Diastolic orthostatic hypertension and cardiovascular prognosis in type 2 diabetes: a prospective cohort study

As described previously [19], CARDIPP (Cardiovascular Risk Factors in Patients with Diabetes—a Prospective Study in Primary Care) is an observational prospective cohort study with the general aim of exploring the impact of cardiovascular risk factors in patients with type 2 diabetes (Clinical Trials.gov number NCT 01049737). Between the years 2005–2008, 761 patients with type 2 diabetes were recruited by nurses specially trained in diabetes care at 22 different primary health care centers in the counties of Östergötland and Jönköping in Sweden. Inclusion criteria were: type 2 diabetes treated in primary care; age 55–65 years; and willingness to participate in the study. The only exclusion criterion was known severe physical or mental disease with short life expectancy. From the total CARDIPP cohort of 761 patients, we excluded for the purpose of this analysis 12 patients for which base-line data were missing for systolic or diastolic blood pressure in either the sitting or the standing position. This yielded a study sample of 749 participants.

The primary endpoint was a composite endpoint of the first non-fatal or fatal event of hospitalization for acute myocardial infarction (ICD-10 code I21), or stroke (ICD-10 codes I60, I61, I63.0–I63.5, I63.8–I63.9, I64) or cardiovascular mortality (ICD-10 codes I00–99). Patients were followed until a primary outcome event occurred, or until December 31st, 2014, by linkage to the Swedish Cause of Death and Inpatient registries (The National Board of Health and Welfare, Stockholm, Sweden) using the national personal identification number of each individual patient, thus ensuring coverage of the entire population.

Office blood pressure was measured by specially trained nurses [20]. Measurements were made manually with the auscultatory method, with appropriately sized cuffs, following a 5 minute wait, with the patient sitting comfortably in a relaxed position with the arm supported at heart level. Three sitting measurements were made, with 1 minute between each measurement. Thereafter, the patient was asked to rise, and one additional measurement was made when the patient had been standing for 2 minutes. Blood pressures were determined to the nearest 2 mmHg. The blood pressure value obtained at the third sitting measurement is referred to as the sitting blood pressure in this report. The orthostatic blood pressure response was calculated as the difference between the third sitting measurement and the standing measurement. The cut-off for abnormal systolic orthostatic blood pressure responses was ≥20 mmHg, as has been proposed for both hypotensive [21] and hypertensive [13] orthostatic blood pressure reactions. Thus, systolic orthostatic hypertension was defined as a rise of systolic blood pressure ≥20 mmHg, with or without an accompanying diastolic blood pressure rise, and systolic orthostatic hypotension was defined as a drop of systolic blood pressure ≥20 mmHg, with or without an accompanying diastolic blood pressure drop. For diastolic orthostatic hypotensive reactions the cut-off was ≥10 mmHg [21] and we applied the same numerical threshold for diastolic orthostatic hypertension, since no consensus criteria exist for this entity [13]. Accordingly, diastolic orthostatic hypertension was defined as a rise of diastolic blood pressure ≥10 mmHg, with or without an accompanying systolic blood pressure rise, and diastolic orthostatic hypotension was defined as a drop of diastolic blood pressure ≥10 mmHg, with or without an accompanying drop of systolic blood pressure. Thus, a normal systolic orthostatic blood pressure response was defined as a change of systolic blood pressure within the range of −19 to +19 mmHg, and a normal diastolic orthostatic blood pressure response was defined as a change of diastolic blood pressure within the range of −9 to +9 mmHg.

To measure aortic PWV, electrocardiogram-gated pulse wave analyses of the carotid and femoral arteries were performed with a Millar pressure tonometer and the SphygmoCor system (Model MM3, AtCor Medical, Sydney, Australia). The pulse wave transit time was calculated by subtracting the time between the ECG R-wave and the arrival of the pulse wave to the carotid measurement site from the time between the ECG R-wave and the arrival of the pulse wave to the femoral measurement site. The surface distance was defined as the distance between the suprasternal notch and the femoral measurement site, subtracted by the distance between the suprasternal notch and the carotid measurement site. The PWV was calculated by dividing the surface distance with the pulse wave transit time. Applanation tonometry measurements were performed in duplicate, and reported as means of the two measurements. Measures of PWV were successfully obtained in 692 patients at base-line.

Carotid IMT was measured in B-mode, using Philips ATL HDI 5000 (Philips Ultrasound, Seattle, USA) with a 4–7 MHz linear transducer [22]. Three consecutive longitudinal images, frozen in diastole, were analyzed with software for off-line measurement of intima-media thickness (Artery Measurement System II; Image and Data Analysis, Gothenburg, Sweden). A section of 10 mm 1–2 cm proximal to the carotid bulb was measured manually by tracing a cursor along the echo wedges. A mean value from the right and left carotid arteries was calculated. Measures of carotid IMT were successfully obtained in 729 patients at base-line.

Blood samples were drawn in the morning following a 10 h over-night fast. The Swedish Mono-S HPLC standard was used for HbA1c analyses [23], but the values were subsequently converted to the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) units (mmol/mol). Creatinine-based values of estimated glomerular filtration rate (eGFR) were calculated according to the Modification of Diet in Renal Disease (MDRD) study equation [24].

For the statistical analyses, SPSS software (IBM SPSS Statistics 23, Chicago, IL, USA) was used. In the main comparisons, the reference group was defined as patients who had a normal systolic and diastolic orthostatic blood pressure response. Differences of base-line characteristics were tested for statistical significance with two-sided independent t test, Chi square test or, where appropriate, Fisher's exact test. With the use of Cox regression models, the associations between the time to a first endpoint event and the presence of diastolic or systolic orthostatic hypertension or hypotension, were calculated as the hazard ratio (HR) for each group with a corresponding 95 % confidence interval (C.I.). Crude HRs were first calculated, and if they were significant, adjusted HRs were then calculated by using multivariate Cox regression models which adjusted for traditional cardiovascular risk factors. The first multivariate model adjusted for age, sex and sitting systolic blood pressure, and the second multivariate model adjusted additionally for smoking status, low density lipoprotein (LDL) cholesterol, body mass index and use of any antihypertensive medication. If the crude hazard ratios were not statistically significant, no further adjustments were made. Statistical significance was defined as P < 0.05. Since the purpose of the study was to present adjusted HRs, and not to screen for independent predictors, no adjustments for multiple testing were performed.

All participants gave written informed consent. The merging of study data with other registries was approved by the National Board of Health and Welfare and by the Swedish Data Inspection Board. The study was approved by the Regional Ethical Review Board in Linköping, Sweden. The study protocol followed the principles expressed in the Declaration of Helsinki.

The study population consisted of 257 women (34.3 %) and 492 men. The majority (88.5 %) were born in Sweden. The most common anti-diabetic treatment strategy was oral anti-diabetics (OAD) and/or non-insulin injectables (NNI) which were used by 40.9 percent of the participants, followed by life-style advice only (28.2 %), combined use of insulin with OAD/NNI (18.0 %) and insulin only (13.0 %). There were 462 participants (61.7 %) who reported a previous diagnosis of hypertension, 67 participants (8.9 %) who reported having had a myocardial infarction and 18 participants (2.4 %) who reported having had a stroke. Background characteristics are presented according to the orthostatic blood pressure reaction (Table 1). During a median follow-up time of 7.8 years (range: 38–3537 days), there were 75 end-point events (42 events related to ischemic heart disease including 37 myocardial infarctions, 27 events related to ischemic stroke, four events related to intracerebral hemorrhage, one event related to subdural bleeding and one event related to congestive heart failure). Fifty-eight events occurred among the 534 patients with normal systolic and diastolic orthostatic blood pressure responses (10.9 %), five events occurred among the 45 patients with systolic orthostatic hypertension (11.1 %), two events occurred among the 24 patients with systolic orthostatic hypotension (8.3 %), seven events occurred among the 140 patients with diastolic orthostatic hypertension (5.0 %) and six events occurred among the 31 patients with diastolic orthostatic hypotension (19.4 %).

The difference between the sitting blood pressure and the standing blood pressure followed normal distribution curves (Fig. 1) for both systolic and diastolic measurements. For the systolic blood pressure change, mean (SD) was 1.1 (10.9) mmHg, median was 0 mmHg and the range was −40 to +50 mmHg (inter-quartile range −6 to +8 mmHg). For the diastolic blood pressure change, mean (SD) was 2.6 (6.8) mmHg, median was 2.0 mmHg and the range was −24 to +25 mmHg (inter-quartile range −2 to +8 mmHg). The most common orthostatic abnormality was diastolic hypertension which was found in 140 patients (18.7 %) followed by systolic hypertension which was found in 45 patients (6.0 %), diastolic hypotension which was found in 31 patients (4.1 %) and systolic hypotension which was found in 24 patients (3.2 %). There were 25 patients (3.4 %) with more than one orthostatic blood pressure abnormality: Thirteen of the patients with systolic orthostatic hypertension also had diastolic orthostatic hypertension, six of the patients with systolic orthostatic hypotension also had diastolic orthostatic hypotension, four of the patients with diastolic orthostatic hypertension also had systolic orthostatic hypotension, and two of the patients with diastolic orthostatic hypotension also had systolic orthostatic hypertension. Overall, there were 534 patients (71.3 %) who had a normal orthostatic blood pressure response, defined as a change of systolic blood pressure within the range of −19 to +19 mmHg and a change of diastolic blood pressure within the range of −9 to +9 mmHg. This group was used as the reference group in all main comparisons. Sitting and standing blood pressures are presented according to the systolic and diastolic orthostatic blood pressure reactions in Table 2.

In a Cox regression analysis that compared patients with systolic orthostatic hypertension (n = 45) with the 534 patients who had a normal systolic and diastolic orthostatic blood pressure response, systolic orthostatic hypertension was not significantly associated with the risk of the combined end-point (HR 1.095, 95 % C.I. 0.439–2.731, P = 0.486). Similar results were obtained when the 45 patients with systolic orthostatic hypertension were compared with the 704 patients without systolic orthostatic hypertension (HR 1.201, 95 % C.I. 0.485–2.976, P = 0.693) or with the 680 patients who had a normal systolic blood pressure response (HR 1.191, 95 % C.I. 0.480–2.954, P = 0.706). Patients with systolic blood pressure rise ≥20 mmHg had significantly (P = 0.001) higher PWV than patients with a normal orthostatic blood pressure response, but similar IMT (Table 2).

In a Cox regression analysis that compared patients with systolic orthostatic hypotension (n = 24) with the 534 patients who had a normal systolic and diastolic orthostatic blood pressure response, systolic orthostatic hypotension was not significantly associated with the risk of the combined end-point (HR 0.750, 95 % C.I. 0.183–3.073, P = 0.690). Similar results were obtained when the 24 patients with systolic orthostatic hypotension were compared with the 725 patients without systolic orthostatic hypotension (HR 0.810, 95 % C.I. 0.199–3.301, P = 0.769) or with the 680 patients who had a normal systolic blood pressure response (HR 0.819, 95 % C.I. 0.201–3.340, P = 0.780). Patients with systolic blood pressure fall ≥ 20 mmHg had non-significantly higher PWV and IMT compared with patients with a normal orthostatic blood pressure response (Table 2).

Patients with diastolic orthostatic hypertension (n = 140) had a significantly lower risk of experiencing the combined end-point compared with the 534 patients who had a normal systolic and diastolic orthostatic blood pressure reaction (HR 0.450, 95 % C.I. 0.206–0.987, P = 0.046). Diastolic orthostatic hypertension remained significantly associated with a decreased risk for cardiovascular events following adjustment for age, sex and sitting systolic blood pressure (HR 0.452, 95 % C.I. 0.206–0.990, P = 0.047, cumulative event rate 65/674) as well as following additional adjustment for smoking status, LDL cholesterol, body mass index and use of any antihypertensive medication (HR 0.335, 95 % C.I. 0.133–0.839, P = 0.020, cumulative event rate 59/616). The results of the fully adjusted model are presented in Table 3. Patients with diastolic orthostatic hypertension did not differ significantly from patients with a normal orthostatic blood pressure response in terms of PWV and IMT (Table 2). Among the patients with diastolic orthostatic hypertension, 88 (62.9 %) had a standing diastolic blood pressure ≤90 mmHg and 72 (51.4 %) had a standing systolic blood pressure ≤140 mmHg.

There was a non-significant trend towards increased risk for the combined end-point when patients with diastolic orthostatic hypotension (n = 31) were compared with the 534 patients who had a normal systolic and diastolic blood pressure response (HR 1.804, 95 % C.I. 0.778–4.183, P = 0.169). The same non-significant trend was observed when patients with diastolic orthostatic hypotension were compared with the 718 patients without diastolic orthostatic hypotension (HR 2.039, 95 % C.I. 0.885–4.696, P = 0.094) or with the 578 patients who had a normal diastolic blood pressure response (HR 1.818, 95 % C.I. 0.786–4.204, P = 0.162). Patients with diastolic orthostatic hypotension had significantly (P = 0.013) higher PWV and significantly (P = 0.010) higher IMT than patients with a normal orthostatic blood pressure response (Table 2).

When patients who had either systolic or diastolic orthostatic hypertension or both (n = 172) were grouped together and compared with the 534 patients with a normal orthostatic blood pressure response, the presence of any hypertensive orthostatic blood pressure response was associated with a decreased risk for the composite end-point of borderline statistical significance (HR 0.530, 95 % C.I. 0.271–1.036, P = 0.064) and with significantly higher PWV (10.8 ± 2.2 m/s vs. 10.2 ± 2.1 m/s, P = 0.006) but similar IMT (0.75 ± 0.19 mm vs. 0.73 ± 0.17 mm, P = 0.156). When patients who had either systolic or diastolic orthostatic hypotension or both (n = 49) were compared with the 534 patients with a normal orthostatic blood pressure response, there was no significant association with the presence of any hypotensive orthostatic blood pressure response and the composite end-point (HR 1.308, 95 % C.I. 0.597–2.866, P = 0.502) but significantly higher values were found for both PWV (11.0 ± 2.4 m/s vs. 10.2 ± 2.1 m/s, P = 0.022) and IMT (0.82 ± 0.25 mm vs. 0.73 ± 0.17 mm, P = 0.014).

Since previous cardiovascular disease is a risk factor for recurrent events, we performed a sensitivity analysis, in which 86 patients were excluded due to reporting either previous myocardial infarction or previous stroke, or due to missing baseline data concerning these variables. When compared with patients with a normal orthostatic blood pressure response, the hazard ratio for the combined end-point was 1.010 (95 % C.I. 0.312–3.272, P = 0.986, n = 510) for systolic orthostatic hypertension, 1.119 (95 % C.I. 0.270–4.637, P = 0.877, n = 493) for systolic orthostatic hypotension, 0.285 (95 % C.I. 0.088–0.923, P = 0.036, n = 595) for diastolic orthostatic hypertension, and 1.728 (95 % C.I. 0.617–4.837, P = 0.298, n = 499) for diastolic orthostatic hypotension. For patients with either systolic or diastolic orthostatic hypertension or both, the hazard ratio was 0.394 (95 % C.I. 0.155–0.999, P = 0.050, n = 624) and for patients with either systolic or diastolic orthostatic hypotension or both, the hazard ratio was 1.342 (95 % C.I. 0.529–3.404, P = 0.536, n = 516).