RESEARCH

OPEN ACCESS
Blood pressure and complications in individuals with type 2

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diabetes and no previous cardiovascular disease:
national population based cohort study
Samuel Adamsson Eryd,1,2,3 Soffia Gudbjörnsdottir,1,2 Karin Manhem,2 Annika Rosengren,2,3
Ann-Marie Svensson,1 Mervete Miftaraj,1 Stefan Franzén,1 Staffan Björck1

1Centre of Registers Västra ABSTRACT non-fatal acute myocardial infarction (adjusted hazard
Götaland, Gothenburg, Sweden OBJECTIVES ratio 0.76, 95% confidence interval 0.64 to 0.91;
2Department of Molecular and
To compare the risk associated with systolic blood P=0.003), total acute myocardial infarction (0.85, 0.72
Clinical Medicine, Sahlgrenska
pressure that meets current recommendations (that is, to 0.99; P=0.04), non-fatal cardiovascular disease
Academy, University of
Gothenburg, Gothenburg, below 140 mm Hg) with the risk associated with lower (0.82, 0.72 to 0.93; P=0.002), total cardiovascular
Sweden levels in patients who have type 2 diabetes and no disease (0.88, 0.79 to 0.99; P=0.04), and non-fatal
3Sahlgrenska University
previous cardiovascular disease. coronary heart disease (0.88, 0.78 to 0.99; P=0.03)
Hospital/Östra Hospital, compared with the reference group (130-139 mm Hg).
Gothenburg, Sweden DESIGN
Population based cohort study with nationwide clinical There was no indication of a J shaped relation between
Correspondence to:
S Adamsson Eryd registries, 2006-12. The mean follow-up was 5.0 years. systolic blood pressure and the endpoints, with the
samuel.adamssoneryd@ exception of heart failure and total mortality.
registercentrum.se SETTING
861 Swedish primary care units and hospital CONCLUSIONS
Additional material is published
online only. To view please visit outpatient clinics. Lower systolic blood pressure than currently
the journal online. recommended is associated with significantly lower
PARTICIPANTS
Cite this as: BMJ 2016;354:i4070 risk of cardiovascular events in patients with type 2
187 106 patients registered in the Swedish national
http://dx.doi.org/10.1136/bmj.i4070 diabetes. The association between low blood pressure
diabetes register who had had type 2 diabetes for at
Accepted: 15 July 2016 and increased mortality could be due to concomitant
least a year, age 75 or younger, and with no previous
disease rather than antihypertensive treatment.
cardiovascular or other major disease.
MAIN OUTCOME MEASURES
Clinical events were obtained from the hospital Introduction
discharge and death registers with respect to acute Several major hypertension guidelines have recently
myocardial infarction, stroke, a composite of acute changed their recommended goal for systolic blood
myocardial infarction and stroke (cardiovascular pressure in patients with diabetes.1-3 Instead of aiming
disease), coronary heart disease, heart failure, and total for below 130 mm Hg, the current guidelines recom-
mortality. Hazard ratios were estimated for different mend below 140 mm Hg. The consequences of the
levels of baseline systolic blood pressure with clinical changed guidelines are unknown.
characteristics and drug prescription data as covariates. Over the past 16 years, during which the previous rec-
RESULTS ommendations were in effect, the average systolic
The group with the lowest systolic blood pressure blood pressure among Swedish primary care patients
(110-119 mm Hg) had a significantly lower risk of with type 2 diabetes has decreased by 15 mm Hg. In
2015, the average blood pressure of 300 000 patients
was 135/76 mm Hg.4 The overall excess risk of death
among individuals with type 2 diabetes has fallen to a
WHAT IS ALREADY KNOWN ON THIS TOPIC historically low 15%.5
Hypertension is one of the major risk factors for cardiovascular disease, and the The reason for the new blood pressure target was the
management of hypertension is a high priority in the treatment of type 2 diabetes lack of randomised studies with conclusive results to
support the goal of below 130 mm Hg, together with
Recent hypertension guidelines have raised the target blood pressure for patients
information based on post hoc analyses of clinical trials
with diabetes from below 130 mm Hg to below 140 mm Hg because of a lack of
and register studies.1 These observational studies have
conclusive randomised studies to support the lower goal, together with
usually shown a J shaped relation between blood pres-
observational studies showing a J shaped relation between blood pressure and
sure and cardiovascular events, with an increased risk
complications
at the highest and lowest levels.
WHAT THIS STUDY ADDS The relevance of this J curve phenomenon has been
Lower systolic blood pressure than currently recommended is associated with a called into question given that observational studies of
significantly lower risk of cardiovascular events in patients with type 2 diabetes clinical trial data could be flawed by uncontrolled con-
founding—that is, major disease is a possible cause of
Adjustment for comorbidity, mainly by exclusion of patients with previous
low blood pressure.6 If so, the problem is exacerbated
cardiovascular disease, eliminates the J curve relation between blood pressure and
by the tendency of clinical trials to focus on patients at
stroke, myocardial infarction, and coronary heart disease
advanced stages of disease and an increased risk of car-
The association between low blood pressure and increased mortality might be
diovascular events as a means of ensuring sufficient
caused by concomitant disease rather than antihypertensive treatment
statistical power and reasonable study size.

the bmj | BMJ 2016;354:i4070 | doi: 10.1136/bmj.i4070 1

RESEARCH

Earlier studies based on the Swedish national blood pressure ≥110 mm Hg, age ≤75, and BMI ≥18. We
­ iabetes register have also shown a tendency toward a
d included 265 638 individuals at 1320 care units. After

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J shaped relation between blood pressure and cardio- exclusion of those at units with fewer than 150 patients
vascular disease in patients with type 2 diabetes. To (see below) or a history of acute myocardial infarction,
ensure statistical significance, however, they included stroke, coronary heart disease, heart failure, atrial fibril-
patients with previous cardiovascular disease. The reg- lation, end stage renal disease, amputation, dementia, or
ister has grown substantially over the past decade, cancer at baseline, 187 106 individuals remained for fur-
enabling appropriate selection of patients while still ther analysis (fig 1). The highest exclusion rate because of
enabling sufficient statistical power. To test our hypoth- previous cardiovascular disease was among patients with
esis that the J curve phenomenon is caused by concom- the lowest blood pressure. The total population before
itant comorbidities, we examined the predictive value exclusion is described in the appendix.
of systolic blood pressure at baseline for future cardio- Type 2 diabetes was defined as either treatment with
vascular events among patients with type 2 diabetes diet only, oral hypoglycaemic agents only, or onset of
after excluding those with a history of cardiovascular or diabetes age ≥40 and treatment with insulin alone or
other major disease. In addition, we used several combined with oral hypoglycaemic agents.
­methods to minimise uncontrolled confounding by
other risk factors. Baseline examinations and definitions
We aimed to compare the risk associated with a sys- The index date was defined as the first examination
tolic blood pressure that meets current recommenda- after the patient had been included in the diabetes reg-
tions with the risk of lower levels in patients who have ister. The inclusion criteria of the presence of diabetes
type 2 diabetes and no previous cardiovascular disease. for at least year ensured that patients had been moni-
tored and treated for a sufficient length of time before
Methods the baseline variables were entered. The clinical char-
This study was based on information from linking the acteristics reported to the diabetes register at baseline
Swedish national diabetes register, hospital discharge (the index date) were age, sex, duration of diabetes,
register, cause of death register, and prescribed drug systolic blood pressure, diastolic blood pressure, HbA1c,
register. type of hypoglycaemic treatment, weight, height, total
cholesterol, high density lipoprotein cholesterol, tri-
Databases glycerides, microalbuminuria and macroalbuminuria,
The diabetes register has been described previously.7 It and smoking status. Blood pressure was measured in
was launched in 1996 as a tool for quality assurance in accordance with national standards in the seated or
diabetes care. The register contains information about supine position by either a physician or nurse with
risk factors, complications, and treatment among either oscillometric or auscultatoric methods. Smoking
patients aged 18 and over. Trained nurses and physi- status was either yes or no.
cians report at least once a year either online or by elec- All laboratory analyses were performed at local labo-
tronic transmission of patients’ charts. Data are ratories. HbA1c values were expressed in mmol/mol in
collected during appointments at specialist clinics and accordance with the International Federation of Clini-
primary healthcare centres nationwide. All patients cal Chemistry (IFCC) standard. Body mass index (BMI)
give their informed consent before inclusion. During was calculated as weight/height2. Low density lipopro-
the study period of 2006-13, the register doubled in size tein cholesterol concentration was calculated in accor-
to about 300 000 patients. In 2015, it covered an esti- dance with Friedewald’s formula.9 Microalbuminuria
mated 90% of Swedish adults with type 2 diabetes.4
The hospital discharge register, cause of death regis-
ter, and prescribed drug register are administered by Individuals with type 2 diabetes entered in national diabetes
the Swedish National Board of Health and Welfare. register 2006-12, diabetes duration ≥1 year, age ≤75,
systolic blood pressure ≥110 mm Hg, BMI ≥18 (n=265 638)
Since 1987, the hospital discharge register has included
data for all inpatient care. As of 2001, data from outpa- Individuals’ history (n=78 532):
tient appointments with both private and public care Myocardial infarction (n=17 103)
Stroke (n=11 379)
providers has also been included. The data concern Cardiovascular disease (n=27 217)
diagnoses, procedures, and length of stay. The cause of Coronary heart disease (n=36 035)
Amputation (n=795)
death register contains data for all Swedes, regardless Heart failure (n=10 219)
of whether they died in Sweden or abroad. The pre- Atrial fibrillation (n=13 053)
Renal disease (n=554)
scribed drug register contains information about all Dementia (n=440)
dispensed prescriptions in Sweden since 1 July 2005.8 Cancer (n=9545)
Individuals listed at care centers
with <150 listed patients (n=21 902)
Study population
Patients with type 2 diabetes who had been entered in the Study population (n=187 106)
diabetes register from 1 January 2006 to 31 December 2012
for whom systolic blood pressure data were available Fig 1 | Enrolment of participants in study of blood pressure
were eligible for inclusion in the study. The inclusion cri- and complications in individuals with type 2 diabetes and
teria were diabetes duration for at least a year, systolic no previous cardiovascular disease

2 doi: 10.1136/bmj.i4070 | BMJ 2016;354:i4070 | the bmj

 RESEARCH

was defined as two positive results for three samples information about at least one laboratory measure-
obtained within one year, with positivity defined as an ment. Details about missing values are provided in the

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albumin/creatinine ratio of 3-30 mg/mmol (about appendix. The highest rate of missing values was for
30-300 mg/g) or urinary albumin clearance of 20-200 low density lipoprotein cholesterol. We used multiple
μg/min (20-300 mg/L) on two out of three consecutive imputation, generating 10 imputed datasets, to avoid a
tests. Macroalbuminuria was defined as an albumin/ reduction in sample size. Risk estimates remained
creatinine ratio >30 mg/mmol (about 300 mg/g) or uri- essentially unchanged after multiple imputations, as
nary albumin clearance >200 μg/min (>300 mg/L). opposed to complete case analysis. We used the Kaplan-
Individuals were defined as current users of drugs if Meier estimator to study incidence of endpoints over
they had a recorded purchase four months or less before time across the blood pressure groups. The propor-
the index date. Renal function measured as estimated tional hazards assumption was confirmed by plotting
glomerular filtration rate (eGFR) was based on the mod- the negative log of the estimated survivor functions
ification of diet in renal disease study equation.10 against time. Cox proportional hazards regression was
used to estimate hazard ratios for the relation between
Follow-up and definition of endpoints systolic blood pressure groups and incidence of various
All individuals were followed from the index date until cardiovascular endpoints. The 130-139 mm Hg group
a first event, death, or the end of follow-up on 31 Decem- was used for reference purposes.
ber 2013. The studied endpoints were non-fatal or total We tested two different models. Both models were
acute myocardial infarction, non-fatal or total stroke, a adjusted for age, sex, duration of diabetes, type of diabe-
composite of acute myocardial infarction and stroke tes treatment, HbA1c, smoking status, low density lipo-
(cardiovascular disease), non-fatal or total coronary protein cholesterol, high density lipoprotein cholesterol,
heart disease, non-fatal heart failure, and total mortal- triglycerides, microalbuminuria, and macroalbuminuria.
ity. Cardiovascular disease was defined as acute myo- BMI and eGFR were used as categorical variables because
cardial infarction or stroke, whichever came first. of their non-linear relation with mortality. The second
We used ICD-10 (international classification of dis- model was also adjusted for thiazide diuretics, loop
eases, 10th revision) for classification of diseases and diuretics, calcium antagonists, spironolactone, β block-
used both primary and contributory diagnoses. Acute ers, and drugs for heart disease. These covariates were
myocardial infarction was defined as a diagnosis of chosen after a separate analysis of their contribution to
myocardial infarction (I21). Stroke was defined as a the model (see appendix for greater detail). As a covariate
diagnosis of intracerebral haemorrhage, cerebral of treatment intensity at the care unit, we used the pro-
infarction, or unspecified stroke (I61, I63, I64). Coronary portion of patients receiving triple therapy—that is, a
heart disease was defined as a diagnosis of non-fatal combination of a thiazide diuretic, calcium antagonist,
myocardial infarction, angina pectoris, subsequent and either a renin-angiotensin system inhibitor or angio-
myocardial infarction, certain current complications tensin II blocker (renin-angiotensin-aldosterone (RAAS)
after myocardial infarction, other acute ischaemic heart blocking agent). The hypothesis was that the approach
disease, chronic ischaemic heart disease, percutaneous offers an indicator for a step-up strategy and thus a mea-
coronary intervention, and/or coronary artery bypass sure of low blood pressure because of antihypertensive
grafting (I20 to I25). Heart failure was defined as a diag- treatment rather than spontaneous low blood pressure.
nosis of heart failure (I50). Fatal events of acute myocar- We chose this covariate after testing several similar vari-
dial infarction, stroke, cardiovascular disease, and ables (see appendix). To avoid outlier bias, we determined
coronary heart disease were included only if the pri- the frequency of use of the triple drug regimen by examin-
mary recorded cause of death was either disease of the ing individuals in the 125-140 mm Hg range at clinics with
circulatory system (I00-I99) or endocrine, nutritional, at least 150 patients. We excluded 21 902 individuals
or metabolic disease (E00-E90). because their clinics had too few patients. A secondary
History of atrial fibrillation was defined as ICD-10 analysis also looked at the relations between systolic
code I48. History of end stage renal disease was defined blood pressure and the various outcomes with individu-
as codes Z94.0, Z49.1, Z49.2, or Z99.2. History of dementia als with previous disease included in the models. The
was defined as codes G300, G301, G308, G309, and F00- appendix provides additional methodological details.
F03. History of cancer was defined as codes C00-C97. All analyses were performed in SAS version 9.4 (SAS
All events were obtaining by linking Swedish per- Institute, Cary, NC).
sonal identity numbers with the hospital discharge reg-
ister and cause of death register. Validation studies of Patient involvement
the hospital discharge register (also known as the No patients were involved in setting the research ques-
national inpatient register) have shown high overall tion or the outcome measures, nor were they involved in
specificity.11 recruitment, or the design and implementation of the
study. There are no plans to involve patients in
Statistics ­dissemination.
The sample was assigned to six groups of systolic blood
pressure: 110-119 mm Hg, 120-129 mm Hg, 130-139 mm Hg, Results
140-149 mm Hg, 150-159 mm Hg, and ≥160 mm Hg. A total of 187 106 individuals were included in the study.
Between 4.8% and 34.7% of participants were missing Table 1 shows the baseline characteristics of the various

the bmj | BMJ 2016;354:i4070 | doi: 10.1136/bmj.i4070 3

RESEARCH

Table 1 | Baseline characteristics of 187 106 participants with various systolic blood pressure levels. Figures are numbers (percentage) unless stated
otherwise

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110-119 mm Hg 120-129 mm Hg 130-139 mm Hg 140-149 mm Hg 150-159 mm Hg ≥160 mm Hg
Characteristics (n=12 829) (n=36 618) (n=49 518) (n=43 687) (n=21 558) (n=22 896)
Mean (SD) systolic blood pressure (mm Hg) 113.0 (3.0) 122.6 (2.9) 132.4 (2.8) 141.8 (2.6) 151.8 (2.6) 168.1 (10.7)
Men 6710 (52.3) 20 936 (57.2) 28 913 (58.4) 25 141 (57.5) 12 363 (57.3) 12 597 (55.0)
Mean (SD) age (years) 55.1 (11.4) 58.0 (10.3) 60.5 (9.4) 62.1 (8.7) 62.9 (8.3) 63.9 (7.9)
Mean (SD) duration of diabetes (years) 4.8 (5.5) 5.2 (5.7) 5.6 (5.9) 6.0 (6.1) 6.4 (6.3) 6.8 (6.6)
Mean (SD) HbA1c (mmol/mol) 51.7 (13.5) 52.3 (13.3) 52.6 (12.8) 53.4 (13.3) 54.0 (13.4) 55.1 (14.4)
Diet treatment only 4121 (32.1) 10 798 (29.5) 14 681 (29.6) 12 677 (29.0) 6170 (28.6) 6232 (27.2)
Tablet treatment only 6216 (48.5) 18 419 (50.3) 24 598 (49.7) 21 319 (48.8) 10 339 (48.0) 10 806 (47.2)
Insulin treatment 1298 (10.1) 3512 (9.6) 4282 (8.6) 3732 (8.5) 1942 (9.0) 2391 (10.4)
Insulin and tablet treatment 1194 (9.3) 3889 (10.6) 5957 (12.0) 5959 (13.6) 3107 (14.4) 3467 (15.1)
Mean (SD) BMI 29.5 (5.6) 30.0 (5.4) 30.3 (5.3) 30.5 (5.4) 30.7 (5.5) 30.6 (5.5)
Mean (SD) LDL (mmol/L) 2.8 (0.9) 2.8 (0.9) 2.9 (0.9) 2.9 (0.9) 2.9 (0.9) 3.0 (1.0)
Mean (SD) HDL (mmol/L) 1.3 (0.4) 1.3 (0.4) 1.3 (0.4) 1.3 (0.4) 1.3 (0.4) 1.3 (0.4)
Mean (SD) cholesterol (mmol/L) 4.9 (1.0) 4.9 (1.0) 4.9 (1.0) 5.0 (1.0) 5.1 (1.0) 5.1 (1.1)
Mean (SD) triglycerides (mmol/L) 1.8 (1.2) 1.8 (1.2) 1.8 (1.2) 1.9 (1.2) 1.9 (1.2) 1.9 (1.2)
Microalbuminuria 923 (10.6) 3022 (11.8) 4580 (13.1) 4650 (15.4) 2584 (17.3) 3216 (20.5)
Macroalbuminuria 345 (3.9) 1178 (4.6) 1721 (4.9) 1832 (6.1) 1127 (7.6) 1591 (10.2)
Mean (SD) eGFR (mL/min/1.73 m2) 90.1 (24.2) 88.7 (24.3) 87.0 (22.9) 86.1 (22.9) 85.4 (23.6) 84.3 (24.9)
Current smoker 2418 (21.9) 6161 (19.5) 7623 (17.9) 6358 (17.0) 3181 (17.4) 3650 (18.8)
Thiazide diuretics 1559 (12.2) 5894 (16.1) 9938 (20.1) 9765 (22.4) 5132 (23.8) 5825 (25.4)
Loop diuretics 718 (5.6) 2092 (5.7) 2979 (6.0) 3069 (7.0) 1756 (8.1) 2145 (9.4)
Calcium antagonists 1137 (8.9) 5196 (14.2) 9371 (18.9) 9806 (22.4) 5354 (24.8) 6016 (26.3)
Spironolactone 260 (2.0) 744 (2.0) 908 (1.8) 829 (1.9) 429 (2.0) 412 (1.8)
β blockers 2020 (15.7) 7158 (19.5) 11 481 (23.2) 11 743 (26.9) 6477 (30.0) 8111 (35.4)
RAAS blockers 3200 (24.9) 12 448 (34.0) 21 030 (42.5) 20 835 (47.7) 11 487 (53.3) 13 380 (58.4)
Mean (SD) No of antihypertensive agents 0.7 (1.1) 0.9 (1.2) 1.1 (1.2) 1.3 (1.3) 1.5 (1.3) 1.6 (1.3)
Drugs for heart disease 367 (2.9) 1101 (3.0) 1483 (3.0) 1364 (3.1) 705 (3.3) 773 (3.4)
Statins 4095 (31.9) 13 630 (37.2) 19 517 (39.4) 16 967 (38.8) 8156 (37.8) 8375 (36.6)
BMI=body mass index; LDL=low density lipoprotein cholesterol; HDL=high density lipoprotein cholesterol; eGFR=estimated glomerular filtration rate; RAAS=renin-angiotensin-aldosterone.

systolic blood pressure groups. The average number of infection; diseases of the nervous, respiratory, and
antihypertensive agents varied from 0.7 in the lowest digestive systems; and external causes of morbidity.
blood pressure group to 1.6 in the highest. The mean Figure 2 shows the cumulative incidence of non-fatal
systolic blood pressure in each of the blood pressure cardiovascular disease for various baseline systolic
categories was skewed to the lower end of the range. blood pressures. The unadjusted risk of developing
Table 2 shows the number of endpoints during a mean non-fatal cardiovascular disease was lowest in the
follow-up period of five years. A total of 12 152 individu- group with lowest baseline systolic blood pressure.
als (6.5%) died during the period, 3663 (30%) of the Figure 3 shows the relation between baseline systolic
deaths were classified as cardiovascular. Table C in the blood pressure and the different endpoints, adjusted
appendix shows the causes of death in the various blood for potential covariates. The lowest systolic blood pres-
pressure groups. The lowest blood pressure group sure group (110-119 mm Hg) was associated with a
(­110-119 mm Hg) had the highest rates of mortality from ­significantly lower risk of non-fatal acute myocardial

Table 2 | Number of events in various systolic blood pressure groups during five year mean follow-up period. Figures are numbers (percentage) of
participants
110-119 mm Hg 120-129 mm Hg 130-139 mm Hg 140-149 mm Hg 150-159 mm Hg ≥160 mm Hg Total
Outcome (n=12 829) (n=36 618) (n=49 518) (n=43 687) (n=21 558) (n=22 896) (n=187 106)
Non-fatal AMI 221 (1.7) 831 (2.3) 1407 (2.8) 1432 (3.3) 833 (3.9) 1065 (4.7) 5789 (3.1)
Fatal AMI 75 (0.6) 225 (0.6) 312 (0.6) 389 (0.9) 241 (1.1) 329 (1.4) 1571 (0.8)
Non-fatal stroke 205 (1.6) 713 (1.9) 1250 (2.5) 1368 (3.1) 814 (3.8) 1173 (5.1) 5223 (3.0)
Fatal stroke 19 (0.1) 78 (0.2) 120 (0.2) 147 (0.3) 111 (0.5) 173 (0.8) 648 (0.4)
Non-fatal CVD 417 (3.3) 1494 (4.1) 2542 (5.1) 2677 (6.1) 1578 (7.3) 2110 (9.2) 10 818 (5.8)
Fatal CVD 144 (1.1) 428 (1.2) 633 (1.3) 745 (1.7) 476 (2.2) 676 (3.0) 3102 (1.7)
Non-fatal CHD 552 (4.3) 1967 (5.4) 3058 (6.2) 3140 (7.2) 1734 (8.0) 2112 (9.2) 12 563 (6.7)
Fatal CHD 129 (1.0) 357 (1.0) 524 (1.1) 617 (1.4) 374 (1.7) 532 (2.3) 2533 (1.4)
Non-fatal heart failure 292 (2.3) 886 (2.4) 1397 (2.8) 1562 (3.6) 989 (4.6) 1326 (5.8) 6452 (3.5)
Total mortality 684 (5.3) 1841 (5.0) 2749 (5.6) 2916 (6.7) 1692 (7.8) 2270 (9.9) 12 152 (6.5)
AMI=myocardial infarction; CVD=cardiovascular disease; CHD=coronary heart disease.

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 RESEARCH

Proportion of patients 0.15

≥160 mm Hg
failure. A secondary analysis showed that systolic blood
pressure also exhibited a more or less a J shaped rela-

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150-159 mm Hg
0.12 tion with all studied outcomes when we included
140-149 mm Hg
130-139 mm Hg patients with previous disease. Accordingly, the J curve
0.09
120-129 mm Hg relation observed in real world data depends on patient
110-119 mm Hg selection and the extent to which comorbidity can be
0.06
adjusted for.
0.03 The new goal of below 140 mm Hg for systolic blood
pressure in patients with diabetes is based on several
0 mainly observational studies.1-3 The European guide-
0 1 2 3 4 5 6 7 8
Time from index (years) lines highlight four studies as providing “supportive
No at risk evidence” against reducing systolic blood pressure to
110-119 mm Hg 11 151 11 012 9732 8362 6951 5422 3973 2459 0 below 130 mm Hg. The most often cited study is the ran-
120-129 mm Hg 31 748 31 325 27 909 24 068 20 086 15 800 11 694 7320 0
130-139 mm Hg 43 114 42 472 38 115 33 112 27 712 22 109 16 577 10 529 0
domised Action to Control Cardiovascular Risk in Dia-
140-149 mm Hg 37 628 37 007 33 575 29 616 25 203 20 390 15 446 10 015 0 betes blood pressure trial (ACCORD BP), which failed to
150-159 mm Hg 18 598 18 251 16 666 14 770 12 721 10 417 7974 5117 0 show any significant benefit for the primary composite
≥160 mm Hg 19 554 19 059 17 466 15 494 13 334 10 933 8388 5241 0
cardiovascular endpoint from intensive antihyperten-
Fig 2 | Kaplan-Meier analysis of non-fatal cardiovascular events, showing proportion of sive treatment.12 The trial did, however, show that the
patients with events (composite of nonfatal myocardial infarction or stroke) in different risk of stroke was reduced by 40% in the group assigned
systolic blood pressure groups to systolic blood pressure below 120 mm Hg. The rate of
cardiovascular events was only half of that which had
i­nfarction (hazard ratio 0.76, 95% confidence interval been expected when the study size was planned. The
0.64 to 0.91; P=0.003), total acute myocardial infarction next two studies were post hoc analyses of clinical trials
(0.85, 0.72 to 0.99; P=0.04), non-fatal cardiovascular showing a J shaped relation between blood pressure
disease (0.82, 0.72 to 0.93; P=0.002), total cardiovascu- and prognosis. Post hoc analysis of data from the Ongo-
lar disease (0.88, 0.79 to 0.99; P=0.04), and non-fatal ing Telmisartan alone and in combination with the
coronary heart disease (0.88, 0.78 to 0.99; P=0.03) than Ramipril Global Endpoint Trial (ONTARGET) showed
the reference group (130-139 mm Hg). Similar trends, that neither myocardial infarction nor cardiovascular
though not significant, were observed for stroke and death was related to baseline systolic blood pressure.13
total coronary heart disease. Based on a subgroup analysis of patients with low
The lowest systolic blood pressure group (110-119 mm Hg) blood pressure who experienced a cardiovascular
was associated with a significantly increased risk of event, the authors concluded that a higher baseline
heart failure and total mortality. Table 3 shows the char- risk, rather than excessive reduction of blood pressure,
acteristics of patients who survived or died in the group was a key determinant of the J curve phenomenon.
with the lowest systolic blood pressure at baseline and A post hoc analysis of data from the International
the reference blood pressure group (130-139 mm Hg). Verapamil SR/Trandolapril Study (INVEST), a compari-
Patients in the lowest blood pressure group who died son of a β blocker and calcium antagonist based antihy-
had the highest rate of smoking (31.8%) as well as the pertensive treatment strategy, showed that patients
most treatment with loop diuretics and spironolactone. with systolic blood pressure below 130 mm Hg did not
Overall, we found no indications of a J shaped rela- experience any favourable effect compared with those
tion between systolic blood pressure and the endpoints, with blood pressure of 130-140 mm Hg. Thus, the
with the exception of heart failure and total mortality. A authors proposed a treatment goal of 130-139 mm Hg.14
secondary analysis, however, presented in the appen- In this study, however, patients with systolic blood
dix, showed that systolic blood pressure exhibited a pressure below 130 mm Hg had the least antihyperten-
more or less J shaped relation with all studied outcomes sive treatment, measured both as the number and dose
when the regression models included individuals who of drugs. The finding indicates that lower blood pres-
had previous disease. sure was not a treatment effect but might have been
caused by other disease.
Discussion The fourth highlighted study, NDR-BP-II, was an
This observational study of 187 106 individuals with observational study of 53 553 individuals with type 2
type 2 diabetes who did not have previous cardiovascu- diabetes that found a J curved relation between blood
lar disease shows that those with systolic blood pres- pressure and several cardiovascular complications.15
sure lower than 120 mm Hg have a significantly lower The national diabetes register has, however, grown con-
long term risk of myocardial infarction, cardiovascular siderably in size over the past decade, enabling appro-
disease, and coronary heart disease than those with a priate selection of patients while still ensuring sufficient
systolic blood pressure of 130-139 mm Hg, which would statistical power, as shown in the present study. While
meet the currently recommended goal. previous studies based on the diabetes register have
Furthermore, we found no J shaped relation between included patients with a history of cardiovascular dis-
systolic blood pressure and stroke, myocardial infarc- ease, we have shown here that excluding them elimi-
tion, or coronary heart disease. We did, however, find a nates the J curve phenomenon for several, but not all,
J shaped relation for both all cause mortality and heart endpoints. Simple adjustment for these comorbidities

the bmj | BMJ 2016;354:i4070 | doi: 10.1136/bmj.i4070 5

RESEARCH

Hazard ratio Hazard ratio P value in the regression models, as in the NDR-BP-II study, was
(95% CI) (95% CI)
Non-fatal AMI not sufficient to eliminate the J curve. These findings

BMJ: first published as 10.1136/bmj.i4070 on 4 August 2016. Downloaded from http://www.bmj.com/ on 12 September 2022 by guest. Protected by copyright.
110-119 mm Hg 0.76 (0.64 to 0.91) 0.003 strengthen the hypothesis that the J curve phenomenon
120-129 mm Hg 0.90 (0.80 to 1.00) 0.05
is caused by more patients with comorbidities in the
130-139 mm Hg 1.00
140-149 mm Hg 1.02 (0.93 to 1.12) 0.69 lowest blood pressure groups.
150-159 mm Hg 1.12 (1.00 to 1.26) 0.05 The results of the Systolic Blood Pressure Interven-
≥160 mm Hg 1.22 (1.10 to 1.37) <0.001 tion Trial (SPRINT) have reset the debate about optimal
Total AMI
110-119 mm Hg 0.85 (0.72 to 0.99) 0.04 levels.16 The randomised design for two different blood
120-129 mm Hg 0.93 (0.84 to 1.03) 0.16 pressure targets was similar to the ACCORD BP study,
130-139 mm Hg 1.00 but more than twice as many patients were included.
140-149 mm Hg 1.06 (0.97 to 1.16) 0.22
150-159 mm Hg 1.17 (1.05 to 1.30) 0.004
Patients with diabetes, however, were excluded.
≥160 mm Hg 1.25 (1.13 to 1.39) <0.001 SPRINT showed that the treatment goal of below
Non-fatal stroke 120 mm Hg was associated with much better outcomes
110-119 mm Hg 0.84 (0.70 to 1.02) 0.07 than below 140 mm Hg. As discussed in a recent edito-
120-129 mm Hg 0.92 (0.82 to 1.04) 0.18
130-139 mm Hg 1.00 rial, these two studies exhibit many similarities and
140-149 mm Hg 1.12 (1.01 to 1.24) 0.03 point to the same conclusion—that is, that more inten-
150-159 mm Hg 1.31 (1.16 to 1.47) <0.001 sive antihypertensive treatment than the current recom-
≥160 mm Hg 1.54 (1.37 to 1.72) <0.001
Total stroke
mendation provides additional protection from
110-119 mm Hg 0.85 (0.71 to 1.03) 0.09 cardiovascular events.17
120-129 mm Hg 0.93 (0.82 to 1.04) 0.19 Several recent reviews and meta-analyses have sum-
130-139 mm Hg 1.00 marised the literature but arrived at different conclu-
140-149 mm Hg 1.12 (1.02 to 1.24) 0.02
150-159 mm Hg 1.31 (1.16 to 1.47) <0.001 sions regarding the benefits of antihypertensive
≥160 mm Hg 1.57 (1.41 to 1.76) <0.001 treatment below 140 mm Hg.6 18-21 We analysed the risk
Non-fatal CVD related to systolic blood pressure at baseline, regardless
110-119 mm Hg 0.82 (0.72 to 0.93) 0.002
120-129 mm Hg 0.92 (0.84 to 0.99) 0.04
of whether it was due to antihypertensive treatment or
130-139 mm Hg 1.00 uncontrolled confounding (concomitant disease, etc).
140-149 mm Hg 1.08 (1.00 to 1.16) 0.05 We tried to minimise uncontrolled confounding in sev-
150-159 mm Hg 1.22 (1.12 to 1.33) <0.001
eral ways. Firstly, we included only patients who had
≥160 mm Hg 1.37 (1.27 to 1.49) <0.001
Total CVD had diabetes for a year or more, which ensured ade-
110-119 mm Hg 0.88 (0.79 to 0.99) 0.04 quate monitoring and treatment before baseline. Like
120-129 mm Hg 0.95 (0.88 to 1.02) 0.18 the ACCORD and NDR-BP-II studies, we had an upper
130-139 mm Hg 1.00
140-149 mm Hg 1.11 (1.04 to 1.19) 0.002
age limit and excluded patients aged ≥76 to minimise
150-159 mm Hg 1.25 (1.16 to 1.36) <0.001 the impact of concomitant disease. We also excluded
≥160 mm Hg 1.41 (1.30 to 1.52) <0.001 those with previous coronary heart disease, stroke,
Non-fatal CHD
atrial fibrillation, cancer, or BMI <18, as well as the few
110-119 mm Hg 0.88 (0.78 to 0.99) 0.03
120-129 mm Hg 0.98 (0.91 to 1.05) 0.56 with systolic blood pressure below 110 mm Hg, which
130-139 mm Hg 1.00 was outside of the scope of the study. In addition, we
140-149 mm Hg 1.06 (0.99 to 1.13) 0.09 used drug prescription data as markers for comorbidity
150-159 mm Hg 1.13 (1.04 to 1.22) 0.004
≥160 mm Hg 1.19 (1.10 to 1.29) <0.001
and treatment intensity. Finally, missing data were
Total CHD imputed to preserve study size and maximise statistical
110-119 mm Hg 0.92 (0.83 to 1.03) 0.16 power.
120-129 mm Hg 1.00 (0.93 to 1.08) 0.93
By selecting patients without previous reports of car-
130-139 mm Hg 1.00
140-149 mm Hg 1.09 (1.03 to 1.17) 0.006 diovascular disease, we eliminated the J curve relation
150-159 mm Hg 1.17 (1.09 to 1.27) <0.001 between blood pressure and stroke, myocardial infarc-
≥160 mm Hg 1.23 (1.14 to 1.32) <0.001 tion, and coronary heart disease. Of concern, however,
Heart failure
110-119 mm Hg 1.20 (1.01 to 1.42) 0.04
is that our adjustments did not eliminate the J curve rela-
120-129 mm Hg 1.02 (0.91 to 1.15) 0.71 tion with total mortality. Worth noting is that the group
130-139 mm Hg 1.00 with the lowest blood pressure also received the least
140-149 mm Hg 1.09 (0.98 to 1.20) 0.11
antihypertensive treatment. We cannot therefore draw
150-159 mm Hg 1.27 (1.13 to 1.43) <0.001
≥160 mm Hg 1.40 (1.25 to 1.56) <0.001 any conclusions about harmful effects of intensive anti-
Total mortality hypertensive treatment. Patients in the group with the
110-119 mm Hg 1.28 (1.15 to 1.42) <0.001 lowest blood pressure who died also had indications of
120-129 mm Hg 1.05 (0.97 to 1.13) 0.22
130-139 mm Hg 1.00
more serious conditions, including a high rate of smok-
140-149 mm Hg 1.05 (0.98 to 1.12) 0.15 ing and treatment with loop diuretics, spironolactone,
150-159 mm Hg 1.16 (1.06 to 1.26) <0.001 and drugs for heart disease. They also had the highest
≥160 mm Hg 1.29 (1.19 to 1.39) <0.001
rates of mortality from infection; diseases of the ner-
0.5 1.0 1.5 2.0 vous, respiratory, and digestive systems; and external
Fig 3 | Hazard ratios in various systolic blood pressure groups for outcomes of non-fatal causes. Thus, this group would seem to include patients
AMI (acute myocardial infarction), total AMI, non-fatal stroke, total stroke, non-fatal CVD with a favourable prognosis, as well as a subgroup with
(cardiovascular disease), total CVD, non-fatal CHD (coronary heart disease), total CHD, complications that led to a high mortality rate. As the
heart failure, and total mortality ONTARGET study concluded, the high m ­ ortality is

6 doi: 10.1136/bmj.i4070 | BMJ 2016;354:i4070 | the bmj

 RESEARCH

Table 3 | Baseline characteristics of individuals who died compared with those who survived in group with lowest blood pressure and in reference group

BMJ: first published as 10.1136/bmj.i4070 on 4 August 2016. Downloaded from http://www.bmj.com/ on 12 September 2022 by guest. Protected by copyright.
Systolic blood pressure 110-119 mm Hg Systolic blood pressure 130-139 mm Hg
Characteristics Alive (n=12 145) Dead (n=684) P value Alive (n=46 769) Dead (n=2749) P value
Mean (SD) systolic blood pressure (mm Hg) 113.0 (3.0) 112.8 (3.0) 0.08 132.4 (2.8) 132.4 (2.8) 0.52
Men 6281 (51.7) 429 (62.7) <0.001 27 132 (58.0) 1781 (64.8) <0.001
Mean (SD) age (years) 54.6 (11.3) 63.9 (8.2) <0.001 60.1 (9.4) 65.9 (7.2) <0.001
Mean (SD) duration of diabetes (years) 4.7 (5.4) 7.3 (6.6) <0.001 5.5 (5.9) 8.0 (6.9) <0.001
Mean (SD) HbA1c (mmol/mol) 51.6 (13.5) 53.6 (14.8) <0.001 52.5 (12.8) 54.4 (14.2) <0.001
Diet treatment only 3936 (32.4) 185 (27.0) <0.001 14 091 (30.1) 590 (21.5) <0.001
Tablet treatment only 5955 (49.0) 261 (38.2) <0.001 23 419 (50.1) 1179 (42.9) <0.001
Insulin treatment 1165 (9.6) 133 (19.4) <0.001 3811 (8.1) 471 (17.1) <0.001
Insulin and tablet treatment 1089 (9.0) 105 (15.4) <0.001 5448 (11.6) 509 (18.5) <0.001
Mean (SD) BMI 29.5 (5.5) 29.0 (6.1) 0.06 30.3 (5.3) 29.6 (5.6) <0.001
Mean (SD) LDL (mmol/L) 2.9 (0.9) 2.7 (1.0) 0.002 2.9 (0.9) 2.7 (0.9) <0.001
Mean (SD) HDL (mmol/L) 1.3 (0.4) 1.3 (0.4) 0.65 1.3 (0.4) 1.3 (0.4) 0.006
Mean (SD) cholesterol (mmol/L) 4.9 (1.0) 4.8 (1.1) 0.26 5.0 (1.0) 4.8 (1.0) <0.001
Mean (SD) triglycerides (mmol/L) 1.8 (1.2) 1.9 (1.2) 0.002 1.8 (1.2) 1.8 (1.1) 0.32
Microalbuminuria 843 (10.2) 80 (16.7) <0.001 4190 (12.7) 390 (19.3) <0.001
Macroalbuminuria 297 (3.6) 48 (10.0) <0.001 1503 (4.6) 218 (10.8) <0.001
eGFR (mL/min/1.73 m2) 90.4 (23.8) 85.6 (30.5) <0.001 87.3 (22.7) 82.9 (26.0) <0.001
Current smoker 2222 (21.4) 196 (31.8) <0.001 6987 (17.4) 636 (26.1) <0.001
Thiazide diuretics 1459 (12.0) 100 (14.6) 0.04 9381 (20.1) 557 (20.3) 0.80
Loop diuretics 580 (4.8) 138 (20.2) <0.001 2601 (5.6) 378 (13.8) <0.001
Calcium antagonists 1041 (8.6) 96 (14.0) <0.001 8725 (18.7) 646 (23.5) <0.001
Spironolactone 208 (1.7) 52 (7.6) <0.001 788 (1.7) 120 (4.4) <0.001
β blockers 1819 (15.0) 201 (29.4) <0.001 10 625 (22.7) 856 (31.1) <0.001
RAAS blockers 2965 (24.4) 235 (34.4) <0.001 19 725 (42.2) 1305 (47.5) <0.001
Mean (SD) No of antihypertensive drugs 0.7 (1.1) 1.2 (1.3) <0.001 1.1 (1.2) 1.4 (1.3) <0.001
Drugs for heart disease 319 (2.6) 48 (7.0) <0.001 1306 (2.8) 177 (6.4) <0.001
Statins 3857 (31.8) 238 (34.8) 0.10 18 422 (39.4) 1095 (39.8) 0.64
BMI=body mass index; LDL=low density lipoprotein cholesterol; HDL=high density lipoprotein cholesterol; eGFR=estimated glomerular filtration rate; RAAS=renin-angiotensin-aldosterone.

­ robably more associated with high baseline risk rather

p and hospital discharge records.22 We believe that this
than excessive reduction in blood pressure.13 difference in the accuracy of outcome measurements
Controlled clinical trials have the advantage of well explains the fact that the almost linear relation between
defined endpoints that can be examined when they systolic blood pressure and risk for the most well
appear and assessed in accordance with strict criteria in defined endpoints was attenuated when we added less
a blinded fashion, while the endpoints in observational accurate and fatal endpoints. The J shaped relation was
studies, such as ours, rely on endpoints with varying pronounced when the outcome was based solely on
degrees of accuracy. Data on stroke and myocardial mortality data.
infarction from the hospital discharge register are
highly reliable.11 These diagnoses are usually based on Strengths and limitations
a clinical evaluation on acute admission to hospital, The main strength of our study is the large number of
which is highly important for ensuing treatment. The participants, including patients from a nationwide dia-
situation for our other endpoints, including heart fail- betes register, with a high participation rate and data
ure and total mortality, is different. Completeness of obtained from day-to-day clinical practice. The size of
reporting and the date of onset are uncertain for heart the register made it possible for us to select participants
failure, angina pectoris, and certain other cardiovascu- suitable for the aims of our study without loss of statis-
lar diagnoses, given that primary care data are not tical power.
included in the hospital discharge register. It is evident We did not examine the effect of blood pressure
from the drug prescription data that some patients who during the follow-up period as this could have intro-
do not have previous diagnoses of major diseases use duced additional confounding. A decline in blood pres-
drugs that are indicated for cardiovascular complica- sure during follow-up can be caused by comorbidity,
tions (spironolactone, furosemide, etc, and possibly changes in treatment or lifestyle, or a disease that is not
β blockers as well). For causes of death, cardiovascular easy to control for. Reliance on a single measurement is
endpoints often appear together with other potentially likely to introduce a regression dilution effect because
fatal diagnoses, such as cancer, infection, or psychiatric of the variability in blood pressure over time. This might
problems. The cause of death register includes all lead to an attenuation of the relation between blood
deaths, regardless of whether they occurred in hospital pressure and outcome.23
or elsewhere. Fewer than 20% of death certificates are The observed skewness of the mean systolic blood
based on autopsy reports.22 Furthermore, considerable pressure in each blood pressure category is possibly
discrepancies have been reported between certificates due to digit preference for the nearest 10 mm Hg.

the bmj | BMJ 2016;354:i4070 | doi: 10.1136/bmj.i4070 7

RESEARCH

The true systolic blood pressure is likely to be closer to 3 American Diabetes Association. Standards of Medical Care in
Diabetes-2016 Abridged for Primary Care Providers. Clin Diabetes
the middle value than that reported.

BMJ: first published as 10.1136/bmj.i4070 on 4 August 2016. Downloaded from http://www.bmj.com/ on 12 September 2022 by guest. Protected by copyright.
2016;34:3-21. doi:10.2337/diaclin.34.1.3.
One limitation of our study is that it did not include 4 Swedish National Diabetes Register. 20 years of successful
improvements. 2016. https://www.ndr.nu/pdfs/20%20years%20
individuals with complications or those aged over 75. of%20successful%20improvements_lowres_singelpage.pdf
We believe that caution should be exercised when using 5 Tancredi M, Rosengren A, Svensson AM, et al. Excess Mortality among
observational studies to draw conclusions about recom- Persons with Type 2 Diabetes. N Engl J Med 2015;373:1720-32.
doi:10.1056/NEJMoa1504347.
mended treatment goals for blood pressure among high 6 Xie X, Atkins E, Lv J, et al. Effects of intensive blood pressure lowering
risk patients. There will always be uncertainty as to on cardiovascular and renal outcomes: updated systematic review
and meta-analysis. Lancet 2016;387:435-43. doi:10.1016/
whether low blood pressure is an effect of treatment or S0140-6736(15)00805-3.
a disease that cannot be controlled for. As a result, our 7 Gudbjörnsdottir S, Cederholm J, Nilsson PM, Eliasson B. Steering
study possibly underestimated the prophylactic effect Committee of the Swedish National Diabetes Register. The National
Diabetes Register in Sweden: an implementation of the St. Vincent
of lower blood pressure because the register based Declaration for Quality Improvement in Diabetes Care. Diabetes Care
design could not fully correct for unreported disease 2003;26:1270-6. doi:10.2337/diacare.26.4.1270.
8 Wettermark B, Hammar N, Fored CM, et al. The new Swedish Prescribed
that leads to low blood pressure and increased risk. Drug Register--opportunities for pharmacoepidemiological research
and experience from the first six months. Pharmacoepidemiol Drug Saf
2007;16:726-35. doi:10.1002/pds.1294.
Conclusions 9 Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration
In conclusion, lower systolic blood pressure than cur- of low-density lipoprotein cholesterol in plasma, without use of the
rently recommended is associated with a significantly preparative ultracentrifuge. Clin Chem 1972;18:499-502.
10 Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. Modification
lower risk of cardiovascular events in patients with type of Diet in Renal Disease Study Group. A more accurate method to
2 diabetes. The association between low blood pressure estimate glomerular filtration rate from serum creatinine: a new
prediction equation. Ann Intern Med 1999;130:461-70.
and increased mortality could be caused by concomi- doi:10.7326/0003-4819-130-6-199903160-00002.
tant disease rather than antihypertensive treatment. 11 Ludvigsson JF, Andersson E, Ekbom A, et al. External review and
We thank the regional coordinators, participating nurses, physicians, validation of the Swedish national inpatient register. BMC Public
and other staff members who have contributed to the national Health 2011;11:450. doi:10.1186/1471-2458-11-450.
12 Cushman WC, Evans GW, Byington RP, et al. ACCORD Study Group.
diabetes register. Most of all, we thank the patients who support the
Effects of intensive blood-pressure control in type 2 diabetes mellitus.
register, both individually and collectively through the Swedish
N Engl J Med 2010;362:1575-85. doi:10.1056/NEJMoa1001286.
Diabetes Federation. 13 Redon J, Mancia G, Sleight P, et al. ONTARGET Investigators. Safety
Contributors: SAE and SB conceived and designed the study, drafted and efficacy of low blood pressures among patients with diabetes:
the manuscript, and are guarantors. SAE, SB, SF, A-MS, and SG subgroup analyses from the ONTARGET (ONgoing Telmisartan Alone
expanded on the study concept and design. SG, A-MS, and MM and in combination with Ramipril Global Endpoint Trial). J Am Coll
contributed to data collection. SAE, SB, and SF performed the Cardiol 2012;59:74-83. doi:10.1016/j.jacc.2011.09.040.
statistical analyses. SF provided statistical expertise. SAE, SB, SF, A-MS, 14 Cooper-DeHoff RM, Gong Y, Handberg EM, et al. Tight blood pressure
KM, AR, and SG interpreted the data. All authors reviewed and critically control and cardiovascular outcomes among hypertensive patients
revised the draft and approved the final version. with diabetes and coronary artery disease. JAMA 2010;304:61-8.
doi:10.1001/jama.2010.884.
Funding: This study was supported by grants from the Region Västra 15 Cederholm J, Gudbjörnsdottir S, Eliasson B, Zethelius B, Eeg-Olofsson
Götaland in Sweden, the Swedish Heart and Lung Foundation, K, Nilsson PM. NDR. Blood pressure and risk of cardiovascular
Diabetes Wellness, the Swedish Diabetes Foundation, the Swedish diseases in type 2 diabetes: further findings from the Swedish
Council for Working Life and Social Research (Epilife), and the Swedish National Diabetes Register (NDR-BP II). J Hypertens 2012;30:2020-30.
Research Council. doi:10.1097/HJH.0b013e3283577bdf.
16 Wright JT Jr, Williamson JD, Whelton PK, et al. SPRINT Research Group. A
Competing interests: All authors have completed the ICMJE uniform
Randomized Trial of Intensive versus Standard Blood-Pressure
disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no
Control. N Engl J Med 2015;373:2103-16. doi:10.1056/NEJMoa1511939.
support from any organisation for the submitted work; no financial 17 Perkovic V, Rodgers A. Redefining Blood-Pressure Targets–SPRINT
relationships with any organisations that might have an interest in the Starts the Marathon. N Engl J Med 2015;373:2175-8. doi:10.1056/
submitted work in the previous three years; no other relationships or NEJMe1513301.
activities that could appear to have influenced the submitted work. 18 Bangalore S, Kumar S, Lobach I, Messerli FH. Blood pressure targets in
Ethical approval: The regional ethical review board at the University subjects with type 2 diabetes mellitus/impaired fasting glucose:
of Gothenburg approved the study. observations from traditional and bayesian random-effects
meta-analyses of randomized trials. Circulation 2011;123:2799-810,
Data sharing: No additional data available. 9, 810. doi:10.1161/CIRCULATIONAHA.110.016337.
Transparency: The lead authors affirm that the manuscript is an 19 Emdin CA, Rahimi K, Neal B, Callender T, Perkovic V, Patel A. Blood
honest, accurate, and transparent account of the study being reported; pressure lowering in type 2 diabetes: a systematic review and
that no important aspects of the study have been omitted; and that meta-analysis. JAMA 2015;313:603-15. doi:10.1001/jama.2014.18574.
any discrepancies from the study as planned have been explained. 20 Brunström M, Carlberg B. Effect of antihypertensive treatment at different
blood pressure levels in patients with diabetes mellitus: systematic
This is an Open Access article distributed in accordance with the review and meta-analyses. BMJ 2016;352:i717. doi:10.1136/bmj.i717.
Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license, 21 Ettehad D, Emdin CA, Kiran A, et al. Blood pressure lowering for prevention
which permits others to distribute, remix, adapt, build upon this work of cardiovascular disease and death: a systematic review and meta-
non-commercially, and license their derivative works on different terms, analysis. Lancet 2016;387:957-67. doi:10.1016/S0140-6736(15)01225-8.
provided the original work is properly cited and the use is non- 22 Johansson LA, Westerling R. Comparing Swedish hospital discharge
commercial. See: http://creativecommons.org/licenses/by-nc/3.0/. records with death certificates: implications for mortality statistics. Int
1 Mancia G, Fagard R, Narkiewicz K, et al. Task Force Members. 2013 J Epidemiol 2000;29:495-502. doi:10.1093/ije/29.3.495.
ESH/ESC Guidelines for the management of arterial hypertension: 23 Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Prospective
the Task Force for the management of arterial hypertension of the Studies Collaboration. Age-specific relevance of usual blood pressure
European Society of Hypertension (ESH) and of the European to vascular mortality: a meta-analysis of individual data for one
Society of Cardiology (ESC). J Hypertens 2013;31:1281-357. million adults in 61 prospective studies. Lancet 2002;360:1903-13.
doi:10.1097/01.hjh.0000431740.32696.cc. doi:10.1016/S0140-6736(02)11911-8.
2 James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for
the management of high blood pressure in adults: report from the © BMJ Publishing Group Ltd 2016
panel members appointed to the Eighth Joint National Committee
(JNC 8). JAMA 2014;311:507-20. doi:10.1001/jama.2013.284427. Appendix 1: Supplementary material

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