Long-term cardiovascular and non-cardiovascular mortality in women and men with type 1 and type 2 diabetes mellitus: a 30-year follow-up in Switzerland.

BACKGROUND: While studies from other countries have shown an excess mortality in diabetic individuals when compared with the general population, comparable long-term data is not available for Switzerland. AIMS: To assess gender-specific cardiovascular and non-cardiovascular mortality of patients with type 1 and type 2 diabetes compared with the general Swiss population between 1974 and 2005. DESIGN: 533 patients (225 type 1, 308 type 2 diabetes, 52.2% men) were followed for 30 years (10349 person-years). RESULTS: Diabetic patients had an increased all-cause mortality compared with the general population (SMR [95% CI] 3.8 [3.5-4.3]). Standardised mortality ratio (SMR) was higher for type 1 compared with type 2 diabetic patients (4.5 [3.8-5.3] vs 3.5 [3.1-4.0], p = 0.032). For cardiovascular and non-cardiovascular deaths SMRs were 5.6 (95% CI 4.8-6.6) and 2.7 (2.3-3.1) and did not differ according to type of diabetes. SMRs for all-cause and cardiovascular mortality were significantly higher in women compared with men in type 1 (p <0.05 and p <0.01) and type 2 diabetes (p <0.001 and p <0.01). In both types of diabetes, SMRs significantly decreased during the last two decades (p for trend 0.004 and 0.002). CONCLUSIONS: Patients with type 1 and type 2 diabetes had an increased long-term mortality compared with the general Swiss population. Excess mortality was higher in type 1 compared with type 2 diabetes and in women compared with men for both types of diabetes, but steadily decreased over the last two decades.

Dehydroepiandrosterone sulfate in the assessment of the hypothalamic-pituitary-adrenal axis.

CONTEXT: The role of dehydroepiandrosterone-sulfate (DHEA-S) in assessing the integrity of the hypothalamic-pituitary-adrenal (HPA) axis in patients with suspected insufficiency is uncertain. OBJECTIVE: The objective of the study was to prospectively evaluate the diagnostic value of DHEA-S on HPA function in consecutive patients with suspected HPA insufficiency with and without pituitary lesions at a tertiary referral center. DESIGN AND PATIENTS: In 70 consecutive patients, insulin tolerance test was accompanied by measurement of basal DHEA-S. Assessment of HPA axis was based on peak cortisol response in insulin tolerance test (normal > or = 550 nmol/liter). To account for the age and gender dependency of DHEA-S, a z-score was calculated using age- and gender-specific reference values of the assay. RESULTS: Individuals with HPA insufficiency had significantly lower z-scores than those with normal HPA function (-1.66 vs. -0.62, P < 0.0001). In individuals up to 30 yr of age, a z-score of -2.0 had 100% sensitivity and specificity regarding HPA function [area under receiver operating characteristics (ROC) curve 1.00], whereas z-scores proved less useful in older individuals. In individuals with pituitary macroadenoma, a z-score below -2.0 had 100% specificity to predict HPA insufficiency (area under ROC curve 0.82). In the absence of a pituitary adenoma, the diagnostic value of the z-score was reduced (area under ROC curve 0.71). CONCLUSIONS: Individuals with HPA insufficiency have lower z-scores for DHEA-S than those with normal HPA function. There is evidence that a z-score could be of diagnostic value in assessing HPA integrity, especially in younger patients and patients with pituitary macroadenoma, but further studies are needed to consolidate these findings.

Outcomes associated with drug-eluting and bare-metal stents: a collaborative network meta-analysis.

BACKGROUND: Whether the two drug-eluting stents approved by the US Food and Drug Administration-a sirolimus-eluting stent and a paclitaxel-eluting stent-are associated with increased risks of death, myocardial infarction, or stent thrombosis compared with bare-metal stents is uncertain. Our aim was to compare the safety and effectiveness of these stents. METHODS: We searched relevant sources from inception to March, 2007, and contacted investigators and manufacturers to identify randomised controlled trials in patients with coronary artery disease that compared drug-eluting with bare-metal stents, or that compared sirolimus-eluting stents head-to-head with paclitaxel-eluting stents. Safety outcomes included mortality, myocardial infarction, and definite stent thrombosis; the effectiveness outcome was target lesion revascularisation. We included 38 trials (18,023 patients) with a follow-up of up to 4 years. Trialists and manufacturers provided additional data on clinical outcomes for 29 trials. We did a network meta-analysis with a mixed-treatment comparison method to combine direct within-trial comparisons between stents with indirect evidence from other trials while maintaining randomisation. FINDINGS: Mortality was similar in the three groups: hazard ratios (HR) were 1.00 (95% credibility interval 0.82-1.25) for sirolimus-eluting versus bare-metal stents, 1.03 (0.84-1.22) for paclitaxel-eluting versus bare-metal stents, and 0.96 (0.83-1.24) for sirolimus-eluting versus paclitaxel-eluting stents. Sirolimus-eluting stents were associated with the lowest risk of myocardial infarction (HR 0.81, 95% credibility interval 0.66-0.97, p=0.030 vs bare-metal stents; 0.83, 0.71-1.00, p=0.045 vs paclitaxel-eluting stents). There were no significant differences in the risk of definite stent thrombosis (0 days to 4 years). However, the risk of late definite stent thrombosis (>30 days) was increased with paclitaxel-eluting stents (HR 2.11, 95% credibility interval 1.19-4.23, p=0.017 vs bare-metal stents; 1.85, 1.02-3.85, p=0.041 vs sirolimus-eluting stents). The reduction in target lesion revascularisation seen with drug-eluting stents compared with bare-metal stents was more pronounced with sirolimus-eluting stents than with paclitaxel-eluting stents (0.70, 0.56-0.84; p=0.0021). INTERPRETATION: The risks of mortality associated with drug-eluting and bare-metal stents are similar. Sirolimus-eluting stents seem to be clinically better than bare-metal and paclitaxel-eluting stents.

Continuous subcutaneous insulin infusion therapy: effects on quality of life.

OBJECTIVE: To compare the diabetes-specific quality of life in subjects with type 1 diabetes treating their diabetes with multiple daily injections (MDI) to that of subjects on continuous subcutaneous insulin infusion (CSII). METHODS: Diabetes-specific quality of life was measured with the DSQOLS-Questionnaire in 81 adult subjects with type 1 diabetes on MDI and 78 subjects on CSII (cross-sectional study). In addition, 19 subjects were followed prospectively, measuring their quality of life before and after switching from MDI to CSII (longitudinal study). RESULTS: Preference-weighted treatment satisfaction score was significantly higher in subjects on CSII than in those on MDI in both the longitudinal (+63 points, 95%CI 37-89) and the cross-sectional study (+14 points, 95%CI 3 to 25). "Diet restrictions" were significantly less of a burden for CSII subjects in both the longitudinal (+6 points, 95%CI 1-10) and the cross-sectional study (+3 points, 95%CI 0 to 6). "Leisure time flexibility" (+3 points, 95%CI 0 to 7), "Physical complaints" (+4 points, 95%CI 1 to 8), "Daily hassles" (+4, 95%CI 0 to 7), and the overall quality of life (+29 points, 95%CI 3 to 54) were significantly better in CSII compared to MDI only in the longitudinal study. Despite a small overall rate of severe hypoglycaemia in both studies, subjects on CSII experienced fewer severe episodes than subjects on MDI. CONCLUSIONS: Subjects with type 1 diabetes on CSII have a better quality of life than type 1 diabetic subjects on MDI. They are more satisfied with their treatment in respect to their metabolic goals as well as psychosocial factors, physical performance and protection from long-term complications and hypoglycaemia. Furthermore, the subjects on CSII experience greater flexibility in their daily routines, leisure time and diet than the subjects on MDI.

Glycemic control and macrovascular disease in types 1 and 2 diabetes mellitus: Meta-analysis of randomized trials.

BACKGROUND: Uncertainty persists concerning the effect of improved long-term glycemic control on macrovascular disease in diabetes mellitus (DM). METHODS: We performed a systematic review and meta-analysis of randomized controlled trials comparing interventions to improve glycemic control with conventional treatment in type 1 and type 2 diabetes. Outcomes included the incidence rate ratios for any macrovascular event, cardiac events, stroke, and peripheral arterial disease, and the number needed to treat intensively during 10 years to prevent one macrovascular event. RESULTS: The analysis was based on 8 randomized comparisons including 1800 patients with type 1 DM (134 macrovascular events, 40 cardiac events, 88 peripheral vascular events, 6 cerebrovascular events, 11293 person-years of follow-up) and 6 comparisons including 4472 patients with type 2 DM (1587 macrovascular events, 1197 cardiac events, 87 peripheral vascular events, 303 cerebrovascular events, 43607 person-years). Combined incidence rate ratios for any macrovascular event were 0.38 (95% CI 0.26-0.56) in type 1 and 0.81 (0.73-0.91) in type 2 DM. In type 1 DM, effect was mainly based on reduction of cardiac and peripheral vascular events and, in type 2 DM, due to reductions in stroke and peripheral vascular events. Effects appear to be particularly important in younger patients with shorter duration of diabetes. CONCLUSIONS: Our data suggest that attempts to improve glycemic control reduce the incidence of macrovascular events both in type 1 and type 2 DM. In absolute terms, benefits are comparable, although effects on specific manifestations of macrovascular disease differ.

Fibrates in the prevention of cardiovascular disease in patients with type 2 diabetes mellitus: meta-analysis of randomised controlled trials.

OBJECTIVE: To assess the impact of lipid lowering treatment with fibrates on cardiovascular endpoints in patients with type 2 diabetes mellitus. METHODS: MEDLINE (from inception to November 2005) and the Cochrane Controlled Trials Register (including Issue 3, 2005) were searched for randomised controlled trials comparing therapy with fibrates to placebo in patients with type 2 diabetes mellitus. Electronic searches were supplemented by manual searching of reference lists, reviews, conference abstracts and specialist journals. Incidence rate ratios (IRRs) were estimated using a fixed effects model. The primary endpoint was the IRR for coronary heart disease (CHD) events (a combination of non fatal myocardial infarction and death due to CHD). Secondary endpoints included: (1) death due to CHD; (2) fatal and non fatal myocardial infarction; and (3) fatal and non fatal stroke. RESULTS: Eight trials and 12 249 patients with type 2 diabetes were included in the analyses. A total of 924 CHD events (418 and 506 in the treatment and placebo groups, respectively) occurred during a follow up of 60 395 person-years (30 106 and 30 289 in treatment and placebo groups). The combined IRR for CHD events was 0.84 (95% confidence interval [CI] 0.74-0.96, p = 0.008). The numbers needed to treat (NNTs) to prevent one CHD event over 10 years were nine and 26 for patients with and without pre-existing CHD, respectively. IRRs for death due to CHD, myocardial infarction and stroke were 0.96 (95% CI 0.77-1.20, p = 0.73), 0.88 (95% CI 0.69-1.12, p = 0.30) and 0.87 (95% CI 0.73-1.05, p = 0.14), respectively. Larger benefits were found when restricting the analysis to trials that were not confounded by unequal provision of additional lipid-lowering therapy. CONCLUSIONS: Fibrates are associated with a substantial reduction of CHD events, but their exact role in lipid lowering treatment of patients with type 2 diabetes mellitus remains to be defined.

Effects of aerobic exercise on ectopic lipids in patients with growth hormone deficiency before and after growth hormone replacement therapy.

Growth hormone replacement therapy (GHRT) increases exercise capacity and insulin resistance while it decreases fat mass in growth hormone-deficient patients (GHD). Ectopic lipids (intramyocellular (IMCL) and intrahepatocellular lipids (IHCL) are related to insulin resistance. The effect of GHRT on ectopic lipids is unknown. It is hypothesized that exercise-induced utilization of ectopic lipids is significantly decreased in GHD patients and normalized by GHRT. GHD (4 females, 6 males) and age/gender/waist-matched control subjects (CS) were studied. VO2max was assessed on a treadmill and insulin sensitivity determined by a two-step hyperinsulinaemic-euglycaemic clamp. Visceral (VAT) and subcutaneous (SAT) fat were quantified by MR-imaging. IHCL and IMCL were measured before and after a 2 h exercise at 50-60% of VO2max using MR-spectroscopy (∆IMCL, ∆IHCL). Identical investigations were performed after 6 months of GHRT. VO2max was similar in GHD and CS and significantly increased after GHRT; GHRT significantly decreased SAT and VAT. 2 h-exercise resulted in a decrease in IMCL (significant in CS and GHRT) and a significant increase in IHCL in CS and GHD pre and post GHRT. GHRT didn't significantly impact on ∆IMCL and ∆IHCL. We conclude that aerobic exercise affects ectopic lipids in patients and controls. GHRT increases exercise capacity without influencing ectopic lipids.

The effect of aerobic exercise on intrahepatocellular and intramyocellular lipids in healthy subjects.

BACKGROUND: Intrahepatocellular (IHCL) and intramyocellular (IMCL) lipids are ectopic lipid stores. Aerobic exercise results in IMCL utilization in subjects over a broad range of exercise capacity. IMCL and IHCL have been related to impaired insulin action at the skeletal muscle and hepatic level, respectively. The acute effect of aerobic exercise on IHCL is unknown. Possible regulatory factors include exercise capacity, insulin sensitivity and fat availability subcutaneous and visceral fat mass). AIM: To concomitantly investigate the effect of aerobic exercise on IHCL and IMCL in healthy subjects, using Magnetic Resonance spectroscopy. METHODS: Normal weight, healthy subjects were included. Visit 1 consisted of a determination of VO2max on a treadmill. Visit 2 comprised the assessment of hepatic and peripheral insulin sensitivity by a two-step hyperinsulinaemic euglycaemic clamp. At Visit 3, subcutaneous and visceral fat mass were assessed by whole body MRI, IHCL and IMCL before and after a 2-hours aerobic exercise (50% of VO(2max)) using ¹H-MR-spectroscopy. RESULTS: Eighteen volunteers (12M, 6F) were enrolled in the study (age, 37.6±3.2 years, mean±SEM; VO(2max), 53.4±2.9 mL/kg/min). Two hours aerobic exercise resulted in a significant decrease in IMCL (-22.6±3.3, % from baseline) and increase in IHCL (+34.9±7.6, % from baseline). There was no significant correlation between the exercise-induced changes in IMCL and IHCL and exercise capacity, subcutaneous and visceral fat mass and hepatic or peripheral insulin sensitivity. CONCLUSIONS: IMCL and IHCL are flexible ectopic lipid stores that are acutely influenced by physical exercise, albeit in different directions. TRIAL REGISTRATION: ClinicalTrial.gov NCT00491582.

Self-monitoring of blood glucose in non-insulin treated patients with type 2 diabetes: a systematic review and meta-analysis.

OBJECTIVE: To assess the effect of self-monitoring of blood glucose (SMBG) on glycaemic control in non-insulin treated patients with type 2 diabetes by means of a systematic review and meta-analysis. RESEARCH DESIGN AND METHODS: MEDLINE and the Cochrane Controlled Trials Register were searched from inception to January 2009 for randomised controlled trials comparing SMBG with non-SMBG or more frequent SMBG with less intensive SMBG. Electronic searches were supplemented by manual searching of reference lists and reviews. The comparison of SMBG with non-SMBG was the primary, the comparison of more frequent SMBG with less intensive SMBG the secondary analysis. Stratified analyses were performed to evaluate modifying factors. MAIN OUTCOME MEASURES: The primary endpoint was glycated haemoglobin A(1c) (HbA(1c)), secondary outcomes included fasting glucose and the occurrence of hypoglycaemia. Using random effects models a weighted mean difference (WMD) was calculated for HbA(1c) and a risk ratio (RR) was calculated for hypoglycaemia. Due to considerable heterogeneity, no combined estimate was computed for fasting glucose. RESULTS: Fifteen trials (3270 patients) were included in the analyses. SMBG was associated with a larger reduction in HbA(1c) compared with non-SMBG (WMD -0.31%, 95% confidence interval -0.44 to -0.17). The beneficial effect associated with SMBG was not attenuated over longer follow-up. SMBG significantly increased the probability of detecting a hypoglycaemia (RR 2.10, 1.37 to 3.22). More frequent SMBG did not result in significant changes of HbA(1c) compared with less intensive SMBG (WMD -0.21%, 95% CI -0.57 to 0.15). CONCLUSIONS: SMBG compared with non-SMBG is associated with a significantly improved glycaemic control in non-insulin treated patients with type 2 diabetes. The added value of more frequent SMBG compared with less intensive SMBG remains uncertain.

Differential effects of antihypertensive treatment on the retinal microcirculation: an anglo-scandinavian cardiac outcomes trial substudy.

Changes in the retinal microcirculation are associated with hypertension and predict cardiovascular mortality. There are few data describing the impact of antihypertensive therapy on retinal vascular changes. This substudy of the Anglo-Scandinavian Cardiac Outcomes Trial compared the effects of an amlodipine-based regimen (373 patients) with an atenolol-based regimen (347 patients) on retinal microvascular measurements made from fundus photographs. The retinal photographs were taken at a stage in the trial when treatments were stable and blood pressure was well controlled. Amlodipine-based treatment was associated with a smaller arteriolar length:diameter ratio than atenolol-based treatment (13.32 [10.75 to 16.04] versus 14.12 [11.27 to 17.81], median [interquartile range]; P<0.01). The association remained significant after adjustment for age, sex, cholesterol, systolic and diastolic blood pressures, body mass index, smoking, and statin treatment. This effect appeared to be largely attributable to shorter retinal arteriolar segment lengths in the amlodipine-treated group and is best explained by the vasodilator effects of amlodipine causing the visible emergence of branching side vessels. Photographic assessment of the retinal vascular network may be a useful approach to evaluating microvascular structural responses in clinical trials of antihypertensive therapy.

Serum amyloid A, C-reactive protein, and retinal microvascular changes in hypertensive diabetic and nondiabetic individuals: an Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) substudy.

OBJECTIVE: To study the association of the inflammatory markers serum amyloid A (SAA) and C-reactive protein (CRP) with retinal microvascular parameters in hypertensive individuals with and without type 2 diabetes. RESEARCH DESIGN AND METHODS: This cross-sectional analysis was a substudy in 711 patients (159 with and 552 without diabetes) of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) based on digital 30-degree images of superior and inferior temporal retinal fields. RESULTS: SAA was associated with arteriolar length-to-diameter ratio positively in nondiabetic patients (P(trend)= 0.028) but negatively in diabetic patients (P(trend)= 0.005). The difference was unlikely to be a chance finding (P = 0.007 for interaction). Similar results were found for the association of SAA with arteriolar tortuosity (P = 0.05 for interaction). Associations were less pronounced for CRP and retinal parameters. CONCLUSIONS: Inflammatory processes are differentially involved in retinal microvascular disease in diabetic compared with nondiabetic hypertensive individuals.

Association of 1,5-anhydroglucitol and 2-h postprandial blood glucose in type 2 diabetic patients.

OBJECTIVE: To assess the association of 1,5-anhydroglucitol (1,5-AG) with 2-h postprandial glucose values in type 2 diabetic patients followed over 12 months in an outpatient setting. RESEARCH DESIGN AND METHODS: In 55 patients, we examined self-measured postprandial blood glucose values for correlations with 1,5-AG values over prespecified preceding time periods (3 days, 1 week, and weekly up to 12 weeks). RESULTS: The correlation coefficients for postprandial glucose values were -0.34 (P < 0.05) for 3 days, -0.38 (P < 0.001) for 1 week, and -0.40 (P < 0.001) for 2 weeks preceding the measurement of 1,5-AG. Correlations declined for time periods >2 weeks before measurement of 1,5-AG. The correlation was lower with fasting/preprandial plasma glucose levels. There was no time dependency for the correlation between A1C and fasting or postprandial glucose. CONCLUSIONS: 1,5-AG best reflected the 2-h postprandial glucose values of the 2 previous weeks.

Drug eluting and bare metal stents in people with and without diabetes: collaborative network meta-analysis.

OBJECTIVE: To compare the effectiveness and safety of three types of stents (sirolimus eluting, paclitaxel eluting, and bare metal) in people with and without diabetes mellitus. DESIGN: Collaborative network meta-analysis. DATA SOURCES: Electronic databases (Medline, Embase, the Cochrane Central Register of Controlled Trials), relevant websites, reference lists, conference abstracts, reviews, book chapters, and proceedings of advisory panels for the US Food and Drug Administration. Manufacturers and trialists provided additional data. REVIEW METHODS: Network meta-analysis with a mixed treatment comparison method to combine direct within trial comparisons between stents with indirect evidence from other trials while maintaining randomisation. Overall mortality was the primary safety end point, target lesion revascularisation the effectiveness end point. RESULTS: 35 trials in 3852 people with diabetes and 10,947 people without diabetes contributed to the analyses. Inconsistency of the network was substantial for overall mortality in people with diabetes and seemed to be related to the duration of dual antiplatelet therapy (P value for interaction 0.02). Restricting the analysis to trials with a duration of dual antiplatelet therapy of six months or more, inconsistency was reduced considerably and hazard ratios for overall mortality were near one for all comparisons in people with diabetes: sirolimus eluting stents compared with bare metal stents 0.88 (95% credibility interval 0.55 to 1.30), paclitaxel eluting stents compared with bare metal stents 0.91 (0.60 to 1.38), and sirolimus eluting stents compared with paclitaxel eluting stents 0.95 (0.63 to 1.43). In people without diabetes, hazard ratios were unaffected by the restriction. Both drug eluting stents were associated with a decrease in revascularisation rates compared with bare metal stents in people both with and without diabetes. CONCLUSION: In trials that specified a duration of dual antiplatelet therapy of six months or more after stent implantation, drug eluting stents seemed safe and effective in people both with and without diabetes.

Exercise capacity in subjects with type 1 diabetes mellitus in eu- and hyperglycaemia.

BACKGROUND: Circumstantial evidence suggests that an increase in plasma glucose availability improves exercise capacity in subjects with type 1 diabetes mellitus. The aim of this study was to assess exercise capacity in eu- and hyperglycaemic conditions in subjects with type 1 diabetes. METHODS: Eight moderately exercise-trained male subjects with type 1 diabetes on continuous subcutaneous insulin infusion were studied. Using identical insulin infusion rates, the patients were randomly allocated to perform two stepwise ergometer tests in eu- and hyperglycaemic clamp conditions. The primary endpoint was the peak power output; the secondary endpoints comprised the rate of perceived exertion, lactate levels, heart rate, and respiratory exchange ratio. RESULTS: Eu- and hyperglycaemic clamp conditions were observed at a plasma glucose concentration of 5.3 +/- 0.6 mmol/L and 12.4 +/- 2.1 mmol/L, respectively (mean +/- SD), and remained stable throughout the physical exercise. Insulin levels were similar in both conditions. Hyperglycaemia did not result in a significant increase in the peak power output compared to euglycaemia (mean paired difference of 4.96 W, 95% CI - 11.3 to 21.2, p = 0.49). Hyperglycaemia did not have a significant impact on the secondary endpoints compared to euglycaemia. Sensitivity analyses confirmed these results. CONCLUSIONS: In subjects with type 1 diabetes, exercise capacity is not influenced by hyperglycaemia. Comparable levels of lactate and similar respiratory exchange ratio suggest that an increase in extracellular glucose availability did not translate into increased intracellular glucose oxidation.