Admission glucose as a prognostic marker for all-cause mortality and cardiovascular disease.

BACKGROUND: Diabetes and prediabetes are known risk factors for cardiovascular disease and associated with increased mortality risk. Whether patients with a random elevated blood glucose level but no history of diabetes are at a higher mortality and cardiovascular risk is not entirely known. METHODS: A retrospective cohort study where patients (18-80 years) with no history of diabetes between 2006 and 2016 attending the emergency department (ED) in Sweden were included. Based on the first (index) blood glucose level patients were categorized into four groups: hypoglycemia (< 3.9 mmol/L), normal glucose tolerance (NGT) (3.9-7.8 mmol/L), dysglycemia (7.8-11.1 mmol/L), and hyperglycemia (> 11.1 mmol/L). Data was collected from four nationwide registers (National Patient Register, National Cause of Death Register, Prescribed Drug Register and Statistics Sweden). Cox regression was used to calculate adjusted hazard ratios (HR) with 95% confidence intervals (CI) for all-cause mortality and cardiovascular outcomes using NGT as reference. RESULTS: 618,694 patients were included during a mean follow-up time of 3.9 years. According to the index blood glucose level: 1871 (0.3%) had hypoglycemia, 525,636 (85%) had NGT, 77,442 (13%) had dysglycemia, and 13,745 (2%) patients had hyperglycemia, respectively. During follow-up 44,532 (7.2%) deaths occurred. After multiple adjustments, mortality risk was highest in patients with hypoglycemia HR 2.58 (2.26-2.96) followed by patients with hyperglycemia HR 1.69 (1.63-1.76) and dysglycemia HR 1.16 (1.13-1.19). Risk for cardiovascular events: i.e., myocardial infarction, stroke and heart failure, were highest among patients with hyperglycemia HR 2.28 (2.13-2.44), HR 1.62 (1.51-1.74) and HR 1.60 (1.46-1.75), respectively. CONCLUSION: Patients with disturbed blood glucose level at ED admission have a higher mortality risk than patients with NGT. Patients with hyperglycemia have almost a two folded increased long-term mortality risk and more than a doubled risk for cardiovascular events compared to patients with NGT.

Long-term prognosis in patients with acute myocardial infarction and newly detected glucose abnormalities: predictive value of oral glucose tolerance test and HbA1c.

BACKGROUND: Disturbances of glucose metabolism can be diagnosed by an oral glucose tolerance test (OGTT) and by glycated haemoglobin (HbA1c). The aim of this study was to investigate the association between newly detected disturbances of glucose metabolism and long-term prognosis after acute myocardial infarction (AMI) and to compare the predictive value of an OGTT and HbA1c. METHODS: Patients under the age of 80 years with no known history of diabetes admitted for AMI at the Department of Cardiology, Danderyd University Hospital, Stockholm, Sweden, from January 1st, 2006 until December 31st, 2013, were investigated with an OGTT and a HbA1c before discharge and were classified as having normal glucose tolerance (NGT), prediabetes or diabetes according to American Diabetes Association (ADA) criteria. Using nationwide, all-inclusive registers, patients were followed for the incidence of combined event [CE (first of myocardial infarction, heart failure, ischaemic stroke or mortality)] for a mean follow-up time of 4.8 years. Cox regression analysis was used to calculate Hazard Ratios (HR) and their 95% confidence intervals (CI). RESULTS: Of the 841 patients who were investigated with both an OGTT and a HbA1c, 139 (17%) patients had NGT, 398 (47%) had prediabetes and 304 (36%) had diabetes according to OGTT. The corresponding figures using HbA1c were 320 (38%), 461 (55%) and 60 (7%). Patients with newly discovered diabetes were older and had a higher body mass index compared to those with NGT. OGTT was not predictive for CE. In contrast, prediabetes identified by a HbA1c was associated with an increased risk for CE (HR 1.31; 95% CI 1.05-1.63) compared to normoglycaemia. When comparing the prognostic value of different glucose and HbA1c cut-offs, only a HbA1c ≥ 39 mmol/mol was significantly associated with CE (HR 95% CI; 1.30:1.05-1.61). CONCLUSION: In this single-centre study, in a recent contemporary cohort, we found that around two thirds of the patients admitted with AMI with no known history of diabetes had disturbed glucose metabolism, in accordance with previous studies. HbA1c in the prediabetes range, but not OGTT, added predictive value on the long-term outcome, in a cohort to whom a pathologic OGTT result was communicated with lifestyle advice.

Effects of exenatide on microvascular reactivity in patients with type 2 diabetes and coronary artery disease: A randomized controlled study.

OBJECTIVE: We studied the effect of the GLP-1RA exenatide on skin microvascular function in patients with T2DM and CAD. METHODS: Thirty-five patients with T2DM, CAD, and HbA1C 42-86 mmol/mol were randomized to treatment with exenatide or conventional non-GLP-1-based therapy for 12 weeks. Skin microvascular function was examined in the forearm by LDF and iontophoretic application of acetyl choline and SNP, and by PORH at baseline and after 12 weeks. Blood samples for fasting plasma glucose, HbA1C, and lipid profile were collected. RESULTS: At 12 weeks, patients on exenatide showed reductions in HbA1C (from 63.5 ± 13 to 60.7 ± 14 mmol/mol, p = .065), body weight (from 92.6 ± 16 to 89 ± 16 kg, p < .001), and systolic blood pressure (from 141 ± 13 to 134 ± 16 mm Hg, p < .05) as compared to the conventionally treated group. There were no significant changes in skin microvascular function between or within the two groups at follow-up. CONCLUSIONS: Three months' daily treatment with the GLP-1RA exenatide in T2DM patients with CAD showed no significant effects on skin microvascular function or blood glucose control, while this study confirms a reduction in body weight and blood pressure by exenatide, as compared to conventional antidiabetic drug treatment.

Preoperative disturbances of glucose metabolism and mortality after coronary artery bypass grafting.

BACKGROUND: Disturbances of glucose metabolism are important risk factors for coronary artery disease and are associated with an increased mortality risk. The aim was to investigate the association between preoperative disturbances of glucose metabolism and long-term all-cause mortality after coronary artery bypass grafting (CABG). METHODS: Patients undergoing a first isolated CABG in 2005-2013 were included. All patients without previously known diabetes underwent an oral glucose tolerance test (OGTT) before surgery. They were categorised as having normal glucose tolerance (NGT), pre-diabetes (impaired glucose tolerance and/or impaired fasting glucose) or newly discovered diabetes. Data were collected from nationwide healthcare registers. Cox regression was used to calculate adjusted HR with 95% CI for death in patients with pre-diabetes and diabetes, using NGT as reference. RESULTS: In total, 497 patients aged 40-86 years were included. According to OGTT, 170 (34%) patients had NGT, 219 (44%) patients with pre-diabetes and 108 (22%) patients had newly discovered diabetes. Baseline characteristics were similar between the groups except for slightly higher age among patients with newly discovered diabetes. There were 133 (27%) deaths during a mean follow-up time of 10 years. The cumulative 10-year survival was 77% (69%-83%), 83% (77%-87%) and 71% (61%-79%) in patients with NGT, pre-diabetes and newly discovered diabetes, respectively. There was no significant difference in all-cause mortality between the groups after multivariable adjustment. CONCLUSION: In this study, patients with pre-diabetes or newly discovered diabetes prior to CABG had similar long-term survival compared with patients with NGT.

Estimated glucose disposal rate and long-term survival in type 2 diabetes after coronary artery bypass grafting.

We performed a nationwide population-based cohort study to investigate the association between estimated glucose disposal rate (eGDR) and long-term survival after coronary artery bypass grafting (CABG) in patients with type 2 diabetes. All patients who underwent primary CABG in Sweden from 2006 to 2013 were identified from the SWEDEHEART register and by record linkage to the National Diabetes Register; all patients with type 2 diabetes were included and formed the study population. Patients were followed until 2013 through national registers for major adverse cardiovascular events and death from any cause. eGDR was calculated using waist circumference, hemoglobin A1c, and presence or the absence of hypertension. The association between eGDR and death was estimated using multivariable Cox regression. A total of 3256 patients were included. During a mean follow-up of 3.1 years (10,227 person-years), in total, 14 % patients died: 17 % (n = 186) in the 1st tertile (lowest eGDR), 14 % (n = 145) in the 2nd tertile, and 13 % (n = 133) in the 3rd tertile (highest eGDR). There was a significant association between eGDR and increased risk of death: adjusted hazard ratio (95 % confidence interval): 1.46 (1.12-1.90) for the 1st eGDR tertile compared to the 3rd and highest eGDR tertile. In conclusion, patients with type 2 diabetes who underwent CABG, a low eGDR, were associated with an increased risk of long-term all-cause mortality that was independent of other cardiovascular and metabolic risk factors. Insulin resistance measured by eGDR could be a useful risk marker in patients with type 2 diabetes and ischemic heart disease.

Electronic cigarettes increase endothelial progenitor cells in the blood of healthy volunteers.

BACKGROUND AND AIMS: The use of electronic cigarettes is increasing dramatically on a global scale and its effects on human health remain uncertain. In the present study, we measured endothelial progenitor cells (EPCs) and microvesicles (MVs) in healthy young volunteers following short-term exposure to inhalation of e-cigarette vapor (ECV) to determine vascular changes. METHODS: Sixteen healthy seldom smokers were randomized into two groups either exposed or not exposed to 10 puffs of ECV for 10 min, in a crossover design. Blood samples were obtained at baseline and 1, 4 and 24 h following exposure. EPCs (CD34 + CD309) and MVs were analyzed by flow cytometry. MVs were phenotyped according to origin (platelet (CD41), endothelial (CD144), leukocytes (CD45), monocytes (CD14)) and nuclear content (SYTO 13 dye). In addition, expression of inflammation markers such P-selectin (CD62P), E-selectin (CD62E), CD40-ligand (CD154) and HMGB1 was investigated. Fractional exhaled nitric oxide (FeNO) was also measured at baseline and after 24 h. RESULTS: EPC levels in blood were significantly increased 1 h following exposure to ECV and returned to baseline values after 24 h. Only E-selectin positive MVs (endothelial origin) were slightly elevated (p < 0.038). FeNO was unaffected by exposure to ECV. CONCLUSIONS: In healthy volunteers, ten puffs of e-cigarette vapor inhalation caused an increase in EPCs. This increase was of the same magnitude as following smoking of one traditional cigarette, as we previously demonstrated. Taken together, these results may represent signs of possible vascular changes after short e-cigarette inhalation. Further studies analyzing potential cardiovascular health effects are critical as the e-cigarette market continues to burgeon.

Relationship between preoperative hemoglobin A1c levels and long-term mortality after coronary artery bypass grafting in patients with type 2 diabetes mellitus.

BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) have an increased risk of coronary heart disease and death. We aimed to investigate the association between preoperative hemoglobin A1c (HbA1c) levels and long-term mortality after coronary artery bypass grafting (CABG) among patients with T2DM. METHODS: All patients with T2DM who underwent CABG in Sweden from 2003 to 2013 were included from the SWEDEHEART register. Information about diabetes was retrieved from the Swedish National Diabetes Register. We used Cox regression to calculate hazard ratios (HR) with 95% confidence intervals (CI) for all-cause mortality and also a combination of death or a major cardiovascular event (MACE). RESULTS: In total, 6313 patients were included. During a mean follow-up time of 5.5 (±3.8) years, (34,482 person-years), 1630 (26%) patients died. After multivariable adjustment, HbA1c was associated with an increased risk of death in patients with HbA1c levels 9.1-10%, and >10% (HR (95% CI): 1.26 (1.04-1.53), and 1.33 (1.05-1.69), respectively). There was an increased risk for death or MACE at HbA1c levels 8.1-9%, 9.1-10%, and >10% (HR (95% CI): 1.17 (1.04-1.33), 1.44 (1.22-1.70), and 1.50 (1.22-1.84), respectively). In patients with insulin-treatment there was no association between HbA1c levels and death. CONCLUSIONS: In patients with T2DM who underwent CABG we found an increased risk of death at HbA1c levels above 9.0%, and also for the combination of death or MACE at HbA1c levels above 8.1%. There was no association between HbA1c levels and death in T2DM patients who were insulin-treated.

Long-term clinical outcome in patients with acute coronary syndrome and dysglycaemia.

BACKGROUND: Diabetes and impaired glucose tolerance (IGT) are major risk factors for atherosclerosis including coronary artery disease (CAD). The present study's aim was to investigate the importance of glucose tolerance for long-term clinical outcome in patients with acute coronary syndrome (ACS). METHODS: A total 1062 consecutive patients, 781 men and 281 women, aged 32-80 years, admitted to the coronary care unit at Danderyd University Hospital, Stockholm, for ACS from 2006 to 2008 were included. At discharge, the patients were categorized according to an oral glucose tolerance test (OGTT) as having normal glucose tolerance (NGT), n = 295 (28%); impaired fasting glucose (IFG) and IGT, n = 299 (28%); diabetes discovered by OGTT, n = 156 (15%); or known diabetes at admission, n = 312 (29%). Mortality and reinfarction rates were studied during a mean follow-up time of 4.0 (±0.8) years. Clinical outcome data were obtained from the Swedish Coronary Angiography and Angioplasty Registry and the Swedish National Registry. RESULTS: There was significantly higher (p < 0.001) mortality within, 30 days, 1 and 3 years in patients with known diabetes as compared to the other groups. During the follow-up, 86 patients (28%) with known diabetes had reinfarction as compared to 36 patients (12%) with NGT and 79 patients (17%) with dysglycaemia (IFG, IGT and diabetes) discovered by OGTT. CONCLUSION: A majority (72% in this study) of patients admitted for ACS have disturbed glucose metabolism, including diabetes, with high prevalence of previously undiagnosed dysglycaemia. Both patients with known diabetes and dysglycaemia discovered by OGTT show a high risk for poor clinical prognosis.

Glycemic Control in Type 1 Diabetes and Long-Term Risk of Cardiovascular Events or Death After Coronary Artery Bypass Grafting.

BACKGROUND: Patients with type 1 diabetes mellitus (T1DM) have a high risk of cardiovascular events. OBJECTIVES: The aim of this study was to investigate whether preoperative hemoglobin A1c (HbA1c) levels could predict cardiovascular events or death after coronary artery bypass grafting (CABG). METHODS: This was a nationwide population-based observational cohort study that included all patients with T1DM who underwent primary isolated nonemergency CABG in Sweden between 1997 and 2012, according to the Swedish National Diabetes Register and the SWEDEHEART (Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies) register. We calculated the crude incidence rates and 95% confidence intervals (CIs) and used Cox regression and multivariable hazard ratios (HRs) to estimate the risk of both all-cause mortality and major adverse cardiovascular events (MACE), defined as myocardial infarction, stroke, heart failure, or repeat revascularization, in relation to HbA1c levels. RESULTS: In total, 764 patients with T1DM were included. During a median follow-up of 4.7 years, 334 (44%) patients died or had MACE (incidence rate: 82 events/1,000 person-years). After multivariable adjustment, the HR (95% CI) for death or MACE in patients with HbA1c levels of 7.1% to 8.0%, 8.1% to 9.0%, 9.1% to 10.0%, and >10.0% were 1.34 (0.82 to 2.21), 1.59 (1.00 to 2.54), 1.73 (1.03 to 2.90), and 2.25 (1.29 to 3.94), respectively, compared with the reference category. When HbA1c was used as a continuous variable, the HR for a 1% increase in HbA1c level was 1.18, and the 95% CI was 1.06 to 1.32. CONCLUSIONS: In patients with T1DM, poor glycemic control before CABG was associated with increased long-term risk of death or MACE. (HeAlth-data Register sTudies of Risk and Outcomes in Cardiac Surgery [HARTROCS]; NCT02276950).

Long-term prognosis in patients with type 1 and 2 diabetes mellitus after coronary artery bypass grafting.

BACKGROUND: Patients with diabetes mellitus (DM) have an increased risk of adverse outcomes after coronary artery bypass grafting (CABG). Previous studies have reported prognosis in relation to treatment with or without insulin, and not to the type of diabetes. OBJECTIVES: This study investigated long-term survival in patients with type 1 DM (T1DM) and type 2 DM (T2DM) following CABG. METHODS: We included all patients from the SWEDEHEART (Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies) register who underwent primary isolated CABG in Sweden during 2003 through 2013. We identified patients with T1DM or T2DM in the Swedish National Diabetes Register. We calculated hazard ratios (HRs) with 95% confidence intervals (CIs) for all-cause mortality in patients with T1DM or T2DM. RESULTS: In total, 39,235 patients were included, of whom 725 (1.8%) had T1DM and 8,208 (21%) had T2DM. Patients with TDM1 were younger (59 vs. 67 years), had reduced kidney function (31% vs. 24%), and had peripheral vascular disease (21% vs. 11%) more often than patients with TDM2 or no diabetes. During a mean follow-up of 5.9±3.2 years (230,085 person-years), 6,765 (17%) patients died. Among patients with T1DM, 152 (21%) died, and among patients with T2DM, 1,549 (19%) died. Adjusted hazard ratio (95% confidence interval) for death in patients with T1DM and T2DM, compared with patients without diabetes, were 2.04 (1.72 to 2.42), and 1.11 (1.05 to 1.18), respectively. CONCLUSIONS: Patients with T1DM had more than double the long-term risk of death after CABG compared with patients without diabetes. The long-term risk of death in patients with T2DM was only slightly increased.

The effects of smoking on levels of endothelial progenitor cells and microparticles in the blood of healthy volunteers.

BACKGROUND: Cigarette smoking, both active and passive, is one of the leading causes of morbidity and mortality in cardiovascular disease. To assess the impact of brief smoking on the vasculature, we determined levels of circulating endothelial progenitor cells (EPCs) and circulating microparticles (MPs) following the smoking of one cigarette by young, healthy intermittent smokers. MATERIALS AND METHODS: 12 healthy volunteers were randomized to either smoking or not smoking in a crossover fashion. Blood sampling was performed at baseline, 1, 4 and 24 hours following smoking/not smoking. The numbers of EPCs and MPs were determined by flow cytometry. MPs were measured from platelets, leukocytes and endothelial cells. Moreover, MPs were also labelled with anti-HMGB1 and SYTO 13 to assess the content of nuclear molecules. RESULTS: Active smoking of one cigarette caused an immediate and significant increase in the numbers of circulating EPCs and MPs of platelet-, endothelial- and leukocyte origin. Levels of MPs containing nuclear molecules were increased, of which the majority were positive for CD41 and CD45 (platelet- and leukocyte origin). CD144 (VE-cadherin) or HMGB1 release did not significantly change during active smoking. CONCLUSION: Brief active smoking of one cigarette generated an acute release of EPC and MPs, of which the latter contained nuclear matter. Together, these results demonstrate acute effects of cigarette smoke on endothelial, platelet and leukocyte function as well as injury to the vascular wall.

Combined treatment with exercise training and acarbose improves metabolic control and cardiovascular risk factor profile in subjects with mild type 2 diabetes.

OBJECTIVE: The effect of exercise training and acarbose on glycemic control, insulin sensitivity, and phenotype was investigated in mild type 2 diabetes. RESEARCH DESIGN AND METHODS: Sixty-two men and women with type 2 diabetes were randomized to 12 weeks of structured exercise training with or without acarbose treatment or to acarbose alone. Glycemic control was determined by HbA(1c) (A1C), insulin sensitivity (M value) by euglycemic-hyperinsulinemic clamp, and regional fat distribution by computerized tomography and dual X-ray absorptiometry. Physical fitness was determined as maximal oxygen uptake (Vo(2max)). All investigations were performed before and after the intervention. RESULTS: Forty-eight subjects completed the study. Exercise improved M value by 92% (P = 0.017) and decreased total and truncal fat (P = 0.002, 0.001) and systolic blood pressure (P = 0.01) but had no significant effect on Vo(2max) or A1C level. The combination of exercise and acarbose significantly decreased fasting plasma glucose, A1C, lipids, and diastolic blood pressure and increased Vo(2max), whereas effects on M value and body composition were comparable with that of exercise alone. Acarbose alone had no significant effect on either M value or A1C but decreased systolic (P = 0.001) and diastolic blood pressure (P = 0.001) and fasting proinsulin level (P = 0.009). Multiple regression analysis showed that addition of acarbose to exercise improved glycemic control. CONCLUSIONS: In subjects with mild type 2 diabetes, exercise training improved insulin sensitivity but had no effect on glycemic control. The addition of acarbose to exercise, however, was associated with significant improvement of glycemic control and possibly cardiovascular risk factors.

Exercise training decreases the concentration of malonyl-CoA and increases the expression and activity of malonyl-CoA decarboxylase in human muscle.

The study was designed to evaluate whether changes in malonyl-CoA and the enzymes that govern its concentration occur in human muscle as a result of physical training. Healthy, middle-aged subjects were studied before and after a 12-wk training program that significantly increased VO2 max by 13% and decreased intra-abdominal fat by 17%. Significant decreases (25-30%) in the concentration of malonyl-CoA were observed after training, 24-36 h after the last bout of exercise. They were accompanied by increases in both the activity (88%) and mRNA (51%) of malonyl-CoA decarboxylase (MCD) in muscle but no changes in the phosphorylation of AMP kinase (AMPK, Thr172) or of acetyl-CoA carboxylase. The abundance of peroxisome proliferator-activated receptor (PPAR)gamma coactivator-1alpha (PGC-1alpha), a regulator of transcription that has been linked to the mediation of MCD expression by PPARalpha, was also increased (3-fold). In studies also conducted 24-36 h after the last bout of exercise, no evidence of increased whole body insulin sensitivity or fatty acid oxidation was observed during an euglycemic hyperinsulinemic clamp. In conclusion, the concentration of malonyl-CoA is diminished in muscle after physical training, most likely because of PGC-1alpha-mediated increases in MCD expression and activity. These changes persist after the increases in AMPK activity and whole body insulin sensitivity and fatty acid oxidation, typically caused by an acute bout of exercise in healthy individuals, have dissipated.

Insulin resistance in type 2 diabetes: association with truncal obesity, impaired fitness, and atypical malonyl coenzyme A regulation.

Abdominal obesity and physical inactivity are associated with insulin resistance in humans and contribute to the development of type 2 diabetes. Likewise, sustained increases in the concentration of malonyl coenzyme A (CoA), an inhibitor of fatty-acid oxidation, have been observed in muscle in association with insulin resistance and type 2 diabetes in various rodents. In the present study, we assessed whether these factors are present in a defined population of slightly overweight (body mass index, 26.2 kg/m2), insulin-resistant patients with type 2 diabetes. Thirteen type 2 diabetic men and 17 sex-, age-, and body mass index-matched control subjects were evaluated. Insulin sensitivity was assessed during a two-step euglycemic insulin clamp (infusion of 0.25 and 1.0 mU/kg x min). The rates of glucose administered during the low-dose insulin clamp were 2.0 +/- 0.2 vs. 0.7 +/- 0.2 mg/kg body weight x min (P < 0.001) in the control and diabetic subjects, respectively; rates during the high-dose insulin clamp were 8.3 +/- 0.7 vs. 4.6 +/- 0.4 mg/kg body weight x min (P < 0.001) for controls and diabetic subjects. The diabetic patients had a significantly lower maximal oxygen uptake than control subjects (29.4 +/- 1.0 vs. 33.4 +/- 1.4 ml/kg x min; P = 0.03) and a greater total body fat mass (3.7 kg), mainly due to an increase in truncal fat (16.5 +/- 0.9 vs. 13.1 +/- 0.9 kg; P = 0.02). The plasma concentration of free fatty acid and the rate of fatty acid oxidation during the clamps were both higher in the diabetic subjects than the control subjects (P = 0.002-0.007). In addition, during the high-dose insulin clamp, the increase in cytosolic citrate and malate in muscle, which parallels and regulates malonyl CoA levels, was significantly less in the diabetic patients (P < 0.05 vs. P < 0.001). Despite this, a similar increase in the concentration of malonyl CoA was observed in the two groups, suggesting an abnormality in malonyl CoA regulation in the diabetic subjects. In conclusion, the results confirm that insulin sensitivity is decreased in slightly overweight men with mild type 2 diabetes and that this correlates closely with an increase in truncal fat mass and a decrease in physical fitness. Whether the unexpectedly high levels of malonyl CoA in muscle, together with the diminished suppression of plasma free fatty acid, explains the insulin resistance of the diabetic patients during the clamp remains to be determined.