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- Materials and methods
- Conflict of interest statement
The general characteristics of the study participants at baseline, within the four systolic BP categories, are shown in Table 1. Higher baseline systolic BP levels were significantly associated with the female gender, increased age, diastolic BP, BP medication use, total cholesterol, triacylglycerol, BMI and proteinuria and a lower prevalence of smoking. Alcohol consumption was lowest in patients with systolic BP between 130–139 and ≥160 mmHg. Among patients without proteinuria, systolic BP was <130 mmHg in 16.3%, 130–139 mmHg in 15.3%, 140–159 mmHg in 38.1% and ≥160 mmHg in 30.3%. The values among patients with proteinuria were 12.7%, 9.8%, 35.0% and 42.5%, respectively.
Table 1. Baseline characteristics and number of subjects with endpoints by systolic blood pressure
|Variables||Baseline systolic BP (mmHg)||P-value|
|<130 ||130–139 ||140–159 ||≥160|
| N ||129||112||327||317|| |
|Age, years||56.0 ± 5.69||57.1 ± 5.01||57.8 ± 5.00||59.2 ± 4.52||<0.001|
|Diastolic BP, mmHg||76.8 ± 9.21||78.8 ± 9.22||86.0 ± 9.37||92.3 ± 11.8||<0.001|
|Duration of diabetes, years||7.9 ± 4.9||7.7 ± 4.3||8.1 ± 3.7||8.0 ± 3.7||0.898|
|Total cholesterol, mmol L−1||6.34 ± 1.49||6.55 ± 1.38||6.70 ± 1.78||6.87 ± 1.76||0.019|
|HDL cholesterol, mmol L−1||1.19 ± 0.35||1.29 ± 0.39||1.21 ± 0.35||1.25 ± 0.37||0.060|
|Triacylglycerol, mmol L−1||1.89 ± 0.99||1.96 ± 1.16||2.64 ± 3.14||2.83 ± 3.27||0.001|
|HbA1, %||10.0 ± 2.9||9.8 ± 2.0||9.9 ± 1.9||9.9 ± 2.3||0.813|
|BMI, kg m−2||28.1 ± 4.88||28.6 ± 5.38||29.6 ± 4.87||29.7 ± 5.78||0.009|
|Estimated GFR, ml min−1 1.73 m−2||90.1 ± 17.3||91.4 ± 19.8||91.3 ± 20.4||88.8 ± 23.0||0.420|
|Physical activity, METs||4.3 ± 2.2||4.2 ± 2.0||3.9 ± 1.7||3.9 ± 1.7||0.091|
|Area of residence, Turku, %||65.9||52.7||54.1||51.1||0.039|
|BP medication, %||17.1||27.7||48.6||64.4||<0.001|
|Current smokers, %||23.3||18.8||17.4||11.7||0.016|
|Alcohol users, %||51.9||29.5||41.6||29.7||<0.001|
|Retinopathy (mild/proliferative), %||21.9||27.3||25.9||29.4||0.42|
|CHD without MI at baseline, %||14.7||14.3||15.6||21.1||0.155|
|Diabetes treatment|| || || || ||0.851|
|Diet alone, %||15.5||10.7||14.7||14.5|| |
|Oral drugs, %||71.3||72.3||72.5||73.2|| |
|Insulin therapy, %||13.2||17.0||12.8||12.3|| |
|Total mortality||83||69||229||229|| |
|Cardiovascular disease mortality||50||46||156||145|| |
|CHD mortality||40||35||104||102|| |
|Urinary protein, mg L−1||130 (80–225)||120 (0–228)||140 (90–230)||170 (100–305)||<0.001|
|<150 mg L−1||77||72||180||143|| |
|≥150 mg L−1||52||40||143||174|| |
Outcome according to systolic blood pressure and proteinuria
During 10 784 patient years of follow-up, a total of 607 (68.9%) patients died, including 395 (44.8%) from CVD. The event rates of total, CVD and CHD mortality according to systolic BP in patients with or without proteinuria are shown in Fig. 1.
Figure 1. Total, cardiovascular disease and coronary heart disease mortality in patients without proteinuria (solid line and open squares) and with proteinuria (dashed line and filled circles) in different systolic blood pressure (BP) categories. Event-rates are expressed per 1000 patient-years of follow-up. Number of patients without proteinuria in the BP groups <130, 130–139, 140–159 and >160 mmHg were 77, 72, 180 and 143, respectively; the numbers of patients with proteinuria were 52, 40, 143 and 174, respectively.
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In Cox regression analyses, a statistically significant interaction between proteinuria and baseline systolic BP (P = 0.01) was observed for total mortality, and a borderline significant interaction (P = 0.05) for CVD mortality. For CHD mortality, the P value for interaction was 0.07 in univariate analysis and 0.10 in multivariate analysis. Owing to this interaction we examined mortality rates among systolic BP categories separately in subjects with and without proteinuria (Table 2). Systolic BP <130 mmHg has been recommended as a target level in diabetic subjects, therefore this BP group was used as a reference for comparison with all other groups .
Table 2. Relative mortality in patients in various systolic BP categories stratified by the presence of proteinuria, compared to those with systolic BP <130 mmHg
|Event||Hazard ratio (95% confidence interval)|
|Systolic BP (mmHg)|
|<130||130–139||140–159||≥160||P for interaction|
|No proteinuria||1.00||1.06 (0.69–1.64)||1.33 (0.92–1.91)||1.14 (0.78–1.67)||0.01|
|Proteinuria||1.00||0.51 (0.31–0.82)*||0.57 (0.40–0.82)*||0.65 (0.46–0.91)*|
|No proteinuria||1.00||1.04 (0.66–1.65)||1.29 (0.88–1.91)||1.10 (0.73–1.68)||0.02|
|Proteinuria||1.00||0.50 (0.30–0.83)*||0.62 (0.42–0.91)*||0.78 (0.53–1.16)|| |
|Cardiovascular disease mortality|
|No proteinuria||1.00||1.32 (0.77–2.27)||1.47 (0.92–2.34)||1.27 (0.78–2.07)||0.05|
|Proteinuria||1.00||0.46 (0.24–0.86)*||0.66 (0.43–1.03)||0.64 (0.42–1.0)*|| |
|No proteinuria||1.00||1.30 (0.73–2.32)||1.33 (0.80–2.21)||1.08 (0.63–1.86)||0.05|
|Proteinuria||1.00||0.43 (0.22–0.84)*||0.61 (0.38–0.97)*||0.62 (0.38–1.02)|| |
|No proteinuria||1.00||1.33 (0.73–2.45)||1.15 (0.67–1.99)||1.12 (0.64–1.96)||0.07|
|Proteinuria||1.00||0.38 (0.18–0.81)*||0.57 (0.35–0.94)*||0.55 (0.33–0.90)*|
|No proteinuria||1.00||1.39 (0.72–2.67)||1.13 (0.63–2.05)||1.09 (0.58–2.04)||0.11|
|Proteinuria||1.00||0.40 (0.18–0.88)||0.61 (0.36–1.05)||0.63 (0.36–1.11)|
After adjustment for confounding factors, patients with proteinuria with systolic BP <130 mmHg had significantly increased (approximately 2-fold higher, P < 0.05) total and CVD mortality than those with systolic BP between 130 and 139 mmHg and increased (approximately 1.6-fold higher, P < 0.05) total and CVD mortality than those with systolic BP between 140 and 159 mmHg. Among patients without proteinuria, systolic BP <130 mmHg tended to be associated with slightly reduced CVD mortality. We observed no interaction between proteinuria and diastolic BP, and therefore only results for systolic BP are shown.
Figure 2 shows Kaplan–Meier curves of cumulative survival for patients in different systolic BP categories stratified by baseline proteinuria level. Among patients without proteinuria, those with systolic BP <130 mmHg tended to have a decreased risk of total mortality. However, among patients with proteinuria, patients with systolic BP <130 mmHg had the worst prognosis with respect to total mortality. This became evident after 2 years of follow-up.
Figure 2. Kaplan–Meier survival curves for total mortality according to different levels of systolic blood pressure (BP) stratified by baseline proteinuria: urinary protein ≤150 mg L−1 (a) and >150 mg L−1 (b). Open circles, systolic BP <130 mmHg; filled circles, systolic BP 130–139 mmHg; open squares, systolic BP 140–159 mmHg; filled squares, systolic BP ≥160 mmHg. P value denotes the difference between the survival curves.
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To study whether the high risk of CVD death in patients with proteinuria and with systolic BP <130 mmHg could be explained by differences in the prevalence of baseline CHD without prior MI, we calculated the prevalence of CHD by symptoms and ECG changes in the population stratified by proteinuria and systolic BP. In patients with proteinuria, the prevalence of CHD was 28.8%, 20.0%, 15.4% and 22.4% in patients with systolic BP <130, 130–139, 140–159 and ≥160 mmHg, respectively (P = 0.18). In patients without proteinuria, the respective prevalence of CHD was 5.2%, 11.1%, 14.4% and 19.6% (P = 0.027).
- Top of page
- Materials and methods
- Conflict of interest statement
To our knowledge, this is the first large population-based long-term follow-up study to investigate the impact of systolic BP on total and CVD mortality in patients with type 2 diabetes with and without proteinuria. Our main finding was that systolic BP <130 mmHg was associated with increased total and CVD mortality among patients with proteinuria compared with those with systolic BP of 130–139 or 140–159 mmHg. Indeed, patients with proteinuria with BP <130 mmHg tended to have a poorer prognosis compared even to those with BP ≥160 mmHg. Patients with systolic BP between 130 and 139 mmHg had the best prognosis in terms of total and CVD mortality. These associations were independent of conventional CVD risk factors, diastolic BP, duration of diabetes, diabetes and BP treatment, glycaemic control, estimated GFR, retinopathy and baseline CHD without MI.
We found that among patients with type 2 diabetes without proteinuria, systolic BP <130 mmHg was associated with a tendency towards slightly lower total and CVD mortality. It is noteworthy that diabetes among the study patients was poorly controlled at baseline. However, the level of glycaemic control during follow-up was unknown; therefore it is unclear how changes in glycaemic control may have influenced the prognosis of these patients. It is known that good glycaemic and BP control have additive positive effects on total and CVD mortality in patients with type 2 diabetes [5, 16], but it is not known whether this additive effect is also observed among patients with proteinuria.
Our findings indicate that patients with type 2 diabetes with proteinuria have an increased risk of mortality when systolic BP is lower than <130 mmHg, compared with higher BP levels. It is worth mentioning that this finding does not necessarily apply to incident nonfatal CVD events such as MI. There is also a possibility that the increased risk in the low BP group may be because of chance given to the limited sample size in the proteinuria group. However, our findings are likely to be valid for several reasons. First, it has been proposed that microalbuminuria and similarly proteinuria may be indicators of generalized endothelial dysfunction [17, 18] and therefore may indicate atherosclerotic disease leading to underperfusion of vital organs when BP is low, thus increasing CVD mortality. This hypothesis is supported by our analyses of baseline data showing that CHD prevalence evidenced by symptoms and ECG findings was only 5.2% among patients without proteinuria and systolic BP <130 mmHg versus 28.8% (i.e. approximately 5-fold increase) in patients with proteinuria and systolic BP <130 mmHg. Secondly, impaired left ventricular systolic function, known to be associated with chronic kidney disease and diabetes, could decrease BP as a result of reduced cardiac output [19-22]. Thus, low systolic BP in such patients may be a marker of underlying disease as the cause of worse prognosis.
Our observations in patients with type 2 diabetes and proteinuria are in line with those in the IDNT trial , a post hoc study in which type 2 diabetic patients with nephropathy and with systolic BP ≤120 mmHg had an increased CVD mortality rate. Again, consistent with the present findings, two studies in type 2 diabetic patients with coronary artery disease showed that the benefits of lowering systolic BP to <130 mmHg were driven mostly by a reduction in stroke incidence whereas CVD and total mortality rate were unchanged or even increased [24, 25]. In the recent ACCORD trial, lowering systolic BP to <120 mmHg in high-risk type 2 diabetic patients did not reduce mortality compared to those with a systolic BP target of <140 mmHg . Previous findings as stated before and also our present finding, suggest that one target BP level may not necessarily fit all type 2 diabetic patients. It appears that there is heterogeneity of the effects on different CVD outcomes (e.g. nonfatal events versus mortality) of intensive BP control and also of lowering BP to <130 mmHg. In addition, the effects may also vary on the basis of the presence or absence of comorbid conditions, such as proteinuria. Therefore, lowering systolic BP to <130 mmHg might not be justified for type 2 diabetic patients with proteinuria or for patients otherwise at high risk of CVD-related mortality. Furthermore, even though the evidence supporting a target systolic BP level <140 mmHg in slowing progression of kidney disease is strong, there are limited data regarding the effects of lowering BP to <130/80 mmHg [14, 27, 28]. The mode and intensity of treatment of BP should be based on the patient's individual CVD risk and possible comorbid conditions rather than on aggressive BP goals recommended by global guidelines alone. Based on a recent meta-analysis, it was concluded that, among patients with type 2 diabetes, the more aggressive target for systolic BP of <130 mmHg has to be balanced between the benefits of lowering stroke incidence and the increased risk of serious adverse events, such as life-threatening events or hospitalization, as well as the lack of benefit for cardiac, renal and retinal outcomes . Furthermore, in type 2 diabetes, proteinuria has been highlighted as an important prognostic marker for cardiac disease, in addition to conventional CVD risk factors . Thus, our results suggest that it might be justifiable to recommend higher systolic BP targets for patients with type 2 diabetes and proteinuria compared with those without proteinuria.
Our study has several strengths. First, our baseline examination was carried out in 1982–1984. As statin treatment did not become common until the second half of the 1990s, it is unlikely that lipid-lowering therapy has caused a major bias in our study. Secondly, unlike many similar epidemiological studies, data regarding glucose control, diabetes duration and mode of diabetes treatment were available. Thirdly, we used the post-glucagon C-peptide measurement to exclude patients with type 1 diabetes. Finally, to avoid a potential bias from possibly increased early mortality because of a severe disease at baseline, we excluded all subjects with possible or definite stroke, possible or definite MI or amputation at baseline.
Our study also has limitations. First, BP was only measured at baseline. Therefore, we lack data on changes in BP during follow-up. Moreover data were not available on the use of angiotensin-converting enzyme (ACE) inhibitors, which are known to improve the prognosis of patients with kidney disease. However, as the first ACE inhibitor captopril was approved by the US Food and Drug Administration in 1981, it is highly unlikely that our study participants were taking these drugs at baseline. Secondly, we measured total urinary protein concentration from spot urine samples instead of measuring urinary albumin excretion rate. Our findings do not apply to subjects with microalbuminuria. On the other hand, our cut-off point for proteinuria, 150 mg L−1, is lower than the commonly used level for clinical proteinuria (300 mg L−1). However, 150 mg L−1 was previously associated with total and CVD mortality , therefore indicating a high risk of CVD. Owing to this limitation, it is likely that our study underestimates rather than overestimates the association of BP and proteinuria with CVD outcomes and total mortality. Thirdly, without the necessary data we were not able to make assumptions about the safe systolic BP levels for patients with renal failure, It should be mentioned that at the time of our baseline examination, risk assessments and interventions for CVD in type 2 diabetes patients were not routinely performed, in contrast to the situation in clinical practice today. These factors are likely to have affected the natural history of patients with proteinuria with respect to CVD risk.
In conclusion, systolic BP <130 mmHg tended to be associated with a slight decrease in total and CVD mortality rate in middle-aged type 2 diabetic patients without proteinuria. Among patients with proteinuria, systolic BP <130 mmHg was associated with a significant increase in total and CVD mortality rate. Patients with a systolic BP level between 130 and 139 mmHg had the best prognosis with respect to total and CVD mortality. These results suggest that type 2 diabetic patients with proteinuria and with systolic BP <130 mmHg may have an increased risk of total and CVD mortality. Further investigation is needed to determine conclusively whether aggressive lowering of (systolic) BP in patients with type 2 diabetes and proteinuria would result in excess risk of CVD outcomes or death.