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BackgroundIt is essential to anticipate and limit the social, economic and sanitary cost of type 2 diabetes (T2D), which is in constant progression worldwide.When blood glucose targets are not achieved with diet and lifestyle intervention, insulin is recommended whether or not the patient is already taking hypoglycaemic drugs. However, the benefit/risk balance of insulin remains controversial. Our aim was to determine the efficacy and safety of insulin vs. hypoglycaemic drugs or diet/placebo on clinically relevant endpoints.MethodsA systematic literature review (Pubmed, Embase, Cochrane Library) including all randomised clinical trials (RCT) analysing insulin vs. hypoglycaemic drugs or diet/placebo, published between 1950 and 2013, was performed. We included all RCTs reporting effects on all-cause mortality, cardiovascular mortality, death by cancer, cardiovascular morbidity, microvascular complications and hypoglycaemia in adults ≥ 18 years with T2D. Two authors independently assessed trial eligibility and extracted the data. Internal validity of studies was analyzed according to the Cochrane Risk of Bias tool. Risk ratios (RR) with 95 % confidence intervals (95 % CI) were calculated, using the fixed effect model in first approach. The I2 statistic assessed heterogeneity. In case of statistical heterogeneity, subgroup and sensitivity analyses then a random effect model were performed. The alpha threshold was 0.05. Primary outcomes were all-cause mortality and cardiovascular mortality. Secondary outcomes were non-fatal cardiovascular events, hypoglycaemic events, death from cancer, and macro- or microvascular complications.ResultsTwenty RCTs were included out of the 1632 initially identified studies. 18 599 patients were analysed: Insulin had no effect vs. hypoglycaemic drugs on all-cause mortality RR = 0.99 (95 % CI =0.92–1.06) and cardiovascular mortality RR = 0.99 (95 % CI =0.90–1.09), nor vs. diet/placebo RR = 0.92 (95 % CI = 0.80–1.07) and RR = 0.95 (95 % CI 0.77–1.18) respectively. No effect was found on secondary outcomes either. However, severe hypoglycaemia was more frequent with insulin compared to hypoglycaemic drugs RR = 1.70 (95 % CI = 1.51–1.91).ConclusionsThere is no significant evidence of long term efficacy of insulin on any clinical outcome in T2D. However, there is a trend to clinically harmful adverse effects such as hypoglycaemia and weight gain. The only benefit could be limited to reducing short term hyperglycemia. This needs to be confirmed with further studies.Electronic supplementary materialThe online version of this article (doi:10.1186/s12902-016-0120-z) contains supplementary material, which is available to authorized users.

BackgroundWe sought to assess the long-term evolution of left ventricular (LV) function using two-dimensional (2D) and three-dimensional (3D) speckle tracking echocardiography (STE) for the detection of preclinical diabetic cardiomyopathy, in asymptomatic type 1 diabetic patients, over a 6-year follow-up.Design and methodsSixty-six asymptomatic type 1 diabetic patients with no cardiovascular risk factors were compared to 26 matched healthy controls. Conventional, 2D and 3D-STE were performed at baseline. A subgroup of 14 patients underwent a 6-year follow-up evaluation.ResultsAt baseline, diabetic patients had similar LV ejection fraction (60 vs 61%; P = NS), but impaired longitudinal function, as assessed by 2D-global longitudinal strain (GLS) (−18.9 ± 2 vs −20.5 ± 2; P = 0.0002) and 3D-GLS (−17.5 ± 2 vs −19 ± 2; P = 0.003). At follow-up, diabetic patients had worsened longitudinal function compared to baseline (2D-GLS: −18.4 ± 1 vs −19.2 ± 1; P = 0.03). Global circumferential (GCS) and radial (GRS) strains were unchanged at baseline and during follow-up. Metabolic status did not correlate with GLS, whereas GCS and GRS showed a good correlation, suggestive of a compensatory increase of circumferential and radial functions in advanced stages of the disease – long-term diabetes (GCS: −26 ± 3 vs −23.3 ± 3; P = 0.008) and in the presence of microvascular complications (GRS: 38.8 ± 9 vs 34.3 ± 8; P = 0.04).ConclusionsSubclinical myocardial dysfunction can be detected by 2D and 3D-STE in type 1 diabetic patients, independently of any other cardiovascular risk factors. Diabetic cardiomyopathy progression was suggested by a mild decrease in longitudinal function at the follow-up, but did not extend to a clinical expression of the disease, as no death or over heart failure was reported.

BackgroundClinicians are sometimes advised to make decisions using thresholds in measured variables, derived from prognostic studies.ObjectivesWe studied why there are conflicting apparently-optimal prognostic thresholds, for example in exercise peak oxygen uptake (pVO2), ejection fraction (EF), and Brain Natriuretic Peptide (BNP) in heart failure (HF).Data Sources and Eligibility CriteriaStudies testing pVO2, EF or BNP prognostic thresholds in heart failure, published between 1990 and 2010, listed on Pubmed.MethodsFirst, we examined studies testing pVO2, EF or BNP prognostic thresholds. Second, we created repeated simulations of 1500 patients to identify whether an apparently-optimal prognostic threshold indicates step change in risk.Results33 studies (8946 patients) tested a pVO2 threshold. 18 found it prognostically significant: the actual reported threshold ranged widely (10–18 ml/kg/min) but was overwhelmingly controlled by the individual study population's mean pVO2 (r = 0.86, p<0.00001). In contrast, the 15 negative publications were testing thresholds 199% further from their means (p = 0.0001). Likewise, of 35 EF studies (10220 patients), the thresholds in the 22 positive reports were strongly determined by study means (r = 0.90, p<0.0001). Similarly, in the 19 positives of 20 BNP studies (9725 patients): r = 0.86 (p<0.0001).Second, survival simulations always discovered a “most significant” threshold, even when there was definitely no step change in mortality. With linear increase in risk, the apparently-optimal threshold was always near the sample mean (r = 0.99, p<0.001).LimitationsThis study cannot report the best threshold for any of these variables; instead it explains how common clinical research procedures routinely produce false thresholds.Key FindingsFirst, shifting (and/or disappearance) of an apparently-optimal prognostic threshold is strongly determined by studies' average pVO2, EF or BNP. Second, apparently-optimal thresholds always appear, even with no step in prognosis.ConclusionsEmphatic therapeutic guidance based on thresholds from observational studies may be ill-founded. We should not assume that optimal thresholds, or any thresholds, exist.

BackgroundDespite pathophysiological relevance and promising experimental data, the usefulness of biomarkers of oxidative stress for cardiac risk prediction is unclear. The aim of our study was to investigate the prognostic value of 6 biomarkers exploring different pathways of oxidative stress for predicting adverse cardiovascular outcomes in patients with type 2 diabetes mellitus beyond established risk factors.Methods and ResultsThe SURDIAGENE (Survie, Diabete de type 2 et Genetique) prospective cohort study consecutively recruited 1468 patients with type 2 diabetes mellitus. Assays were performed at baseline, and incident cases of major adverse cardiovascular events (MACE)—first occurrence of cardiovascular death, nonfatal myocardial infarction, or stroke—were recorded during a median of 64 months. Advanced oxidation protein products, oxidative hemolysis inhibition assay, ischemia‐modified albumin, and total reductive capacity of plasma were not associated with the risk of MACE in univariate analyses. Fluorescent advanced glycation end products and carbonyls were associated with MACE (hazard ratio=1.38 per SD, 95% confidence interval 1.24‐1.54, P<0.001 and hazard ratio=1.15 per SD, 95% confidence interval 1.04‐1.27, P=0.006, respectively) in univariate analysis, but when added to a multivariate predictive model including traditional risk factors for MACE, these markers did not significantly improve c‐statistics or integrated discrimination index of the model.ConclusionsThese plasma concentrations of 6 markers, which cover a broad spectrum of oxidative processes, were not significantly associated with MACE occurrence and were not able to improve MACE risk discrimination and classification beyond classical risk factors in type 2 diabetes mellitus patients.