A latent class model for competing risks.

Survival data analysis becomes complex when the proportional hazards assumption is violated at population level or when crude hazard rates are no longer estimators of marginal ones. We develop a Bayesian survival analysis method to deal with these situations, on the basis of assuming that the complexities are induced by latent cohort or disease heterogeneity that is not captured by covariates and that proportional hazards hold at the level of individuals. This leads to a description from which risk-specific marginal hazard rates and survival functions are fully accessible, 'decontaminated' of the effects of informative censoring, and which includes Cox, random effects and latent class models as special cases. Simulated data confirm that our approach can map a cohort's substructure and remove heterogeneity-induced informative censoring effects. Application to data from the Uppsala Longitudinal Study of Adult Men cohort leads to plausible alternative explanations for previous counter-intuitive inferences on prostate cancer. The importance of managing cardiovascular disease as a comorbidity in women diagnosed with breast cancer is suggested on application to data from the Swedish Apolipoprotein Mortality Risk Study. Copyright © 2017 John Wiley & Sons, Ltd.

A coordinated cross-disciplinary research initiative to address an increased incidence of narcolepsy following the 2009-2010 Pandemrix vaccination programme in Sweden.

In response to the 2009-2010 influenza A(H1N1)pdm09 pandemic, a mass vaccination programme with the AS03-adjuvanted influenza A(H1N1) vaccine Pandemrix was initiated in Sweden. Unexpectedly, there were a number of narcolepsy cases amongst vaccinated children and adolescents reported. In this review, we summarize the results of a joint cross-disciplinary national research effort to investigate the adverse reaction signal from the spontaneous reporting system and to better understand possible causative mechanisms. A three- to fourfold increased risk of narcolepsy in vaccinated children and adolescents was verified by epidemiological studies. Of importance, no risk increase was observed for the other neurological and autoimmune diseases studied. Genetic studies confirmed the association with the allele HLA-DQB1*06:02, which is known to be related to sporadic narcolepsy. Furthermore, a number of studies using cellular and molecular experimental models investigated possible links between influenza vaccination and narcolepsy. Serum analysis, using a peptide microarray platform, showed that individuals who received Pandemrix exhibited a different epitope reactivity pattern to neuraminidase and haemagglutinin, as compared to individuals who were infected with H1N1. Patients with narcolepsy were also found to have increased levels of interferon-gamma production in response to streptococcus-associated antigens. The chain of patient-related events and the study results emerging over time were subjected to intense nationwide media attention. The importance of transparent communication and collaboration with patient representatives to maintain public trust in vaccination programmes is also discussed in the review. Organizational challenges due to this unexpected event delayed the initiation of some of the research projects, still the main objectives of this joint, cross-disciplinary research effort were reached, and important insights were acquired for future, similar situations in which a fast and effective task force may be required to evaluate vaccination-related adverse events.

LDL-cholesterol versus non-HDL-to-HDL-cholesterol ratio and risk for coronary heart disease in type 2 diabetes.

AIMS: We assessed the association between different blood lipid measures and risk of fatal/nonfatal coronary heart disease (CHD), which has been less analysed previously in type 2 diabetes. DESIGN, METHODS: Observational study of 46,786 patients with type 2 diabetes, aged 30-70 years, from the Swedish National Diabetes Register, followed for a mean of 5.8 years until 2009. Baseline and updated mean low-density lipoprotein (LDL)-, high-density lipoprotein (HDL)-, non-HDL-cholesterol, and non-HDL-to-HDL-cholesterol ratio were measured. RESULTS: Hazard ratios (HR) for CHD with quartiles 2-4 of baseline lipid measures, with lowest quartile 1 as reference: 1.03-1.29-1.63 for LDL; 1.23-1.41-1.95 for non-HDL; 1.29-1.39-1.57 for HDL; and 1.31-1.67-2.01 for non-HDL:HDL, all p < 0.001 except for quartile 2 of LDL, when adjusted for clinical characteristics and nonlipid risk factors. A similar picture was seen with updated mean values. Splines with absolute 6-year CHD rates in a Cox model showed decreasing rates only down to around 3 mmol/l for LDL, with linearly decreasing rates to the lowest level of non-HDL:HDL. Non-HDL and HDL were independent additive risk factors for CHD risk. HRs per 1 SD continuous decrease in baseline or updated mean HDL were 1.14-1.17 when fully adjusted as above, and 1.08-1.13 when also adjusted for non-HDL (p < 0.001). HRs were 1.13-1.16 adjusted for LDL, and 1.22-1.26 adjusted for total cholesterol and triglycerides (p < 0.001). Splines showed progressively increasing 6-year CHD rates with lower HDL down to 0.5 mmol/l. CONCLUSIONS: This study suggests that lower levels of non-HDL:HDL are a better risk marker for CHD than LDL-cholesterol below 3 mmol/l.

Level of physical activity associated with risk of cardiovascular diseases and mortality in patients with type-2 diabetes: report from the Swedish National Diabetes Register.

AIMS: To estimate risks of coronary heart disease (CHD), cardiovascular disease (CVD), and total mortality with low or higher levels of physical activity (PA) assessed with questionnaire, in an observational study of patients with type-2 diabetes from the Swedish National Diabetes Register. SUBJECTS AND METHODS: A total of 15,462 patients (60 years), were followed for 5 years from baseline in 2004 until 2009, with 760 CVD events and 427 total mortality events based on 54,344 person-years. RESULTS: Comparing 6963 patients with low baseline PA (never or 1-2 times/week for 30 min) and 8499 patients with higher baseline PA (regular 3 times/week or more), hazard ratios for fatal/nonfatal CHD, fatal/nonfatal CVD, fatal CVD, and total mortality were 1.25 (95% CI 1.05-1.48; p = 0.01), 1.26 (95% CI 1.09-1.45; p = 0.002), 1.69 (95% CI 1.18-2.41; p = 0.004), and 1.48 (95% CI 1.22-1.79; p < 0.001), adjusting for age, sex, diabetes duration, diabetes treatment, and smoking (model 1). Adjusting also for HbA1c, systolic blood pressure, low- and high-density lipoprotein cholesterol, triglycerides, body mass index, and albuminuria (model 2), HRs were 1.19 (95% CI 1.00-1.42; p = 0.049), 1.18 (95% CI 1.02-1.36; p = 0.04), 1.54 (95% CI 1.07-2.22; p = 0.02), and 1.41 (95% CI 1.16-1.72; p < 0.001), respectively. Corresponding results (model 2), comparing 4166 patients having low PA both baseline and at follow up with all other 11,296 patients were 1.68 (95% CI 1.41-2.01), 1.68 (95% CI 1.45-1.96), 2.12 (95% CI 1.48-3.03), and 2.03 (95% CI 1.66-2.48) (all p < 0.001) and compared to 2797 patients with low baseline PA and higher PA at follow up were 2.51 (95% CI 1.87-3.38), 2.54 (95% CI 1.98-3.27), 3.26 (95% CI 1.74-6.10), and 2.91 (95% CI 2.08-4.07) (all p < 0.001). CONCLUSIONS: This large observational study of patients with type-2 diabetes showed considerably increased risks for CVD and mortality with low PA.

Serum fatty-acid composition and the risk of Alzheimer's disease: a longitudinal population-based study.

BACKGROUND/OBJECTIVES: It is unknown if a specific fatty-acid composition influences the development of Alzheimer's disease (AD). Nutrition is a possible target for prevention of dementia and especially omega-3-based fatty acids (n-3 FAs) have previously been suggested to be beneficial for cognition. The objective was to ascertain whether serum FAs predicts the risk of incident AD and dementia in a longitudinal population-based cohort. SUBJECTS/METHODS: Uppsala Longitudinal Study of Adult Men started in 1970. The proportions of FAs in serum cholesteryl esters were estimated in men (n=2009) who were 50 years old at baseline. During a 35 year follow-up time, 213 men had developed dementia, out of which 91 AD. The associations were analyzed with Cox proportional hazards and logistic regression; adjusted for age, education and vascular risk factors. RESULTS: Subjects with a higher proportion of saturated FAs had a decreased risk of AD in crude and multi-adjusted models (hazard ratio for 1-s.d. increase in palmitic acid 0.72; 95% confidence intervals: 0.59-0.89). These associations persisted even in the group of approximately 85-year-old survivors. n-3 FAs FAs were not associated with decreased risk of AD or dementia. CONCLUSIONS: In contrast to experimental studies, saturated FAs were inversely associated with risk of AD. No evidence of a protective effect of n-3 FAs against dementia was found. The results remained essentially unchanged if competing risk from mortality was taken into account.

Anti-androgen prescribing patterns, patient treatment adherence and influencing factors; results from the nationwide PCBaSe Sweden.

PURPOSE: Adherence has not been studied in male oncology populations. The aim of this study on both the prescriber and user perspectives in prostate cancer treatment was to analyse real-life prescribing patterns of anti-androgens (AA), primarily bicalutamide, and factors influencing the patients' adherence to treatment. METHODS: A nationwide clinical cohort of incident prostate cancer, PCBaSe, was linked to the Swedish Prescribed Drug Register. Men with a planned first line monotherapy AA treatment were identified; dosages and extent of off-label treatment were investigated. Cumulative incidence proportions for reasons for drug discontinuation were calculated. Factors potentially influencing adherence were explored using the medical possession ratio based on the individual prescribed daily dose. RESULTS: First line monotherapy AA was planned in 4.4 % of all incident cases and in 2.1 % of low risk disease cases. Among 1,406 men prescribed bicalutamide, 1,109 (79 %) received the approved daily dose of 150 mg. Discontinuation reasons differed with disease severity. Off-label, low-dose prescription associated with age above 75 years and disease categorised as low risk was noted in 297 men (21 %). Sixty percent of the men adhered well, i.e. to ≥80 %. Age above 75 years and less severe disease were both negatively associated with adherence. CONCLUSIONS: Patient age and tumour risk group influenced the prescriber's choice of dose, pointing to important issues for critical reflection. Possible over-treatment was noted in low risk disease. Interventions to increase adherence in older men and in men with less severe disease are worth considering after critically reviewing the appropriateness of the treatment indication, especially in the latter case.

Glucose-lowering treatment and clinical results in 163 121 patients with type 2 diabetes: an observational study from the Swedish national diabetes register.

AIMS: To analyse clinical characteristics and treatment results in unselected type 2 diabetes mellitus (T2DM) patients, with non-pharmacological treatment as well as the most commonly used pharmacological glucose-lowering treatment regimens, in everyday clinical practice. METHODS: In this population-based cross-sectional study, information was linked from the Swedish National Diabetes Register, Prescribed Drug Register and Patient Register. T2DM patients with non-pharmacological treatment and T2DM patients continuously using the 12 most common pharmacological treatment regimens were included in the study (n = 163121). RESULTS: There were statistically significant differences in clinical characteristics between the groups. Patients with insulin-based treatment regimens had the longest duration of diabetes and more cardiovascular risk factors than the T2DM-population in general. The proportion of patients reaching HbA1c ≤ 7% varied between 70.1% (metformin) and 25.0% [premixed insulin (PMI) + SU) in patients with pharmacological treatment. 84.8% of the patients with non-pharmacological treatment reached target. Compared to patients on metformin, patients on other pharmacological treatments had a lower likelihood, with hazard ratios ranging from 0.58; 95% confidence interval (CI), 0.54-0.63 to 0.97;0.94-0.99, of having HbA1c ≤ 7% (adjusted for covariates). Patients on insulin-based treatments had the lowest likelihood, while non-pharmacological treatment was associated with an increased likelihood of having HbA1c ≤ 7%. CONCLUSION: This nation-wide study shows insufficiently reached treatment goals for haemoglobin A1c (HbA1c) in all treatment groups. Patients on insulin-based treatment regimens had the longest duration of diabetes, more cardiovascular risk factors and the highest proportions of patients not reaching HbA1c target.

Relationship between body mass index and mortality among Europeans.

BACKGROUND/OBJECTIVES: To investigate the relationship between body mass index (BMI) and mortality from various causes. SUBJECTS/METHODS: Data of 72,947 European men and 62,798 women aged 24-99 years at baseline were collaboratively analyzed. Both absolute and relative mortality risks were estimated within each BMI categories. The hazard ratio was estimated using Cox regression analysis adjusting for age, cohort and smoking status. RESULTS: Over a median follow-up of 16.8 years, 29,071 participants died, 13,502 from cardiovascular disease (CVD) and 8748 from cancers of all types. All-cause and cancer mortality showed a U-shaped relationship: decreased first, leveled off, and then increased with increasing BMI with the lowest mortality risk approximately between 23.0 and 28.0 kg/m(2) of BMI in men and 21.0 and 28.0 kg/m(2) in women. The U-shaped relationship held for all-cause mortality but disappeared for cancer mortality among non-smokers. The CVD mortality was constant until a BMI of approximately 28.0 kg/m(2) and then increased gradually in both men and women, which was independent of age, cohort and smoking status. CONCLUSIONS: A U-shaped relationship of BMI with all-cause mortality but a graded relationship with CVD mortality at BMI >28.0 kg/m(2) was detected. The relationship between cancer mortality and BMI largely depended on smoking status, and need to be further investigated with site-specific cancers.

A new model for 5-year risk of cardiovascular disease in Type 1 diabetes; from the Swedish National Diabetes Register (NDR).

AIMS: We assessed the association between risk factors and cardiovascular disease in an observational study of patients with Type 1 diabetes from the Swedish National Diabetes Register. METHODS: A derivation sample of 3661 patients, aged 30-65 years, 6.1% with previous cardiovascular disease, baseline 2002, and 197 cardiovascular disease events when followed for 5 years until 2007. A separate validation data set of 4484 patients, baseline 2003, 201 cardiovascular disease events when followed for 4 years. RESULTS: Adjusted hazard ratios at Cox regression for fatal/non-fatal cardiovascular disease were: diabetes duration 2.76 (2.21-3.44); onset age 1.47 (1.21-1.78); log ratio total cholesterol:HDL cholesterol 1.26 (1.09-1.45); log HbA(1c) 1.19 (1.03-1.38); log systolic blood pressure 1.17 (1.01-1.34) (1 SD increase in continuous variables); smoker 1.76 (1.27-2.46); macroalbuminuria (> 200 µg/min) 1.52 (1.10-2.10); previous cardiovascular disease 3.51 (2.54-4.84). All eight variables were used to elaborate a risk equation for 5-year cardiovascular disease risk. Regarding calibration in the derivation data set, ratio predicted 5-year risk (mean 5.4 ± 7.9%) to observed event rate was 1.0. Discrimination was sufficient, with C-statistic 0.83, sensitivity and specificity 72 and 77%, respectively, for the top quartile of predicted risk. Similarly, calibration and discrimination were adequate in the validation data set: ratio of predicted 4-year risk/observed rate 0.94, C-statistic 0.80, sensitivity and specificity 62 and 77%, respectively, for the top quartile. CONCLUSIONS: This 5-year cardiovascular disease risk model from a large observational study of patients with Type 1 diabetes in routine care showed adequate calibration and discrimination and can be useful for clinical practice. It should also be tested in patients with Type 1 diabetes from other countries.

Additive effects of glycaemia and dyslipidaemia on risk of cardiovascular diseases in type 2 diabetes: an observational study from the Swedish National Diabetes Register.

AIMS/HYPOTHESIS: The study aimed to assess the relative importance of the control of HbA(1c) and total cholesterol/HDL-cholesterol ratio (TC/HDL) on risk of cardiovascular disease (CVD). METHODS: In 22,135 participants with type 2 diabetes (age 30-75 years, 15% with previous CVD) followed for 5 years, baseline and annually updated mean HbA(1c) and TC/HDL were analysed and also categorised in combinations of quartiles. Outcomes were fatal/non-fatal CHD, stroke, CVD and total mortality. RESULTS: In all participants, HRs per 1 SD increase in updated mean HbA(1c) or TC/HDL using Cox regression analysis were 1.13 (95% CI 1.07, 1.19) and 1.31 (1.25, 1.37) for CHD, 1.15 (1.06, 1.24) and 1.25 (1.17, 1.34) for stroke, 1.13 (1.08, 1.18) and 1.29 (1.24, 1.34) for CVD (all p < 0.001), and 1.07 (1.02, 1-13; p = 0.01) and 1.18 (1.12, 1.24; p < 0.001) for total mortality, respectively, adjusted for clinical characteristics and traditional risk factors. The p value for the interaction between HbA(1c) and TC/HDL was 0.02 for CHD, 0.6 for stroke and 0.1 for CVD. Adjusted mean 5-year event rates in a Cox model, in combinations of quartiles of updated mean TC/HDL and HbA(1c) (lowest <3.1 mmol/l and 5.0-6.4% [31-46 mmol/mol]; <3.1 mmol/l and ≥7.8% [≥62 mmol/mol]; ≥4.6 mmol/l and 5.0-6.4% 31-46 mmol/mol; and highest ≥4.6 mmol/l and ≥7.8% [≥62 mmol/mol]), were 4.8%, 7.0%, 9.1% and 14.5% for CHD, and 7.1%, 9.9%, 12.8% and 19.4% for CVD, respectively. Adjusted HRs for highest vs lowest combinations were 2.24 (1.58-3.18) for CHD and 2.43 (1.79-3.29) for CVD (p < 0.001). CONCLUSIONS/INTERPRETATION: Hyperglycaemia and hyperlipidaemia were less than additive for CHD and additive for other endpoints, with the lowest risk at lowest combination levels and a considerable increase in absolute risk at high combination levels.

Plasma levels of glucagon like peptide-1 associate with diastolic function in elderly men.

AIMS: Congestive heart failure is a major cause of morbidity and mortality in diabetes. Besides the glycaemic effects of glucagon-like peptide 1 (GLP-1) mimetics, their effects on the heart are of interest. METHODS: We aimed to investigate longitudinal relationships between plasma levels of fasting GLP-1 (fGLP-1), 60-min oral glucose tolerance test-stimulated GLP-1 levels (60GLP-1), and the dynamic GLP-1 response after oral glucose tolerance test (ΔGLP-1 = 60GLP-1 - fGLP-1) and incidence of hospitalized congestive heart failure, during a follow-up time of a maximum of 9.8 years in 71-year-old men. We also investigated, cross-sectionally, the association between GLP-1 and left ventricular function as estimated by echocardiography. R: During the follow-up period, 16 of 290 participants with normal glucose tolerance experienced a congestive heart failure event (rate 0.7/100 person-years at risk), as did eight of 136 participants (rate 0.8/100 person-years at risk) with impaired glucose tolerance and nine of 72 participants (rate 1.7/100 person-years at risk) with Type 2 diabetes mellitus. Although GLP-1 concentrations did not predict congestive heart failure (fGLP-1: HR 0.98, 95% CI 0.4-2.4; 60GLP-1: HR 1.1, 95% CI 0.4-2.6; ΔGLP-1: HR 0.9, 95% CI 0.3-2.3), there was an association between left ventricular diastolic function (E/A ratio) and fGLP-1 (r = 0.19, P = 0.001), 60GLP-1 (r = 0.20, P < 0.001) and ΔGLP-1 (r = 0.18, P = 0.004). There was a lack of differences in plasma levels of GLP-1 between the groups with Type 2 diabetes and normal glucose tolerance. CONCLUSIONS: There were no longitudinal associations between GLP-1 levels and incidence of hospitalization for congestive heart failure. However, without any causality proven, GLP-1 levels did correlate, cross-sectionally, with left ventricular diastolic function in this cohort, suggesting that pathways including GLP-1 might be involved in the regulation of cardiac diastolic function.

New aspects of HbA1c as a risk factor for cardiovascular diseases in type 2 diabetes: an observational study from the Swedish National Diabetes Register (NDR).

AIMS: To analyse the association between glycosylated haemoglobin A1c (HbA1c) and cardiovascular disease (CVD) in patients with type 2 diabetes in the Swedish National Diabetes Register (NDR). METHODS: An observational study of 18 334 patients (age 30-79 years, previous CVD in 18%, baseline HbA1c 5.0-10.9%) who were followed for 6 years (mean 5.6 years) from 1997/1998 until 2003. RESULTS: Hazard ratios per 1% unit increase in baseline or updated mean HbA1c for fatal/nonfatal coronary heart disease (CHD), CVD and total mortality were 1.11-1.13, 1.10-1.11 and 1.09-1.10, respectively (all P < 0.001), adjusted for several risk factors and clinical characteristics in Cox regression. Adjusted 6-year event rates increased with higher baseline or updated mean HbA1c with no J-shaped risk curves, in all patients and also when subgrouping by shorter (mean 3 years) or longer (mean 14 years) diabetes duration, by presence or absence of previous CVD, or by treatment with oral hypoglycaemic agents (OHAs) or insulin. Risk reductions of 20% for CHD and 16% for CVD (P < 0.001) were found in patients with a baseline mean HbA1c of 6.5%, compared to those with a mean level of 7.5%. Compared to OHA-treated patients, insulin-treated patients had an increased risk of total mortality, due almost exclusively to an increased risk of non-CVD mortality, and due less to a weakly significant increased risk of fatal CVD. HbA1c was not associated with non-CVD mortality. CONCLUSIONS: This observational study showed progressively increasing risks of CHD, CVD and total mortality with higher HbA1c, and no risk increase at low HbA1c levels even with longer diabetes duration, previous CVD or treatment with either insulin or OHAs. Patients achieving HbA1c <7% showed benefits for risk reduction.

Diabetes, prediabetes and cancer mortality.

AIMS/HYPOTHESIS: We aimed to investigate the risk of cancer mortality in relation to the glucose tolerance status classified according to the 2 h OGTT. METHODS: Data from 17 European population-based or occupational cohorts involved in the DECODE study comprising 26,460 men and 18,195 women aged 25-90 years were collaboratively analysed. The cohorts were recruited between 1966 and 2004 and followed for 5.9 to 36.8 years. Cox proportional hazards analysis with adjustment for cohort, age, BMI, total cholesterol, blood pressure and smoking status was used to estimate HRs for cancer mortality. RESULTS: Compared with people in the normal glucose category, multivariable adjusted HRs (95% CI) for cancer mortality were 1.13 (1.00, 1.28), 1.27 (1.02, 1.57) and 1.71 (1.35, 2.17) in men with prediabetes, previously undiagnosed diabetes and known diabetes, respectively; in women they were 1.11 (0.94, 1.30), 1.31 (1.00, 1.70) and 1.43 (1.01, 2.02), respectively. Significant increases in deaths from cancer of the stomach, colon-rectum and liver in men with prediabetes and diabetes, and deaths from cancers of the liver and pancreas in women with diabetes were also observed. In individuals without known diabetes, the HR (95% CI) for cancer mortality corresponding to a one standard deviation increase in fasting plasma glucose was 1.06 (1.02, 1.09) and in 2 h plasma glucose was 1.07 (1.03, 1.11). CONCLUSIONS/INTERPRETATION: Diabetes and prediabetes were associated with an increased risk of cancer death, particularly death from liver cancer. Mortality from all cancers rose linearly with increasing glucose concentrations.

Cognitive function and risk of stroke in elderly men.

OBJECTIVE: Vascular risk factors are associated with ischemic changes in the cerebral white matter. We studied the predictive value of cognitive test performance especially related to subcortico-frontal pathways, together with a cognitive screening test, for later incidence of fatal or nonfatal stroke or TIAs and stroke subtypes. METHODS: A sample of 930 70-year-old men without previous stroke/TIA from the community-based Uppsala Longitudinal Study of Adult Men was investigated at baseline using Trail Making Tests (TMT) A and B and the Mini-Mental State Examination (MMSE). RESULTS: During up to 13 years of follow-up, 166 men developed a stroke or TIA; 105 participants had a brain infarction. In Cox proportional hazards analyses adjusting for education, social group, and traditional cardiovascular risk factors, a 1-SD increase in TMT-B time was associated with a higher risk for brain infarction (hazard ratio 1.48, 95% confidence interval 1.11-1.97). The risk of brain infarction was more than threefold higher in the highest (TMT-B = 146-240 s) compared to the lowest (TMT-B = 43-84 s) TMT-B quartile. TMT-A and MMSE results were not consistently related to stroke outcomes. CONCLUSION: Impaired performance in elderly men measured by Trail Making Test B, a cognitive test especially reflecting subcortico-frontal activities, was an independent predictor of subsequent brain infarction in this community-based sample of elderly men. Our results extend previous findings of cognitive decline as an independent predictor of stroke and indicate that the risk of brain infarction is increased already in the subclinical phase of cognitive deficit.

Reduced plasma levels of glucagon-like peptide-1 in elderly men are associated with impaired glucose tolerance but not with coronary heart disease.

AIMS/HYPOTHESIS: Besides the insulinotropic effects of glucagon-like peptide-1 (GLP-1) mimetics, their effects on endothelial dysfunction and myocardial ischaemia are of interest. No previous study has investigated associations between plasma levels of GLP-1 and CHD. METHODS: We investigated longitudinal relationships of fasting GLP-1 with the dynamic GLP-1 response after OGTT (difference between 60 min OGTT-stimulated and fasting GLP-1 levels [DeltaGLP-1]) and CHD in a population-based cohort of 71-year-old men. In the same cohort, we also cross-sectionally investigated the association between stimulated GLP-1 levels and: (1) cardiovascular risk factors (blood pressure, lipids, urinary albumin, waist circumference and insulin sensitivity index [M/I] assessed by euglycaemic-hyperinsulinaemic clamp); and (2) impaired glucose tolerance (IGT) and type 2 diabetes mellitus. RESULTS: During the follow-up period (maximum 13.8 years), of 294 participants with normal glucose tolerance (NGT), 69 experienced a CHD event (13.8 years), as did 42 of 141 with IGT and 32 of 74 with type 2 diabetes mellitus. DeltaGLP-1 did not predict CHD (HR 1.0, 95% CI 0.52-2.28). The prevalence of IGT was associated with DeltaGLP-1, lowest vs highest quartile (OR 0.3, 95% CI 0.12-0.58), with no such association for type 2 diabetes mellitus (OR 1.0, 95% CI 0.38-2.86). M/I was significantly associated with DeltaGLP-1 in the type 2 diabetes mellitus group (r = 0.38, p < 0.01), but not in the IGT (r = 0.11, p = 0.28) or NGT (r = 0.10, p = 0.16) groups. CONCLUSIONS/INTERPRETATION: Impaired GLP-1 secretion is associated with IGT, but not with type 2 diabetes mellitus. This finding in the latter group might be confounded by oral glucose-lowering treatment. GLP-1 does not predict CHD. Although DeltaGLP-1 was associated with insulin sensitivity in the type 2 diabetes mellitus group, GLP-1 does not seem to be a predictor of CHD in insulin-resistant patients.

Pulse pressure strongly predicts cardiovascular disease risk in patients with type 2 diabetes from the Swedish National Diabetes Register (NDR).

OBJECTIVES: To analyze pulse pressure (PP) as a risk predictor for coronary heart disease (CHD), stroke and cardiovascular disease (CVD; CHD and/or stroke) in type 2 diabetic patients. METHODS: A total of 11,128 female and male type 2 diabetic patients with known baseline PP values and no CVD, aged 50-74 years, were followed for a mean duration of 5.6 years (1998-2003). A subgroup of 5521 patients with known mean PP values (mean values at baseline and at the end of the study) was also included. RESULTS: Hazard ratios (HRs) with 95% CI for fatal/nonfatal CHD with baseline or mean PP>or=75mmHg, compared to <75mmHg, were 1.23 (1.07-1.40; P=0.003) and 1.32 (1.07-1.62; P=0.009), respectively, after adjusting for mean blood pressure (MBP), age, gender, diabetes duration, HbA(1c), body mass index (BMI), lipid-reducing drugs, microalbuminuria > 20microg/min, antihypertensive drugs and hypoglycaemic treatment, using Cox regression analyses. Fully-adjusted respective HRs for stroke were 1.17 (0.98-1.39) and 1.21 (0.90-1.61) and, for CVD, 1.23 (1.10-1.37; P<0.001) and 1.28 (1.07-1.52; P=0.007). Fully-adjusted HRs for baseline PP increased per quartile and, CHD, stroke or CVD, were 1.09 (1.03-1.16; P=0.004), 1.14 (1.05-1.23; P=0.002) and 1.11 (1.05-1.17; P<0.001), respectively. The data suggest that, if a mean PP>or=75mmHg were to be avoided, then 15% and 17% of CHD and or CVD, cases, respectively, in such a cohort might be prevented after multivariable adjustments, with a further 10% of cases avoided if also adjusted for MBP and age. Increasing baseline MBP, age and microalbuminuria were independently and significantly associated (P<0.001) with increasing baseline or mean PP. CONCLUSION: Increased PP is a powerful independent risk predictor of CVD in type 2 diabetic patients, and lowering PP can lead to a marked reduction in risk.

Vasoreactivity is rapidly improved in obese subjects after gastric bypass surgery.

BACKGROUND: Obesity is associated with increased risk of cardiovascular disease. We investigated vasoreactivity in conduit and resistance arteries in morbidly obese subjects, and the effect of weight loss after gastric bypass surgery. METHODS: A total of 19 obese subjects (body mass index (BMI): 43.8+/-3.1 kg m(-2), 75% female, mean age 41 years) were investigated before surgery and after 1 and 12 months of surgery. Nineteen non-obese controls matched for age and gender were examined. Vasoreactivity was evaluated by ultrasound to measure flow-mediated dilation (FMD, evaluating a conduit vessel) and pulse-wave analysis with terbutaline provocation (change in reflectance index (RI), evaluating resistance vessels). RESULTS: Before surgery, the obese showed a low change in RI (18+/-12 vs 37+/-15% in controls, P=0.0001), but not significantly regarding FMD (7.9+/-6.4 vs 8.9+/-5.4% in controls). Surgery resulted in a weight loss of 9% at 1 month and 30% at 1 year. Change in RI markedly improved to 36+/-12% at 1 month (P=0.0001 vs baseline) and further to 44+/-11% at 1 year (P=0.014 vs 1 month). FMD did not change significantly. Heart rate and brachial artery diameter were reduced, with no significant change in blood pressure. The improvement in resistance vessel vasodilation, estimated as change in RI, was not correlated to changes in weight or measures of glucose and lipid metabolism. CONCLUSIONS: Obese patients showed impaired vasoreactivity in resistance arteries that was normalized already 1 month after gastric bypass surgery. The basis for this remarkable outcome, not significantly related to changes in body weight and metabolic variables, remains to be clarified.

Glucose metabolism and the risk of Alzheimer's disease and dementia: a population-based 12 year follow-up study in 71-year-old men.

AIMS/HYPOTHESIS: Accumulating evidence suggests that diabetes increases the risk of dementia, but few studies have addressed possible mechanisms underlying this relationship. The aim of our study was to investigate the longitudinal association of glucose metabolism, insulin secretion and insulin action with the development of Alzheimer's disease and vascular dementia. METHODS: The Uppsala Longitudinal Study of Adult Men is an ongoing observational study in Sweden in which 1,125 men aged 71 years and free from dementia underwent an OGTT and a euglycaemic insulin clamp between 1990 and 1995. During a median follow-up of 12 years, 257 persons developed dementia or cognitive impairment, of whom 81 had Alzheimer's disease and 26 vascular dementia. Associations were analysed with the Cox proportional hazards method. RESULTS: Low early insulin response to oral glucose challenge, but not low insulin sensitivity, was associated with a higher risk of Alzheimer's disease (HR for 1 SD decrease 1.32; 95% CI 1.02, 1.69) after adjustment for diabetes, blood pressure, body mass index, cholesterol, smoking and educational level. Low insulin sensitivity was associated with a higher risk of vascular dementia (HR for 1 SD decrease 1.55; 95% CI 1.02, 2.35), but not after multiple adjustments. Diabetes increased the risk of any dementia and cognitive impairment by 63%. CONCLUSIONS/INTERPRETATION: In this community-based study, low early insulin response was associated with increased risk of subsequent Alzheimer's disease, whereas low insulin sensitivity was not. Vascular dementia was not related to early insulin response. We suggest that glucometabolic disturbances are linked differentially to the pathogenesis of these two main dementia subtypes.

Risk factor control in patients with Type 2 diabetes and coronary heart disease: findings from the Swedish National Diabetes Register (NDR).

AIMS: Patients with Type 2 diabetes and coronary heart disease (CHD) are infrequently treated to risk factor targets in current guidelines. We aimed to examine risk factor management and control levels in a large sample of patients with Type 2 diabetes with CHD. METHODS: This was an observational study of 1612 patients with first incidence of CHD before 2002, and of 4570 patients with first incidence of CHD before 2005, from the Swedish National Diabetes Register (NDR). RESULTS: In patients with CHD 1-2 years before follow-up, the achievement of cardiovascular risk factor targets (follow-up 2002/follow-up 2005) was: HbA(1c) < 7%, 47%/54% (P < 0.01); blood pressure < or = 130/80 mmHg, 31%/40% (P < 0.001); total cholesterol < 4.5 mmol/l, 47%/60% (P < 0.001); and low-density lipoprotein-cholesterol < 2.5 mmol/l, 49%/65% (P < 0.001). Use of medication: antihypertensives, 90%/94% (P < 0.01); lipid-lowering drugs, 75%/86% (P < 0.001); and aspirin, 85%/89% (P < 0.05). A high prevalence of adverse lifestyle characteristics prevailed (2002/2005): overweight [body mass index (BMI) > or = 25 kg/m(2)], 86%/85%; obesity (BMI > or = 30 kg/m(2)), 41%/42%; smokers in age group < 65 years, 16-23%/18-19%; as well as waist circumference > or = 102 cm (men) or > or = 88 cm (women), 68% in 2005. CONCLUSIONS: Patients with a combination of Type 2 diabetes and CHD showed an increased use of lipid-lowering drugs over time, corresponding to improving blood lipid levels. A discrepancy existed between the prevalent use of antihypertensive drugs and the low proportion reaching blood pressure targets. Regretfully, a high prevalence of adverse lifestyle characteristics prevailed. Evidence-based therapy with professional lifestyle intervention and drugs seems urgent for improved quality of secondary prevention in these patients.

Insulin sensitivity measured by the euglycaemic insulin clamp and proinsulin levels as predictors of stroke in elderly men.

AIMS/HYPOTHESIS: Our aim was to investigate the predictive power of a panel of variables in glucose and insulin metabolism for the incidence of stroke or transient ischaemic attacks (TIA). We hypothesised that proinsulin and insulin resistance contributes to an increase of risk for fatal and non-fatal stroke/TIA, independently of diabetes and established risk factors. METHODS: The study is based on the Uppsala Longitudinal Study of Adult Men cohort. The examinations were performed at age 70 years. RESULTS: In 1,151 men free from stroke at baseline, 150 developed stroke or TIA during a median follow-up of 8.8 years. In unadjusted Cox proportional hazards analyses, a 1 SD increase of a predictor variable was associated with an increased risk for stroke/TIA, e.g. plasma insulin (HR 1.19, 95% CI 1.01-1.40), fasting intact proinsulin (HR 1.28, 95% CI 1.09-1.49); whereas a 1 SD increase in insulin sensitivity measured by the euglycaemic insulin clamp method decreased the risk for stroke/TIA (HR 0.81, 95% CI 0.68-0.96). The predictive values of fasting intact proinsulin and insulin sensitivity endured but not that of plasma insulin when adjusting for diabetes. In models adjusting for diabetes, hypertension, atrial fibrillation, electrocardiographic left ventricular hypertrophy, serum cholesterol and smoking, proinsulin remained as a significant predictor of later stroke/TIA (HR 1.22, 95% CI 1.00-1.48) whereas clamp insulin sensitivity did not (HR 0.87, 95% CI 0.71-1.07). CONCLUSIONS/INTERPRETATION: Fasting intact proinsulin level and insulin sensitivity at clamp predicted subsequent fatal and non-fatal stroke/TIA, independently of diabetes in elderly men whereas fasting insulin did not.