Linda Mellbin

Does hypoglycaemia increase the risk of cardiovascular events? A report from the ORIGIN trial.

AIMS Hypoglycaemia caused by glucose-lowering therapy has been linked to cardiovascular (CV) events. The ORIGIN trial provides an opportunity to further assess this relationship. METHODS AND RESULTS A total of 12 537 participants with dysglycaemia and high CV-risk were randomized to basal insulin glargine titrated to a fasting glucose of ≤ 5.3 mmol/L (95 mg/dL) or standard glycaemic care. Non-severe hypoglycaemia was defined as symptoms confirmed by glucose ≤ 54 mg/dL and severe hypoglycaemia as a requirement for assistance or glucose ≤ 36 mg/dL. Outcomes were: (i) the composite of CV death, non-fatal myocardial infarction or stroke; (ii) mortality; (iii) CV mortality; and (iv) arrhythmic death. Hazards were estimated before and after adjustment for a hypoglycaemia propensity score. During a median of 6.2 years (IQR: 5.8-6.7), non-severe hypoglycaemic episodes occurred in 41.7 and 14.4% glargine and standard group participants, respectively, while severe episodes occurred in 5.7 and 1.8%, respectively. Non-severe hypoglycaemia was not associated with any outcome following adjustment. Conversely, severe hypoglycaemia was associated with a greater risk for the primary outcome (HR: 1.58; 95% CI: 1.24-2.02, P < 0.001), mortality (HR: 1.74; 95% CI: 1.39-2.19, P < 0.001), CV death (HR: 1.71; 95% CI: 1.27-2.30, P < 0.001) and arrhythmic death (HR: 1.77; 95% CI: 1.17-2.67, P = 0.007). Similar findings were noted for severe nocturnal hypoglycaemia for the primary outcome and mortality. The severe hypoglycaemia hazard for all four outcomes was higher with standard care than with insulin glargine. CONCLUSION Severe hypoglycaemia is associated with an increased risk for CV outcomes in people at high CV risk and dysglycaemia. Although allocation to insulin glargine vs. standard care was associated with an increased risk of severe and non-severe hypoglycaemia, the relative risk of CV outcomes with hypoglycaemia was lower with insulin glargine-based glucose-lowering therapy than with the standard glycaemic control. Trial Registration (ORIGIN ClinicalTrials.gov number NCT00069784).

ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD - summary.

ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD - summary.

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.

Diabetes, prediabetes and cardiovascular risk

The increase in the incidence of diabetes and prediabetes, the association with cardiovascular disease and the accompanying high morbidity and mortality make glucose perturbations a serious public health issue. The poor prognosis among patients with type 2 diabetes and cardiovascular disease may relate to several factors. There seems to be a misconception among cardiologists that diabetes is a nonfrequent, almost unexciting disease and if it exists, it is labelled as ‘mild’ and/or ‘easy to treat.’ If screened with an oral glucose tolerance test approximately two-thirds of patients with coronary artery disease, stable and unstable, and earlier unknown glucometabolic perturbations indeed have impaired glucose tolerance or newly detected diabetes. Both conditions are related to an increase in cardiovascular mortality and morbidity. The European guidelines for diabetes, prediabetes and cardiovascular disease recommend that all patients with cardiovascular disease manifestations are screened with an oral glucose tolerance test. Many cardiologists seem more focused on the manifestation of the cardiac condition, not fully understanding the need for simultaneous and aggressive interactions directed towards the underlying metabolic disorder and the frequently existing concomitant risk factors. Treatment must be multifactorial and target driven. Treatment targets are stricter for patients with diabetes than those without diabetes. Patient management according to such standards is highly rewarding but necessitates transprofessional collaboration between cardiologists and diabetologists to be successfully accomplished. Eur J Cardiovasc Prev Rehabil 17 (Suppl 1):S9-S14

Complement Activation and Prognosis in Patients With Type 2 Diabetes and Myocardial Infarction: A report from the DIGAMI 2 trial

OBJECTIVE The activation of the complement system may be involved in the pathology of myocardial infarction (MI) and type 2 diabetes. To explore their potential as prognostic markers, we characterized two factors in the complement cascade, the end product sC5b-9 and the mannose-binding lectin–associated Ser protease-2 (MASP-2), in type 2 diabetic patients with suspected MI. RESEARCH DESIGN AND METHODS Plasma sC5b-9 and MASP-2 were determined in patients with MI and type 2 diabetes (n = 397; median age 70; male 68%). The adjudicated end points were cardiovascular events (CVEs), including cardiovascular mortality and nonfatal MI or stroke. RESULTS The median sC5b-9 was 134 μg/L (interquartile range [IQR] 101–190 μg/L) and the median MASP-2 was 333 μg/L (IQR 235–463 μg/L), with no significant correlation between them. Women had higher sC5b-9 than men (median 152 vs. 130 μg/L; P = 0.02). Both sC5b-9 and MASP-2 were correlated to age and creatinine clearance, while MASP-2 was also correlated to BMI. During a median follow-up of 2.4 years, CVEs occurred in 141 patients (36%). Both sC5b-9 (hazard ratio 1.37 [95% CI 1.13–1.65]; P < 0.01) and MASP-2 (0.68 [0.51–0.92]; P = 0.01) predicted CVEs in unadjusted analyses. After multiple adjustments, the predictive capacity remained for sC5b-9 (1.30 [1.02–1.66]; P = 0.04) but not for MASP-2. CONCLUSIONS In type 2 diabetic patients with MI, high levels of sC5b-9 predict future CVE. This indicates that the complement system may play a significant role in the pathology of the subsequent myocardial damage and that the pathways leading to complement activation warrant further exploration as potential therapeutic targets to improve the prognosis for these patients.

Fasting glucose, HbA1c, or oral glucose tolerance testing for the detection of glucose abnormalities in patients with acute coronary syndromes

Background: Due to the negative prognostic impact, it is important to accurately detect undiagnosed glucose perturbations in patients with acute coronary syndromes (ACS). Design: This study compares oral glucose tolerance test (OGTT) to fasting plasma glucose (FPG) and HbA1c as screening tools. Methods: Patients hospitalized for ACS had an OGTT, FPG, and HbA1c measured 4–21 (median 6) days after admission as a screening process for an intervention study. Results: Out of 174 patients, 75 (43%) had a normal glucose tolerance, 63 (36%) impaired glucose tolerance (IGT), and 36 (21%) diabetes type 2 (T2DM). Of these, 20 were non-eligible, and of the remaining 79 patients, 52 had IGT and 27 T2DM according to the OGTT. In patients with IGT, the median FPG was 6.0 mmol/l and the median HbA1c was 39 mmol/mol. The corresponding levels in patients with T2DM were 6.3 mmol/l and 41 mmol/mol, respectively. Seventeen of the 27 patients with T2DM according to OGTT had not been disclosed if the screening had been based on FPG. HbA1c identified two patients. Conclusions: Compared to OGTT, the use of FPG or HbA1c alone leaves a majority of patients with IGT or T2DM undetected when screening for unknown glucose perturbations as a part of total risk assessment of patients with ACS.

The relationship between glycaemic variability and cardiovascular complications in patients with acute myocardial infarction and type 2 diabetes: a report from the DIGAMI 2 trial

AIMS Hyperglycaemia during hospitalization for acute myocardial infarction (AMI) is a risk predictor, but attempts to improve the prognosis by insulin-based glucose control have not been consistently successful. Increased glycaemic variability, a potential effect of insulin treatment, has been linked to a worse prognosis in critically ill patients. The present aim was to study the possibility of such a relation in patients with type 2 diabetes (T2DM) and AMI. METHOD AND RESULTS We studied 578 T2DM patients who had glucose levels measured hourly while receiving an insulin-glucose infusion during the first 48 h of hospitalization for AMI. Three measures of glycaemic variability: root mean square error (RMSE), range, and slope were studied in relation to a composite endpoint of mortality, stroke, and reinfarction and to mortality. In unadjusted analyses, the mean level of glycaemic variability did not differ between patients who died during 12 months of follow-up compared with those who survived. In a Cox regression model adjusting for age and previous congestive heart failure, there was no increased risk for the composite endpoint associated with increased glycaemic variability; RMSE: hazard ratio (HR) 1.09 [95% confidence interval (CI) 0.93-1.27; P = 0.28], range: HR 1.01 (95% CI: 0.98-1.05; P = 0.47), and slope: HR 1.01 (95% CI: 0.99-1.04; P = 0.40). There was furthermore no increased risk in mortality; RMSE HR 1.14 (95% CI: 0.93-1.38; P = 0.21), range HR 1.03 (95% CI: 0.98-1.08; P = 0.28), and slope HR 1.01 (95% CI: 0.98-1.04; P = 0.55). CONCLUSION The 1-year risk for death, reinfarction, or stroke did not relate to glycaemic variability in T2DM patients with AMI treated with insulin infusion.

Copeptin, IGFBP-1, and Cardiovascular Prognosis in Patients With Type 2 Diabetes and Acute Myocardial Infarction A report from the DIGAMI 2 trial

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.

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.

Detection of Circulating hcmv-miR-UL112-3p in Patients with Glioblastoma, Rheumatoid Arthritis, Diabetes Mellitus and Healthy Controls

Background microRNAs (miRNA) are 18–22 nucleotides long non-coding RNAs that regulate gene expression at a post-transcriptional level. Human cytomegalovirus (HCMV) encodes at least 26 known mature miRNAs. hcmv-miR-UL112-3p (miR-UL112-3p) is the most well characterized HCMV miRNA, which is suggested to play role in establishment and maintenance of viral latency. Elevated miR-UL112-3p levels have been reported to be present in plasma of patients with hypertension. Objectives In this study, we aimed to quantify miR-UL112-3p levels in the plasma/serum of patients with Diabetes Mellitus (DM; from the DIGAMI-2 cohort), Glioblastoma multiforme (GBM), Rheumatoid Arthritis (RA) and Healthy Controls (HC). Study Design Total RNA was isolated from plasma/serum samples of 87 patients and controls, a TaqMan miRNA assay was performed to detect miR-UL112-3p and the copy numbers were normalized to 10 ng of total RNA. HCMV IgG and IgM were analysed using ELISA. Results HCMV miR-UL112-3p was detected in 14/27 (52%) of DM, 5/20 (25%) of GBM, 1/20 (5%) of RA patients and in 2/20 (10%) of HC, respectively. Anti-HCMV IgG was detected in 85%, 65%, 75% of patients and 70% of HC, respectively. Anti-HCMV IgM was found only in one GBM patient of 87 examined patients and controls. Conclusions A higher prevalence of miR-UL112-3p was detected in DM and GBM patients than in RA patients and HC. Elevated levels of miR-UL112-3p and higher prevalence of HCMV IgG were observed in DM patients. Whether the presence of circulating miR-UL112-3p denotes a biomarker of HCMV latency or active replication in patients warrants further investigation.