[Hyperglycemia and cardiovascular risk: lessons from randomized trials]. / Hyperglycémie et risque cardiovasculaire: bilan des grandes études.

Diabetes is a major cardiovascular risk factor However, hyperglycemia is much more closely associated with microangiopathy than with macrovascular complications. Epidemiologic studies have shown a 15% increase of myocardial infarction for 1% increase in HbA1c level. It is accepted but not absolutely demonstrated, that reduction of HbA1c results in an equal reduction of cardiovascular events. An initial good glycemic control has long-term benefical effects on the risk of cardiovascular disease. On the contrary, benefit of an intensive glucose control is not demonstrated in diabetic patients with previous myocardial infarction. Two recent studies (ACCORD and VADT) showed an increase of cardiovascular mortality by severe hypoglycemia. In diabetic patients with previous myocardial infarction, glycemic goal must be modulated by the hypoglycaemic risk. A goal of 7.5% HbA1c seems reasonable for the diabetic patients treated by sulfonylureas or insulin, at risk of hypoglycaemia. HbA1c target < 7% remains the general goal and HbA1c target < 6.5% is appropriated to the patients treated by insulin sensitizing medications without risk of hypoglycaemia.

OPADIA Study: Is a Patient Questionnaire Useful for Enhancing Physician-Patient Shared Decision Making on Physical Activity Micro-objectives in Diabetes?

INTRODUCTION: Regular physical activity (PA) is recommended by all type 2 diabetes mellitus (T2DM) management guidelines. The OPADIA study aimed to determine whether using a specific patient questionnaire (Optima-PA©) could help T2DM patients increase their PA by leading to better physician-patient communication and improved levels of shared decision making concerning Specific, Measurable, Acceptable, Realistic, Timely (SMART)-PA micro-objectives. METHODS: Physicians participating in this multicentre, prospective, randomised, real-life study were allocated to a standard group (T2DM patients managed according to usual clinical practice, n = 24) or the OPTIMA-PA group (additional use of the questionnaire, n = 30). The main outcome was the percentage of inclusion visits ending with the setting up of at least one SMART-PA micro-objective. Other outcomes were the impact of the OPTIMA-PA questionnaire on patient perceptions of shared decision making (ENTRED questionnaire) and the impact of the OPTIMA-PA questionnaire and establishing SMART-PA micro-objectives as well as patient-perceived physician empathy (ENTRED questionnaire) and GP aptitude for patient-centredness (SEPCQ scores) on patient PA levels over a 3-month period (IPAQ-SF scores). RESULTS: One hundred twenty-two patients were included in the standard group and 134 in the OPTIMA-PA group. Unexpectedly, more inclusion visits ended with SMART-PA micro-objectives being set up in the standard group (p < 0.001): 81.1% (n = 99/122) versus 59.7% (n = 80/134). However, fewer patients in the OPTIMA-PA group felt that GPs made decisions alone (32% versus 60%; p < 0.0001). Positive correlations were also observed between GP patient-centredness and patient-perceived GP empathy or increased patient PA over the study period. CONCLUSION: Although the OPTIMA-PA questionnaire did not directly promote setting up of SMART-PA micro-objectives in T2DM patients, the OPADIA study demonstrated that this tool was effective at improving patient-physician relationships by increasing patient involvement in therapeutic decision making. Our study also highlighted the importance of GP aptitude for patient-centredness for improving PA in T2DM patients.

Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial.

BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH) is a liver disease that complicates insulin-resistant states. This trial tested the efficacy and safety of rosiglitazone, an insulin-sensitizing agent, in patients with NASH. METHODS: Sixty-three patients with histologically proven NASH were randomly assigned to receive rosiglitazone (4 mg/day for the first month and 8 mg/day thereafter; n = 32) or placebo (n = 31) for 1 year. Liver biopsy was performed at the end of treatment. End points were improvement in the histologic score of steatosis, normalization of serum transaminase levels, and improvement in necroinflammation and fibrosis. RESULTS: More patients treated with rosiglitazone than receiving placebo had improved steatosis (47% vs 16%; P = .014) and normalized transaminase levels (38% vs 7%; P = .005), although only half of patients responded. There was no improvement in other histologic lesions, including fibrosis, and a composite score of activity, the nonalcoholic fatty liver disease activity score. Improvement of steatosis correlated with reduction of transaminase levels (r = 0.36; P < .005), improvement in insulin sensitivity (r = 0.34; P = .008), and increase in adiponectin levels (r = -0.54; P < .01) but not with weight variations. Independent predictors of response were rosiglitazone treatment, the absence of diabetes, and massive steatosis. Weight gain was the main adverse effect (mean gain of 1.5 kg in the rosiglitazone group vs -1 kg in the placebo group; P < .01), and painful swollen legs was the main reason for dose reduction/discontinuation. Serum hemoglobin level was slightly but significantly reduced. There was no hepatic toxicity. CONCLUSIONS: In patients with NASH, rosiglitazone improves steatosis and transaminase levels despite weight gain, an effect related to an improvement in insulin sensitivity. However, there is no improvement in other parameters of liver injury.

Screening for liver fibrosis by using a noninvasive biomarker in patients with diabetes.

BACKGROUND & AIMS: Patients with diabetes are at risk for nonalcoholic fatty liver disease leading to advanced fibrosis, cirrhosis, and liver cancer. We examined the efficacy of a screening strategy with a noninvasive fibrosis biomarker (FibroTest) in patients with diabetes. METHODS: We prospectively studied 1131 consecutive patients without a history of liver disease seen for diabetes. The biomarker data were obtained, and patients with presumed advanced fibrosis were reinvestigated by a hepatologist using elastography and, if necessary, ultrasonography, endoscopy, or liver biopsy. RESULTS: The biomarker predicted advanced fibrosis in 63 of 1131 (5.6%) patients. A total of 45 patients was reinvestigated, and advanced fibrosis was confirmed in 32 patients, a 2.8% (32/1131) prevalence of confirmed advanced fibrosis, 5 cases of cirrhosis, and 4 cases of hepatocellular carcinoma. In the population with type 2 diabetes who were 45 years or older, the prevalence of confirmed advanced fibrosis was 4.3% (30/696), and hepatocellular carcinoma was 5.7 of 1000 (4/696). CONCLUSIONS: The fibrosis biomarker might be used for the detection of advanced fibrosis in patients with type 2 diabetes.

An example of clinical controversy related to evidence-based medecine / Un exemple de controverse en clinique liée à l'EBM

An example of clinical controversy related to EBM. The DCCT study for type 1 diabetes (1993) and UKPDS for type 2 (1998) had demonstrated the benefit of the hypoglycemic treatment with, for 1 point of HbA1c less, 30% less microangiopathy events. The cardiovascular benefit was less obvious, as these studies were performed in patients with primary prevention. The benefit became significant only during the follow-up, 10 years after the end of the study. After these results, it became unethical to consider randomized studies in which patients in the control group would have HbA1c greater than or equal to 8%. More recent studies in type 2 diabetics with a very high cardiovascular risk therefore compared "intensive" treatment to "good" treatment. The "super intensive" treatment of the ACCORD study, with an objective of HbA1c lower than 6%, resulted in increased mortality leading to premature discontinuation of the study. The excess cardiovascular mortality was correlated with the occurrence of very severe hypoglycaemia, three times more frequent in the "super intensive" group. In contrast to the concept "the lower is the better", patients with high cardiovascular risk should avoid the risk of severe hypoglycaemia secondary to treatment. In addition, the drug industry was asked to demonstrate the cardiovascular safety of the new antidiabetic molecules, regardless of their hypoglycemic effect, by conducting randomized double-blind studies with an identical target of HbA1c between the two groups. The adaptation of glycemic targets to cardiovascular risk in case of risk of hypoglycemia on the one hand, and the poor understanding of the methodology of cardiovascular safety studies on the other hand, have led to a radical questioning of the benefit of treating hyperglycemia with potentially serious consequences for patients.

Un exemple de controverse en clinique liée à L'EBM. Les études DCCT pour le diabète de type 1 (1993) et UKPDS pour le type 2 (1998) avaient apporté la preuve du bénéfice du traitement hypoglycémiant avec, pour 1 point d'hémoglobine glyquée (HbA1c) en moins, 30 % en moins de survenue d'évènements de microangiopathie. Le bénéfice cardiovasculaire était moins évident, ces études ayant été réalisées chez des patients en prévention primaire. Le bénéfice ne devenait significatif que lors du suivi, 10 ans après la fin de l'étude. Après ces résultats, il devenait non éthique d'envisager des études randomisées dont les patients du groupe contrôle auraient une HbA1c supérieure ou égale à 8 %. Les études plus récentes réalisées chez des diabétiques de type 2 à très haut risque cardiovasculaire ont donc comparé un traitement « intensif ¼ à un « bon ¼ traitement. Le traitement « super intensif ¼ de l'étude ACCORD visant une HbA1c inférieure à 6 % a entraîné une augmentation de la mortalité provoquant l'arrêt prématuré de l'étude. La surmortalité cardiovasculaire était corrélée à la survenue d'hypoglycémies très sévères, trois fois plus fréquentes dans le groupe « super intensif ¼. À l'opposé du concept « the lower is the better ¼, il faut donc chez les patients à haut risque cardiovasculaire éviter le risque d'hypoglycémie sévère secondaire au traitement. De plus il a été demandé aux industriels de démontrer la sécurité cardiovasculaire des nouvelles molécules antidiabétiques, indépendamment de leur effet hypoglycémiant, en réalisant des études randomisées en double aveugle avec un objectif d'HbA1c identique entre les deux groupes. L'adaptation des objectifs glycémiques au risque cardiovasculaire en cas de risque d'hypoglycémie d'une part, et la mauvaise compréhension de la méthodologie des études de sécurité cardiovasculaire d'autre part ont suscité une remise en cause radicale du bienfait du traitement de l'hyperglycémie aux conséquences potentiellement graves pour les patients.

[Insulin in the treatment of ischemic stroke]. / Place de l'insuline dans le traitement des accidents ischémiques cérébraux.

Hyperglycemia is correlated with poor prognosis in ischemic strokes and also increases the risk of hemorrhagic transformation after thrombolysis. The toxicity of hyperglycemia, already well established in animals, is beginning to be clear for humans. On the other hand, the beneficial effect of insulin remains controversial in animals and has never been demonstrated in humans. Preliminary data, which suggest that the speed and quality of glycemic control may be decisive in the efficacy of treatment, merit testing in a randomized trial.

Breaking Barriers to Effective Type 2 Diabetes Management: Findings from the use of the OPTIMA© Questionnaire in Clinical Practice.

BACKGROUND: The OPTIMA© (MSD, Courbevoie, France) questionnaire was developed to promote shared decisions and the set-up of specific micro-objectives in clinical practice by optimizing communication between type 2 diabetes (T2DM) patients and their physicians. The present study aimed to assess OPTIMA in clinical practice. METHODS: A cross-sectional multicenter observational study was conducted in France from 2012 to 2014. During routine consultation, patients completed one of the five modules of the OPTIMA questionnaire (Physical activity, Diet, Treatment, Knowledge of the disease or Self-monitoring of blood glucose). The rate of SMART (specific, measurable, acceptable, realistic, timely) micro-objective set-up following the use of the questionnaire was assessed. Data on how patients felt about their diabetes management (beliefs concerning actions, how easy they were to do and how often they were done in practice) were gathered. Finally, patients' and physicians' opinions on OPTIMA were assessed using the PRAgmatic Content and face validity Test (PRAC-Test© (Mapi, Lyon, France) evaluation questionnaire. RESULTS: Overall, 807 patients were included by 186 physicians. While 92.7 % of consultations led to the set-up of a micro-objective, only 22.3 % were SMART micro-objectives: Physical activity module (34.3 %), Diet module (9.6 %), Treatment module (16.4 %), Knowledge of the disease module (25.2 %), and self-monitoring of blood glucose module (29.5 %). Among patients completing the Physical activity module, 79.0 % reported that they believed physical activity was useful, 35.0 % that it was easy, and 25.8 % that they regularly practised it. PRAC-Test results showed that OPTIMA was a useful and easy-to-use questionnaire that promotes communication between physicians and their patients according to 92.8 % of patients and 69.4 % of physicians. CONCLUSION: The OPTIMA questionnaire facilitates communication between patients and their physicians and promotes the set-up of micro-objectives concerning T2DM management. The Physical activity module was the most likely of the five modules in the questionnaire to lead to the set-up of SMART micro-objectives. FUNDING: MSD France.

Nonremovable, windowed, fiberglass cast boot in the treatment of diabetic plantar ulcers: efficacy, safety, and compliance.

OBJECTIVE: To compare the efficacy, safety, and compliance of a nonremovable fiberglass cast boot and off-loading shoes in the treatment of diabetic plantar ulcers. RESEARCH DESIGN AND METHODS: Patients (n = 93) with noninfected, nonischemic plantar ulcers were included in this prospective nonrandomized study. Treatment used a nonremovable fiberglass cast boot for longer standing and deeper ulcers (n = 42) and a half shoe or heel-relief shoe for other ulcers (n = 51). We evaluated off-loading therapy, compliance, and complications in both groups. RESULTS: The healing rate was significantly higher with the cast boot than with the off-loading shoe (81 vs. 70%, P = 0.017), with healing times of 68.6 +/- 35.1 vs. 134.2 +/- 133.0 days, respectively, and hazard ratio 1.68 (95% CI 1.04-2.70); complete compliance with treatment was 98 vs. 10% (P = 0.001), respectively. Secondary osteomyelitis developed in 3 patients in the cast boot group and 13 patients in the off-loading shoe group (P = 0.026). CONCLUSIONS: A nonremovable fiberglass cast boot was effective in healing diabetic plantar ulcers and in decreasing the risk of secondary osteomyelitis. The cast boot forced compliance with off-loading, thus promoting healing.

Adipose tissue IL-6 content correlates with resistance to insulin activation of glucose uptake both in vivo and in vitro.

Obesity and type 2 diabetes are associated with insulin resistance, the mechanisms of which remain poorly understood. A significant correlation between circulating IL-6 level and insulin sensitivity has recently been found in humans. Because adipose tissue could be a significant source of IL-6, we analyzed the relationship between the levels of adipose tissue IL-6 and insulin action in vivo, during a hyperinsulinemic normoglycemic clamp, and in vitro by measuring glucose transport in adipocytes from 12 obese subjects with (n = 7) or without (n = 5) diabetes. We observed an inverse correlation between adipose tissue IL-6 content and maximal insulin-responsiveness measured in vivo (P < 0.02) and in vitro (P < 0.02). Conversely, there was no significant correlation between these two later parameters and adipose tissue leptin or tumor necrosis factor-alpha protein contents. Furthermore, we showed, for the first time, the presence of immunoreactive IL-6 receptors in the plasma membrane of human abdominal sc adipocytes. This suggests that locally secreted IL-6 could act on adipocytes by an autocrine/paracrine mechanism. In conclusion, increased IL-6 production by sc adipose cells might participate to the insulin-resistant state observed in human obesity.