Innovative therapy, monoclonal antibodies, and beyond: Highlights from the eighth annual meeting.

The eighth annual conference of "Innovative therapy, monoclonal antibodies, and beyond" was held in Milan on Jan. 26, 2018, and hosted by Fondazione IRCCS-Istituto Nazionale dei Tumori (Fondazione IRCCS INT). The conference was divided into two main scientific sessions, of i) pre-clinical assays and novel biotargets, and ii) clinical translation, as well as a third session of presentations from young investigators, which focused on recent achievements within Fondazione IRCCS INT on immunotherapy and targeted therapies. Presentations in the first session addressed the issue of cancer immunotherapy activity with respect to tumor heterogeneity, with key topics addressing: 1) tumor heterogeneity and targeted therapy, with the definition of the evolutionary Index as an indicator of tumor heterogeneity in both space and time; 2) the analysis of cancer evolution, with the introduction of the TRACERx Consortium-a multi-million pound UK research project focused on non-small cell lung cancer (NSCLC); 3) the use of anti-estrogen agents to boost immune recognition of breast cancer cells; and 4) the high degree of functional plasticity within the NK cell repertoire, including the expansion of adaptive NK cells following viral challenges. The second session addressed: 1) the effectiveness of radiotherapy to enhance the proportion of patients responsive to immune-checkpoint blockers (ICBs); 2) the use of MDSC scores in selecting melanoma patients with high probability to be responsive to ICBs; and 3) the relevance of the gut microbiome as a predictive factor, and the potential of its perturbation in increasing the immune response rate to ICBs. Overall, a picture emerged of tumor heterogeneity as the main limitation that impairs the effectiveness of anti-cancer therapies. Thus, the choice of a specific therapy based on reproducible and selective predictive biomarkers is an urgent unmet clinical need that should be addressed in order to increase the proportion of long-term responding patients and to improve the sustainability of novel drugs.

Increased incidence of chronic GvHD and CMV disease in patients with vitamin D deficiency before allogeneic stem cell transplantation.

Vitamin D has emerged as a central player in the immune system, with its deficiency being implicated in the pathogenesis of several autoimmune diseases, including chronic GvHD. This is a retrospective cohort analysis of 166 patients, who underwent allogeneic hematopoietic stem cell transplantation (HSCT) at the Karolinska University Hospital, evaluating GvHD, graft failure, infectious complications and survival after HSCT in relation to pre-transplantation vitamin D levels. Most of the patients were deficient in vitamin D before HSCT (median 42 nmol/L). In multivariate analysis, vitamin D level before HSCT was identified as a significant independent risk factor for development of cGvHD. The increased incidence of cGvHD was not coupled to better disease-free survival; instead there was a trend towards lower overall survival in the vitamin D-deficient patients. In addition, we found a significant correlation between vitamin D deficiency and incidence of CMV disease, with no case of CMV disease occurring in patients with sufficient levels of vitamin D before HSCT. Our results support a role of vitamin D in immune tolerance following HSCT. These findings could be highly relevant for the care of HSCT patients, and prospective, randomized studies on the effect of vitamin D supplementation are therefore needed.

Practices in prescribing protein substitutes for PKU in Europe: No uniformity of approach.

BACKGROUND: There appears little consensus concerning protein requirements in phenylketonuria (PKU). METHODS: A questionnaire completed by 63 European and Turkish IMD centres from 18 countries collected data on prescribed total protein intake (natural/intact protein and phenylalanine-free protein substitute [PS]) by age, administration frequency and method, monitoring, and type of protein substitute. Data were analysed by European region using descriptive statistics. RESULTS: The amount of total protein (from PS and natural/intact protein) varied according to the European region. Higher median amounts of total protein were prescribed in infants and children in Northern Europe (n=24 centres) (infants <1 year, >2-3g/kg/day; 1-3 years of age, >2-3 g/kg/day; 4-10 years of age, >1.5-2.5 g/kg/day) and Southern Europe (n=10 centres) (infants <1 year, 2.5 g/kg/day, 1-3 years of age, 2 g/kg/day; 4-10 years of age, 1.5-2 g/kg/day), than by Eastern Europe (n=4 centres) (infants <1 year, 2.5 g/kg/day, 1-3 years of age, >2-2.5 g/kg/day; 4-10 years of age, >1.5-2 g/kg/day) and with Western Europe (n=25 centres) giving the least (infants <1 year, >2-2.5 g/kg/day, 1-3 years of age, 1.5-2 g/kg/day; 4-10 years of age, 1-1.5 g/kg/day). Total protein prescription was similar in patients aged >10 years (1-1.5 g/kg/day) and maternal patients (1-1.5 g/kg/day). CONCLUSIONS: The amounts of total protein prescribed varied between European countries and appeared to be influenced by geographical region. In PKU, all gave higher than the recommended 2007 WHO/FAO/UNU safe levels of protein intake for the general population.

Prognostic implications of glucose-lowering treatment in patients with acute myocardial infarction and diabetes: experiences from an extended follow-up of the Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) 2 Study.

AIMS/HYPOTHESIS: This post hoc analysis from the Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) 2 trial reports on extended long-term outcome in relation to glucose-lowering agents in patients with myocardial infarction and type 2 diabetes. METHODS: Patients were randomised as follows: group 1, insulin-based treatment; group 2, insulin during hospitalisation followed by conventional glucose control; and group 3, conventional treatment. Treatment according to the above protocol lasted 2.1 years. Using the total DIGAMI 2 cohort as an epidemiological database, this study presents mortality rates in the randomised groups, and mortality and morbidity rates by glucose-lowering treatment during an extended period of follow-up (median 4.1 and max 8.1 years). RESULTS: Follow-up data were available in 1,145 of the 1,253 patients. The mortality rate was 31% (72% cardiovascular) without significant differences between treatment groups. The total number of fatal malignancies was 37, with a trend towards a higher risk in group 1. The HR for death from malignant disease, compared with group 2, was 1.77 (95% CI 0.87-3.61; p = 0.11) and 3.60 (95% CI 1.24-10.50; p = 0.02) compared with group 3. Insulin treatment was associated with non-fatal cardiovascular events (OR 1.89 95% CI 1.35-2.63; p = 0.0002), but not with mortality (OR 1.30, 95% CI 0.93-1.81; p = 0.13). Metformin was associated with a lower mortality rate (HR 0.65, 95% CI 0.47-0.90; p = 0.01) and a lower risk of death from malignancies (HR 0.25, 95% CI 0.08-0.83; p = 0.02). CONCLUSIONS/INTERPRETATION: Patients with type 2 diabetes and myocardial infarction have a poor prognosis. Glucose-lowering drugs appear to be of prognostic importance. Insulin may be associated with an increased risk of non-fatal cardiac events, while metformin seems to be protective against risk of death.

Mannose-binding lectin genotype and phenotype in patients with type 2 diabetes and myocardial infarction: a report from the DIGAMI 2 trial.

OBJECTIVE: The present study characterizes mannose-binding lectin (MBL), an activator of the complement system and thereby important for inflammatory activation, in patients with diabetes and myocardial infarction. RESEARCH DESIGN AND METHODS: Serum (S)-MBL was determined at hospital admission in 387 patients with type 2 diabetes (median age 70 years; 68% male) with myocardial infarction, and genotyping was performed in 287 patients. Cardiovascular events (cardiovascular mortality and nonfatal myocardial infarction or stroke) were recorded during 2.5 years. RESULTS: Median S-MBL was 1,212 µg/l (interquartile range [IQR] 346-2,681 µg/l). Of the subjects, 54% in the geno- and phenotype subgroup had a high-coding MBL genotype (median S-MBL=2,658 µg/l [IQR 1,715-3,829]) and 46% a low-coding MBL genotype (373 µg/l [100-765]). S-MBL did not correlate with age, BMI, creatinine clearance, glucose, or A1C. Cardiovascular events occurred in 136 (35%) patients. S-MBL did not predict events in univariable analyses (hazard ratio 0.93 [95% CI 0.85-1.01]; P=0.09). In unadjusted analyses, the risk of events was lower in patients with a high genotype and S-MBL above the median for their genotype (0.49 [0.26-0.92]; P=0.026) than for patients with a low genotype and S-MBL below the median for their genotype. The prediction capacity of the geno- and phenotype model was of borderline significance in adjusted Cox regression. CONCLUSIONS: Patients with type 2 diabetes and myocardial infarction have MBL genotypes that are similar to those known in the general population. The combination of a low-coding MBL genotype with a low S-MBL appears to be prognostically unfavorable, but the association is blunted by traditional risk markers.

Reduced DNAM-1 expression on bone marrow NK cells associated with impaired killing of CD34+ blasts in myelodysplastic syndrome.

Myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal stem-cell disorders characterized by ineffective hematopoiesis and risk of progression to acute myeloid leukemia. Increased apoptosis and suppressed functions of peripheral blood natural killer (NK) cells have been described in MDS patients, but only limited information is available on the phenotypic and functional integrity of NK cells in the bone marrow. In a cohort of 41 patients with distinct clinical subtypes of MDS, we here show that NK cells in the bone marrow show decreased surface expression of the activating receptors DNAM-1 and NKG2D. Notably, decreased receptor expression correlated with elevated bone marrow blast counts and was associated with impaired NK-cell responsiveness to stimulation with the K562 cell line, or co-activation by NKG2D or DNAM-1 in combination with the 2B4 receptor. Furthermore, antibody-masking experiments revealed a central role for DNAM-1 in NK cell-mediated killing of freshly isolated MDS blasts. Thus, given the emerging evidence for NK cell-mediated immune surveillance of neoplastic cells, we speculate that reduced expression of DNAM-1 on bone marrow NK cells may facilitate disease progression in patients with MDS.

Effect of gender on prognosis in patients with myocardial infarction and type 2 diabetes.

BACKGROUND: Diabetes is associated with a markedly increased cardiovascular risk, but the role of gender on the combined effects of diabetes and myocardial infarction has been less well explored. METHODS: The Diabetes Mellitus and Insulin Glucose Infusion in Acute Myocardial Infarction 2 (DIGAMI2) trial recruited 837 men and 416 women with type 2 diabetes hospitalized due to myocardial infarction and followed for a median of 2.1 years. The effects of gender on diabetes-specific risk factors and conventional cardiovascular risk predictors of unfavourable outcome were analysed using a Cox proportional hazards model. RESULTS: Women were older, more frequently had hypertension and previous heart failure than men, and were more often treated with diuretics. More men were smokers. Treatment during hospitalization, at discharge and during follow-up, did not differ significantly, apart from the more frequent use of diuretics in women. Total mortality did not differ between genders, but the combined cardiovascular end-point of death, re-infarction or stroke was more common in women (38.9% vs. 32.1%). This difference disappeared after age adjustment. Age and previous heart failure were independent risk predictors in both genders, whereas diabetes complications were an additional risk factor in women only. Blood glucose level at randomization and updated glucose concentration during follow-up were independent predictors of poor outcome in men but not in women. CONCLUSIONS: Age and not gender itself explained the increased cardiovascular event rate seen in women compared with men. A heavier risk factor burden was seen amongst women. Improved risk factor control instituted before the development of a myocardial infarction should be attempted as a possible means of improving the outcome.

Identification of a novel KIR3DL1*072 allele by sequence-based typing.

We report a novel KIR3DL1*072 allele that was found using a sequence-based typing approach.

High sense of coherence in adolescence is a protective factor in the longitudinal development of ADHD symptoms.

UNLABELLED: The key feature of salutogenesis is that good health can be directly sustained by positive factors. The Sense of Coherence (SOC) scale was developed by Antonovsky as a measure related to the concept of salutogenesis including aspects of comprehensibility, manageability and meaningfulness. AIM: The aim was to investigate whether Sense of Coherence can serve as a salutogenetic factor modifying the long-term development of Attention Deficit Hyperactivity Disorder (ADHD) Symptoms. SUBJECTS AND METHODS: Twin study of Child and Adolescent Development (TCHAD) is a longitudinal study of all twin pairs born in Sweden between May 1985 and December 1986. The present project is a sub-sample of 312 individuals (135 boys and 177 girls). At 16 years of age, the young persons and their parents were interviewed with K-SADS especially symptoms of ADHD. The young person also completed the SOC questionnaire. At 21 years of age, the young person completed a questionnaire about symptoms of ADHD. FINDINGS: Higher (worse) ADHD scores at 16 years of age were associated with higher (worse) ADHD scores at 21 years of age. However, this relationship was stronger for lower (worse) SOC. A higher (better) SOC at 16 years was associated with lower (better) ADHD at 21 years and this relationship was stronger for higher (worse) ADHD at 16 years. CONCLUSION: A high Sense of Coherence in adolescence was a protective factor for the long-term development of ADHD.

Risk factors associated with the dramatic increase in the prevalence of diabetes in the adult Chinese population in Qingdao, China.

OBJECTIVE: To investigate the major risk factors and their association with the dramatic increase in the prevalence of diabetes from 2001-2002 to 2006 in Qingdao, China. METHODS: Population-based cross-sectional studies on diabetes were performed in 4598 men and 7026 women aged 35-74 years. The 2006 World Health Organization diagnostic criteria for diabetes were used. RESULTS: The crude prevalence of diabetes was 11.3% in both men and women in urban areas and 5.3% and 8.9% in rural areas in 2001-2002. This increased to 19.2% and 16.1% in urban areas and 14.2% and 13.8% in rural areas in 2006 for men and women, respectively. The increase in diabetes prevalence from 2001-2002 to 2006 was paralleled by an increased body mass index in rural areas but not in urban areas. The major risk factors associated with diabetes were age, family history of diabetes, obesity, hypertension and high triglycerides. The multivariate adjusted odds ratio and 95% confidence interval for diabetes corresponding to a one standard deviation increase in waist circumference was 1.81 (1.47, 2.23) in urban men, 1.64 (1.26, 2.13) in rural men, 1.98 (1.66, 2.37) in urban women and 2.02 (1.63, 2.51) in rural women. Low socio-economic classes had a higher risk for diabetes in urban areas but a lower risk in rural areas, both associated with increased waist circumference. CONCLUSION: Established risk factors are of great importance for the prevalence of diabetes in the urban and rural Chinese populations and changes in these factors could explain the recent dramatic increase in diabetes prevalence, particularly in rural areas. Considering the high prevalence of obesity and physical inactivity, intervention is urgently required in China.

Insulin-induced weight gain and cardiovascular events in patients with type 2 diabetes. A report from the DIGAMI 2 study.

AIM: We investigated whether insulin treatment-induced weight gain was accompanied by increased cardiovascular (CV) mortality and morbidity in the second Diabetes Insulin Glucose in Acute Myocardial Infarction (DIGAMI 2) study. METHODS: We studied the 865 patients who survived during 12 months without any change in their glucose-lowering (GL) therapy. They were divided into four subgroups according to GL treatment: group I, no pharmacological GL treatment (n = 99); group II, oral hypoglycaemic agents (n = 250); group III, new insulin treatment (n = 245) and group IV, insulin before inclusion continued during the first year of follow up (n = 271). RESULTS: Patients who started on insulin (group III) experienced an average body weight increase of 2.3 (1.5-3.2) kg during the first year of treatment, whereas weight remained unchanged in groups I, II and IV. The incidence of non-fatal reinfarction was higher in group III compared with the other groups (hazard ratio (HR) = 2.5, p = 0.011) and CV mortality was higher in group IV (HR = 2.4, p = 0.003). When the subjects were grouped in quartiles according to maximal body weight increase, those in the lowest quartile experienced the highest CV mortality. Each kilogram increase in weight reduced the risk for CV death with 6%. The incidence of reinfarction did not differ between quartiles. CONCLUSIONS: Initiation of insulin treatment after myocardial infarction was associated with a significant increase in weight and incidence of reinfarction. The increase in weight did, however, not explain the increased rate of reinfarction.

Prognostic implications of hypoglycaemic episodes during hospitalisation for myocardial infarction in patients with type 2 diabetes: a report from the DIGAMI 2 trial.

OBJECTIVE: To explore if hypoglycaemic episodes during hospitalisation influence the subsequent prognosis in patients with diabetes and acute myocardial infarction. DESIGN, SETTING AND PATIENTS: Within the framework of the clinical trial DIGAMI 2 hypoglycaemic episodes (blood glucose <3.0 mmol/l with or without symptoms) were recorded in 1253 patients (mean age 68 years; 67% males) with type 2 diabetes and myocardial infarction. The patients were followed during a median of 2.1 years. A total of 947 patients were randomised to an initial insulin infusion while 306 received routinely used glucose lowering therapy. MAIN OUTCOME MEASURES: Unadjusted and adjusted (age, sex, smoking, previous infarction, heart failure, renal function, diabetes duration, coronary interventions, pharmacological treatment and B-glucose at hospital admission) hazard ratios (HR) and 95% confidence intervals (CI) for total mortality and cardiovascular events (death, re-infarction or stroke) were related to hypoglycaemic episodes during the index hospitalisation. RESULTS: During the first 24 hours hypoglycaemic episodes were noted in 111 (12%) insulin-treated (symptomatic 23%) and three (1.0%) routinely treated patients (symptomatic 33%). Symptomatic hypoglycaemia related to mortality (unadjusted HR 1.99; 95% CI 1.20 to 3.29; p = 0.0074) but this difference disappeared following adjustment (HR 1.09; 95% CI 0.64 to 1.87; p = 0.7403). Body weight (OR 0.97; 95% CI 0.95 to 0.98; p<0.0001) and diabetes duration (OR 1.03; 95% CI 1.01 to 1.05; p = 0.0085) were independent predictors of hypoglycaemia CONCLUSIONS: Hypoglycaemia during the initial hospitalisation was not an independent risk factor for future morbidity or mortality in patients with type 2 diabetes and myocardial infarction. Such episodes were, however, more prevalent in patients at high risk for other reasons.

Increasing glucose levels and BMI predict future heart failure experience from the Reykjavík Study.

BACKGROUND: Heart failure is common in diabetes and ischaemic heart disease is the most likely link. Still, it has been suggested that the relation extends beyond such disease. METHODS: 7060 subjects with two or more visits in the Reykjavík Study were followed--during 30 years from 1967. All underwent oral glucose tolerance tests. Disease status was defined according to the glycaemic level and presence of heart failure. The incidence and predictive factors for these diseases were determined. FINDINGS: Age and sex standardized incidence of heart failure was 5.3/1000/year, of diabetes 4.6/1000/year and abnormal glucose regulation 12.6/1000/year. Body mass index (BMI) and fasting glucose predicted the development of these conditions (p<0.001). Increasing fasting glucose by 1 mmol/l increased the risk for heart failure by 14% (p=0.04) after adjusting for IHD, BMI and other risk factors for CVD. There was a strong association between diabetes and heart failure, OR 3.0 (2.3-4.0), and abnormal glucose regulation and heart failure, OR 1.8 (1.5-2.3). Diabetes and heart failure were, however, not independent predictors of each other. INTERPRETATION: There was an independent relationship between increases in fasting glucose and development of heart failure. BMI was a strong predictor of heart failure. Although fasting glucose and BMI were significant risk factors for glucose disturbances and heart failure the conditions themselves did not independently predict each other.

Oral glucose tolerance test is needed for appropriate classification of glucose regulation in patients with coronary artery disease: a report from the Euro Heart Survey on Diabetes and the Heart.

BACKGROUND: Patients with coronary artery disease (CAD) and abnormal glucose regulation (AGR) are at high risk for subsequent cardiovascular events, underlining the importance of accurate glucometabolic assessment in clinical practice. OBJECTIVE: To investigate different methods to identify glucose disturbances among patients with acute and stable coronary heart disease. METHODS: Consecutive patients referred to cardiologists were prospectively enrolled at 110 centres in 25 countries (n = 4961). Fasting plasma glucose (FPG) and glycaemia 2 h after a 75-g glucose load were requested in patients without known glucose abnormalities (n = 3362). Glucose metabolism was classified according to the World Health Organization and American Diabetes Association (ADA; 1997, 2004) criteria as normal, impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or diabetes. RESULTS: Data on FPG and 2-h post-load glycaemia were available for 1867 patients, of whom 870 (47%) had normal glucose regulation, 87 (5%) had IFG, 591 (32%) had IGT and 319 (17%) had diabetes. If classification had been based on the ADA criterion from 1997, the proportion of misclassified (underdiagnosed) patients would have been 39%. The ADA 2004 criterion would have overdiagnosed 8% and underdiagnosed 33% of the patients, resulting in a total misclassification rate of 41%. For ethical concerns and practical reasons, oral glucose tolerance test (OGTT) was not conducted in 1495 of eligible patients. These patients were more often women, had higher age and waist circumference, and were therefore more likely to have AGR than those who were included. A model based on easily available clinical and laboratory variables, including FPG, high-density lipoprotein cholesterol, age and the logarithm of glycated haemoglobin A1c, misclassified 44% of the patients, of whom 18% were overdiagnosed and 26% were underdiagnosed. CONCLUSION: An OGTT is still the most appropriate method for the clinical assessment of glucometabolic status in patients with coronary heart disease.

Beta cell dysfunction in patients with acute myocardial infarction but without previously known type 2 diabetes: a report from the GAMI study.

AIMS/HYPOTHESIS: Patients with acute myocardial infarction (AMI) but without previously known type 2 diabetes have a high prevalence of undiagnosed IGT and type 2 diabetes. Such perturbations have dismal prognostic implications. The aim of this study was to characterise AMI patients in terms of insulin resistance and beta cell function. METHODS: A total of 168 consecutive AMI patients were classified by means of an OGTT before hospital discharge as having NGT, IGT or type 2 diabetes. The homeostasis model assessment (HOMA-IR) was used to estimate insulin resistance. Beta cell responsiveness was quantified as insulinogenic index (IGI) at 30 min (DeltaI(30)/DeltaG(30)). RESULTS: According to the HOMA-IR, patients with type 2 diabetes were more insulin resistant than those with IGT or NGT (p=0.003). Beta cell responsiveness deteriorated with decreasing glucose tolerance as measured by the IGI (median [quartile 1, quartile 3] in pmol/mmol: NGT, 70.1 [42.7, 101.4]; IGT, 48.7 [34.7, 86.8], type 2 diabetes, 38.1 [25.7, 61.6]; p<0.001). The IGI was significantly related to admission capillary blood glucose (r=-0.218, p=0.010) and to the area under the curve for glucose (r=-0.475, p<0.001). CONCLUSIONS/INTERPRETATION: Glucose abnormalities are very common in patients with AMI but without previously known type 2 diabetes. To a significant extent, this seems to be related to impaired beta cell function and implies that dysglycaemia immediately after an infarction is not a stress epiphenomenon but reflects stable disturbances of glucose regulation preceding the AMI. Early beta cell dysfunction may have important pathophysiological implications and may serve as a future target for treatment strategies.

Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity.

AIMS: Patients with diabetes have an unfavourable prognosis after an acute myocardial infarction. In the first DIGAMI study, an insulin-based glucose management improved survival. In DIGAMI 2, three treatment strategies were compared: group 1, acute insulin-glucose infusion followed by insulin-based long-term glucose control; group 2, insulin-glucose infusion followed by standard glucose control; and group 3, routine metabolic management according to local practice. METHODS AND RESULTS: DIGAMI 2 recruited 1253 patients (mean age 68 years; 67% males) with type 2 diabetes and suspected acute myocardial infarction randomly assigned to groups 1 (n=474), 2 (n=473), and 3 (n=306). The primary endpoint was all-cause mortality between groups 1 and 2, and a difference was hypothesized as the primary objective. The secondary objective was to compare total mortality between groups 2 and 3, whereas morbidity differences served as tertiary objectives. The median study duration was 2.1 (interquartile range 1.03-3.00) years. At randomization, HbA1c was 7.2, 7.3, and 7.3% in groups 1, 2, and 3, respectively, whereas blood glucose was 12.8, 12.5, and 12.9 mmol/L, respectively. Blood glucose was significantly reduced after 24 h in all groups, more in groups 1 and 2 (9.1 and 9.1 mmol/L) receiving insulin-glucose infusion than in group 3 (10.0 mmol/L). Long-term glucose-lowering treatment differed between groups with multidose insulin (> or =3 doses/day) given to 15 and 13% of patients in groups 2 and 3, respectively compared with 42% in group 1 at hospital discharge. By the end of follow-up, HbA1c did not differ significantly among groups 1-3 ( approximately 6.8%). The corresponding values for fasting blood glucose were 8.0, 8.3, and 8.6 mmol/L. Hence, the target fasting blood glucose for patients in group 1 of 5-7 mmol/L was never reached. The study mortality (groups 1-3 combined) was 18.4%. Mortality between groups 1 (23.4%) and 2 (22.6%; primary endpoint) did not differ significantly (HR 1.03; 95% CI 0.79-1.34; P=0.831), nor did mortality between groups 2 (22.6%) and 3 (19.3%; secondary endpoint) (HR 1.23; CI 0.89-1.69; P=0.203). There were no significant differences in morbidity expressed as non-fatal reinfarctions and strokes among the three groups. CONCLUSION: DIGAMI 2 did not support the fact that an acutely introduced, long-term insulin treatment improves survival in type 2 diabetic patients following myocardial infarction when compared with a conventional management at similar levels of glucose control or that insulin-based treatment lowers the number of non-fatal myocardial reinfarctions and strokes. However, an epidemiological analysis confirms that the glucose level is a strong, independent predictor of long-term mortality in this patient category, underlining that glucose control seems to be an important part of their management.

An overview of the role of insulin in the treatment of hyperglycemia during acute myocardial ischemia.

Hyperglycemia on admission to the coronary care unit is associated with poor outcome. It has now been reasonably well established that intravenous insulin infusion during acute myocardial infarction has a protective role and reduces mortality. The present article reviews the current understanding of the cardioprotective effect of insulin and the recent advances in this area.

Newly detected abnormal glucose tolerance: an important predictor of long-term outcome after myocardial infarction.

AIMS: Recent data revealed that patients with myocardial infarction (MI) have a high prevalence of previously unknown diabetes mellitus (DM) and impaired glucose tolerance (IGT). The added prognostic importance of this finding has not been prospectively explored. To investigate whether a newly detected abnormal glucose tolerance (IGT or DM) assessed early after an MI, is related to long-term prognosis. METHODS AND RESULTS: Patients (n=168; age 63.5+/-9.3 years) with MI, no previous DM and admission blood glucose <11.0 mmol/l were followed for major cardiovascular events defined as the composite of cardiovascular death, non-fatal MI, non-fatal stroke or severe heart failure (HF). According to an oral glucose tolerance test (OGTT) before hospital discharge, 55 patients had normal and 113 abnormal glucose tolerance (GT). During the follow-up of median 34 months there were eight cardiovascular deaths, 15 patients had a recurrent MI, six had a stroke and ten severe HF. All patients who died from cardiovascular causes had abnormal GT. The composite cardiovascular event occurred in 31 (18%) patients. The probability of remaining free from cardiovascular events was significantly higher in patients with normal than abnormal GT (p=0.002). Together with previous MI, abnormal GT was the strongest predictor of future cardiovascular events (hazard ratio 4.18; CI 1.26-13.84; p=0.019). CONCLUSIONS: Abnormal glucose tolerance is a strong risk factor for future cardiovascular events after myocardial infarction. Since it is common and possible to detect even during the hospital phase it may be a target for novel secondary preventive efforts.

Abnormal glucose tolerance--a common risk factor in patients with acute myocardial infarction in comparison with population-based controls.

BACKGROUND: A high prevalence of newly detected diabetes and impaired glucose tolerance (abnormal glucose tolerance) was recently reported in patients with acute myocardial infarction. It is important to verify whether this finding is specific for the patients or attributable to the population, from which they were recruited. OBJECTIVE: To verify whether abnormal glucose tolerance is more prevalent in patients than in controls chosen from the same population and to compare metabolic characteristics between the two groups. DESIGN AND SUBJECTS: The metabolic state was assessed in patients (n = 181) admitted with acute myocardial infarction and no history of diabetes before discharge and after 3 months. Sex- and age-matched controls (n = 185) without previously known diabetes or cardiovascular disease except hypertension were recruited from the general population. MAIN OUTCOME MEASURES: Oral glucose tolerance test, glucosylated haemoglobin A1c (HbA1c), insulin, proinsulin, lipid profile, fibrinolytic function and inflammatory markers. RESULTS: Abnormal glucose tolerance was more common (number/all classified) in patients at discharge 113/168 (67%) and after 3 months 95/145 (66%) than in controls 65/185 (35%) (P < 0.001). Dyslipidaemia (70% vs. 29%; P < 0.001) and previously treated hypertension (32% vs. 18%; P = 0.028) were more frequent amongst patients whilst obesity (18% vs. 24%) did not differ significantly. Blood glucose, HbA1c, proinsulin, proinsulin/insulin ratio, triglycerides, insulin resistance (by HOMA) and fibrinogen were consistently higher in patients than controls (P < 0.01). CONCLUSIONS: Abnormal glucose tolerance was almost twice as common amongst patients with acute myocardial infarction as in matched controls. Impaired glycaemic control accompanied by insulin resistance, dyslipidaemia, hypertension, together with increased plasma fibrinogen and proinsulin levels were main features characterizing patients.