant, treated uncontrolled, and untreated subjects, using a treated controlled group as a control [11, 23]. Accordingly, this concept was applied to the present study and RH was defined as previously described [6, 7]. Namely, the BP goal in the present study was firstly <130/80 mmHg in accordance with the guideline recommended by the JSH in 2014 [20]. Since the recent BP goal by 8th JNC was <140/80 for subjects with diabetes [21], we in parallel analyzed the present data by the BP goal <140/80. Subjects were divided into groups based on whether their BP reached the goal or not and the number of antihypertensive drugs. There were 5 groups in terms of hypertension status as follows: No hypertension; BP achieved without drugs; Untreated hypertension; BP not achieved without drugs; Treated uncontrolled hypertension; BP not achieved with ≤2 drugs; Treated controlled hypertension; BP achieved with ≤3 drugs. RH was defined as using more than 4 antihypertensive drugs or failure to achieve the goal even after using a minimum of three antihypertensive drugs from different classes, , one of which was ideally a diuretic (6, 7).

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Statistical analysis Data are expressed as the mean ± SD if normally distributed, otherwise as median (interquartile range). Statistical significance of the differences among the five subgroups was determined via a chi-squared test with a Bonferroni correction to adjust the probability for categorical variables, one way analysis of variance (ANOVA) followed by Dunnett’s test, which compared each subgroup to the treated controlled group for normally distributed continuous variables, or the Kruskal-Wallis test followed by the Mann-Whitney test with a Bonferroni correction for non-normally distributed continuous variables. Multivariate logistic regression analysis was performed to explore the clinical variables associated with an presence of RH with covariates of sex, age, BMI, HbA1C, variability in systolic BP, HDL-cholesterol, LDL-cholesterol, triglycerides, albuminuria stage, eGFR, retinopathy, any CVD and family history of hypertension. A P-value under 5% (two-tailed) was considered significant. All analyses were performed with the statistical software package SPSS (SPSS Japan, Tokyo, Japan).

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Results Clinical characteristics according to groups by hypertension status as compared to treated controlled hypertension as a control group A total of 1,737 subjects with T2DM were studied. Table 1 indicates the percentage of subjects according to the number of antihypertensive drugs and achievement of the BP goals of <130/80 and 140/90 mmHg. The percentage of subjects who achieved the BP goal <130/80 was 70.6% for all subjects (1,227/1,737), and it was 68.4% in treated subjects (707/1,040). The percentage of subjects who achieved a BP goal <140/90 was 93.8% in all subjects (1,630/1,737) and 93.2% in treated subjects (970/1,040). The clinical characteristics of subjects with respect to hypertension status with a BP goal <130/80 are presented in Table 2. Treated controlled hypertension comprised 33.7%, RH 17.0%, treated uncontrolled 9.2%, untreated hypertension 10.2%, and no hypertension 29.9%, respectively. When compared to the treated controlled group in terms of clinical characteristics, subjects with RH were characterized by higher values of BMI, HbA1C, systolic BP, diastolic BP, visit-to-visit variability in systolic BP,

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LDL-cholesterol, triglycerides, albuminuria, and lower values of HDL-cholesterol and eGFR. Among subjects with RH, 41.3% (122/295) achieved BP <130/80. On the other hand, treated uncontrolled subjects were younger and had the significantly smaller number of prescribed antihypertensive drugs, but showed worse cardiovascular risks (high values for BMI, HbA1C, LDL and albuminuria). The proportion with a family history of hypertension was relatively higher in subjects with RH and treated uncontrolled hypertension. Subjects who were not categorized as hypertension (no hypertension) were younger and characterized by lower values of BMI, duration of diabetes, systolic BP, variability in systolic BP and albuminuria, higher eGFR values, and lower rates of prevalent stoke and family history of hypertension. Regarding previous events of CVD, although stroke was less frequent in subjects with untreated hypertension and no hypertension, proportion of any CVD event was not significantly different among the groups. The average rates of taking prescribed antihypertensive tablets during the one-year observation were 95.8%, 95.6%, and 95.5% in treated controlled, RH, and treated uncontrolled subjects, respectively. The clinical characteristics when the BP goal was set at <140/90 are presented in Supplemental Table S1. Accordingly, the number of subjects with treated controlled and no hypertension increased and of those with resistant, treated uncontrolled and untreated hypertension decreased. The prevalence of RH was 13.1% in all subjects and was 21.8% (227/1,040) among all treated subjects. Among the subjects with RH, 84.6% (192/227) achieved BP <140/90, which increased in comparison to BP <130/80. 11 Page 10 of 31

However, the comparison in terms of the clinical features between RH subjects and treated controlled subjects showed a similar pattern to those for BP goal <130/80.

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Factors associated with RH Factors independently associated with the presence of RH defined by BP goal <130/80 were explored by multivariate logistic regression analysis in all subjects and in subjects only with treated controlled hypertension and RH (Table 3). Age, BMI, visit-to visit variability in systolic BP triglycerides, albuminuria, eGFR, retinopathy, and family history of hypertension remained independently associated with RH in all subjects, and age was cancelled out when the analysis was done in subjects with treated controlled hypertension and RH. Similar patterns were found when these analyses were performed with the BP goal <140/90 (Supplemental Table S2). Based on the significant associations of albuminuria and eGFR with RH, the prevalence of RH according to the stratification of these levels and the ORs adjusted for age and BMI are shown in Figure 1. Low eGFR was highly associated with RH, even among those with normoalbuminuria, and macroalbuminuria indicated several fold higher ORs for RH both in the analyses of BP goals <130/80 and 140/90 mmHg.

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Discussion This study carefully investigated the office BP values in primary care practice with a large number of outpatients with T2DM. Subjects with RH in T2DM were not uncommon and characterized by the accumulation of cardiovascular risk factors (unfavorable profiles for BMI, HbA1C, lipids, albuminuria, and eGFR) and higher visit-to-visit variability in systolic BP. Interestingly, the family history of hypertension, which associates with the genetic predisposition to hypertension, was identified as an independent factor associated with RH in the multiple logistic regression analysis. These findings may indicate that RH is attributed to the gene-environmental interactions of cardiovascular risk factors. In addition, the assessment of the status of BP control including RH in primary diabetes care is considered to be important in order to improve the current BP management and to identify patients at risk for renal and cardiovascular complications. This is the first study to show the prevalence of RH in a large population with T2DM attending to a clinic in Japan. In this study, the prevalence rates of RH among the treated subjects were 28.4% and 21.8%, with BP goals of <130/80 and <140/90 mmHg, respectively. A multicenter study including 15,773 subjects with T2DM in Italy (the renal insufficiency and cardiovascular events study, RIACE) indicated that the prevalence of RH was 21.2% among the treated subjects with a BP goal of <139/80 mmHg [24]. In the RIACE study 23.8% of subjects were on target with 1-3 drugs and 47.3% had uncontrolled hypertension with 0-2 drugs. In our study the corresponding prevalence rates were 33.7% (585/1737) and 19.4% (337/1737), respectively, which indicates more titrated BP management in our study leading to the higher rate of RH. In general population, Sierra et al. found that 12% of 68,045 treated hypertensive patients (32.3% had T2DM) had RH with an average BP control of 164/90 mmHg [9]. In NHANES, where 47% of participants achieved a BP goal <140/90, RH comprised 28.0% in treated patients [11]. In subjects with type 1 diabetes mellitus, the FinnDiane Study Group recently reported that the prevalence of RH with BP goals of <130/80 was 7.9% for all patients (n = 3,678) and 21.2% for the treated subjects (n = 1,370) [25]. These results clearly indicate that the prevalence of RH in primary clinical practice is not uncommon in subjects with T2DM as well as other populations. In this study, it is important to note that the prevalence of RH was estimated under the condition that achievement rates of the BP goals <130/80 and <140/90 exceeded 70% and 93% with adequate adherence, respectively. This would again contribute to the high rate of RH we found. The present study design is less likely to include the pseudo-hypertension because of adequate adherence, multiple BP 13

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measurements and frequent attendance, and might therefore reasonably estimate the prevalence of RH in subjects with T2DM. If the low rates of adherence and/or achievement of BP goal such as reported by above previous studies [9, 11, 24] were improved, the rate of RH would become much higher. Thus, we consider that we should emphasize RH as unmet clinical issue in order to improve the prognosis in subjects with T2DM although several issues such as the definition of RH remain unclear. A previous large population-based study indicated that antihypertensive treatment failure is uncommon and that hypertension can be generally controlled with continued titration of antihypertensive treatments [26]. This previous study defined refractory hypertension as uncontrolled hypertension on ≥5 drugs, and the prevalence

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rates of resistant and refractory hypertension in subjects with hypertension were 14.5% and 0.5%, respectively [26]. Actually in our study, only 28 subjects used ≥5 drugs (data not shown), and 58.7% with the BP goal <130/80 and 15.4% with the BP goal <140/90 were not on goal among RH subjects. In addition, the treated uncontrolled subjects showed the smaller number of prescribed antihypertensive drugs in comparison to the treated controlled group. These results suggest the need for further titration of antihypertensive drugs to achieve the BP goal. This study showed that RH in subjects with T2DM was characterized by the accumulation of cardiovascular risks as well as previous reports in hypertensive and general populations [10, 11, 23]. We found a significantly higher visit-to-visit variability in systolic BP, which has been recently reported as a strong predictor of cardiovascular events and mortality in general population and T2DM [27, 28]. Our study also suggested that RH is associated with the genetic predisposition to hypertension which is reported as renal and cardiovascular risk factors [19, 29-31]. In addition, the graded increase in the prevalence and risk of RH according to increasing albuminuria and decreasing eGFR levels were observed as previously reported by other studies [25, 32]. Taken together with these results, the assessment of RH in primary diabetes care is important to identify a high-risk population for renal and cardiovascular complications. In addition, it warrants the urgent need for interventional therapy to improve prognosis in subjects with RH [13], including weight loss, dietary salt restriction, moderation of alcohol intake, increased physical activity, ingestion of a high-fiber, low-fat diet and titration of antihypertensive drugs [6]. It is very important to decide which antihypertensive drugs should be added to subjects with RH as a future strategy to reduce BP levels. Recent reports suggested the usefulness of adding spironolactone to subjects with RH [7, 33, 34]. Antihypertensive and antialbuminuric benefits of spironolactone when added to subjects with T2DM and 14 Page 13 of 31

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RH have been shown [33]. In our study, spironolactone was used only in 1% and 9.6% of uncontrolled treated and RH subjects, respectively (data not shown), and this should be considered with careful monitoring against hyperkalemia and gynaecomastia. We should mention several limitations and arguments. First, this study did not systematically incorporate home BP or ambulatory BP monitoring. Home BP monitoring was done aggressively for subjects not achieving BP goal; however, this was not necessarily performed for subjects who achieved the BP goal and had no hypertension. A Japanese general population-based study reported the prevalence rates of white coat and masked hypertension to be 8% and 22%, respectively [35], and masked hypertension was reportedly higher in subjects with diabetes than those without diabetes [36]. The possible involvement of white-coat hypertension in RH and masked hypertension in treated controlled hypertension may influence the prevalence of RH. Importantly, subjects with treated uncontrolled and masked hypertension may potentially contribute to increasing the prevalence of RH. Therefore, this may not alter our message that RH is common. Second, measurements of aldosterone or other hormones associated with secondary hypertension were not performed. It is important to recognize, as recently reported, that the risk of primary aldosteronism increases with the severity of hypertension, including RH [12, 37]. Third, lifestyle factors contributing to treatment resistance, i.e. sedentary lifestyle and excess sodium intake, were not evaluated. Fourth, the study included only Japanese subjects seen at a single institution and cannot be generalized to other populations. Although it was a selected population, the fact that the study was concentrated in T2DM subjects with intensive continued titration and adequate adherence achieving 93% with <140/90 mmHg is very important and worthy in terms of estimating RH prevalence. Fifth, use of antihypertensive drugs was obtained from the last visit during the study period while BP values were obtained over the 1-year study period. Since subjects were regular attenders to the clinic for many years before study entry with stabilized BP control and treatment changes during the period were rare, this method was employed to increase the accuracy of the office BP estimation. Finally, the accuracy of self-reported family history remains a problem, although concordance rates of family history were around 80% in our previous study [19]. In conclusion, the prevalence and clinical characterizations of RH were studied in a large number of subjects with T2DM with careful assessment of office BP and high rates of adherence and BP goal achievement. RH among subjects with T2DM in primary care was common and characterized by the accumulation of known cardiovascular risks and genetic predisposition. Its prevalence particularly increased 15

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with worsening albuminuria and eGFR levels in a graded manner. Therefore, the assessment of RH may be important to identify subjects at high risk for renal and cardiovascular complications and intervention trials for RH in T2DM are warranted.

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Acknowledgement We thank Mr. Suguho Takahashi, Jiyugaoka Medical Clinic, Obihiro, for his skillful data collection.

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Source of funding The study is supported by research fund at Jiyugaoka Medical Clinic, Internal Medicine.

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Conflicts of interest/Disclosure statement Nothing to declare. All authors have approved the final article.

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treatment? Curr Hypertens Rep 2002; 4:278-285. De Nicola L1, Gabbai FB, Agarwal R, Chiodini P, Borrelli S, Bellizzi V, et al. Prevalence and prognostic role of resistant hypertension in chronic kidney disease patients. J Am Coll Cardiol 2013; 61:2461-2467. Yokoyama H, Tomonaga O, Hirayama M, Ishii A, Takeda M, Babazono T, et al. Predictors of the progression of diabetic nephropathy and the beneficial effect of angiotensin-converting enzyme inhibitors in NIDDM patients. Diabetologia 1997; 40:405-411. Kumar R, Sharma RK, Agarwal S. Genetic predisposition for development of nephropathy in type 2 diabetes mellitus. Biochem Genet 2013; 51:865-875. Pezzolesi MG, Krolewski AS. The genetic risk of kidney disease in type 2 diabetes. Med Clin North Am 2013; 97:91-107. Yokoyama H, Kawai K, Ohishi M, Sone H; Japan Diabetes Data Management Study Group. Familial predisposition to cardiovascular risk and disease contributes to cardiovascular risk and disease interacting with other cardiovascular risk factors in diabetes: implication for common soil (JDDM 14). Atherosclerosis 2008; 201:332-328. Shimamoto K, Ando K, Fujita T, Hasebe N, Higaki J, Horiuchi M, et al. Japanese Society of Hypertension Committee for Guidelines for the Management of Hypertension. The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2014). Hypertens Res 2014; 37:253-387. James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014; 311:507-520. Matsuo S, Imai E, Horio M. Collaborators developing the Japanese equation for estimated GFR. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis 2009; 53:982–992. De la Sierra A1, Banegas JR, Oliveras A, Gorostidi M, Segura J, de la Cruz JJ, et al. Clinical differences between resistant hypertensives and patients treated and controlled with three or less drugs. J Hypertens 2012; 30:1211-1216. Solini A, Zoppini G, Orsi E, Fondelli C, Trevisan R, Vedovato M, et al. Resistant hypertension in patients with type 2 diabetes: clinical correlates and association with complications. J Hypertens 2014; 32:2401-2410. Lithovius R, Harjutsalo V, Forsblom C, Saraheimo M, Groop PH. FinnDiane Study Group. Antihypertensive treatment and resistant hypertension in patients with type

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M

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d

27.

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1 diabetes by stages of diabetic nephropathy. Diabetes Care 2014; 37:709-717. Calhoun DA, Booth JN 3rd, Oparil S, Irvin MR, Shimbo D, Lackland DT, et al. Refractory hypertension: determination of prevalence, risk factors, and comorbidities in a large, population-based cohort. Hypertension 2014; 63:451-458. Hsieh YT, Tu ST, Cho TJ, Chang SJ, Chen JF, Hsieh MC. Visit-to-visit variability in blood pressure strongly predicts all-cause mortality in patients with type 2 diabetes: a 5·5-year prospective analysis. Eur J Clin Invest 2012; 42:245-253. Johansson JK, Niiranen TJ, Puukka PJ, Jula AM. Prognostic value of the variability in home-measured blood pressure and heart rate: the Finn-Home Study. Hypertension 2012; 59:212-218. Kikkawa R1, Araki S, Haneda M, Kajiwara N, Hidaka H, Shigeta Y. Hypertension and the development of complications in patients with non-insulin dependent diabetes mellitus in Japan. J Am Soc Nephrol 1992; 3 (Suppl 4):S120-S125. Fogarty DG, Krolewski AS. Genetic susceptibility and the role of hypertension in diabetic nephropathy. Curr Opin Nephrol Hypertens 1997; 6:184-191. Rudnicki M, Mayer G. Significance of genetic polymorphisms of the renin-angiotensin-aldosterone system in cardiovascular and renal disease. Pharmacogenomics 2009; 10:463-476. Tanner RM, Calhoun DA, Bell EK, Bowling CB, Gutiérrez OM, Irvin MR, et al. Prevalence of apparent treatment-resistant hypertension among individuals with CKD. Clin J Am Soc Nephrol 2013; 8:1583-1590. Oxlund CS, Henriksen JE, Tarnow L, Schousboe K, Gram J, Jacobsen IA. Low dose spironolactone reduces blood pressure in patients with resistant hypertension and type 2 diabetes mellitus: a double blind randomized clinical trial. J Hypertens 2013; 31:2094-2102. Václavík J, Sedlák R, Plachy M, Navrátil K, Plásek J, Jarkovsky J, Václavík T, et al. Addition of spironolactone in patients with resistant arterial hypertension (ASPIRANT): a randomized, double-blind, placebo-controlled trial. Hypertension 2011; 57:1069-1075. Fukuhara M, Arima H, Ninomiya T, Hata J, Hirakawa Y, Doi Y, et al. White-coat and masked hypertension are associated with carotid atherosclerosis in a general population: the Hisayama study. Stroke 2013; 44:1512-1517. Franklin SS, Thijs L, Li Y, Hansen TW, Boggia J, Liu Y, et al. International Database on Ambulatory blood pressure in Relation to Cardiovascular Outcomes Investigators. Masked hypertension in diabetes mellitus: treatment implications for clinical practice. Hypertension 2013; 61:964-971.

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37. Calhoun DA. Hyperaldosteronism as a common cause of resistant hypertension. Annu Rev Med 2013; 64:233-247.

21 Page 20 of 31

Figure legend

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Figure 1. Prevalence of RH analyzed by using BP goal (a) <130/80 and (b) <140/90 mmHg according to the stage of albuminuria and eGFR, and the OR of RH adjusted for age and BMI compared with a group (reference) of normoalbuminuria and eGFR ≥60

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ml/min/1.73m2.

22 Page 21 of 31

ip t cr

1

a) BP goal <130/80 mmHg BP on goal BP not on goal

520 (29.9) 177 (10.2)

200 (11.5) 80(4.6)

b) BP goal <140/90 mmHg BP on goal BP not on goal

660 (38.0) 37(2.1)

Total

697 (40.1)

2

3

≥4

Total

218 (12.6) 80 (4.6)

167 (9.6) 82 (4.7)

122 (7.0) 91 (5.2)

1227 (70.6) 510 (29.4)

258 (14.9) 22 (1.3)

285 (16.4) 13 (0.7)

235 (13.5) 14 (0.8)

192 (11.1) 21(1.2)

1630 (93.8) 107 (6.2)

280 (16.1)

298 (17.2)

249 (14.3)

213 (12.3)

1737 (100)

M an

0

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ce pt

ed

Number of drug

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Table 1. Distribution of subjects according to the number of antihypertensive drugs and achievement of the BP goals of <130/80 and 140/90 mmHg

23

Page 22 of 31

ip t cr

295 (17.0) 67.5 66.4 ± 10.6 27.7 ± 4.8 ‡ 6.9 ± 0.8 ‡ 14.1 ± 8.4

Treated uncontrolled hypertension

M an

585 (33.7) 69.6 67.8 ± 9.7 26.2 ± 3.7 6.7 ± 0.6 13.9 ± 8.5

ce pt

ed

Resistant hypertension

Untreated hypertension

No hypertension

P-value by ANOVA

160 (9.2) 71.9 63.1 ± 11.6 ‡ 27.2 ± 4.9 * 6.9 ± 0.8 ‡ 11.8 ± 7.7 †

177 (10.2) 70.6 58.8 ± 12.3 ‡ 26.6 ± 5.6 6.9 ± 0.8 ‡ 10.2 ± 6.9 ‡

520 (29.9) 68.7 61.7 ± 11.7 ‡ 24.9 ± 3.7 ‡ 6.8 ± 0.7 11.3 ± 7.9 ‡

<0.001 <0.001 <0.001 <0.001

120.9 ± 5.3

130.6 ± 9.1 ‡

134.4 ± 6.5 ‡

134.1 ± 6.5 ‡

119.5 ± 6.2 †

<0.001

8.0 ± 3.6

9.0 ± 4.2 †

7.7 ± 3.8

7.1 ± 5.0 *

6.9 ± 3.5 ‡

<0.001

Ac

N (%) Men (%) Age (years) BMI (kg/m2) HbA1C (%) Known duration of diabetes (years) Systolic BP (mmHg) Visit-to visit variability in systolic BP (%) Diastolic BP (mmHg) HDL cholesterol (mg/dl) LDL cholesterol

Treated controlled hypertension

us

Table 2. Clinical characteristics of patients with type 2 diabetes according to groups classified by achievement of blood pressure goals <130/80 mmHg and antihypertensive drugs

64.1 ± 7.7

67.0 ± 9.2 ‡

74.2 ± 9.7 ‡

75.3 ± 12.3 ‡

66.4 ± 7.2 ‡

<0.001

56.3 ± 14.2

52.8 ± 14.1 †

55.2 ± 15.6

58.3 ± 14.8

58.3 ± 15.3

<0.001

109.5 ± 24.4

115.2 ± 28.8 †

116.0 ± 26.2 *

114.0 ± 23.8

113.4 ± 24.8 *a)

<0.01 24

Page 23 of 31

ip t cr 46.4 ‡ 33.9 19.7

67.6 ± 18.1

62.6 ± 21.0 †

26.3 4.4 7.7 10.8 55.0

1.9 ± 0.8

ß-Blockers (%) Diuretics (%) Other (%)

91.6 53.2 19.5 28.2 1.0

us

63.9 30.1 6.0

150.5 (114.7-211.7)

141.5 (107.3-197.0)

136.3 (98.0-188.0)

58.8 * 35.0 6.3

69.5 28.8 1.7

84.0 ‡ 14.0 1.9

73.0 ± 17.9 †

81.3 ± 18.2 ‡

79.6 ± 19.9 ‡

43.7 ‡ 5.8 10.2 14.9 60.7

26.9 5.0 8.8 11.9 63.8 *

20.9 4.5 1.7 † 6.5 49.7

13.8 ‡ 2.7 4.2 * 6.7 43.3 ‡

3.8 ± 0.6 ‡

1.5±0.5 ‡

0‡

0‡

99.7 ‡ 92.9 ‡ 86.1 ‡ 81.7 ‡ 13.9 ‡

85.0 * 41.3 † 6.9 ‡ 15.0 † 0.6

0 0 0 0 0

0 0 0 0 0

ed

M an

161.0 (118.0-230.8) ‡

Ac

Retinopathy, (%) CAD, (%) Stroke, (%) Any CVD, (%) Family history of hypertension, (%) Number of antihypertensive drugs RASI (%) CCB (%)

136.0 (102.3-193.7)

ce pt

(mg/dl) Triglycerides (mg/dl) Albuminuria Normo-, (%) Micro-, (%) Macro-, (%) eGFR (mL/min/1.73m2)

<0.001

<0.001

<0.001

25

Page 24 of 31

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Ac

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ed

M an

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Data are the mean ± SD, median (interquartile range), or %. eGFR, estimated glomerular filtration rate. CAD, coronary artery disease. RASI, renin-angiotensin system inhibitor. CCB, calcium channel blocker. Other indicates prazosin, clonidine, and/or methyl-dopa. * P<0.05, †P<0.01, ‡P<0.001 vs. subjects with treated controlled hypertension by Dunett’s test after ANOVA for continuous variables and chi-squared tests for categorical variables after Bonferroni’s correction.

26

Page 25 of 31

ip t cr

In all subjects

In subjects with treated controlled and RH

P-value

Odds ratio (95% CI)

P-value

1.04 (0.75-1.43)

0.82

0.91 (0.65-1.28)

0.60

Age (years)

1.02 (1.00-1.04)

<0.05

1.00 (0.98-1.02)

0.86

2

BMI (kg/m )

1.09 (1.06-1.13)

<0.001

1.06 (1.02-1.10)

<0.01

HbA1C (%)

1.10 (0.91-1.34)

0.34

1.15 (0.93-1.43)

0.19

Variability in systolic BP (%)

1.05 (1.02-1.08)

<0.01

1.05 (1.01-1.09)

<0.05

1.00 (0.99-1.01)

0.88

1.00 (0.99-1.01)

0.85

1.00 (1.00-1.01)

0.59

1.00 (1.00-1.01)

0.63

2.90 (1.36-6.19)

<0.01

2.41 (1.08-5.37)

<0.05

1.00

−

1.00

−

1.48 (1.07-2.03)

<0.05

1.21 (0.87-1.69)

0.25

3.35 (2.04-5.51)

<0.001

2.53 (1.51-4.25)

<0.001

eGFR (mL/min/1.73m )

0.98 (0.97-0.99)

<0.001

0.99 (0.98-1.00)

<0.05

Retinopathy N (%)

1.86 (1.36-2.55)

<0.001

1.61 (1.16-2.23)

<0.01

Any CVD, (%)

1.16 (0.75-1.78)

0.51

1.22 (0.78-1.91)

0.39

Family history of hypertension

1.63 (1.21-2.19)

<0.01

1.29 (0.94-1.76)

0.12

Male

HDL cholesterol (mg/dl) LDL cholesterol (mg/dl) Normoalbuminuria Microalbuminuria Macroalbuminuria

Ac

2

ce pt

Triglycerides (log, mg/dl)

ed

M an

Odds ratio (95% CI)

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Table 3 Multivariate logistic regression analysis to explore variables associated with resistant hypertension defined by a BP goal of <130/80

27

Page 26 of 31

ip t cr

227(13.1) 66.1 66.9 ± 10.1 27.9 ± 4.7 ‡ 6.9 ± 0.9 † 14.2 ± 8.5

Treated uncontrolled hypertension

M an

778 (44.8) 70.7 66.7 ± 10.3 26.5 ± 4.0 6.7 ± 0.7 13.5 ± 8.4

ce pt

ed

Resistant hypertension

Untreated hypertension

No hypertension

P-value by ANOVA

35(2.0) 60.0 63.9 ± 13.0 27.4 ± 5.2 7.2 ± 1.1 ‡ 12.4 ± 7.6

37(2.1) 75.7 59.5 ± 10.5 ‡ 26.5 ± 4.2 6.9 ± 0.9 10.2 ± 8.0

660 (38.0) 68.8 61.1 ± 12.0 ‡ 25.3 ± 4.3 ‡ 6.8 ± 0.7 11.1 ± 7.6 ‡

<0.001 <0.001 <0.001 <0.001

123.8 ± 7.1

129.8 ± 10.0 ‡

142.9 ± 5.5 ‡

141.7 ± 7.8 ‡

122.2 ± 7.8 ‡

<0.001

7.9 ± 3.6

9.3 ± 4.3 ‡

8.8 ± 4.8

9.2 ± 9.3

6.8 ± 3.4 ‡

<0.001

66.1 ± 8.8

66.1 ± 9.1

76.9 ± 11.7 ‡

80.9 ± 18.2 ‡

68.0 ± 8.4 ‡

<0.001

55.6 ± 14.3

52.9 ± 14.2

59.0 ± 18.6

56.9 ± 14.2

58.4 ± 15.3 †

<0.001

110.6 ± 25.2

116.6 ± 29.3 †

115.6 ± 22.4

122.9 ± 23.7 *

113.0 ± 24.5

<0.01

Ac

N (%) Men (%) Age (years) BMI (kg/m2) HbA1C (%) Known duration of diabetes (years) Systolic BP (mmHg) Visit-to visit variability in systolic BP (%) Diastolic BP (mmHg) HDL cholesterol (mg/dl) LDL cholesterol

Treated controlled hypertension

us

Supplemental Table S1. Clinical characteristics of patients with type 2 diabetes according to groups classified by achievement of blood pressure goals <140/90 mmHg and antihypertensive drugs

28

Page 27 of 31

ip t cr 42.7 ‡ 34.4 22.9

68.7 ± 18.3

60.5 ± 20.9 ‡

26.3 4.4 8.0 10.8 56.9

2.0 ± 0.8

ß-Blockers (%) Diuretics (%) Other (%)

91.3 53.6 21.1 29.2 1.0

us

62.9 31.0 6.2

125.7 (109.3-170.8)

161.3 (131.0-211.3)

135.3 (99.2-189.5)

54.3 * 37.1 8.6

70.3 27.0 2.7

80.9 ‡ 17.3 1.8

72.3 ± 19.2

77.4 ± 18.8 *

80.2 ± 19.6 ‡

48.9 ‡ 6.6 10.6 16.3 60.4

28.6 5.7 8.6 14.7 65.7

24.3 0 0 0 48.6

15.2 ‡ 3.3 3.8 † 7.0 44.7 ‡

4.1 ± 0.5 ‡

1.4 ± 0.5 ‡

0‡

0‡

100 ‡ 97.8 ‡ 93.8 ‡ 87.2 ‡ 17.6 ‡

82.9 34.3 * 5.7 * 14.3 0

0 0 0 0 0

0 0

ed

M an

163.7 (120.7-240.0) ‡

Ac

Retinopathy, (%) CAD, (%) Stroke, (%) Any CVD, (%) Family history of hypertension, (%) Number of antihypertensive drugs RASI (%) CCB (%)

143.5 (103.7-198.5)

ce pt

(mg/dl) Triglycerides (mg/dl) Albuminuria Normo-, (%) Micro-, (%) Macro-, (%) eGFR (mL/min/1.73m2)

<0.001

<0.001

<0.001

0 0 0 29

Page 28 of 31

ip t cr

Ac

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ed

M an

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Data are the mean ± SD, median (interquartile range), or %. eGFR, estimated glomerular filtration rate. CAD, coronary artery disease. RASI, renin-angiotensin system inhibitor. CCB, calcium channel blocker. Other indicates prazosin, clonidine, and/or methyl-dopa. * P<0.05, †P<0.01, ‡P<0.001 vs. subjects with treated controlled hypertension by Dunett’s test after ANOVA for continuous variables and chi-squared tests for categorical variables after Bonferroni’s correction.

30

Page 29 of 31

ip t cr

In subjects with treated controlled and RH

P-value

Odds ratio (95% CI)

P-value

Male

0.99 (0.70-1.42)

0.97

0.88 (0.61-1.28)

0.51

Age (years)

1.03 (1.01-1.05)

<0.05

1.01 (0.99-1.03)

0.31

BMI (kg/m2)

1.10 (1.06-1.15)

<0.001

1.08 (1.03-1.13)

<0.01

HbA1C (%)

0.94 (0.75-1.17)

0.57

1.02 (0.80-1.30)

0.86

Variability in systolic BP (%)

1.06 (1.02-1.10)

<0.01

1.06 (1.02-1.11)

<0.01

1.01 (0.99-1.02)

0.42

1.01 (0.99-1.02)

0.28

1.00 (1.00-1.01)

0.25

1.00 (1.00-1.01)

0.25

4.20 (1.78-9.88)

<0.01

3.64 (1.50-8.88)

<0.01

1.00

−

1.00

−

1.57 (1.09-2.26)

<0.05

1.33 (0.92-1.93)

0.14

3.75 (2.21-6.36)

<0.001

2.96 (1.71-5.12)

<0.001

0.98 (0.97-0.99)

<0.001

0.99 (0.98-1.00)

<0.05

Retinopathy N (%)

2.34 (1.65-3.33)

<0.001

2.06 (1.43-2.96)

<0.001

Any CVD, (%)

1.30 (0.81-2.07)

0.28

1.33 (0.82-2.18)

0.25

1.63 (1.17-2.28)

<0.01

1.40 (0.98-2.00)

0.06

M an

Odds ratio (95% CI)

ed

In all subjects

us

Supplemental Table S2. Multivariate logistic regression analysis to explore variables associated with resistant hypertension defined by a BP goal of <140/90

HDL cholesterol (mg/dl) Triglycerides (log, mg/dl) Normoalbuminuria Microalbuminuria Macroalbuminuria

Ac

eGFR (mL/min/1.73m2)

ce pt

LDL cholesterol (mg/dl)

Family history of hypertension

31

Page 30 of 31

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M an

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i

Figure

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