The prognostic value of blood pH and lactate and metformin concentrations in severe metformin-associated lactic acidosis

AIMS: Analysis of the prognostic values of blood pH and lactate and plasma metformin concentrations in severe metformin-associated lactic acidosis may help to resolve the following paradox: metformin provides impressive, beneficial effects but is also associated with life-threatening adverse effects. RESEARCH DESIGN AND METHODS: On the basis of 869 pharmacovigilance reports on MALA with available data on arterial pH and lactate concentration, plasma metformin concentration and outcome, we selected cases with a pH < 7.0 and a lactate concentration >10 mmol/L. Outcomes were compared with those described for severe metformin-independent lactic acidosis. RESULTS: Fifty-six patients met the above-mentioned criteria. The mean arterial pH and lactate values were 6.75 ± 0.17 and 23.07 ± 6.94 mmol/L, respectively. The survival rate was 53%, even with pH values as low as 6.5 and lactate and metformin concentrations as high as 35.3 mmol/L and 160 mg/L (normal < 1 mg/L), respectively. Survivors and non-survivors did not differ significantly in terms of the mean arterial pH and lactate concentration. The mean metformin concentration was higher in patients who subsequently died but this difference was due to a very high value (188 mg/L) in one patient in this group, in whom several triggering factors were combined. Sepsis, multidrug overdoses and the presence of at least two triggering factors for lactic acidosis were observed significantly more frequently in non-survivors (p = 0.007, 0.04, and 0.005, respectively). This contrasts with a study of metformin-independent lactic acidosis in which there were no survivors, despite less severe acidosis on average (mean pH: 6.86). CONCLUSIONS: In 56 cases of severe metformin-associated lactic acidosis, blood pH and lactate did not have prognostic value. One can reasonably rule out the extent of metformin accumulation as a prognostic factor. Ultimately, the determinants of metformin-associated lactic acidosis appear to be the nature and number of triggering factors. Strikingly, most patients survived - despite a mean pH that is incompatible with a favorable outcome under other circumstances

The Association between 25-Hydroxyvitamin D and Hemoglobin A1c Levels in Patients with Type 2 Diabetes and Stage 1–5 Chronic Kidney Disease

Aim. To examine the relationship between plasma 25-hydroxyvitamin D (25(OH)D) levels and blood hemoglobin A1c (HbA1c) levels in diabetic patients at various stages of chronic kidney disease (CKD). Methods. We screened for data collected between 2003 and 2012. The correlation between 25(OH)D and HbA1c levels was studied in patients categorized according to the severity of CKD and their vitamin D status. A multivariate linear regression model was used to determine whether 25(OH)D and HbA1c levels were independently associated after adjustment for a number of covariates (including erythrocyte metformin levels). Results. We identified 542 reports from 245 patients. The mean HbA1c value was 6.7±1.0% in vitamin D sufficiency, 7.3±1.5% in insufficiency, and 8.4±2.0% in deficiency (P<0.0001). There was a negative correlation between 25(OH)D and HbA1c levels for the population as a whole (r=-0.387, P<0.0001) and in the CKD severity subgroups (r=-0.384, P<0.0001 and r=-0.333, P<0.0001 for CKD stages 1–3 and 4-5, resp.). In the multivariate analysis, the 25(OH)D level was the only factor associated with HbA1c (P<0.0001). Conclusion. 25(OH)D levels were negatively correlated with HbA1c levels independently of study covariates

Association between metformin use and below-the-knee arterial calcification score in type 2 diabetic patients.

BACKGROUND Vascular calcification (VC) is common in type 2 diabetes, and is associated with cardiovascular complications. Recent preclinical data suggest that metformin inhibits VC both in vitro and in animal models. However, metformin's effects in patients with diabetic VC have not previously been characterized. The present study investigated the association between metformin use and lower-limb arterial calcification in patients with type 2 diabetes and high cardiovascular risk. METHODS The DIACART cross-sectional cohort study included 198 patients with type 2 diabetes but without severe chronic kidney disease. Below-the-knee calcification scores were assessed by computed tomography and supplemented by colour duplex ultrasonography. Data on anti-diabetic drugs were carefully collected from the patients' medical records and during patient interviews. Biochemical and clinical data were studied as potential confounding factors. RESULTS Metformin-treated patients had a significantly lower calcification score than metformin-free patients (mean ± standard deviation: 2033 ± 4514 and 4684 ± 9291, respectively; p = 0.01). A univariate analysis showed that metformin was associated with a significantly lower prevalence of severe below-the-knee arterial calcification (p = 0.02). VC was not significantly associated with the use of other antidiabetic drugs, including sulfonylureas, insulin, gliptin, and glucagon like peptide-1 analogues. A multivariate logistic regression analysis indicated that the association between metformin use and calcification score (odds ratio [95% confidence interval] = 0.33 [0.11-0.98]; p = 0.045) was independent of age, gender, tobacco use, renal function, previous cardiovascular disease, diabetes duration, neuropathy, retinopathy, HbA1c levels, and inflammation. CONCLUSIONS In patients with type 2 diabetes, metformin use was independently associated with a lower below-the-knee arterial calcification score. This association may contribute to metformin's well-known vascular protective effect. Further prospective investigations of metformin's potential ability to inhibit VC in patients with and without type 2 diabetes are now needed to confirm these results

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p&lt;0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (&lt;1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (&lt;1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Sexualisation perinatale de la reponse corticotrope au stress chez le rat

SIGLEINIST T 75012 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Pharmacocinétique de la metformine (Lecture critique de la littérature)

La metformine est l antidiabétique oral de référence dans le traitement du diabète de type 2. Ses caractéristiques pharmacologiques et pharmacocinétiques sont bien connues. C est ainsi qu il est dit, classiquement, que la metformine est éliminée inchangée presque exclusivement par le rein avec une clairance de 320 à 640 ml/min. Cette clairance est élevée, mais variable malgré tout selon les études. Une telle variabilité pour un paramètre important est précisément le fondement de notre travail. C est ainsi que nous avons voulu reprendre la littérature pour une lecture critique, et ceci dans la visée de repérer les éventuelles variations significatives des paramètres pharmacocinétiques considérées dans leur ensemble et dans l ensemble aussi des études réalisées, de tenter d en comprendre la signification, et en définitive de nous interroger quant à la portée des observations sur la pratique diabétologique quotidienne. Nous avons ainsi retenu 58 études, à partir de 19 essais différents. A partir de ces études, nous avons dégagé des critères démographiques (sexe, âge, IMC, poids, etc.), que nous avons croisés avec les paramètres pharmacocinétiques et aussi avec les modalités d administration de metformine (posologie, voie d administration, etc.). Nous avons complété l analyse descriptive par une analyse statistique : moyennes arithmétiques, moyennes pondérées, et comparaisons de sous-groupes (ex. sujets non diabétiques/diabétiques). Nous montrons que la plupart des études ont été réalisées en dehors du champ habituel de prescription, i.e. chez des sujets adultes relativement jeunes, non diabétiques, de poids normal, et à fonction rénale normale. Cependant, même dans cette population saine , des écarts significatifs (par ex. d un facteur 2, voire plus) de moyennes apparaissent pour plusieurs paramètres. Ces différences apparaissent plus encore quand on fait la comparaison entre sujets non diabétiques et diabétiques, même quand ces derniers ne présentent pas d altération de la fonction rénale (comme l atteste une clairance moyenne de la créatinine comparable dans les deux groupes). L ensemble des nos observations incite à la prudence dans l extrapolation des observations issues de sujets sains aux sujets diabétiques, en particulier pour l initiation du traitement chez le sujet âgéAMIENS-BU Santé (800212102) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF