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1.  Impact of newly diagnosed abnormal glucose regulation on long-term prognosis in low risk patients with ST-elevation myocardial infarction: A follow-up study 
Background
Patients with acute myocardial infarction and newly detected abnormal glucose regulation have been shown to have a less favourable prognosis compared to patients with normal glucose regulation. The importance and timing of oral glucose tolerance testing (OGTT) in patients with acute myocardial infarction without known diabetes is uncertain. The aim of the present study was to evaluate the impact of abnormal glucose regulation classified by an OGTT in-hospital and at three-month follow-up on clinical outcome in patients with acute ST elevation myocardial infarction (STEMI) without known diabetes.
Methods
Patients (n = 224, age 58 years) with a primary percutanous coronary intervention (PCI) treated STEMI were followed for clinical events (all-cause mortality, non-fatal myocardial re-infarction, recurrent ischemia causing hospital admission, and stroke). The patients were classified by a standardised 75 g OGTT at two time points, first, at a median time of 16.5 hours after hospital admission, then at three-month follow-up. Based on the OGTT results, the patients were categorised according to the WHO criteria and the term abnormal glucose regulation was defined as the sum of impaired fasting glucose, impaired glucose tolerance and type 2-diabetes.
Results
The number of patients diagnosed with abnormal glucose regulation in-hospital and at three-month was 105 (47%) and 50 (25%), respectively. During the follow up time of (median) 33 (27, 39) months, 58 (25.9%) patients experienced a new clinical event. There were six deaths, 15 non-fatal re-infarction, 33 recurrent ischemia, and four strokes. Kaplan-Meier analysis of survival free of composite end-points showed similar results in patients with abnormal and normal glucose regulation, both when classified in-hospital (p = 0.4) and re-classified three months later (p = 0.3).
Conclusions
Patients with a primary PCI treated STEMI, without previously known diabetes, appear to have an excellent long-term prognosis, independent of the glucometabolic state classified by an OGTT in-hospital or at three-month follow-up.
Trial registration
The trial is registered at http://www.clinicaltrials.gov, NCT00926133.
doi:10.1186/1472-6823-11-14
PMCID: PMC3173358  PMID: 21801387
2.  Comparison of prognosis for men with type 2 diabetes mellitus and men with cardiovascular disease 
Background
People with type 2 diabetes mellitus are at high risk for cardiovascular disease. In some studies, the mortality rate among people with this condition has been equivalent to that among people with cardiovascular disease. We compared cardiovascular mortality between incident cases of diabetes and cardiovascular disease.
Methods
The study population was part of a random sample of 4376 men from Quebec, Canada, aged 35 to 64 years, who did not have cardiovascular disease in 1974 and who were followed until 1998. Three groups of incident cases were identified: diabetes without cardiovascular disease, first cardiovascular event (myocardial infarction, unstable angina or stroke) without diabetes, and both cardiovascular disease and diabetes. These cases were age-matched to a control group without diabetes or cardiovascular disease.
Results
During the 24-year follow-up period, new diabetes without cardiovascular disease was documented in 137 men. A first cardiovascular event without diabetes was documented in 527 men. Relative to the 627 controls, men with 1 of the 2 diseases of interest had higher cardiovascular mortality (age-adjusted relative risk [RR] 3.11, 95% confidence interval [CI] 1.96–4.92) for those with diabetes and 4.46 (95% CI 3.15–6.30) for those with cardiovascular disease). However, within the first 5 years after diagnosis, men with cardiovascular disease had higher cardiovascular mortality than men with diabetes (age-adjusted RR 2.03, 95% CI 1.01–4.08).
Interpretation
Men with isolated type 2 diabetes and men with isolated cardiovascular disease had similar cardiovascular mortality rates several years after initial diagnosis of either condition. These findings reinforce the need to prevent and optimally manage diabetes and cardiovascular disease.
doi:10.1503/cmaj.071027
PMCID: PMC2612049  PMID: 19124789
3.  Newly diagnosed glucose intolerance and prognosis after acute myocardial infarction: comparison of post-challenge versus fasting glucose concentrations 
Heart  2012;98(11):848-854.
Background
Recent studies have demonstrated that newly diagnosed glucose intolerance is common among patients with acute myocardial infarction (AMI). The purpose of this study was to assess the long-term clinical cardiovascular outcomes in participants with AMI with abnormal fasting glucose compared with normal fasting glucose and an abnormal oral glucose tolerance test (OGTT) compared with a normal OGTT.
Methods
A prospective study was performed in 275 consecutive patients with AMI, 85 of whom had pre-diagnosed diabetes mellitus (DM). Those without DM were divided into two groups based on the 75 g OGTT at the time of discharge. Abnormal glucose tolerance (AGT) was defined as 2 h glucose ≥140 mg/dl; 78 patients had normal glucose tolerance (NGT) and 112 had AGT. The same patients were also reclassified into the normal fasting glucose group (NFG; n=168) or the impaired fasting glucose group (IFG; n=22). The association between the glucometabolic status and long-term major adverse cardiovascular event rates was evaluated.
Results
Kaplan–Meier survival curves showed that the AGT group had a worse prognosis than the NGT group and an equivalent prognosis to the DM group (p<0.0005). Cox proportional hazard model analysis showed that the HR of AGT to NGT for major adverse cardiovascular event rates was 2.65 (95% CI 1.37 to 5.15, p=0.004) while the HR of DM to NGT was 3.27 (1.68 to 6.38, p=0.0005). However, Cox HR of IFG to NFG for major adverse cardiovascular event rates was 1.83 (0.86 to 3.87), which was not significant.
Conclusion
In patients with AMI, an abnormal OGTT is a better risk factor for future adverse cardiovascular events than impaired fasting blood glucose.
doi:10.1136/heartjnl-2012-301629
PMCID: PMC3351853  PMID: 22581733
Acute myocardial infarction; diabetes mellitus; postprandial hyperglycemia; cardiovascular events; prognosis; microvascular dysfunction; clinical cardiology; clinical coronary heart disease; diabetes; coronary hemodynamics; coronary artery disease; valvular disease; imaging and diagnostics; diabetic heart disease; peripheral vascular disease; diastolic dysfunction; endocarditis; surgery-valve; MRI; coronary artery disease; risk factors; EBM; heart failure
4.  Abnormal glucose regulation in patients with acute ST- elevation myocardial infarction-a cohort study on 224 patients 
Background
A high prevalence of impaired glucose tolerance and unknown type 2-diabetes in patients with coronary heart disease and no previous diagnosis of diabetes have been reported. The aims of the present study were to investigate the prevalence of abnormal glucose regulation (AGR) 3 months after an acute ST-elevation myocardial infarction (STEMI) in patients without known glucometabolic disturbance, to evaluate the reliability of a 75-g oral glucose tolerance test (OGTT) performed very early after an acute STEMI to predict the presence of AGR at 3 months, and to study other potential predictors measured in-hospital for AGR at 3 months.
Methods
This was an observational cohort study prospectively enrolling 224 STEMI patients treated with primary PCI. An OGTT was performed very early after an acute STEMI and was repeated in 200 patients after 3 months. We summarised the exact agreement observed, and assessed the observed reproducibility of the OGTTs performed in-hospital and at follow up. The patients were classified into glucometabolic categories defined according to the World Health Organisation criteria. AGR was defined as the sum of impaired fasting glucose, impaired glucose tolerance and type 2-diabetes.
Results
The prevalence of AGR at three months was 24.9% (95% CI 19.1, 31.4%), reduced from 46.9% (95% CI 40.2, 53.6) when measured in-hospital. Only, 108 of 201 (54%) patients remained in the same glucometabolic category after a repeated OGTT. High levels of HbA1c and admission plasma glucose in-hospital significantly predicted AGR at 3 months (p < 0.001, p = 0.040, respectively), and fasting plasma glucose was predictive when patients with large myocardial infarction were excluded (p < 0.001).
Conclusion
The prevalence of AGR in STEMI patients was lower than expected. HbA1c, admission plasma glucose and fasting plasma glucose measured in-hospital seem to be useful as early markers of longstanding glucometabolic disturbance. An OGTT performed very early after a STEMI did not provide reliable information on long-term glucometabolic state and should probably not be recommended.
doi:10.1186/1475-2840-8-6
PMCID: PMC2646717  PMID: 19183453
5.  Impact of timing to coronary angiography in acute coronary syndrome on contemporary clinical practice 
Recent studies appear to suggest a correlation between timing to coronary angiography and clinical outcome among patients with acute coronary syndrome (ACS). We aim to study 12-month outcomes of ACS patients who are stratified according to early (≤24 hours), intermediate (>24 to <48 hours) and delayed (≥48 hours) coronary angiography. This is a prospective observational study of patients with ACS defined as either unstable angina pectoris or non-ST elevation myocardial infarction (MI) admitted between October 2008 and July 2009. Baseline clinical characteristics of age, gender, cardiovascular risk factors (diabetes mellitus, hypertension, dyslipidemia) and TIMI score were analyzed and adjusted for outcomes. The primary outcome was combined major adverse cardiovascular events (MACE) of death or non-fatal MI, as well as target vessel revascularization (TVR) up to 12 months. This study consisted of 642 patients (75% males, mean age 60±13) with median follow-up of 7 months and median TIMI score of 4. Over half (50.2%) were categorized as high-risk (TIMI score ≥4). 281 patients (43.5%) had early angiography, 170 (26.5%) had angiography between >24 to <48 hours and 191(30%) patients had delayed angiography ≥48 hours. In high-risk patients, the primary outcome occurred in 10.9% of patients in the early group, as compared with 13.2% in intermediate group and 23.9% in delayed group (p=0.015) at six months. However, in low-risk patients (TIMI scores <4), there was no significant difference between the groups (7.1% vs. 3.4% vs. 5.9%, p=0.316) at six months. Compared to the intermediate and delayed groups, patients in the early group had lower overall MACE at 12 months (21% vs. 14% vs. 10%, p=0.006) that was largely related to a lower frequency of death at 12 months (11% vs. 7% vs. 4.6%, p=0.03). There were no differences in rates of TVR between the groups (4% vs. 7% vs. 3.5%, p=0.14). In this observational analysis, an early strategy to coronary angiography was associated with improved survival at one year while an early to intermediate strategy benefitted the subgroup of high-risk patients with significant reductions in cardiovascular events at six months.
PMCID: PMC3427977  PMID: 22937494
Myocardial infarction; acute coronary syndrome; coronary angiography
6.  Ten year mortality in relation to original size of myocardial infarct: results from the Gothenburg metoprolol study. 
British Heart Journal  1994;71(3):238-241.
OBJECTIVE--To describe the relation between the extent of a myocardial infarct, measured according to maximum serum enzyme activity of lactate dehydrogenase, and mortality at 10 years. PATIENTS--In 759 patients with acute myocardial infarction in whom serum activity of heat stable lactate dehydrogenase had been determined every 12 hours for 108 hours after randomisation in an early intervention trial with metoprolol. MAIN OUTCOME MEASURE--Mortality at 10 years in relation to quartile of maximum serum lactate dehydrogenase activity and history of cardiovascular disease. RESULTS--Among all patients mortality at 10 years was 39% in the lowest quartile, 51% in the second quartile, 50% in the third, and 59% in the fourth (p < 0.001 for relation between infarct size and 10 year mortality). Among patients without a history of myocardial infarction, angina pectoris, diabetes mellitus, or hypertension the mortality in each quartile was 29%, 32%, 41%, and 56%, respectively (p < 0.001 for relation between infarct size and 10 year mortality). Among patients with any of these risk indicators the association between the estimated infarct size and mortality at 10 years was weak (p < 0.05). CONCLUSION--Estimated size of a myocardial infarct and mortality over 10 years seem to be related but mainly in patients without a history of cardiovascular disease.
PMCID: PMC483660  PMID: 8142192
7.  Cardiac complications in type 2 diabetic patients with mild anginal symptoms and documented reversible myocardial perfusion defects 
Netherlands Heart Journal  2006;14(12):409-416.
Background/Objective
To compare early invasive treatment with continued pharmacological treatment in patients with diabetes mellitus type 2, mild anginal symptoms and documented myocardial ischaemia.
Methods
Patients with type 2 diabetes mellitus and mild anginal symptoms underwent myocardial perfusion scintigraphy (MPS). Patients with myocardial ischaemia were randomly assigned to early invasive or continued pharmacological treatment. All patients were followed for the occurrence of MACE (death, nonfatal myocardial infarction or hospitalisation for unstable angina pectoris).
Results
A total of 156 patients were randomised when the sponsor (ZonMW) prematurely terminated the study because of a slow recruitment rate. With a mean follow-up of 2.1±0.6 years, 9 of 79 patients assigned to early invasive treatment developed MACE compared with 10 of 77 patients randomised to continued pharmacological treatment, annual event rate 5.4 vs. 6.3%, hazard ratio 0.89, 95% CI 0.36 to 2.20, p=0.34. Due to the limited number of included patients and the low event rate, the study did not have sufficient power for the study objective.
Conclusion
Patients with diabetes mellitus type 2, mild anginal symptoms and documented myocardial ischaemia, under appropriate medical treatment, have a lower than anticipated annual event rate of MACE of ±5 to 6% which questions the beneficial effect of early revascularisation.
PMCID: PMC2557327
diabetes mellitus type 2; angina pectoris; randomised controlled trials; myocardial revascularisation; drug therapy
8.  Raised plasma endothelin in unstable angina and non-Q wave myocardial infarction: relation to cardiovascular outcome. 
British Heart Journal  1994;72(5):436-441.
BACKGROUND--Among patients with independent evidence of coronary disease and recent onset unstable angina or non-Q wave myocardial infarction the incidence of subsequent cardiovascular events is high. Markers predictive of adverse cardiac outcome in unstable angina and non-Q wave myocardial infarction need to be defined more accurately. Endothelin-1 is a potent endothelium derived vasoconstrictor peptide that may play a part in the pathophysiology of acute myocardial ischaemia. AIM AND STUDY DESIGN--In a study that specifically identified high risk patients a group of 16 consecutive patients with either unstable angina at rest or non-Q wave myocardial infarction were prospectively investigated to establish whether these conditions are associated with high plasma immunoreactive endothelin and whether endothelin concentration at presentation is related to cardiovascular events within the next 12 weeks. Controls consisted of a group of 40 healthy subjects. RESULTS--Patients had significantly higher mean (SD) plasma endothelin at presentation than did healthy controls (7.4 (1.1) v 5.0 (1.2) pg/ml, P < 0.0001). At nine weeks plasma endothelin was still significantly higher in those patients who had subsequent cardiovascular events, (n = 9, acute myocardial infarction or refractory angina with electrocardiographic changes and revascularisation procedures, 8.5 (2.6) pg/ml, P < 0.005 v controls) whereas its concentration returned to normal in those patients who had a favourable outcome (n = 7, 5.9 (0.7) pg/ml). Compared with those patients who had an uneventful course, patients with subsequent events had significantly higher plasma endothelin, both at presentation and at nine weeks (P < 0.05 on both occasions). IMPLICATIONS--Endothelin may contribute to the pathophysiology of acute coronary syndromes and may relate to subsequent cardiovascular outcome.
PMCID: PMC1025610  PMID: 7818960
9.  C-reactive Protein and Coronary Artery Calcium in Asymptomatic Women with Systemic Lupus Erythematosus or Rheumatoid Arthritis 
The American journal of cardiology  2008;102(6):755-760.
Patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) have increased risk for atherosclerotic cardiovascular disease. We compared the presence of coronary artery calcium (CAC) in age- and race-matched women with SLE, RA, and healthy controls without diabetes mellitus or history of myocardial infarct, angina pectoris or stroke, and investigated its relation with traditional risk factors, inflammation, and endothelial activation. Study subjects completed cardiovascular risk factor assessment and electron-beam computed tomography that measured CAC. Both female patient groups had similar prevalence and extent of CAC as well as a significant increased odds of having any CAC (odds ratio 1.87, 95% CI 1.09-3.21) and more extensive CAC (odds ratio 4.04, 95% CI 1.42-11.56 for CAC score>100) when compared to healthy controls. After controlling for differences in cardiovascular risk factors, including insulin resistance and hypertension, the results remained statistically significant. After adjustment for differences in levels of C-reactive protein and/or soluble intercellular adhesion molecule-1, however, women with chronic inflammatory diseases no longer had significantly increased odds of having any CAC or more extensive CAC when compared to controls. In conclusion, asymptomatic and non-diabetic women with chronic inflammatory diseases had significantly increased odds of having CAC and more extensive CAC when compared to age- and race-matched healthy controls. The increased odds for coronary artery calcium may in part result from higher levels of inflammation and endothelial activation in these patients.
doi:10.1016/j.amjcard.2008.04.059
PMCID: PMC2563802  PMID: 18774002
10.  Post-load hyperglycemia as an important predictor of long-term adverse cardiac events after acute myocardial infarction: a scientific study 
Background
Diabetes mellitus (DM) and impaired glucose tolerance (IGT) are risk factors for acute myocardial infarction (AMI). However, it is unknown whether hyperglycemic state is associated with increased major adverse cardiovascular events (MACE) after AMI. In this study, we evaluated the relationship between glucometabolic status and MACE in patients after AMI, and determined the critical level of 2 h post-load plasma glucose that may be used to predict MACE.
Methods
AMI patients (n = 422) were divided into 4 groups as follows: normal glucose tolerance (NGT) group, IGT group, newly diagnosed DM (NDM) group, and previously known DM (PDM) group. MACE of the 4 groups were compared for 2 years from AMI onset.
Results
The NDM group had a significantly higher event rate than the IGT and NGT groups and had a similar event rate curve to PDM group. The logistic models analyses revealed that 2 h post-load plasma glucose values of ≥160 mg/dL was the only independent predictor of long-term MACE after AMI (p = 0.028, OR: 1.85, 95% CI: 1.07-3.21). The 2-year cardiac event rate of patients with a 2 h post-load hyperglycemia of ≥160 mg/dL was significantly higher than that of patients with 2 h post-load glucose of <160 mg/dL (32.2% vs. 19.8%, p < 0.05) and was similar to that of PDM group (37.4%, p = 0.513).
Conclusions
NDM increases the risk of MACE after AMI as does PDM. Particularly, post-AMI patients with a 2 h post-load hyperglycemia ≥160 mg/dL may need adjunctive therapy after AMI.
doi:10.1186/1475-2840-9-75
PMCID: PMC2996353  PMID: 21070650
11.  Peripheral Endothelial Function and Cardiovascular Events in High‐Risk Patients 
Background
Endothelial dysfunction is a key component of vascular vulnerability. Reactive hyperemia index (RHI), as assessed by the peripheral arterial tonometry, can noninvasively evaluate endothelial function. This study was designed to determine the additional prognostic value of endothelial function to the Synergy Between PCI With Taxus and Cardiac Surgery Score (SYNTAXsc) and the Framingham Risk Score (FRS) in predicting cardiovascular events in high‐risk patients.
Methods and Results
We undertook a two‐center prospective study in 528 stable patients at high‐risk for cardiovascular events from the years 2006–2011. The RHI was measured before coronary angiography and coronary complexity was assessed by SYNTAXsc. After optimal therapies including coronary revascularization, there was follow‐up with patients until August 2012. Cardiovascular events consist of cardiovascular death, myocardial infarction, unstable angina, ischemic stroke, coronary revascularization, heart failure‐induced hospitalization, aortic disease, and peripheral arterial disease. During 1468 person‐years of follow‐up, 105 patients developed cardiovascular events. Multivariate Cox proportional hazards analysis identified B‐type natriuretic peptide (BNP), SYNTAXsc, and RHI as independent cardiovascular event predictors (hazard ratio [95% confidence interval]: natural logarithm of BNP per 0.1: 1.019 [1.002 to 1.037]; P=0.023, SYNTAXsc per tertile: 2.426 [1.825 to 3.225]; P<0.0001, RHI per 0.1: 0.761 [0.673 to 0.859]; P<0.0001). When RHI was added to the FRS, BNP, and SYNTAXsc, net reclassification index was significantly improved (27.5%; P<0.0001), with a significant increase in the C‐statistic (from 0.728 [0.679 to 0.778] to 0.766 [0.726 to 0.806]; P=0.031).
Conclusions
Advanced endothelial dysfunction significantly correlated with near future cardiovascular events in high‐risk patients. This physiological vascular measurement improved risk discrimination when added to the FRS, BNP, and SYNTAXsc.
Clinical Trial Registration
URL: clinicaltrials.gov (http://www.clinicaltrials.gov). Unique identifier: NCT00737945.
doi:10.1161/JAHA.113.000426
PMCID: PMC3886751  PMID: 24275629
cardiovascular events; endothelial dysfunction; follow‐up study
12.  Risk stratification in unstable angina and non-Q wave myocardial infarction using soluble cell adhesion molecules 
Heart  2001;85(6):623-627.
OBJECTIVE—To assess prospectively the prognostic value of soluble cellular adhesion molecules (CAMs) in patients with unstable angina and non-Q wave myocardial infarction and to compare their prognostic accuracy with that of C reactive protein (CRP).
DESIGN AND SETTING—Prospective observational study of patients presenting acutely with unstable angina and non-Q wave myocardial infarction to a single south Dublin hospital.
METHODS—Patients with Braunwald IIIA unstable angina and non-Q wave myocardial infarction had serum samples taken at presentation before initiation of antithrombotic treatment and were followed for six months. The primary end point was the occurrence of major adverse cardiovascular events (recurrent unstable angina, non-fatal myocardial infarction, and cardiovascular death) at six months. Concentrations of soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble endothelial selectin, and soluble platelet selectin were measured using an enzyme linked immunosorbent assay technique. CRP was measured with an immunophelometric assay.
RESULTS—91 patients (73 men and 18 women, mean (SD) age 61 (11) years) were studied; 27 patients (30%) had major adverse cardiac events during the six months of follow up. Concentration of CRP were significantly raised in patients who had an ischaemic event (mean (SEM) 11.5 (6.4) mg/l v 5.4 (2.5) mg/l, p < 0.001). Concentrations of sVCAM-1 were also significantly raised in the ischaemic event group (979 (30) ng/ml v 729 (22) ng/ml, p < 0.001). Both sVCAM-1 and CRP concentrations correlated strongly with the occurrence of an adverse event. The sensitivity of CRP > 3 mg/l and sVCAM-1 > 780 ng/ml for predicting future events was > 90%. There was no difference in concentrations of sICAM-1, soluble endothelin selectin, or soluble platelet selectin between event and non-event groups.
CONCLUSION—Raised concentrations of sVCAM-1 and CRP are predictive of an increased risk of major adverse cardiovascular events six months after presentation with unstable angina and non-Q wave myocardial infarction. These findings suggest that the intensity of the vascular inflammatory process at the time of presentation is a determinant of clinical outcome in unstable coronary artery disease. 


Keywords: cell adhesion molecules; risk stratification; unstable angina
doi:10.1136/heart.85.6.623
PMCID: PMC1729754  PMID: 11359739
13.  Interleukin-6 and activin A are independently associated with cardiovascular events and mortality in type 2 diabetes: the prospective Asker and Bærum Cardiovascular Diabetes (ABCD) cohort study 
Background
Novel and robust cardiovascular (CV) markers are needed to improve CV morbidity and mortality risk prediction in type 2 diabetes (T2D). We assessed the long term predictive value of 4 novel CV risk markers for major CV events and mortality.
Methods
We included patients with T2D who had cytokines (interleukin [IL]-6 and activin A [actA]), a maximum stress ECG test (evaluated by the normalization pattern in early recovery phase) and echocardiography (evaluated by a measure of the left ventricular filling pressure - E/Em) assessed at baseline. The primary endpoint was time to first of any of the following events: myocardial infarction, stroke, hospitalization for unstable angina pectoris and death. All outcomes were adjudicated by independent experts. We used Cox proportional hazard modeling, Harrell C-statistic and the net reclassification improvement (NRI) to assess the additional value beyond conventional markers (age, gender, prior CV disease, HDL, creatinine, diastolic BP, microalbuminuria).
Results
At baseline the study cohort (n = 135, mean age/diabetes duration/HbA1c: 59 yrs/7 yrs/7.6% [59 mmol/mol], 26% females) had moderate elevated CV risk (42% microalbuminuria, mean Framingham 10 year CV-risk 9.6%). During 8.6 yrs/1153.7 person years, 26 patients experienced 36 events. All 4 novel risk markers were significantly associated with increased risk of the primary endpoint, however, only IL-6 and actA improved C-statistic and NRI (+0.119/43.2%, +0.065/20.3% respectively) compared with the conventional CV risk factors.
Conclusions
IL-6 and actA may provide prognostic information on CV events and mortality in T2D beyond conventional CV risk factors.
Trial registration
ClinicalTrials.gov: NCT00133718
doi:10.1186/1475-2840-12-126
PMCID: PMC3766106  PMID: 23987834
Type 2 diabetes; Cardiovascular event; MACE; Inflammatory marker; Cardiovascular risk; Risk prediction
14.  Prevalence of diabetes and other cardiovascular risk factors in an Iranian population with acute coronary syndrome 
Background
Coronary artery disease is the leading cause of death in industrialized countries and most patients with diabetes die from complications of atherosclerosis. The objective of this study was to determine the presence of diabetes mellitus and other conventional coronary heart disease risk factors (cigarette smoking, hypertension and hyperlipidemia) in patients with acute coronary events in an Iranian population.
Methods
The study included 514 patients with unstable angina or myocardial infarction (MI) out of 720 patients admitted to CCU ward of a general hospital from March 2003 to March 2005. History of diabetes, hypertension and cigarette smoking, demographic indices, coronary heart disease and diabetes mellitus treatment, myocardial enzymes, serum triglycerides (TG) and cholesterol and fasting and non fasting blood glucose levels and HbA1C of diabetics were recorded of admission sheets. The data were structured to appropriate one way ANOVA, T tests, and chi square test with SPSS 13 product for windows.
Results
Out of all patients 35.8% were female, 30% were diabetics (Duration 13.4 ± 8.7 years), 42% were smoker and 91% were hypertensive. Twenty four percent had MI and 76% had unstable angina. MI was significantly higher in diabetic patients (36.4% vs. 19.2%, P < 0.001). Location and extension of MI and myocardial enzymes did not differ between diabetics and non-diabetic patients. Diabetic patients were older than non diabetics (65 ± 11.6 vs. 59.7 ± 12.5 years, p < 0.05). Five (66.7%) out of 9 patients with fatal MI were diabetics (Odds Ratio = 2.98). Age, duration of diabetes and HbA1c levels, did not differ between diabetic patients with or without MI. Hypertension and current smoking was significantly higher in patients with MI compared to patients with unstable angina (p < 0.05). Serum TG, HDL-C, LDL-C and total cholesterol level did not differ between patients with MI and unstable angina. Diabetic patients compare to non diabetic patients were more hypertensive (96% vs. 88.7%, p < 0.005) and had higher serum triglyceride (TG over 200 mg/dl, 35.1% vs. 26.4, p <0.05). Diabetes was more frequent among women than men (36.4% vs. 26.4%, p < 0.05). Women were older than men (65 ± 11.6 vs. 59.2 ± 13 years, p < 0.005) and had higher total serum cholesterol (200 ± 41.8 vs. 192 ± 42.5 mg/dl, p < 0.05) and HDL-C levels (49.7 ± 22 vs. 40 ± 13 mg/dl, p < 0.005). Ninety seven percent of all patients had at least one of cardiovascular risk factors (hypertension, smoking, diabetes, high cholesterol and low HDL-cholesterol levels).
Conclusion
In this study 19 out of 20 patients with acute coronary event have at least one of conventional cardiac risk factors. Diabetes and hypertension are leading risk factors, which may directly or indirectly interfere and predict more serious complications of coronary heart disease.
doi:10.1186/1475-2840-5-15
PMCID: PMC1550715  PMID: 16842631
15.  Cardiovascular safety with linagliptin in patients with type 2 diabetes mellitus: a pre-specified, prospective, and adjudicated meta-analysis of a phase 3 programme 
Background
This study investigated the cardiovascular (CV) safety profile of the dipeptidyl peptidase (DPP)-4 inhibitor linagliptin versus comparator treatments.
Methods
This was a pre-specified meta-analysis of CV events in linagliptin or comparator-treated patients with type 2 diabetes mellitus (T2DM) from eight Phase 3 studies. All suspected CV events were prospectively adjudicated by a blinded independent expert committee. The primary endpoint was a composite of CV death, stroke, myocardial infarction, and hospitalization for unstable angina. Three secondary composite endpoints derived from the adjudicated CV events were also pre-specified. Risk estimates were calculated using several statistical methods including Cox regression analysis.
Results
Of 5239 treated patients (mean ± SD HbA1c 65 ± 10 mmol/mol [8.0 ± 0.9%], age 58 ± 10 years, BMI 29 ± 5 kg/m2), 3319 received linagliptin once daily (5 mg, 3159; 10 mg, 160) and 1920 received comparators (placebo, 977; glimepiride 1-4 mg, 781; voglibose 0.6 mg, 162). Cumulative exposure (patient-years) was 2060 for linagliptin and 1372 for comparators. Primary CV events occurred in 11 (0.3%) patients receiving linagliptin and 23 (1.2%) receiving comparators. The hazard ratio (HR) for the primary endpoint showed significantly lower risk with linagliptin than comparators (HR 0.34 [95% confidence interval (CI) 0.16-0.70]) as did estimates for all secondary endpoints (HR ranging from 0.34 to 0.55 [all upper 95% CIs < 1.0]).
Conclusions
These results from a large Phase 3 programme support the hypothesis that linagliptin may have CV benefits in patients with T2DM.
doi:10.1186/1475-2840-11-3
PMCID: PMC3286367  PMID: 22234149
Cardiovascular risk; DPP-4 inhibitor; linagliptin; meta-analysis; type 2 diabetes mellitus
16.  Plasma Pentraxin 3 Levels Do Not Predict Coronary Events but Reflect Metabolic Disorders in Patients with Coronary Artery Disease in the CARE Trial 
PLoS ONE  2014;9(4):e94073.
Chronic inflammation closely associates with obesity, metabolic syndrome, diabetes mellitus, and atherosclerosis. Evidence indicates that the immunomodulator pentraxin 3 (PTX3) may serve as a biomarker of these cardiometabolic disorders, but whether PTX3 predicts cardiovascular complications is unknown. We examined the association of plasma PTX3 levels with recurrent coronary events via a prospective, nested, case-control design in the CARE trial. Among 4159 patients who had a prior myocardial infarction 3 to 20 months before enrollment and also had total cholesterol levels <240 mg/dL and LDL cholesterol levels between 115 and 175 mg/dL, we measured plasma PTX3 levels at baseline by high-sensitivity ELISA in 413 cases with recurrent myocardial infarction or coronary death during a 5-year follow-up period, and in 366 sex- and age-matched controls. Cases with recurrent coronary events and controls had similar PTX3 levels, and PTX3 did not predict recurrent coronary events — a finding that contrasts with that of C-reactive protein (CRP) and serum amyloid A (SAA) in this cohort. We then associated PTX3 levels with metabolic disorders. Low plasma PTX3 levels correlated with high body-mass index, waist circumference, and triglycerides; and with low HDL cholesterol. Overall, PTX3 levels correlated inversely with the number of metabolic syndrome components. PTX3 levels also correlated inversely with apoCIII and tissue plasminogen activator, but did not associate with CRP. Although the study further links low PTX3 levels with various features associated with metabolic syndrome, the results do not indicate that PTX3 can predict recurrent coronary events among MI survivors.
doi:10.1371/journal.pone.0094073
PMCID: PMC3976379  PMID: 24705587
17.  Postchallenge responses of nitrotyrosine and TNF-alpha during 75-g oral glucose tolerance test are associated with the presence of coronary artery diseases in patients with prediabetes 
Background
Meta-analysis has demonstrated an exponential relationship between 2-hr postchallenge hyperglycemia and coronary artery disease (CAD). Pulsatile hyperglycemia can acutely increase proinflammatory cytokines by oxidative stress. We hypothesized that postchallenge proinflammatory and nitrosative responses after 75 g oral glucose tolerance tests (75 g-OGTT) might be associated with CAD in patients without previously recognized type 2 diabetes mellitus (T2DM).
Methods
Serial changes of plasma glucose (PG), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and nitrotyrosine levels were analyzed during 75 g-OGTT in 120 patients (81 male; age 62 ± 11 years) before coronary angiography. Patients were classified as normal (NGT; 42%), impaired (IGT; 34%) and diabetic (T2DM; 24%) glucose tolerance by 75 g-OGTT.
Results
Postchallenge hyperglycemia elicited TNF-α, IL-6 and nitrotyrosine levels time-dependently, and 2-hr median levels of TNF-α (7.1 versus 6.4 pg/ml; P < 0.05) and nitrotyrosine (1.01 versus 0.83 μmol/l; P < 0.05), but not IL-6 or PG, were significantly higher in patients with CAD in either IGT or T2DM groups. After adjusting risk factors and glucose tolerance status, 2-hr nitrotyrosine in highest quartiles (OR: 3.1, P < 0.05) remained an independent predictor of CAD by logistic regression analysis.
Conclusions
These results highlight postchallenge proinflammatory and nitrosative responses by 75 g-OGTT, rather than hyperglycemia per se, are associated with CAD in patients without previous recognized diabetes.
doi:10.1186/1475-2840-11-21
PMCID: PMC3316140  PMID: 22397368
Postchallenge hyperglycemia; Inflammation; Oxidative stress; Nitrotyrosine oral; Glucose tolerance test; Coronary artery disease
18.  Post Hoc Subgroup Analysis of the HEART2D Trial Demonstrates Lower Cardiovascular Risk in Older Patients Targeting Postprandial Versus Fasting/Premeal Glycemia 
Diabetes Care  2011;34(7):1511-1513.
OBJECTIVE
To identify the Hyperglycemia and Its Effect After Acute Myocardial Infarction on Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus (HEART2D) trial subgroups with treatment difference.
RESEARCH DESIGN AND METHODS
In 1,115 type 2 diabetic patients who had suffered from an acute myocardial infarction (AMI), the HEART2D trial compared two insulin strategies targeting postprandial or fasting/premeal glycemia on time until first cardiovascular event (cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization, or hospitalization for acute coronary syndrome). The HEART2D trial ended prematurely for futility. We used the classification and regression tree (CART) to identify baseline subgroups with potential treatment differences.
RESULTS
CART estimated the age of >65.7 years to best predict the difference in time to first event. In the subgroup aged >65.7 years (prandial, n = 189; basal, n = 210), prandial patients had a significantly longer time to first event and a lower proportion experienced a first event (n = 56 [29.6%] vs. n = 85 [40.5%]; hazard ratio 0.69 [95% CI 0.49–0.96]; P = 0.029), despite similar A1C levels.
CONCLUSIONS
Older type 2 diabetic AMI survivors may have a lower risk for a subsequent cardiovascular event with insulin targeting postprandial versus fasting/premeal glycemia.
doi:10.2337/dc10-2375
PMCID: PMC3120208  PMID: 21593301
19.  Cardiovascular Benefits and Diabetes Risks of Statin Therapy in Primary Prevention 
Lancet  2012;380(9841):565-571.
Background
As statin therapy increases risks of diabetes, the balance of benefit and risk in primary prevention for these agents has become controversial. We undertook an analysis of participants from the JUPITER trial to address the balance of vascular benefits and diabetes hazard of statin use.
Methods
In the randomized, double-blind JUPITER trial, 17,603 men and women without prior cardiovascular disease or diabetes were randomly allocated to rosuvastatin 20 mg or placebo and followed for up to 5 years for the trial primary endpoint (myocardial infarction, stroke, hospitalization for unstable angina, arterial revascularization, or cardiovascular death) and the protocol pre-specified secondary endpoints of venous thromboembolism (VTE), all-cause mortality, and incident diabetes. To address balance of vascular benefits and diabetes hazard, participants were stratified on the basis of having none or at least one of the following major risk factors for developing diabetes: metabolic syndrome, impaired fasting glucose, body mass index >30 kg/m2, or HbA1c > 6 percent.
Findings
Trial participants with one or more major diabetes risk factor (N=11,508) were at higher risk of developing diabetes; for such individuals, statin allocation was associated with a 39 percent reduction in the primary endpoint (P=0.0001), a 36 percent reduction in VTE (P=0.08), a 17 percent reduction in total mortality (P=0.15) and a 28 percent increase in diabetes (P=0.01). Thus, for those with diabetes risk factors, 93 vascular events or deaths were avoided for every 54 new cases of diabetes diagnosed. For trial participants with no major diabetes risk factor (N=6,095), statin allocation was associated with a 52 percent reduction in the primary endpoint (P=0.0001), a 53 percent reduction in VTE (P=0.05), a 22 percent reduction in total mortality (P=0.08) and no increase in diabetes (HR 0.99, P= 0.99). For such individuals, a total of 86 vascular events or deaths were avoided with no new cases of diabetes diagnosed. In analysis limited to the 486 participants who developed diabetes during follow-up (270 on rosuvastatin vs. 216 on placebo group, P=0.01), the point estimate of cardiovascular risk reduction associated with statin therapy (hazard ratio 0.63) was consistent with that observed for the trial as a whole (hazard ratio 0.56). As compared to placebo, statin allocation accelerated the average time to diagnosis of diabetes by 5.4 weeks.
Interpretation
In the JUPITER primary prevention trial, the cardiovascular and mortality benefits of statin therapy exceed the diabetes hazard, including among those at higher risk for developing diabetes
doi:10.1016/S0140-6736(12)61190-8
PMCID: PMC3774022  PMID: 22883507
20.  Copeptin, IGFBP-1, and Cardiovascular Prognosis in Patients With Type 2 Diabetes and Acute Myocardial Infarction 
Diabetes Care  2010;33(7):1604-1606.
OBJECTIVE
To determine whether C-terminal provasopressin (copeptin) explains the prognostic importance of insulin growth factor binding protein-1 (IGFBP-1) in patients with myocardial infarction and type 2 diabetes.
RESEARCH DESIGN AND METHODS
Copeptin and IGFBP-1 were analyzed in 393 patients participating in the Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) 2 trial.
RESULTS
Copeptin was associated with IGFBP-1 (Spearman rank correlation test, r = 0.53; P < 0.001). During follow-up there were 138 cardiovascular events (cardiovascular death, myocardial infarction, and stroke). In univariate Cox proportional hazard regression analyses both biomarkers were predictors of events: the hazard ratio for log copeptin was 1.59 (95% CI 1.41–1.81; P < 0.001) and for log IGFBP-1 was 1.49 (1.26–1.77; P < 0.001). In the final model, adjusting for age and renal function, copeptin was the only independent predictor (1.35 [1.16–1.57]; P < 0.001).
CONCLUSIONS
Copeptin is an independent predictor of cardiovascular events and appears to at least partly explain the prognostic impact of IGFBP-1 in patients with type 2 diabetes and myocardial infarction. Copeptin may be a pathogenic factor to address to improve outcome in these patients.
doi:10.2337/dc10-0088
PMCID: PMC2890367  PMID: 20413521
21.  Efficacy of n-3 polyunsaturated fatty acids and feasibility of optimizing preventive strategies in patients at high cardiovascular risk: rationale, design and baseline characteristics of the Rischio and Prevenzione study, a large randomised trial in general practice 
Trials  2010;11:68.
Background
The optimization of preventive strategies in patients at high risk of cardiovascular events and the evaluation of bottlenecks and limitations of transferring current guidelines to the real world of clinical practice are important limiting steps to cardiovascular prevention. Treatment with n-3 polyunsaturated fatty acids improves prognosis after myocardial infarction, but evidence of this benefit is lacking in patients at high cardiovascular risk, but without a history of myocardial infarction.
Methods/design
Patients were eligible if their general practitioner (GP) considered them at high cardiovascular risk because of a cardiovascular disease other than myocardial infarction, or multiple risk factors (at least four major risk factors in non-diabetic patients and one in diabetics).
Patients were randomly allocated to treatment with n-3 polyunsaturated fatty acids (1 g daily) or placebo in a double-blind study and followed up for five years by their GPs to assess the efficacy of the treatment in preventing cardiovascular mortality (including sudden death) and hospitalization for cardiovascular reasons. The secondary, epidemiological, aim of the study is to assess whether it is feasible to adopt current guidelines in everyday clinical practice, with a view to optimizing all the available preventive strategies in people at high cardiovascular risk.
A nation-wide network of 860 GPs admitted 12,513 patients to the study between February 2004 and March 2007. The mean age was 64 years and 62% were males. Diabetes mellitus plus one or more cardiovascular risk factors was the main inclusion criterion (47%). About 30% of patients were included because of a history of atherosclerotic cardiovascular disease, 21% for four or more risk factors, and less than 1% for other reasons.
Discussion
The Rischio and Prevenzione (R&P) project provides a feasible model to test the efficacy of n-3 polyunsaturated fatty acid therapy in patients at high cardiovascular risk with no history of myocardial infarction, and to assess how to implement recommended preventive strategies in general practice.
Trial registration
ClinicalTrials.gov NCT00317707
doi:10.1186/1745-6215-11-68
PMCID: PMC2909229  PMID: 20509875
22.  Effects of oral glucose-lowering drugs on long term outcomes in patients with diabetes mellitus following myocardial infarction not treated with emergent percutaneous coronary intervention - a retrospective nationwide cohort study 
Background
The optimum oral pharmacological treatment of diabetes mellitus to reduce cardiovascular disease and mortality following myocardial infarction has not been established. We therefore set out to investigate the association between individual oral glucose-lowering drugs and cardiovascular outcomes following myocardial infarction in patients with diabetes mellitus not treated with emergent percutaneous coronary intervention.
Materials and methods
All patients aged 30 years or older receiving glucose-lowering drugs (GLDs) and admitted with myocardial infarction (MI) not treated with emergent percutaneous coronary intervention in Denmark during 1997-2006 were identified by individual-level linkage of nationwide registries of hospitalizations and drug dispensing from pharmacies. Multivariable Cox regression models adjusted for age, sex, calendar year, comorbidity, and concomitant pharmacotherapy were used to assess differences in the composite endpoint of non-fatal MI and cardiovascular mortality between individual GLDs, using metformin monotherapy as reference.
Results
The study comprised 9876 users of GLDs admitted with MI. The mean age was 72.3 years and 56.5% of patients were men. A total of 3649 received sulfonylureas and 711 received metformin at admission. The average length of follow-up was 2.2 (SD 2.6) years. A total of 6,171 patients experienced the composite study endpoint. The sulfonylureas glibenclamide, glimepiride, glipizide, and tolbutamide were associated with increased risk of cardiovascular mortality and/or nonfatal MI with hazard ratios [HRs] of 1.31 (95% confidence interval [CI] 1.17-1.46), 1.19 (1.06-1.32), 1.25 (1.11-1.42), and 1.18 (1.03-1.34), respectively, compared with metformin. Gliclazide was the only sulfonylurea not associated with increased risk compared with metformin (HR 1.03 [0.88-1.22]).
Conclusions
In patients with diabetes mellitus admitted with MI not treated with emergent percutaneous coronary intervention, monotherapy treatment with the sulfonylureas glibenclamide, glimepiride, glipizide, and tolbutamide was associated with increased cardiovascular risk compared with metformin monotherapy.
doi:10.1186/1475-2840-9-54
PMCID: PMC2946277  PMID: 20843380
23.  Prognostic Value of Coronary Computed Tomographic Angiography in Diabetic Patients Without Known Coronary Artery Disease 
Diabetes Care  2010;33(6):1358-1363.
OBJECTIVE
Diabetic patients have a high prevalence of coronary artery disease (CAD), but timely diagnosis of CAD remains challenging. We assessed the ability of coronary computed tomography angiography (CCTA) to detect CAD in diabetic patients and to predict subsequent cardiac events.
RESEARCH DESIGN AND METHODS
We analyzed 140 diabetic patients without known CAD undergoing CCTA; 1,782 patients without diabetes were used as a control group. Besides calcium scoring and the degree of the most severe stenosis, the atherosclerotic burden score counting the number of segments having either a nonstenotic plaque or a stenosis was recorded. The primary end point was a composite of hard cardiac events defined as all-cause death, nonfatal myocardial infarction, or unstable angina requiring hospitalization.
RESULTS
During a mean follow-up of 33 months, there were seven events in the diabetic group and 24 events in the control group. The best predictor in diabetic patients was the atherosclerotic burden score: the annual event rate ranged from 0.5% for patients with <5 lesions to 9.6% for patients with >9 lesions, resulting in a hazard ratio (HR) of 1.3 (95% CI 1.1–1.7) for each additional lesion (P = 0.005). For comparison, in nondiabetic patients the annual event rate ranged from 0.3 to 2.2%, respectively, resulting in an HR of 1.2 (95% CI 1.1–1.3, P < 0.001). The atherosclerotic burden score improved the prognostic value of conventional risk factors significantly (P < 0.001).
CONCLUSIONS
In diabetic patients without known CAD, CCTA can identify a patient group at particularly high risk for subsequent hard cardiac events.
doi:10.2337/dc09-2104
PMCID: PMC2875454  PMID: 20200300
24.  Aspirin for primary prevention of cardiovascular disease in diabetes mellitus 
Nature reviews. Endocrinology  2010;6(11):619-628.
Aspirin is effective for the prevention of cardiovascular events in patients with a history of vascular disease, as so-called secondary prevention. In general populations with no history of previous myocardial infarction or stroke, aspirin also seems useful for primary prevention of cardiovascular events, although the absolute benefits are smaller than those seen in patients with previous cardiovascular disease. Patients with diabetes mellitus are at an increased risk of cardiovascular events, but new trials have raised questions about the benefit of aspirin for primary prevention in patients with this disorder. This Review comprehensively examines the basic pharmacology of aspirin and provides an overview of the randomized, controlled trials of aspirin therapy that have included patients with diabetes mellitus. On the basis of currently available evidence from primary prevention trials, aspirin is estimated to reduce the relative risk of myocardial infarction and stroke by about 10% in patients with diabetes mellitus; however, aspirin also increases the risk of gastrointestinal bleeding. As such, low-dose aspirin therapy (75–162 mg) is reasonable for patients with diabetes mellitus and a 10-year risk of cardiovascular events >10%. Results from upcoming large trials will help clarify the effects of aspirin with greater precision, including whether the benefits differ between men and women.
doi:10.1038/nrendo.2010.169
PMCID: PMC3145323  PMID: 20856266
25.  Prognostic value of myocardial perfusion scintigraphy in type 2 diabetic patients with mild, stable angina pectoris 
Journal of Nuclear Cardiology  2009;16(4):524-532.
Aim
To determine the prognostic value of reversible myocardial perfusion defects on myocardial perfusion scintigraphy (MPS) in patients with type 2 diabetes mellitus and mild anginal complaints.
Methods and results
In the MERIDIAN trial, patients with diabetes mellitus type 2, stable, mild anginal symptoms (Canadian Cardiovascular Society classification (CCS) I-II/IV) and reversible perfusion defects were randomized to either continued pharmacological treatment or early invasive treatment. In this sub analysis, the severity of the myocardial perfusion defect was related to the occurrence of cardiac death and non-fatal myocardial infarction, in 319 patients (63% male, 65 ± 9 years). During follow-up (2.2 ± 0.6 years), 14 patients had a cardiac event: 3 in 171 patients without myocardial ischemia and 11 in 148 patients with myocardial ischemia. Annual event rates rose from 0.8% to 5.8% with increasing severity of myocardial ischemia. Multivariable analysis identified the presence of severe myocardial ischemia (hazard ratio (HR) 5.45, 95%CI 1.89-15.71) and insulin use (HR 4.00, 95%CI 1.25-12.75) as independent predictors of cardiac events.
Conclusions
Type 2 diabetics with mild anginal symptoms with no or moderate myocardial ischemia have a low annual cardiac event rate. In patients with severe myocardial ischemia event rate increased 3-6 fold.
doi:10.1007/s12350-009-9111-z
PMCID: PMC2708338  PMID: 19536605
Diabetes mellitus, type 2; angina pectoris; myocardial ischemia; SPECT; prognosis

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