Blood pressure and complications in individuals with type 2 diabetes and no previous cardiovascular disease: national population based cohort study

Databases

The diabetes register has been described previously.7 It was launched in 1996 as a tool for quality assurance in diabetes care. The register contains information about risk factors, complications, and treatment among patients aged 18 and over. Trained nurses and physicians report at least once a year either online or by electronic transmission of patients’ charts. Data are collected during appointments at specialist clinics and primary healthcare centres nationwide. All patients give their informed consent before inclusion. During the study period of 2006-13, the register doubled in size to about 300 000 patients. In 2015, it covered an estimated 90% of Swedish adults with type 2 diabetes.4

The hospital discharge register, cause of death register, and prescribed drug register are administered by the Swedish National Board of Health and Welfare. Since 1987, the hospital discharge register has included data for all inpatient care. As of 2001, data from outpatient appointments with both private and public care providers has also been included. The data concern diagnoses, procedures, and length of stay. The cause of death register contains data for all Swedes, regardless of whether they died in Sweden or abroad. The prescribed drug register contains information about all dispensed prescriptions in Sweden since 1 July 2005.8

Study population

Patients with type 2 diabetes who had been entered in the diabetes register from 1 January 2006 to 31 December 2012 for whom systolic blood pressure data were available were eligible for inclusion in the study. The inclusion criteria were diabetes duration for at least a year, systolic blood pressure ≥110 mm Hg, age ≤75, and BMI ≥18. We included 265 638 individuals at 1320 care units. After exclusion of those at units with fewer than 150 patients (see below) or a history of acute myocardial infarction, stroke, coronary heart disease, heart failure, atrial fibrillation, end stage renal disease, amputation, dementia, or cancer at baseline, 187 106 individuals remained for further analysis (fig 1⇓). The highest exclusion rate because of previous cardiovascular disease was among patients with the lowest blood pressure. The total population before exclusion is described in the appendix.

Fig 1 Enrolment of participants in study of blood pressure and complications in individuals with type 2 diabetes and no previous cardiovascular disease

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Type 2 diabetes was defined as either treatment with diet only, oral hypoglycaemic agents only, or onset of diabetes age ≥40 and treatment with insulin alone or combined with oral hypoglycaemic agents.

Baseline examinations and definitions

The index date was defined as the first examination after the patient had been included in the diabetes register. The inclusion criteria of the presence of diabetes for at least year ensured that patients had been monitored and treated for a sufficient length of time before the baseline variables were entered. The clinical characteristics reported to the diabetes register at baseline (the index date) were age, sex, duration of diabetes, systolic blood pressure, diastolic blood pressure, HbA_1c, type of hypoglycaemic treatment, weight, height, total cholesterol, high density lipoprotein cholesterol, triglycerides, microalbuminuria and macroalbuminuria, and smoking status. Blood pressure was measured in accordance with national standards in the seated or supine position by either a physician or nurse with either oscillometric or auscultatoric methods. Smoking status was either yes or no.

All laboratory analyses were performed at local laboratories. HbA_1c values were expressed in mmol/mol in accordance with the International Federation of Clinical Chemistry (IFCC) standard. Body mass index (BMI) was calculated as weight/height². Low density lipoprotein cholesterol concentration was calculated in accordance with Friedewald’s formula.9 Microalbuminuria was defined as two positive results for three samples obtained within one year, with positivity defined as an albumin/creatinine ratio of 3-30 mg/mmol (about 30-300 mg/g) or urinary albumin clearance of 20-200 μg/min (20-300 mg/L) on two out of three consecutive tests. Macroalbuminuria was defined as an albumin/creatinine ratio >30 mg/mmol (about 300 mg/g) or urinary albumin clearance >200 μg/min (>300 mg/L). Individuals were defined as current users of drugs if they had a recorded purchase four months or less before the index date. Renal function measured as estimated glomerular filtration rate (eGFR) was based on the modification of diet in renal disease study equation.10

Follow-up and definition of endpoints

All individuals were followed from the index date until a first event, death, or the end of follow-up on 31 December 2013. The studied endpoints were non-fatal or total acute myocardial infarction, non-fatal or total stroke, a composite of acute myocardial infarction and stroke (cardiovascular disease), non-fatal or total coronary heart disease, non-fatal heart failure, and total mortality. Cardiovascular disease was defined as acute myocardial infarction or stroke, whichever came first.

We used ICD-10 (international classification of diseases, 10th revision) for classification of diseases and used both primary and contributory diagnoses. Acute myocardial infarction was defined as a diagnosis of myocardial infarction (I21). Stroke was defined as a diagnosis of intracerebral haemorrhage, cerebral infarction, or unspecified stroke (I61, I63, I64). Coronary heart disease was defined as a diagnosis of non-fatal myocardial infarction, angina pectoris, subsequent myocardial infarction, certain current complications after myocardial infarction, other acute ischaemic heart disease, chronic ischaemic heart disease, percutaneous coronary intervention, and/or coronary artery bypass grafting (I20 to I25). Heart failure was defined as a diagnosis of heart failure (I50). Fatal events of acute myocardial infarction, stroke, cardiovascular disease, and coronary heart disease were included only if the primary recorded cause of death was either disease of the circulatory system (I00-I99) or endocrine, nutritional, or metabolic disease (E00-E90).

History of atrial fibrillation was defined as ICD-10 code I48. History of end stage renal disease was defined as codes Z94.0, Z49.1, Z49.2, or Z99.2. History of dementia was defined as codes G300, G301, G308, G309, and F00-F03. History of cancer was defined as codes C00-C97.

All events were obtaining by linking Swedish personal identity numbers with the hospital discharge register and cause of death register. Validation studies of the hospital discharge register (also known as the national inpatient register) have shown high overall specificity.11

Statistics

The sample was assigned to six groups of systolic blood pressure: 110-119 mm Hg, 120-129 mm Hg, 130-139 mm Hg, 140-149 mm Hg, 150-159 mm Hg, and ≥160 mm Hg. Between 4.8% and 34.7% of participants were missing information about at least one laboratory measurement. Details about missing values are provided in the appendix. The highest rate of missing values was for low density lipoprotein cholesterol. We used multiple imputation, generating 10 imputed datasets, to avoid a reduction in sample size. Risk estimates remained essentially unchanged after multiple imputations, as opposed to complete case analysis. We used the Kaplan-Meier estimator to study incidence of endpoints over time across the blood pressure groups. The proportional hazards assumption was confirmed by plotting the negative log of the estimated survivor functions against time. Cox proportional hazards regression was used to estimate hazard ratios for the relation between systolic blood pressure groups and incidence of various cardiovascular endpoints. The 130-139 mm Hg group was used for reference purposes.

We tested two different models. Both models were adjusted for age, sex, duration of diabetes, type of diabetes treatment, HbA_1c, smoking status, low density lipoprotein cholesterol, high density lipoprotein cholesterol, triglycerides, microalbuminuria, and macroalbuminuria. BMI and eGFR were used as categorical variables because of their non-linear relation with mortality. The second model was also adjusted for thiazide diuretics, loop diuretics, calcium antagonists, spironolactone, β blockers, and drugs for heart disease. These covariates were chosen after a separate analysis of their contribution to the model (see appendix for greater detail). As a covariate of treatment intensity at the care unit, we used the proportion of patients receiving triple therapy—that is, a combination of a thiazide diuretic, calcium antagonist, and either a renin-angiotensin system inhibitor or angiotensin II blocker (renin-angiotensin-aldosterone (RAAS) blocking agent). The hypothesis was that the approach offers an indicator for a step-up strategy and thus a measure of low blood pressure because of antihypertensive treatment rather than spontaneous low blood pressure. We chose this covariate after testing several similar variables (see appendix). To avoid outlier bias, we determined the frequency of use of the triple drug regimen by examining individuals in the 125-140 mm Hg range at clinics with at least 150 patients. We excluded 21 902 individuals because their clinics had too few patients. A secondary analysis also looked at the relations between systolic blood pressure and the various outcomes with individuals with previous disease included in the models. The appendix provides additional methodological details.

All analyses were performed in SAS version 9.4 (SAS Institute, Cary, NC).

Patient involvement

No patients were involved in setting the research question or the outcome measures, nor were they involved in recruitment, or the design and implementation of the study. There are no plans to involve patients in dissemination.