Abstract
Context:
Blood pressure (BP) control can reduce the risk of stroke among diabetic patients; however, it is not known whether the lowest risk of stroke is among diabetic patients with the lowest BP level.
Objective:
Our objective was to investigate the race-specific association of different levels of BP with stroke risk among diabetic patients in the Louisiana State University Hospital-based longitudinal study.
Design, Setting, and Participants:
We prospectively investigated the race-specific association of different levels of BP at baseline and during an average of 6.7 years of follow-up with incident stroke risk among 17 536 African American and 12 618 white diabetic patients within the Louisiana State University Hospital System.
Main Outcome Measure:
We evaluated incident stroke until May 31, 2012.
Results:
During follow-up, 2949 incident cases of stroke were identified. The multivariable-adjusted hazard ratios of stroke associated with different levels of systolic/diastolic BP at baseline (<110/65, 110–119/65–69, 120–129/70–80 [reference group], 130–139/80–90, 140–159/90–100, and ≥160/100 mm Hg) were 1.88 (95% confidence interval = 1.38–2.56), 1.05 (0.80–1.42), 1.00, 1.05 (0.86–1.27), 1.12 (0.94–1.34), and 1.47 (1.24–1.75) for African American diabetic patients and 1.42 (1.06–1.91), 1.22 (0.95–1.57), 1.00, 0.88 (0.72–1.06), 1.02 (0.86–1.21), and 1.28 (1.07–1.54) for white diabetic patients, respectively. A U-shaped association of isolated systolic or diastolic BP at baseline and during follow-up with stroke risk was observed among both African American and white diabetic patients. The U-shaped association was confirmed in both patients who were and were not taking antihypertensive drugs.
Conclusions:
The current study suggests a U-shaped association between BP and the risk of stroke. Aggressive BP control (<110/65 mm Hg) and high BP (≥160/100 mm Hg) are associated with an increased risk of stroke among both African American and white patients with type 2 diabetes.
Hypertension and diabetes are two important public health problems in the United States. Hypertension is a prevalent condition affecting approximately 65 million Americans (1), and diabetes is considered the epidemic of the 21st century, affecting approximately 24 million Americans (2). About 70% of diabetic people aged >40 years are affected by hypertension, with black and Hispanic individuals affected disproportionately compared with the rest of the population (3, 4). Previous guidelines recommend that blood pressure (BP) goals should be more aggressive (<130/80 mm Hg) in diabetic patients than in people without diabetes (<140/90 mm Hg) (5, 6), but the newest version of American Diabetes Association (ADA) guidelines revised the target to be <140/80 mm Hg (7). Aggressive targets for BP in type 2 diabetes have been questioned recently because recent data from more contemporary populations with hypertension and diabetes do not confirm the benefit to coronary heart disease (CHD) of intensive BP control (8, 9). These data showed that aggressive BP control was more closely associated with a decreased stroke risk than CHD risk (8, 10, 11). Some studies have shown that among patients with a history of stroke or CHD, BP lowering to low-normal levels is likely to be safe and maximally protective for the majority (12–14).
There is significant uncertainty about the optimal target BP in the diabetes population. In addition, most studies use only a single baseline measurement of BP to predict stroke risk, which may produce potential bias. Moreover, very few studies have assessed the race-specific association of BP with stroke risk. The aim of the present study is to examine the race-specific association between different levels of BP and the risk of incident stroke among African American and white diabetic patients in the Louisiana State University (LSU) Hospital-Based Longitudinal Study (LSUHLS).
Subjects and Methods
Study population
LSU Health Care Services Division (LSUHCSD) operates 7 public hospitals and affiliated clinics in Louisiana, which provide quality medical care to the residents of Louisiana regardless of their income or insurance coverage (15, 16). Overall, LSUHCSD facilities have served about 1.6 million patients (35% of the Louisiana population) since 1997. Administrative (name, address, date of birth, gender, race/ethnicity, types of insurance, family income, and smoking status), anthropometric (date of examination, measurements of body weight, height, and BP for each visit), laboratory (test code, test collection date, test result values, and abnormal flag), clinical diagnosis, and medication data collected at these facilities are available in electronic form for both inpatients and outpatients from 1997. Using these data, we have established the LSUHLS. A cohort of diabetic patients was set up by using the International Classification of Disease (ICD)-9 (250) through the LSUHLS database between January 1, 1999, and December 31, 2009. Both inpatients and outpatients were included, and all patients were under primary care. LSUHCSD's internal diabetes disease management guidelines call for physician confirmation of diabetes diagnoses by applying the ADA criteria: a fasting plasma glucose level ≥126 mg/dL, 2-hour glucose level ≥200 mg/dL after a 75-g 2-hour oral glucose tolerance test, and 1 or more classic symptoms plus a random plasma glucose level ≥200 mg/dL (17). We have validated the diabetes diagnosis in LSUHCSD hospitals. The agreement of diabetes diagnosis was 97%: 20 919 of a sample of 21 566 hospital discharge diagnoses based on ICD codes also had physician-confirmed diabetes by using the ADA diabetes diagnosis criteria. The first record of diabetes diagnosis was used to establish the baseline for each patient in the present analyses due to the design of the cohort study. These newly diagnosed diabetes participants had benefited from LSUHCSD hospitals for 2.8 (1.8–6.1) years before the baseline.
The present study included 30 154 diabetic patients (12 618 white and 17 536 African American) who were 30 to 94 years of age without a history of stroke or CHD and with complete repeated data on all risk factor variables. In these diabetic patients, about 78.9% of patients qualify for free care (by virtue of being low income and uninsured, any individual or family unit whose income is at or below 200% of the federal poverty level), about 5.1% of patients are self-pay (uninsured, but incomes not low enough to qualify for free care), about 5.1% of patients are covered by Medicaid, about 8.9% of patients have Medicare, and about 2.2% of patients are covered by commercial insurance. The study and analysis plan were approved by the Pennington Biomedical Research Center and LSU Health Sciences Center Institutional Review Boards, LSU System. We did not obtain informed consent from participants involved in our study because we used anonymized data compiled from electronic medical records.
Baseline and follow-up measurements
The patient's characteristics, including age of diabetes diagnosis, gender, race/ethnicity, family income, smoking status, types of health insurance, body weight, height, body mass index (BMI), BP, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, glycosylated hemoglobin (HbA1c), estimated glomerular filtration rate (eGFR), and medication (antihypertensive drug, cholesterol-lowing drug, and antidiabetic drug) within half a year after the diabetes diagnosis (baseline) and during follow-up after the diabetes diagnosis (follow-up) were extracted from the computerized hospitalization records. BP was measured from the right arm of the participant after 5 minutes of sitting using a mercury sphygmomanometer or electronic BP meter in each visit (16). BP was measured first at baseline and second as an updated mean of annual measurement of systolic BP, calculated for each participant from baseline to each year of follow-up. For example, at 1 year, the updated mean is the average of the baseline and 1-year values, and at 3 years, it is the average of baseline, 1-year, 2-year, and 3-year values. In case of an event during follow-up, the period for estimating updated mean BP was from baseline to the year before this event occurred (18, 19). The average number of BP measurements during the follow-up period was 14.6 times.
Prospective follow-up
Follow-up information was obtained from the LSUHLS inpatient and outpatient database by using the unique number assigned to every patient who visits the LSUHCSD hospitals. The diagnosis of stroke was the primary endpoint of interest of the study and was defined according to the ICD-9: stroke (ICD-9 codes 430–436). Since 1997, diagnoses of stroke were made by the treating physicians based on a clinical assessment and examinations as considered relevant by the clinician in charge of treatments. Follow-up of each cohort member continued until the date of the diagnosis of stroke, the date of the last visit if the subject stopped use of LSUHCSD hospitals, death, or May 31, 2012 (20).
Statistical analyses
The association between BP and the risk of stroke was analyzed by using Cox proportional hazards models. The proportional hazards assumption in the Cox model was assessed with graphical methods, and with models including time-by covariate interactions. Systolic and diastolic BP were evaluated in the following 2 ways: 1) as 6 categories (systolic BP <110, 110–119, 120–129 [reference group], 130–139, 140–159, and ≥160 mm Hg; diastolic BP <65, 65–69, 70–79 [reference group], 80–89, 90–100, and ≥100 mm Hg; and systolic/diastolic BP <110/65, 110–119/65–69, 120–129/70–79 [reference group], 130–139/80–89, 140–159/90–99, and ≥160/100 mm Hg) and 2) as a continuous variable. We categorized BP groups according to guidelines (5, 6, 21) and the target of a randomized controlled trials (RCTs) (8, 9). All analyses were adjusted for age and sex as well as for smoking, income, type of insurance, HbA1c, LDL cholesterol, eGFR, use of antihypertensive drugs, diabetes medications, and cholesterol-lowering agents. Because the interaction between sex and BP with stroke risk was not statistically significant among both white and African Americans, data for men and women were combined in the analyses. We stratified the samples by race because there was a significant interaction between race and BP on stroke risk. To avoid the potential bias due to severe diseases at baseline, additional analyses were carried out excluding the subjects who were diagnosed with stroke during the first 2 years of follow-up. We used restricted cubic splines in Cox models to test whether there is a dose-response or nonlinear association of BP as a continuous variable with stroke risk. Statistical significance was considered to be P < .05. All statistical analyses were performed with PASW for Windows version 20.0 (IBM SPSS Inc) and SAS for Windows version 9.3 (SAS Institute).
Results
General characteristics of the study population are presented by race in Table 1. During a mean follow-up period of 6.7 years, 2949 subjects (1321 white and 1628 African American) developed incident stroke (2848 ischemic, 115 hemorrhagic). A significantly increased risk of stroke was observed among both African American and white diabetic patients with systolic BP <110 mm Hg and ≥160 mm Hg (Table 2). After further adjustment for other confounding factors (smoking, income, type of insurance, BMI, HbA1c, LDL cholesterol, eGFR, use of antihypertensive drugs, use of diabetes medications, and use of cholesterol-lowering agents), this U-shaped association remained significant among white (P trend < .001) and African American (P trend < .001) diabetic patients. The same U-shaped association remained significant with diastolic BP <65 mm Hg and ≥100 mm Hg among both African American (P trend < .001) and white diabetic patients (P trend = 0.014) (Table 2). When systolic or diastolic BP was considered as a continuous variable by using restricted cubic splines, a nadir of the U-shaped association of BP with stroke risk was observed at 120 to 130 mm Hg systolic and 70 to 80 mm Hg diastolic (Table 2 and Figure 1).
Table 1.
Baseline Characteristics of African American and White Patients With Diabetesa
| African American | White | P Value | |
|---|---|---|---|
| No. of participants | 17 536 | 12 618 | |
| Male, n (%) | 6106 (34.8) | 4770 (37.8) | .001 |
| Age, mean (SD), yr | 50.41 (10.0) | 52.48 (10.2) | .001 |
| Income, mean (SD), $/family | 12 044 (11 031) | 13 490 (11 999) | .001 |
| Body mass index, mean (SD) | 33.9 (8.5) | 35.0 (8.9) | .001 |
| Baseline BP, mean (SD), mm Hg | |||
| Systolic | 147 (25) | 142 (22) | .001 |
| Diastolic | 82 (14) | 78 (13) | .001 |
| BP during follow-up, mean (SD), mm Hg | |||
| Systolic | 143 (17) | 139 (15) | .001 |
| Diastolic | 80 (10) | 76 (9) | .001 |
| HbA1c, mean (SD), % | 8.1 (2.7) | 7.4 (2.2) | .001 |
| LDL cholesterol, mean (SD), mg/dL | 114 (40) | 112 (41) | .001 |
| GFR (mL/min/1.73 m2), n (%) | .001 | ||
| ≥90 | 9694 (55.4) | 4838 (38.4) | |
| 60–89 | 6000 (34.3) | 5813 (46.2) | |
| 30–59 | 1532 (8.7) | 1760 (14.0) | |
| 15–29 | 185 (1.1) | 134 (1.1) | |
| <15 | 100 (0.6) | 46 (0.4) | |
| Current smoker, n (%) | 5703 (32.5) | 4661 (36.9) | .001 |
| Type of insurance, n (%) | .001 | ||
| Free | 13 891 (79.2) | 9840 (78.0) | |
| Self-pay | 1039 (5.9) | 506 (4.0) | |
| Medicaid | 1034 (5.9) | 502 (4.0) | |
| Medicare | 1275 (7.3) | 1398 (11.1) | |
| Commercial | 297 (1.7) | 372 (3.0) | |
| Uses of medications, n (%) | |||
| Glucose-lowering medication | 13 350 (76.1) | 7965 (63.1) | .001 |
| Lipid-lowering medication | 10 648 (60.7) | 8373 (66.4) | .001 |
| Antihypertensive medication | 14 818 (84.5) | 10 286 (81.5) | .001 |
| Angiotensin-converting enzyme inhibitor | 11 679 (66.6) | 8088 (64.1) | .001 |
| Angiotensin II receptor blockers | 3910 (22.3) | 2423 (19.2) | .001 |
| β-Blockers | 8259 (47.1) | 6057 (48.0) | .001 |
| Calcium channel blocker | 7593 (43.3) | 3356 (26.6) | .001 |
| Diuretics | 11 469 (65.4) | 7142 (56.6) | .001 |
| Other antihypertensive medications | 4156 (23.7) | 2095 (16.6) | .001 |
Values represent mean or percentage. BMI was calculated as the weight in kilograms divided by the square of the height in meters.
Table 2.
HR (95% CI) of Stroke According to Different Levels of Systolic BP and Diastolic BP at Baseline and During Follow-up Among African American and White Patients With Diabetes
| Systolic BP, mm Hg |
P for Trend | Diastolic BP, mm Hg |
P for Trend | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| <110 | 110–119 | 120–129 | 130–139 | 140–159 | ≥160 | <65 | 65–69 | 70–79 | 80–89 | 90–99 | ≥100 | |||
| Baseline | ||||||||||||||
| African American | 738 | 1306 | 2272 | 2987 | 5625 | 4608 | 1523 | 1435 | 4614 | 5200 | 3080 | 1684 | ||
| No. of cases | 87 | 91 | 162 | 220 | 503 | 565 | 183 | 131 | 406 | 427 | 265 | 216 | ||
| Person-years | 4727 | 9019 | 15 541 | 20 836 | 39 935 | 33 430 | 10 823 | 10 377 | 33 165 | 36 630 | 21 369 | 11 125 | ||
| Age and sex adjustment HR (95% CI) | 1.70 (1.31–2.21) | 0.99 (0.76–1.27) | 1.00 | 0.97 (0.80–1.19) | 1.12 (0.94–1.34) | 1.49 (1.25–1.77) | .001 | 1.26 (1.05–1.50) | 0.97 (0.80–1.18) | 1.00 | 1.02 (0.89–1.17) | 1.12 (0.96–1.31) | 1.81 (1.53–2.14) | .001 |
| Multivariable adjustment HR (95% CI)a | 1.60 (1.23–2.07) | 0.97 (0.75–1.26) | 1.00 | 1.00 (0.82–1.22) | 1.14 (0.96–1.37) | 1.47 (1.23–1.75) | .001 | 1.21 (1.02–1.44) | 0.97 (0.79–1.18) | 1.00 | 1.03 (0.90–1.18) | 1.11 (0.95–1.30) | 1.74 (1.47–2.06) | .001 |
| Multivariable adjustment HR (95% CI)b | 1.64 (1.26–2.13) | 0.98 (0.76–1.26) | 1.00 | 1.00 (0.82–1.22) | 1.13 (0.94–1.35) | 1.46 (1.22–1.73) | .001 | 1.21 (1.01–1.44) | 0.96 (0.79–1.17) | 1.00 | 1.03 (0.90–1.18) | 1.11 (0.95–1.30) | 1.76 (1.49–2.08) | .001 |
| White | 662 | 1204 | 1907 | 2386 | 4059 | 2400 | 1723 | 1296 | 3889 | 3522 | 1605 | 583 | ||
| No. of cases | 93 | 111 | 170 | 215 | 423 | 309 | 248 | 163 | 363 | 347 | 138 | 62 | ||
| Person-years | 3934 | 7383 | 11 909 | 14 860 | 25 478 | 14 957 | 11 169 | 8208 | 24 832 | 21 413 | 9640 | 3258 | ||
| Age and sex adjustment HR (95% CI) | 1.74 (1.35–2.24) | 1.06 (0.83–1.34) | 1.00 | 0.98 (0.80–1.20) | 1.10 (0.92–1.32) | 1.34 (1.11–1.61) | .001 | 1.30 (1.11–1.53) | 1.26 (1.04–1.51) | 1.00 | 1.21 (1.04–1.40) | 1.15 (0.94–1.40) | 1.55 (1.18–2.03) | .003 |
| Multivariable adjustment HR (95% CI)a | 1.61 (1.25–2.08) | 1.04 (0.82–1.32) | 1.00 | 1.00 (0.82–1.22) | 1.14 (0.95–1.36) | 1.39 (1.15–1.68) | .001 | 1.22 (1.03–1.44) | 1.21 (1.00–1.45) | 1.00 | 1.22 (1.05–1.41) | 1.16 (0.95–1.42) | 1.52 (1.16–2.00) | .016 |
| Multivariable adjustment HR (95% CI)b | 1.61 (1.25–2.08) | 1.05 (0.82–1.33) | 1.00 | 1.00 (0.82–1.23) | 1.13 (0.95–1.36) | 1.40 (1.16–1.69) | .001 | 1.21 (1.02–1.42) | 1.21 (1.00–1.45) | 1.00 | 1.22 (1.06–1.42) | 1.17 (0.96–1.43) | 1.54 (1.17–2.02) | .014 |
| Follow-up | ||||||||||||||
| African American | 225 | 828 | 2565 | 4395 | 6848 | 2674 | 731 | 1562 | 7064 | 5848 | 1825 | 505 | ||
| No. of cases | 28 | 47 | 184 | 333 | 683 | 352 | 100 | 173 | 607 | 521 | 157 | 69 | ||
| Person-years | 1282 | 5222 | 17 153 | 30 786 | 50 262 | 18 776 | 5256 | 11 981 | 51 470 | 40 159 | 11 607 | 3012 | ||
| Age and sex adjustment HR (95% CI) | 1.92 (1.29–2.85) | 0.84 (0.61–1.16) | 1.00 | 0.96 (0.80–1.15) | 1.15 (0.98–1.36) | 1.59 (1.33–1.91) | .001 | 1.20 (0.97–1.49) | 1.05 (0.88–1.24) | 1.00 | 1.24 (1.10–1.40) | 1.37 (1.15–1.64) | 2.45 (1.90–3.15) | .001 |
| Multivariable adjustment HR (95% CI)a | 1.62 (1.09–2.43) | 0.81 (0.59–1.11) | 1.00 | 0.98 (0.82–1.18) | 1.18 (1.00–1.39) | 1.51 (1.26–1.81) | .001 | 1.13 (0.91–1.41) | 1.05 (0.88–1.24) | 1.00 | 1.23 (1.09–1.39) | 1.28 (1.07–1.54) | 2.16 (1.68–2.79) | .001 |
| Multivariable adjustment HR (95% CI)b | 1.68 (1.12–2.51) | 0.83 (0.60–1.15) | 1.00 | 0.96 (0.80–1.15) | 1.15 (0.98–1.36) | 1.50 (1.25–1.80) | .001 | 1.11 (0.89–1.38) | 1.03 (0.87–1.22) | 1.00 | 1.24 (1.10–1.40) | 1.32 (1.10–1.58) | 2.19 (1.69–2.82) | .001 |
| White | 177 | 873 | 2,514 | 3,672 | 4,332 | 1,049 | 1199 | 1965 | 5853 | 2925 | 578 | 97 | ||
| No. of cases | 28 | 88 | 245 | 337 | 474 | 149 | 232 | 249 | 566 | 223 | 44 | 7 | ||
| Person-years | 921 | 4971 | 15 029 | 23 411 | 27 893 | 6291 | 7726 | 13,284 | 37 255 | 16 775 | 3007 | 469 | ||
| Age and sex adjustment HR (95% CI) | 1.82 (1.23–2.70) | 1.17 (0.92–1.50) | 1.00 | 0.88 (0.75–1.04) | 0.97 (0.83–1.13) | 1.31 (1.06–1.60) | .001 | 1.55 (1.32–1.81) | 1.07 (0.92–1.24) | 1.00 | 1.02 (0.87–1.19) | 1.17 (0.86–1.59) | 1.15 (0.55–2.43) | .001 |
| Multivariable adjustment HR (95% CI)a | 1.53 (1.03–2.27) | 1.10 (0.86–1.41) | 1.00 | 0.91 (0.77–1.07) | 1.00 (0.85–1.17) | 1.32 (1.07–1.62) | .002 | 1.43 (1.22–1.67) | 1.04 (0.89–1.21) | 1.00 | 1.01 (0.86–1.18) | 1.09 (0.80–1.49) | 1.09 (0.52–2.31) | .001 |
| Multivariable adjustment HR (95% CI)b | 1.52 (1.02–2.26) | 1.12 (0.87–1.43) | 1.00 | 0.91 (0.77–1.07) | 1.00 (0.85–1.17) | 1.36 (1.10–1.67) | .001 | 1.39 (1.19–1.63) | 1.02 (0.88–1.18) | 1.00 | 1.03 (0.88–1.20) | 1.15 (0.84–1.57) | 1.20 (0.57–2.53) | .002 |
Adjusted for age, gender, BMI, LDL cholesterol, HbA1c, GFR, type of insurance, income, and smoking.
Adjusted for age, gender, BMI, LDL cholesterol, HbA1c, GFR, type of insurance, income, smoking, and use of antihypertensive drugs and glucose-lowering and cholesterol-lowering agents.
Figure 1.
HRs for incident stroke by systolic BP in African American (A) and white (C) and diastolic BP in African American (B) and white (D) subjects, adjusted for age, gender, BMI, LDL cholesterol, HbA1c, GFR, type of insurance, income, smoking, use of antihypertensive drugs, glucose-lowering agents, and cholesterol-lowering agents.
The multivariable-adjusted hazard ratios (HRs) of stroke associated with different levels of joint systolic/diastolic BP at baseline (<110/65, 110–119/65–69, 120–129/70–80 [reference group], 130–139/80–90, 140–159/90–100, and ≥ 160/100 mm Hg) were 1.88 (95% confidence interval [CI] 1.38–2.56), 1.05 (0.80–1.42), 1.00, 1.05 (0.86–1.27), 1.12 (0.94–1.34), and 1.47 (1.24–1.75) (P trend < .001) for African American diabetic patients, and 1.42 (1.06–1.91), 1.22 (0.95–1.57), 1.00, 0.88 (0.72–1.06), 1.02 (0.86–1.21), and 1.28 (1.07–1.54) (P trend < .001) for white diabetic patients, respectively (Table 3).
Table 3.
HR (95% CI) of Stroke According to Different Levels of Systolic/Diastolic BP at Baseline and During Follow-up Among African American and White Patients With Diabetes
| Systolic/Diastolic BP (mm Hg) |
P for Trend | ||||||
|---|---|---|---|---|---|---|---|
| <110/65 | 110–119/65–69 | 120–129/70–79 | 130–139/80–89 | 140–159/90–99 | ≥160/100 | ||
| Baseline | |||||||
| African American | 370 | 709 | 2308 | 3457 | 5772 | 4920 | |
| No. of cases | 54 | 58 | 166 | 257 | 503 | 590 | |
| Person-years | 2449 | 4903 | 15 887 | 24 053 | 40 862 | 35 334 | |
| Age adjustment HR (95% CI) | 1.91 (1.41–2.60) | 1.09 (0.81–1.48) | 1.00 | 1.01 (0.83–1.23) | 1.10 (0.92–1.31) | 1.49 (1.25–1.77) | .001 |
| Multivariable adjustment HR (95% CI)a | 1.84 (1.35–2.50) | 1.07 (0.80–1.45) | 1.00 | 1.05 (0.86–1.28) | 1.14 (0.96–1.36) | 1.49 (1.25–1.77) | .001 |
| Multivariable adjustment HR (95% CI)b | 1.88 (1.38–2.56) | 1.05 (0.80–1.42) | 1.00 | 1.05 (0.86–1.27) | 1.12 (0.94–1.34) | 1.47 (1.24–1.75) | .001 |
| White | 385 | 720 | 1998 | 2776 | 4201 | 2538 | |
| No. of cases | 57 | 93 | 192 | 233 | 425 | 321 | |
| Person-years | 2325 | 4346 | 12 541 | 17 190 | 26 395 | 15 722 | |
| Age adjustment HR (95% CI) | 1.54 (1.15–2.07) | 1.27 (0.99–1.62) | 1.00 | 0.85 (0.71–1.03) | 0.99 (0.83–1.17) | 1.23 (1.02–1.47) | .001 |
| Multivariable adjustment HR (95% CI)a | 1.42 (1.06–1.92) | 1.22 (0.95–1.57) | 1.00 | 0.88 (0.72–1.06) | 1.03 (0.87–1.22) | 1.28 (1.07–1.54) | .001 |
| Multivariable adjustment HR (95% CI)b | 1.42 (1.06–1.91) | 1.22 (0.95–1.57) | 1.00 | 0.88 (0.72–1.06) | 1.02 (0.86–1.21) | 1.28 (1.07–1.54) | .001 |
| Follow-up | |||||||
| African American | 94 | 405 | 2580 | 4780 | 6926 | 2749 | |
| No. of cases | 11 | 36 | 180 | 359 | 682 | 360 | |
| Person-years | 593 | 2557 | 17 441 | 33 038 | 50 638 | 19 217 | |
| Age adjustment HR (95% CI) | 1.56 (0.85–2.87) | 1.26 (0.88–1.80) | 1.00 | 1.01 (0.85–1.21) | 1.19 (1.01–1.41) | 1.67 (1.39–1.99) | .001 |
| Multivariable adjustment HR (95% CI)a | 1.36 (0.74–2.50) | 1.17 (0.82–1.68) | 1.00 | 1.04 (0.87–1.25) | 1.22 (1.03–1.44) | 1.58 (1.32–1.90) | .001 |
| Multivariable adjustment HR (95% CI)b | 1.38 (0.75–2.54) | 1.15 (0.81–1.65) | 1.00 | 1.02 (0.85–1.22) | 1.19 (1.01–1.41) | 1.57 (1.31–1.88) | .001 |
| White | 102 | 585 | 2596 | 3899 | 4361 | 1072 | |
| No. of cases | 20 | 74 | 255 | 346 | 475 | 151 | |
| Person-years | 521 | 3412 | 15 733 | 24 392 | 28 053 | 6399 | |
| Age adjustment HR (95% CI) | 2.00 (1.27–3.15) | 1.32 (1.02–1.71) | 1.00 | 0.87 (0.74–1.02) | 0.96 (0.82–1.12) | 1.30 (1.06–1.59) | .001 |
| Multivariable adjustment HR (95% CI)a | 1.64 (1.03–2.60) | 1.24 (0.95–1.61) | 1.00 | 0.91 (0.77–1.07) | 1.00 (0.85–1.16) | 1.32 (1.07–1.61) | .001 |
| Multivariable adjustment HR (95% CI)b | 1.60 (1.01–2.54) | 1.24 (0.95–1.60) | 1.00 | 0.90 (0.77–1.06) | 1.00 (0.85–1.16) | 1.35 (1.10–1.66) | .001 |
Adjusted for age, gender, BMI, LDL cholesterol, HbA1c, GFR, type of insurance, income, and smoking.
Adjusted for age, gender, BMI, LDL cholesterol, HbA1c, GFR, type of insurance, income, smoking, and use of antihypertensive drugs and glucose-lowering and cholesterol-lowering agents.
The U-shaped association of BP with stroke risk was confirmed among African American and white diabetic patients with antihypertensive treatments (all P trend < .001). For the patients without antihypertensive treatments, only the lowest group of systolic BP or systolic/diastolic BP (only baseline value) is a risk factor for stroke, whereas BP higher than 160 does not increase the risk for stroke (Table 4). After excluding the subjects who were diagnosed with stroke during the first 2 years of follow-up (n = 869), the multivariable-adjusted HRs of stroke associated with different levels of BP did not change (data not shown).
Table 4.
HR (95% CI) of Stroke According to Different Levels of BP at Baseline and During Follow-up Among Diabetic Patients Using (n = 25 104) and Not Using (n = 5050) Antihypertensive Drugsa
| Systolic BP, mm Hg |
P for Trend | Diastolic BP, mm Hg |
Diastolic BP, mm Hg |
P for Trend | Systolic/Diastolic BP, mm Hg |
P for Trend | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| <110 | 110–119 | 120–129 | 130–139 | 140–159 | ≥160 | <65 | 65–69 | 70–79 | 80–89 | 90–99 | ≥100 | <110/65 | 110–119/65–69 | 120–129/70–79 | 130–139/80–89 | 140–159/90–99 | ≥160/100 | ||||
| Baseline | |||||||||||||||||||||
| Using antihypertensive drugs | 1.69 (1.35–2.11) | 1.08 (0.88–1.33) | 1.00 | 1.05 (0.89–1.24) | 1.20 (1.04–1.40) | 1.54 (1.32–1.79) | .001 | 1.33 (1.15–1.53) | 1.14 (0.97–1.34) | 1.00 | 1.18 (1.05–1.33) | 1.21 (1.05–1.39) | 1.90 (1.62–2.23) | .001 | 1.71 (1.31–2.23) | 1.35 (1.08–1.69) | 1.00 | 1.03 (0.87–1.21) | 1.15 (0.99–1.33) | 1.52 (1.31–1.76) | .001 |
| No using antihypertensive drugs | 1.43 (1.04–1.96) | 0.85 (0.61–1.18) | 1.00 | 0.87 (0.66–1.15) | 0.93 (0.73–1.19) | 1.18 (0.92–1.51) | .003 | 0.96 (0.77–1.19) | 0.95 (0.74–1.23) | 1.00 | 0.94 (0.76–1.15) | 0.99 (0.77–1.28) | 1.38 (1.01–1.88) | .293 | 1.44 (1.00–2.07) | 0.82 (0.57–1.17) | 1.00 | 0.82 (0.63–1.06) | 0.89 (0.71–1.12) | 1.07 (0.85–1.36) | .012 |
| Follow-up | |||||||||||||||||||||
| Using antihypertensive drugs | 1.92 (1.28–2.87) | 1.14 (0.90–1.45) | 1.00 | 1.02 (0.89–1.18) | 1.18 (1.04–1.35) | 1.57 (1.34–1.84) | .001 | 1.36 (1.16–1.58) | 1.01 (0.88–1.15) | 1.00 | 1.18 (1.06–1.32) | 1.39 (1.16–1.66) | 2.39 (1.78–3.21) | .001 | 2.60 (1.61–4.19) | 1.42 (1.09–1.84) | 1.00 | 1.07 (0.93–1.23) | 1.22 (1.07–1.40) | 1.65 (1.40–1.93) | .001 |
| No using antihypertensive drugs | 1.22 (0.82–1.81) | 0.74 (0.53–1.04) | 1.00 | 0.71 (0.56–0.91) | 0.83 (0.66–1.03) | 1.12 (0.88–1.42) | .001 | 1.18 (0.94–1.48) | 1.09 (0.88–1.36) | 1.00 | 1.12 (0.92–1.37) | 1.03 (0.76–1.41) | 1.66 (1.11–2.49) | .181 | 0.81 (0.46–1.43) | 0.88 (0.62–1.25) | 1.00 | 0.71 (0.56–0.90) | 0.80 (0.65–0.99) | 1.08 (0.86–1.37) | .003 |
Adjusted for age, gender, BMI, LDL cholesterol, HbA1c, GFR, type of insurance, income, smoking, and use of glucose-lowering and cholesterol-lowering agents.
There was a significant interaction between age and BP on stroke risk (Table 5). When stratified by age, the U-shaped association of BP at baseline with stroke risk was more significant in diabetic patients aged 30 to 49 and 50 to 59 years and weakened in diabetic patients aged ≥60 years.
Table 5.
HR (95% CI) of Stroke According to Different Levels of BP at Baseline and During Follow-up Among Diabetic Patients Stratified by Agea
| Age Groups, y | Systolic BP, mm Hg |
P for Trend | P for Interaction of Age and BP | Diastolic BP, mm Hg |
|||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| <110 | 110–119 | 120–129 | 130–139 | 140–159 | ≥160 | <65 | 65–69 | 70–79 | |||
| Baseline | .001 | ||||||||||
| <50 | 1.66 (1.23–2.23) | 0.93 (0.69–1.24) | 1.00 | 0.95 (0.74–1.22) | 1.13 (0.91–1.41) | 1.63 (1.31–2.03) | .001 | 1.22 (0.95–1.58) | 1.05 (0.79–1.40) | 1.00 | |
| 50–59 | 1.36 (0.98–1.88) | 1.11 (0.83–1.49) | 1.00 | 1.09 (0.86–1.38) | 1.17 (0.95–1.44) | 1.54 (1.25–1.90) | .010 | 1.19 (0.97–1.44) | 1.05 (0.85–1.31) | 1.00 | |
| 60–94 | 1.79 (1.29–2.49) | 0.98 (0.70–1.36) | 1.00 | 0.96 (0.74–1.26) | 1.13 (0.89–1.42) | 1.19 (0.93–1.51) | .003 | 1.23 (1.02–1.49) | 1.15 (0.92–1.43) | 1.00 | |
| Follow-up | .001 | ||||||||||
| <50 | 1.91 (1.18–3.11) | 0.98 (0.71–1.37) | 1.00 | 1.04 (0.84–1.29) | 1.28 (1.05–1.57) | 2.07 (1.64–2.60) | .001 | 1.43 (1.02–2.00) | 1.03 (0.81–1.32) | 1.00 | |
| 50–59 | 1.19 (0.70–2.03) | 1.11 (0.81–1.52) | 1.00 | 0.95 (0.77–1.16) | 1.17 (0.97–1.41) | 1.39 (1.12–1.73) | .004 | 1.52 (1.25–1.86) | 1.09 (0.91–1.31) | 1.00 | |
| 60–94 | 1.46 (0.92–2.31) | 0.85 (0.59–1.24) | 1.00 | 0.81 (0.65–1.01) | 0.81 (0.66–0.99) | 1.03 (0.80–1.31) | .017 | 1.20 (0.99–1.15) | 1.04 (0.87–1.24) | 1.00 | |
Adjusted for age, gender, BMI, LDL cholesterol, HbA1c, GFR, type of insurance, income, smoking, and use of antihypertensive drugs and glucose-lowering and cholesterol-lowering agents.
Table 6.
HR (95% CI) of Stroke According to Different Levels of BP at Baseline and During Follow-up Among Diabetic Patients Stratified by Agea
| Diastolic BP, mm Hg |
P for Trend | Systolic/Diastolic BP. mm Hg |
Systolic/Diastolic BP. mm Hg |
P for Trend | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| 80–89 | 90–99 | ≥100 | <110/65 | 110–119/65–69 | 120–129/70–79 | 130–139/80–89 | 140–159/90–99 | ≥160/100 | ||
| 1.18 (0.98–1.40) | 1.29 (1.06–1.58) | 1.91 (1.53–2.38) | .001 | 1.90 (1.32–2.73) | 1.11 (0.78–1.58) | 1.00 | 1.01 (0.80–1.28) | 1.15 (0.93–1.42) | 1.68 (1.36–2.09) | .001 |
| 1.04 (0.89–1.22) | 0.97 (0.80–1.19) | 1.58 (1.27–1.98) | .001 | 1.32 (0.90–1.94) | 1.15 (0.83–1.58) | 1.00 | 0.97 (0.78–1.22) | 1.04 (0.85–1.27) | 1.40 (1.15–1.71) | .001 |
| 1.06 (0.87–1.29) | 1.13 (0.88–1.46) | 1.52 (1.08–2.13) | .107 | 1.60 (1.31–2.15) | 1.19 (0.86–1.64) | 1.00 | 0.88 (0.68–1.14) | 1.06 (0.85–1.33) | 1.13 (0.89–1.43) | .024 |
| 1.19 (1.02–1.39) | 1.55 (1.25–1.92) | 2.07 (1.49–2.88) | .001 | 3.09 (1.66–5.73) | 1.11 (0.74–1.67) | 1.00 | 1.09 (0.89–1.35) | 1.31 (1.07–1.60) | 2.13 (1.69–2.67) | .001 |
| 1.11 (0.96–1.28) | 1.01 (0.77–1.33) | 2.15 (1.44–3.22) | .001 | 0.96 (0.45–2.06) | 1.34 (0.96–1.87) | 1.00 | 0.95 (0.78–1.16) | 1.17 (0.98–1.41) | 1.40 (1.13–1.74) | .002 |
| 1.12 (0.92–1.38) | 0.87 (0.56–1.36) | 1.51 (0.74–3.06) | .329 | 1.09 (0.61–1.94) | 1.04 (0.72–1.49) | 1.00 | 0.82 (0.66–1.02) | 0.82 (0.67–1.00) | 1.04 (0.82–1.33) | .077 |
P = .001, for interaction of age and BP.
Adjusted for age, gender, BMI, LDL cholesterol, HbA1c, GFR, type of insurance, income, smoking, and use of antihypertensive drugs and glucose-lowering and cholesterol-lowering agents.
When we did an additional analysis by using an updated mean of BP during follow-up, we found almost the same U-shaped associations between baseline BP levels and updated mean levels of BP with stroke risk among both African American and white diabetic patients (Tables 2–5). When we did another analysis by different type of stroke, the result of ischemic stroke is similar to the total stroke. Because the numbers of incident hemorrhagic stroke are too small, we did not present the results for hemorrhagic stroke.
Discussion
Our study found a U-shaped association between BP at baseline and during follow-up with the risk of stroke among both African American and white diabetic patients. In addition, we found that this U-shaped association was present in different age groups, especially among diabetic patients aged <50 years.
The benefits of treating hypertension in diabetes patients were well documented in several early RCTs (18, 22, 23). In the United Kingdom Prospective Diabetes Study, no threshold of BP was observed for any endpoint (CHD and stroke risks) during a median follow-up time of 10.5 years (18). The recent analysis from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study confirmed that there was a significant reduction for fatal and nonfatal stroke in the intensively treated (systolic BP <120 mm Hg) among diabetic patients compared with standard therapy (systolic BP <140 mm Hg), but there is an increased incidence of serious adverse events in the intensive group (8). Other RCTs and 2 meta-analyses demonstrates beyond a reasonable doubt that intensive BP control (below 130/80 mm Hg) significantly reduces the risk of stroke (11, 24, 25). However, the limitations of these RCTs include the low-incident stroke events, short follow-up time, high loss to follow-up rates, and strict inclusion and exclusion criteria that limit their applicability to diabetic patients in clinical practice. It has been indicated that observational studies and RCTs overall produced similar results, and observational studies, especially from hospital-based cohorts, may reflect everyday clinical practice.
A recent Swedish observational study of patients with type 2 diabetes demonstrates that the risk curves of stroke increased progressively with higher baseline or updated mean systolic BP ranging from 110 to 180 mm Hg, with no J/U curves (19). But when analyzing the effect of BP on the risk for cardiovascular disease (CVD) in observational studies, different methods to present the effect of BP on CVD by Cox regression will impact the interpretation and should be regarded with respect to clinical applicability. For example, Cederholm et al (26) further analyzed the Swedish study data by use of figures of restricted cubic regression splines showed a striking U curve in the lower tail of the systolic BP distribution and a nadir of around 135 mm Hg. In the present study, we found a U-shaped association by various BP intervals of clinical relevance or by use of figures of restricted cubic regression splines to present BP as a continuous variable at baseline and during follow-up with stroke risk among both African American and white diabetic patients. The most benefit for stroke risk was in those diabetic patients who achieved BP of 120–130/70–80 mm Hg. Aggressive BP control (<110/65 mm Hg) and high BP (≥160/100 mm Hg) are associated with an increased risk of stroke among both African American and white patients with type 2 diabetes (Tables 2 and 3 and Figure 1). In the Cederholm study, risk increase was significant only for systolic BP >140 mm Hg, which is different from our study. We categorized the sample into 6 groups including 140–159/90–99 and over 160/100 mm Hg groups. The sample size is big enough to make the power big enough to detect the difference. In addition, we found that this U-shaped association was present in diabetic patients with antihypertensive treatment and in diabetic patients with different age groups, especially 30 to 49 and 50 to 59 years old. The sample size in the patients without antihypertensive treatments (n = 5050) is relatively small, and the U-shaped association is less obvious. For follow-up systolic BP in the patients without antihypertensive treatments, the lowest risk is seen in these two groups (130–139 and 140–159 mm Hg).
The guidelines targets (<130/80 mm Hg) for BP treatment have been questioned to be too aggressive because recent data do not show the benefit for CHD reduction (8, 9). But the protection for stroke risk has been clearly shown with the BP reduction (8, 10, 11). The risk of stroke continued to decrease down to achieve systolic BP values of 115 mm Hg, with no evidence of an upward J curve inflection (11). Thus, the author assumed that the lower systolic BP with the lower risk did not apply to CHD outcome but was correct for stroke. Potential explanations of this difference between different organs are unclear. Some studies have suggested that the brain has the ability to autoregulate pressures and hence show protection over a wider range of BP. Potential explanations of this U-shape association of BP and stroke in our diabetic patients are unclear. Lower BP has been shown to be more common with comorbidities at older ages and is often reflective of poor health. Elderly patients with type 2 diabetes represent a population that is highly enriched with underlying CVD and may be more prone than others to display the U-shaped or inversed association. We carried out sensitivity analyses excluding participants who were diagnosed with stroke during the first 2 years of follow-up (n = 869), which can reduce the possibility of potential bias due to poor health during the subclinical stage before the diagnosis of stroke. The association of lower BP control (<110/65 mm Hg) with the increased stroke risk in the elder group did not change; on the other hand, the harm of uncontrolled BP (≥160/100 mm Hg) seemed to decrease compared with other 2 younger groups. This might suggest lower BP control is more harmful than uncontrolled BP for the elder patients.
There are several strengths in our study, including the large sample size, high proportion of African Americans, long follow-up time, and the use of administrative databases to avoid differential recall bias. We have used both baseline BP levels and updated mean values of BP during follow-up in the analyses, which can avoid potential bias from a single baseline measurement. In addition, participants in this study use the same public healthcare system, which minimizes the influence from the accessibility of healthcare, particularly in comparing African Americans and whites. One limitation of our study is that our analysis was not performed on a representative sample of the population, which limits the generalizability of this study; however, LSUHCSD hospitals are public hospitals and cover over 1.6 million patients, most of whom are low-income persons in Louisiana. The results of the present study will have wide applicability for the population with low income and without health insurance in the United States. Second, the validity of stroke diagnoses in our study has not been confirmed by specialists. However, the method using hospital discharge registers to diagnose stroke has been widely used in American and European cohort studies, such as the Kaiser Permanente Medical Care Program (27, 28), the Atherosclerosis Risk in Communities (ARIC) Study (29), the Framingham Study (30), and the National FINRISK Survey (31). The validity of the diagnoses of stroke by using hospital discharge registers in these cohort studies is available (agreement 75%–90%) (28, 32). Third, even though our analyses adjusted for an extensive set of confounding factors, residual confounding due to the measurement error in the assessment of confounding factors, unmeasured factors such as physical activity, education, and dietary factors, cannot be excluded.
Our study demonstrates that aggressive BP control (<110/65 mm Hg) and high BP (≥160/100 mm Hg) are associated with an increased risk of stroke among both African American and white type 2 diabetes patients. Previous guidelines BP targets (<130/80 mm Hg) may provide cerebrovascular protection, and maintaining BP between 120–129/70–79 mm Hg may be recommended for high-risk patients for preventing a cerebrovascular event.
Acknowledgments
This work was supported by Louisiana State University's Improving Clinical Outcomes Network (LSU ICON).
Disclosure Summary: The authors have no relevant financial interest to declare.
For editorial see page 3588
- BMI
- body mass index
- BP
- blood pressure
- CHD
- coronary heart disease
- CI
- confidence interval
- CVD
- cardiovascular disease
- eGFR
- estimated glomerular filtration rate
- HbA1c
- glycosylated hemoglobin
- HR
- hazard ratio
- ICD
- International Classification of Disease
- LDL
- low-density lipoprotein
- LSU
- Louisiana State University
- LSUHCSD
- LSU Health Care Services Division
- LSUHLS
- LSU Hospital-Based Longitudinal Study
- RCT
- randomized controlled trial.
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