Sunlight Exposure and Vitamin D Levels in Older People- An Intervention Study in Swedish Nursing Homes.

OBJECTIVES: Older people are recommended to take oral vitamin D supplements, but the main source of vitamin D is sunlight. Our aim was to explore whether active encouragement to spend time outdoors could increase the levels of serum 25-hydroxyvitamin D (25(OH)D) and increase the mental well-being of nursing home residents. DESIGN: A cluster randomized intervention trial. SETTING: Nursing homes in southern Sweden. PARTICIPANTS: In total 40 people >65 years. INTERVENTION: The intervention group was encouraged to go outside for 20-30 minutes between 11 a.m. and 3 p.m. every day for two months during the summer of 2018. MEASUREMENTS: We analyzed serum 25(OH)D before and after the summer. Data from SF-36 questionnaires measuring vitality and mental health were used for the analyses. RESULTS: In the intervention group, the baseline median (interquartile range (IQR)) of serum 25(OH)D was 42.5 (23.0) nmol/l and in the control group it was 52.0 (36.0) nmol/l. In the intervention group, the 25(OH)D levels increased significantly during the summer (p=0.011). In the control group, there was no significant change. The intervention group reported better self-perceived mental health after the summer compared to before the summer (p=0.015). In the control group, there was no difference in mental health. CONCLUSION: Active encouragement to spend time outdoors during summertime improved the levels of serum 25(OH)D and self-perceived mental health significantly in older people in nursing homes and could complement or replace oral vitamin D supplementation in the summer.

Using proximity extension proteomics assay to discover novel biomarkers associated with circulating leptin levels in patients with type 2 diabetes.

We aimed to discover novel associations between leptin and circulating proteins which could link leptin to the development of cardiovascular disease in patients with type 2 diabetes (T2DM). In a discovery phase, we investigated associations between 88 plasma proteins, assessed with a proximity extension assay, and plasma leptin in a cohort of middle-aged patients with T2DM. Associations passing the significance threshold of a False discovery rate of 5% (corresponding to p < 0.0017) were replicated in patients with T2DM in an independent cohort. We also investigated if proteins mediated the longitudinal association between plasma leptin and the incidence of major cardiovascular events (MACE). One protein, adipocyte fatty acid binding protein (A-FABP), was significantly associated with leptin in both the discovery phase [95% CI (0.06, 0.17) p = 0.00002] and the replication cohort [95% CI (0.12, 0.39) p = 0.0003]. Multiplicative interaction analyses in the two cohorts suggest a stronger association between A-FABP and leptin in men than in women. In longitudinal analyses, the association between leptin and MACE was slightly attenuated after adding A-FABP to the multivariate model. Our analysis identified a consistent association between leptin and A-FABP in two independent cohorts of patients with T2DM, particularly in men.Trial registration: ClinicalTrials.gov identifier NCT01049737.

Differences in molecular epidemiology of Staphylococcus aureus and Escherichia coli in nursing home residents and people in unassisted living situations.

BACKGROUND: The usefulness of colonization pressure as a working model and proxy for infection transmission is limited due to the inability to grade or quantify the specific risk within environments that are subject to change. AIM: To elaborate on the colonization pressure model by comparing the molecular epidemiology of two bacteria, Staphylococcus aureus and Escherichia coli, among residents in a nursing home and people in unassisted living situations. METHODS: A cross-sectional study of 73 elderly residents from a village in south-central Sweden was conducted. Of these, 35 were residents of a nursing home, and 34 lived in an own place of residence in the same geographical area. Samples of two representative bacterial species were collected from multiple body sites and analysed for molecular diversity. FINDINGS: Combining all body sites, 47% of the participants were colonized with S. aureus and 93% with E. coli. The nursing home group, the group in unassisted living situations, and both units combined, held 16, 17, and 29 different S. aureus spa types, respectively. The corresponding numbers of different E. coli serogenotypes were 34, 28, and 48. Diabetes mellitus was associated with more frequent colonization with S. aureus. CONCLUSION: The molecular diversity of bacteria found within different forms of accommodation was within the same range. Hospital quality hygiene might have contributed to the absence of homogenization of the molecular diversity within the nursing home group. Diabetes mellitus might have played a role in a patient selection characterized by advanced age.

The impact of using sagittal abdominal diameter to predict major cardiovascular events in European patients with type 2 diabetes.

BACKGROUND AND AIMS: Obesity is associated with diabetes type 2 and one of the most important risk factors for cardiovascular disease. We explored if sagittal abdominal diameter (SAD) is a better predictor of major cardiovascular events than waist circumference (WC) and body mass index (BMI) in type 2 diabetes. METHODS AND RESULTS: The CARDIPP study consists of a cohort of patients with type 2 diabetes. In this study we used data from 635 participants with no previous myocardial infarction or stroke, with a mean follow-up time of 7.1 years. SAD, WC and BMI were measured at baseline and the end-point was first cardiovascular event, measured as a composite of ICD-10 codes for acute myocardial infarction, stroke or cardiovascular mortality. SAD was significantly higher in the major cardiovascular event group compared to participants that did not suffer a major cardiovascular event during follow-up (p < 0.001). SAD >25 cm was the only anthropometric measurement that remained associated with major cardiovascular events when adjusted for modifiable and non-modifiable factors (hazard ratio 2.81, 95% confidence interval 1.37-5.76, p = 0.005). CONCLUSION: SAD with the cut off level of >25 cm, if confirmed in larger studies, may be used as a more independent risk-assessment tool compared with WC in clinical practice, to identify persons with type 2 diabetes at high cardiovascular risk. ClinicalTrials.gov: NCT01049737.

Association between serum 25(OH)D3 and cardiovascular morbidity and mortality in people with Type 2 diabetes: a community-based cohort study.

AIM: We aimed to explore the association between vitamin D and cardiovascular morbidity and mortality in people with Type 2 diabetes recruited from a community-based study because there is limited and inconsistent research of this group. METHODS: A prospective community-based cohort study among people aged 55-66 years with Type 2 diabetes as part of The Cardiovascular Risk in Type 2 Diabetes - A Prospective Study in Primary Care (CARDIPP). We analysed serum 25-hydroxyvitamin D3 [25(OH)D3 ] at baseline. Cox regression analyses were used to calculate hazard ratios (HR) for the first myocardial infarction, stroke or cardiovascular mortality according to 25(OH)D3 . RESULTS: We examined 698 people with a mean follow-up of 7.3 years. Serum 25(OH)D3 was inversely associated with the risk of cardiovascular morbidity and mortality: HR 0.98 [95% confidence interval (CI) 0.96 to 0.99, P = 0.001]. Compared with the fourth quartile (Q4) [25(OH)D3 > 61.8 nmol/l], HR (with 95% CI) was 3.46 (1.60 to 7.47) in Q1 [25(OH)D3 < 35.5 nmol/l] (P = 0.002); 2.26 (1.01 to 5.06) in Q2 [25(OH)D3 35.5-47.5 nmol/l] (P = 0.047); and 1.62 (0.70 to 3.76) in Q3 [25(OH)D3 47.5-61.8 nmol/l] (P = 0.26) when adjusting for age, sex and season. The results remained significant after adjusting also for cardiovascular risk factors, physiological variables including parathyroid hormone and previous cardiovascular disease (P = 0.027). CONCLUSIONS: Low 25(OH)D3 is associated with an increased risk of cardiovascular morbidity and mortality in people with Type 2 diabetes independent of parathyroid hormone. Vitamin D could be considered as a prognostic factor. Future studies are needed to explore whether vitamin D deficiency is a modifiable risk factor in Type 2 diabetes.

The association between endostatin and kidney disease and mortality in patients with type 2 diabetes.

AIM: Circulating endostatin, a biologically active derivate of collagen XVIII, is considered to be a marker of kidney disease and a risk factor for its related mortality. However, less is known of the role of endostatin in diabetes and the development of diabetic nephropathy. For this reason, our study investigated the associations between circulating endostatin and the prevalence and progression of kidney disease, and its mortality risk in patients with type 2 diabetes (T2D). METHODS: This was a cohort study of 607 patients with T2D (mean age: 61 years, 44% women). Estimated glomerular filtration rate (eGFR), calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation, was used to assess the patients' kidney function decline and mortality. RESULTS: Of the total study cohort, 20 patients declined by ≥20% in eGFR over 4 years, and 44 died during the follow-up (mean duration: 6.7 years). At baseline, participants with diabetic nephropathy (defined as eGFR<60mL/min/1.73m2) and/or microalbuminuria [defined as a urinary albumin-to-creatinine ratio (ACR)>3g/mol] had higher median levels of endostatin than those without nephropathy (62.7µg/L vs 57.4µg/L, respectively; P=0.031). In longitudinal analyses adjusted for age, gender, baseline eGFR and ACR, higher endostatin levels were associated with a higher risk of decline (≥20% in eGFR, OR per 1 SD increase: 1.73, 95% CI: 1.13-2.65) and a higher risk of mortality (HR per 1 SD increase: 1.57, 95% CI: 1.19-2.07). CONCLUSION: In patients with T2D, circulating endostatin levels can predict the progression of kidney disease and mortality independently of established kidney disease markers. The clinical usefulness of endostatin as a risk marker in such patients merits further studies.

Pedometer-determined physical activity level and change in arterial stiffness in Type 2 diabetes over 4 years.

AIM: To explore prospectively the correlation between the level of pedometer-determined physical activity at the start of the study and the change in pulse wave velocity from baseline to 4 years later in people with Type 2 diabetes. METHODS: We analysed data from 135 men and 53 women with Type 2 diabetes, aged 54-66 years. Physical activity was measured with waist-mounted pedometers on 3 consecutive days and the numbers of steps/day at baseline were classified into four groups: <5000 steps/day, 5000-7499 steps/day, 7500-9999 steps/day and ≥10 000 steps/day. Pulse wave velocity was measured using applanation tonometry over the carotid and femoral arteries at baseline and after 4 years. RESULTS: The mean (±sd; range) number of steps/day was 8022 (±3765; 956-20 921). The participants with the lowest level of physical activity had a more pronounced increase in the change in pulse wave velocity compared with the participants with the highest. When change in pulse wave velocity was analysed as a continuous variable and adjusted for sex, age, diabetes duration, HbA1c , BMI, systolic blood pressure, pulse wave velocity at baseline, ß-blocker use, statin use, unemployment, smoking and diabetes medication, the number of steps/day at baseline was significantly associated with a less steep increase in change in pulse wave velocity (P=0.005). Every 1000 extra steps at baseline corresponded to a lower increase in change in pulse wave velocity of 0.103 m/s. CONCLUSIONS: We found that a high level of pedometer-determined physical activity was associated with a slower progression of arterial stiffness over 4 years in middle-aged people with Type 2 diabetes.

Use of antidiabetic and antidepressant drugs is associated with increased risk of myocardial infarction: a nationwide register study.

AIMS: To explore the gender- and age-specific risk of developing a first myocardial infarction in people treated with antidiabetic and/or antidepressant drugs compared with people with no pharmaceutical treatment for diabetes or depression. METHODS: A cohort of all Swedish residents aged 45-84 years (n = 4 083 719) was followed for a period of 3 years. Data were derived from three nationwide registers. The prescription and dispensing of antidiabetic and antidepressant drugs were used as markers of disease. All study subjects were reallocated according to treatment and the treatment categories were updated every year. Data were analysed using a Cox regression model with a time-dependent variable. The outcome of interest was first fatal or non-fatal myocardial infarction. RESULTS: During follow-up, 42 840 people had a first myocardial infarction, 3511 of which were fatal. Women aged 45-64 years, receiving both antidiabetic and antidepressant drugs had a hazard ratio for myocardial infarction of 7.4 (95% CI 6.3-8.6) compared with women receiving neither. The corresponding hazard ratio for men was 3.1 (95% CI 2.8-3.6). CONCLUSIONS: The combined use of antidiabetic and antidepressant drugs was associated with a higher risk of myocardial infarction compared with use of either group of drugs alone. The increase in relative risk was greater in middle-aged women than in middle-aged men.

The Swedish CArdioPulmonary BioImage Study: objectives and design.

Cardiopulmonary diseases are major causes of death worldwide, but currently recommended strategies for diagnosis and prevention may be outdated because of recent changes in risk factor patterns. The Swedish CArdioPulmonarybioImage Study (SCAPIS) combines the use of new imaging technologies, advances in large-scale 'omics' and epidemiological analyses to extensively characterize a Swedish cohort of 30 000 men and women aged between 50 and 64 years. The information obtained will be used to improve risk prediction of cardiopulmonary diseases and optimize the ability to study disease mechanisms. A comprehensive pilot study in 1111 individuals, which was completed in 2012, demonstrated the feasibility and financial and ethical consequences of SCAPIS. Recruitment to the national, multicentre study has recently started.

Efficacy and tolerability of saxagliptin compared with glimepiride in elderly patients with type 2 diabetes: a randomized, controlled study (GENERATION).

AIMS: To assess the efficacy and safety of adjunctive saxagliptin vs glimepiride in elderly patients with type 2 diabetes (T2D) and inadequate glycaemic control. METHODS: In this multinational, randomized, double-blind, phase IIIb/IV study (GENERATION; NCT01006603), patients aged ≥65 years were randomized (1 : 1) to receive saxagliptin 5 mg/day or glimepiride ≤6 mg/day, added to metformin, during a 52-week treatment period. The primary endpoint was achievement of glycated haemoglobin (HbA1c) <7.0% at week 52 without confirmed/severe hypoglycaemia. The key secondary endpoint was incidence of confirmed/severe hypoglycaemia. Safety and tolerability were also assessed. RESULTS: Of 720 patients randomized (360 in each treatment group; mean age 72.6 years; mean T2D duration 7.6 years), 574 (79.8%) completed the study (saxagliptin 80.3%; glimepiride 79.2%). Similar proportions of patients achieved the primary endpoint with saxagliptin and glimepiride (37.9 vs 38.2%; odds ratio 0.99, 95% confidence interval 0.73, 1.34; p = 0.9415); however, a significant treatment-by-age interaction effect was detected (p = 0.0389): saxagliptin was numerically (but not significantly) superior to glimepiride for patients aged <75 years (39.2 vs 33.3%) and numerically inferior for patients aged ≥75 years (35.9 vs 45.5%). The incidence of confirmed/severe hypoglycaemia was lower with saxagliptin vs glimepiride (1.1 vs 15.3%; nominal p < 0.0001). Saxagliptin was generally well tolerated, with similar incidences of adverse events compared with glimepiride. CONCLUSION: As avoiding hypoglycaemia is a key clinical objective in elderly patients, saxagliptin is a suitable alternative to glimepiride in patients with T2D aged ≥65 years.

Prevalence and incidence of diabetes mellitus: a nationwide population-based pharmaco-epidemiological study in Sweden.

AIM: To investigate the changes in prevalence and incidence of pharmacologically and non-pharmacologically treated diabetes in Sweden during 2005 to 2013. METHODS: We obtained data on gender, date of birth and pharmacologically and non-pharmacologically treated diabetes from national registers for all Swedish residents. RESULTS: During the study period a total of 240 871 new cases of pharmacologically treated diabetes was found. The age-standardized incidence during the follow-up was 4.34 and 3.16 per 1000 individuals in men and women, respectively. A decreasing time trend in incidence for men of 0.6% per year (0.994, 95% CI 0.989-0.999) and for women of 0.7% per year (0.993, 95% CI 0.986-0.999) was observed. The age-standardized prevalence increased from 41.9 and 29.9 per 1000 in 2005/2006 to 50.8 and 34.6 in 2012/2013 in men and women, respectively. This corresponds to an annually increasing time trend for both men (1.024, 95% CI 1.022-1.027) and women (1.019, 95% CI 1.016-1.021). The total age-standardized prevalence of pharmacologically and non-pharmacologically treated diabetes (2012) was 46.9 per 1000 (55.6 for men and 38.8 for women). This corresponds to an annually increasing time trend (2010-2012) for both men (1.017, 95% CI 1.013-1.021) and women (1.012, 95% CI 1.008-1.016). CONCLUSIONS: The prevalence of pharmacologically treated diabetes increased moderately during 8 years of follow-up, while the incidence decreased modestly. This is in contrast to the results reported by most other studies. The total prevalence of diabetes (both pharmacologically and non-pharmacologically treated) in Sweden is relatively low, from a global viewpoint.

Randomization to a low-carbohydrate diet advice improves health related quality of life compared with a low-fat diet at similar weight-loss in Type 2 diabetes mellitus.

AIMS: To compare the effects on health-related quality of life (HRQoL) of a 2-year intervention with a low-fat diet (LFD) or a low-carbohydrate diet (LCD) based on four group-meetings to achieve compliance. To describe different aspects of taking part in the intervention following the LFD or LCD. METHODS: Prospective, randomized trial of 61 adults with Type 2 diabetes mellitus. The SF-36 questionnaire was used at baseline, 6, 12 and 24 months. Patients on LFD aimed for 55-60 energy percent (E%) and those on LCD for 20 E% from carbohydrates. The patients were interviewed about their experiences of the intervention. RESULTS: Mean body-mass-index was 32.7 ± 5.4 kg/m(2) at baseline. Weight-loss did not differ between groups and was maximal at 6 months, LFD: -3.99 ± 4.1 kg, LCD: -4.31 ± 3.6 kg (p<0.001 within groups). There was an increase in the physical component score of SF-36 from 44.1 (10.0) to 46.7 (10.5) at 12 months in the LCD group (p < 0.009) while no change occurred in the LFD group (p < 0.03 between groups). At 12 months the physical function, bodily pain and general health scores improved within the LCD group (p values 0.042-0.009) while there was no change within the LFD group. CONCLUSIONS: Weight-changes did not differ between the diet groups while improvements in HRQoL only occurred after one year during treatment with LCD. No changes of HRQoL occurred in the LFD group in spite of a similar reduction in body weight.

Microalbuminuria, but not reduced eGFR, is associated with cardiovascular subclinical organ damage in type 2 diabetes.

AIM: This study explored the association between reduced estimated glomerular filtration rate (eGFR) and microalbuminuria vs. subclinical organ damage in patients with type 2 diabetes. METHODS: Data from middle-aged patients with type 2 diabetes (n=706) treated in primary care were analyzed for microalbuminura, defined as a urinary albumin/creatinine ratio (uACR)≥3.0mmol/mol, and reduced eGFR, defined as<60mL/min/1.73m(2), in relation to blood pressure, pulse wave velocity (PWV), left ventricular mass index (LVMI), and carotid intima-media thickness (IMT) and lumen diameter (LD). RESULTS: Patients with microalbuminuria had significantly higher 24-h ambulatory systolic blood pressure (ASBP) compared with subjects with uACR<3mg/mmol: 137 vs. 128mmHg (P<0.001). There were no differences in ASBP in patients with eGFR<60mL/min/1.73m(2). However, patients with vs. without microalbuminuria had increased PWV (11.4 vs. 10.1m/s; P<0.001), LVMI (134.4 vs. 118.6g/m(2); P<0.001), LD (7.01±0.93 vs. 6.46±0.74mm; P<0.001) and IMT (0.78 vs. 0.74mm; P=0.047), respectively. The associations between uACR vs. PWV and LVMI were more robust after adjusting for age, diabetes duration, ASBP, HbA1c, LDL-cholesterol, and antihypertensive and lipid-lowering therapy compared with uACR vs. IMT. There were no statistically significant differences in PWV, LVMI or IMT between patients with reduced (<60mL/min/1.73m(2)) vs. normal eGFR. CONCLUSION: Levels of urinary albumin excretion, but not reduced eGFR, were associated with increased arterial stiffness, left ventricular mass and atherosclerosis in patients with type 2 diabetes.

Abdominal obesity and low-grade systemic inflammation as markers of subclinical organ damage in type 2 diabetes.

AIM: This study aimed to explore the associations between abdominal obesity, inflammatory markers and subclinical organ damage in 740 middle-aged patients with type 2 diabetes. METHODS: Waist circumference (WC) and sagittal abdominal diameter (SAD) were measured, and blood samples were analyzed for C-reactive protein (CRP) and IL-6. Carotid intima-media thickness (IMT) was evaluated by ultrasonography, and aortic pulse wave velocity (PWV) measured with applanation tonometry. RESULTS: Abdominal obesity as determined by SAD and WC was significantly correlated with IL-6 (WC: r=0.27, P<0.001; SAD: r=031, P<0.001), CRP (WC: r=0.29, P<0.001; SAD: r=0.29, P<0.001), IMT (WC: r=0.09, P=0.013; SAD: r=0.11, P=0.003) and PWV (WC: r=0.18, P<0.001; SAD: r=0.21, P<0.001). In multiple linear regressions with IMT and PWV as dependent variables, and age, gender, statin use, systolic blood pressure (SBP), body mass index (BMI), CRP and HbA1c as independent variables, both SAD and WC remained associated with IMT and PWV. On stepwise linear regression and entering both SAD and WC, the association between SAD and PWV was stronger than the association between WC and PWV. CONCLUSION: Both SAD and WC are feasible measures of obesity, and both provide information on inflammation, atherosclerosis and arterial stiffness in type 2 diabetes, while SAD appears to be slightly more robustly associated with subclinical organ damage than WC.

Changes in body mass index following newly diagnosed type 2 diabetes and risk of cardiovascular mortality: a cohort study of 8486 primary-care patients.

AIMS: Elevated body mass index (BMI) is associated with an increased risk of type 2 diabetes and cardiovascular disease (CVD). This study explored the association between BMI changes in the first 18 months of newly diagnosed type 2 diabetes and the risk of long-term CVD mortality. METHODS: A total of 8486 patients with newly diagnosed type 2 diabetes and no previous history of CVD or cancer were identified from 84 primary-care centres in Sweden. During the first year after diagnosis, patients were grouped according to BMI change: 'Increase', or ≥+1 BMI unit; 'unchanged', or between +1 and-1 BMI unit; and 'decrease', or ≤-1 BMI unit. Associations between BMI change and CVD mortality, defined as death from stroke, myocardial infarction or sudden death, were estimated using adjusted Cox proportional hazards models (NCT 01121315). RESULTS: Baseline mean age was 60.0 years and mean BMI was 30.2kg/m(2). Patients were followed for up to 9 years (median: 4.6 years). During the first 18 months, 53.4% had no change in their BMI, while 32.2% decreased and 14.4% increased. Compared with patients with unchanged BMI, those with an increased BMI had higher risks of CVD mortality (hazard ratio: 1.63, 95% CI: 1.11-2.39) and all-cause mortality (1.33, 1.01-1.76). BMI decreases had no association with these risks compared with unchanged BMI: 1.06 (0.76-1.48) and 1.06 (0.85-1.33), respectively. CONCLUSION: Increased BMI within the first 18 months of type 2 diabetes diagnosis was associated with an increased long-term risk of CVD mortality. However, BMI decrease did not lower the long-term risk of mortality.

Avoidance of weight gain is important for oral type 2 diabetes treatments in Sweden and Germany: patient preferences.

AIMS: The aim of the study was to quantify patient preferences for outcomes associated with oral antidiabetic medications (OAMs) in Sweden and Germany through a discrete-choice experiment. METHODS: Adults taking OAMs who had a self-reported physician's diagnosis of type 2 diabetes mellitus (T2DM) made a series of nine choices between pairs of hypothetical profiles. Each profile had a predefined range of attributes: blood glucose control, frequency of mild-to-moderate hypoglycaemia, annual severe hypoglycaemic events, annual weight gain, pill burden and frequency of administration, and cost. Choice questions were based on an experimental design with known statistical properties. Bivariate probit analysis estimated the probabilities of choice of medication administration from patient characteristics and, conditional on that choice, preferences for treatment outcomes. RESULTS: The final sample consisted of 188 Swedish and 195 German patients. For both countries, weight gain was the most important attribute, followed by blood glucose control. Avoiding a 5-kg weight gain was 1.5 times more important in Sweden and 2.3 times more important in Germany than achieving moderate blood glucose control, thereby, suggesting that blood glucose control is relatively more important to Swedish than to German patients. Least important outcomes were the number of daily pills (Sweden) and frequency of mild-to-moderate hypoglycaemia (Germany). CONCLUSION: Patients in both Sweden and Germany preferred OAMs not associated with weight gain.

Associations of HbA1c and educational level with risk of cardiovascular events in 32,871 drug-treated patients with Type 2 diabetes: a cohort study in primary care.

AIMS: To explore the association of HbA1c and educational level with risk of cardiovascular events and mortality in patients with Type 2 diabetes. METHODS: A cohort of 32 871 patients with Type 2 diabetes aged 35 years and older identified by extracting data from electronic patient records for all patients who had a diagnosis of Type 2 diabetes and had glucose-lowering agents prescribed between 1999 and 2009 at 84 primary care centres in Sweden. Associations of mean HbA1c levels and educational level with risks of cardiovascular events and all-cause mortality were analysed. RESULTS: The associations of HbA1c with risk of all-cause and cardiovascular mortality were J-shaped, with the lowest risk observed for cardiovascular mortality at an HbA1c level of 51 mmol/mol (6.8%) for subjects on oral agents and 56 mmol/mol (7.3%) in insulin-treated patients. The lowest risk observed for all-cause mortality was at an HbA1c level of 51 mmol/mol (6.8%) for subjects on oral agents and 56 mmol/mol (7.3%) in insulin-treated patients. There was an increased risk for cardiovascular death [hazard ratio 1.6 (1.2-2.1), P = 0.0008] at the lowest HbA1c decile for subjects in the low education category. For subjects with higher education there was no evident J curve for cardiovascular death [hazard ratio 1.2 (0.8-1.6), P = 0.3873]. CONCLUSIONS: Our results lend support to the recent American Diabetes Association/ European Association for the Study of Diabetes position statement that emphasizes the importance of additional factors, including the propensity for hypoglycaemia, which should influence HbA1c targets and treatment choices for individual patients. (Clinical Trials Registry No; NCT 01121315).