Lactic acidosis: relationship between metformin levels, lactate concentration and mortality.

AIM: The role of metformin in lactic acidosis is regularly questioned. Arguments against a causal role for metformin in lactic acidosis occurrence are the lack of correlation between plasma metformin and lactate levels, as well as between metformin plasma levels and mortality. We aim to analyse these correlations in a large series of lactic acidosis cases recorded in the French nationwide pharmacovigilance database. METHODS: All cases of lactic acidosis spontaneously reported between 1985 and October 2013 associated with metformin exposure were extracted from the pharmacovigilance database. We assessed the statistical correlations between prescribed daily doses of metformin, plasma concentrations of metformin and lactate, pH and plasma creatinine, as well as the relationship between mortality and these variables. RESULTS: Seven hundred and twenty-seven cases of lactic acidosis were reported during the period. Metformin plasma concentration was documented for 260 patients, lactate plasma concentration for 556 patients, pH for 502 patients, creatinine for 397 patients and the vital outcome for 713 patients. Metformin plasma concentration, lactate concentration, pH and plasma creatinine were all correlated (P < 0.001). There were significant differences between surviving and deceased patients in terms of metformin plasma levels (25.2 vs. 37.4 mg/l, P = 0.002) and lactate concentrations (10.8 vs. 16.3 mmol/l, P < 0.001). Thirty per cent of patients died when metformin concentration was > 5 mg/l compared with 11% for patients with concentration < 5 mg/l (P = 0.003). CONCLUSIONS: Our data suggest that metformin accumulation contributes to the pathogenesis and prognosis of lactic acidosis.

Predicting factors of hypoglycaemia in elderly type 2 diabetes patients: Contributions of the GERODIAB study.

The burden of hypoglycaemia is important, particularly in elderly type 2 diabetes (T2D) patients. Unfortunately, however, few studies are available concerning this population. GERODIAB is a prospective, multicentre, observational study that aims to describe the 5-year morbidity and mortality of 987 T2D patients aged 70 years and older. After analyzing the frequency of and factors associated with hypoglycaemia in the 6 months prior to study inclusion, it was found that hypoglycaemia was associated with retinopathy, lower levels of LDL cholesterol and altered mini-Geriatric Depression Scale (GDS) scores.

Access of children and adolescents with type 1 diabetes to insulin pump therapy has greatly increased in France since 2001.

AIM: Insulin pump therapy is an emerging option in the management of type 1 diabetes (T1D), but it often remains unused. For this reason, in 2007, a French national survey was carried out to update the frequency of insulin pump use in the paediatric population compared with a previous survey done in 2001. METHODS: The present survey was performed in hospital departments involved in paediatric diabetes management (n = 67) and in adult departments involved in adolescent diabetes management (n = 113). The number of T1D children (age < 18 years) treated in each department, with or without the use of an insulin pump, and the number of insulin pump therapies initiated during the previous year were collected. RESULTS: A total of 60 paediatric and 28 adult centres responded, involving 9073 T1D children and adolescents (93% in paediatric departments). Of these patients, 1461 (16%) were treated by insulin pump, 89% of which were managed in paediatric centres. However, pump use was more frequent in adult than in paediatric centres (32% versus 18%, respectively). Also, 38% of insulin pumps were initiated during the year prior to the survey. In addition, in 2001, 140 children were treated with insulin pump in 13 paediatric centres (versus 56 centres in 2007). CONCLUSION: The number of centres using insulin pump therapy for diabetic children and the number of children treated by insulin pump were increased fourfold and 10-fold, respectively, from 2001 to 2007, indicating greater access to pump therapy in the French paediatric population. The present survey is still ongoing to evaluate the decision-making criteria that influence the initiation of insulin pump therapy in T1D paediatric patients.

When to treat a diabetic patient using an external insulin pump. Expert consensus. Société francophone du diabète (ex ALFEDIAM) 2009.

For years, external insulin pumps have enjoyed proven efficacy as an intensive diabetes treatment to improve glycaemic control and reduce hypoglycaemia. Since the last ALFEDIAM guidelines in 1995, however, basal-bolus treatment using a combination of long- and short-acting insulin analogues have emerged and could challenge, at a lower cost, the efficacy of pumps using rapid-acting insulin analogues, considered the 'gold standard' of insulin treatment. Nevertheless, given its theoretical and practical advantages, some patients will derive more benefit from pump treatment. These cases have been carefully evaluated in the literature by a panel of experts appointed by ALFEDIAM to determine the indications for pump treatment. In patients with type 1 diabetes, persistent elevated HbA(1c) despite multiple daily injections (MDI), and repeated hypoglycaemia and high glycaemic variability, represent the most validated indications. In patients with type 2 diabetes, pump treatment may be indicated in cases of MDI failure to achieve HbA(1c) targets. Absolute contraindications are rare, and comprise severe psychiatric disorders, rapidly progressing ischaemic or proliferative retinopathy before laser treatment and exposure to high magnetic fields. Relative contraindications are mostly related to the patient's lack of compliance or inability to cope with the treatment, and need to be evaluated individually to clearly assess the benefit/risk ratio for the given patient. However, as these conditions are progressive, there should also be annual reassessment of the appropriateness of pump treatment. Specific education on pump treatment initially and throughout the follow-up, delivered by experienced medical and paramedical teams, are the best guarantees of treatment efficacy and safety.

Key priorities in managing glucose control in older people with diabetes.

Older people with diabetes represent a major and increasing proportion of our elderly population and their care requires better organisation. Targets for risk factor control and pathways of care must be adjusted to the subject's general health status. It is thus advisable to screen for frailty. We have carried out a detailed literature review of the studies published on diabetes in older people since 1990. Studies were considered if they included groups or subgroups of diabetic patients > 65 years old. This review discusses the elaboration of general targets for care, the approach to risk factor control, the screening and the specific prevention or management of complications, the integration of geriatric concepts in diabetes care and the specificity of education with respect to frailty status.

Treatment of diabetes mellitus using an external insulin pump: the state of the art.

The aim of diabetes treatment is to achieve tight glucose control to avoid the development of chronic diabetic complications while reducing the frequency of hypoglycaemic episodes. Continuous subcutaneous insulin infusion (CSII) using an external pump is an intensive diabetes therapy recognized to improve metabolic control and glycaemic instability, and to reduce the frequency of severe hypoglycaemia. For years, the theoretical advantages of the insulin pump (constancy of basal delivery, adjustable basal rates, and low insulin depots allowing the reduction of glycaemic variability) have contributed to its reported superiority compared with multiple daily injections (MDI). However, insulin pump therapy is now challenged by new MDI regimens based on long-acting insulin analogues that could replace the use of CSII. As a consequence, health professionals now have to determine which patients are likely to benefit the most from CSII. Recently, several studies reported that children and adolescents, and patients whose blood glucose imbalance was initially the most pronounced with basal-bolus regimens, would particularly benefit from CSII. Other indications were also proposed in marginal clinical situations with highly selected patients in whom a significant improvement of blood glucose was demonstrated. Finally, the use of CSII in type 2 diabetic patients now appears to be a good alternative to the ineffective MDI regimens observed in some of these patients. However, past experience with CSII indicates that candidates for insulin pump therapy must be carefully selected and strongly motivated to improve their glucose control. Use of CSII also requires strict medical supervision by physicians and a regular programme of patient education by paramedical teams, to ensure optimal responsible use of this technique by healthcare professionals.

Diabetes and education in the elderly.

Diabetes mellitus (DM) in the elderly is a chronic disease where self management is a key aspect. This includes lifestyle modification (diet and exercise), medication compliance and hypoglycaemia management. Education is an important part of this process and the specific needs of the older population with DM have been underlined. The literature has shown that education through a multidisciplinary approach may improve the glycaemic control in selected elderly patients with DM. This article will focus on the evidences from the medical literature and the multiple challenges of teaching in this population.

Continuous intraperitoneal insulin infusion does not increase the risk of organ-specific autoimmune disease in type 1 diabetic patients: results of a multicentric, comparative study.

AIM: The purpose of this national multicenter prospective study by the French EVADIAC group was to investigate the possibility that continuous intraperitoneal insulin infusion using an implanted pump (CIpii) increases the risk of autoimmune disease in type 1 diabetic patients as it increased anti-insulin immunogenicity. METHODS: Prevalence of clinical (Hashimoto's disease, hyperthyroidism, gastric atrophic disease and vitiligo) and subclinical (presence of anti-thyroperoxidase antibodies, anti-intrinsic factor antibodies, abnormal TSH levels) autoimmune diseases was estimated by comparing two groups of patients already treated by either CIpii (n=154) or external pump (CSII) (n=121) for an average of 6 years. Incidence of autoimmune disease was determined by comparing the same measurements one year after inclusion. RESULTS: No significant difference was observed for the total prevalence of clinical and subclinical auto-immune thyroid and gastric di-seases (35.6% and 3.2% respectively in the CIpii group versus 40.4% and 2.6% in the CSII group). No significant difference for the incidence of clinical and subclinical auto-immune diseases was observed: 7.2% and 0% in CIpii and 7.3% and 1.7% in CSII. CONCLUSION: As previously shown AIA (anti-insulin antibodies) levels were higher in CIpii than in CSII (32.9% vs 20.2%, P<0.0001) but no correlation was observed with either clinical or subclinical autoimmune disease. This large-scale study eliminates the possibility that CIpii increases the risk of autoimmune disease.

Alternatives routes of insulin delivery.

Optimal glycaemic control is necessary to prevent diabetes-related complications. An intensive treatment, which could mimic physiological insulin secretion, would be the best one. However subcutaneous insulin treatment is not physiologic and represents a heavy burden for patients with type 1 and type 2 diabetes mellitus. Consequently, more acceptable, at least as effective, alternative routes of insulin delivery have been developed over the past years. Up to now, only pulmonary administration of insulin (inhaled insulin) has become a feasible alternative to cover mealtime insulin requirements and one of the various administration systems was recently approved for clinical use in Europe and the United States. But, due to advances in technology, other routes, such as transdermal or oral (buccal and intestinal) insulin administration, could become feasible in a near future, and they could be combined together to offer non-invasive, efficacious and more physiological way of insulin administration to patients with diabetes.

Six-year follow-up of a cohort of 203 patients with diabetes after screening for silent myocardial ischaemia.

AIMS: To determine the prognosis of patients with Type 1 or Type 2 diabetes, 6 years after screening for silent myocardial ischaemia (SMI). METHODS: Two hundred and three asymptomatic patients with diabetes underwent systematic SMI screening. From the results of this screening, they were allocated to one of three groups: patients (n = 171) with negative screening; patients (n = 32) with positive screening; and patients (n = 21) with positive screening and coronary stenosis. Six years after the initial assessment, all patients were re-assessed. All events [death, cardiac death, non-fatal major cardiac events (NFMCEs)--acute myocardial infarction, ventricular rhythm disorders, heart failure, unstable angina] were recorded. RESULTS: Fifteen patients were lost to follow-up. Patients (n = 20) with positive SMI screening and coronary stenosis had a higher risk of NFMCEs (35% vs. 7%, P < 0.001), and a higher mortality rate (35% vs. 15%, P < 0.05) compared with patients (n = 157) with negative screening. SMI-positive patients (n = 31) had a higher NFMCE rate compared with negative SMI screening patients, although overall mortality rate was no different. Cancer was the leading cause of death (36.4%). In multivariate analysis, major cardiac events (cardiac death and NFMCE) were related to baseline age, body mass index and coronary stenosis (P < 0.01). CONCLUSIONS: Patients with diabetes and SMI have a very poor prognosis as assessed by cardiac events or death, especially in the presence of coronary stenosis.

What could be the reasons for giving up the implanted pump treatment?

The development of implanted insulin pump treatment has been particularly intense in France and French implanting centers joined to form an association called EVADIAC. The data collected by EVADIAC have clearly documented benefits as well possible problems with this treatment mode. In comparison with SC administration, intraperitoneal (IP) insulin infusion via an implanted pump achieves good metabolic control, improves long-term stability of diabetes and significantly reduces the risk of severe hypoglycemia. Problems can involve pump slowdown, catheter obstruction or local complication at the implantation site. With respect to the benefits, the rate of complications is highly acceptable. However, amongst the implanted diabetic patients, some elect to give up such a treatment mode. In a retrospective study we intended to examine their reasons for giving up this treatment. In our center, the patients who elected by themselves to give up the implanted pump account for 16% of all treated patients. This group of patients did not have, as compared to other implanted patients, less benefits nor more restrictions or incidents that could have impaired their well being. The reasons for giving up the implanted pump seem more often to be related to the refusal of a strict and institutional management linked to this treatment.

Hypoglycaemia in elderly diabetic patients.

Occurring in the elderly diabetic patients, hypoglycaemia may have serious consequences in terms of morbidity and mortality, but this severe prognosis is nowadays less frequently observed. The clinical manifestations may be somewhat different from those observed in young subjects: symptoms are less frequent, generally neurologic manifestations. The rate of severe hypoglycaemia remains low (about 1.4 episode per 100 patient-years), but increases rapidly in the very elderly and also with insulin therapy, co-morbid conditions especially renal insufficiency, and associated treatments, as well as with unawareness of symptoms. Prevention requires reinforced education for the patient and caregiver, particularly concerning diet, knowledge of signs of hypoglycaemia, and appropriate treatment. Self-monitoring of blood glucose, by the patient when possible, or by a familial or medical caregiver, should be encouraged in order to detect asymptomatic episodes of hypoglycaemia and better adapt antidiabetic treatment.

Reproducibility of plasma insulin kinetics during intraperitoneal insulin treatment by programmable pumps.

OBJECTIVE: To study the reproducibility of plasma insulin kinetics during intraperitoneal (IP) insulin therapy using an implanted programmable pump in patients with type 1, insulin dependent, diabetes mellitus (IDDM). RESEARCH DESIGN AND METHODS: In a group of ten type 1 IDDM patients beginning chronic IP insulin treatment with an implanted pump, plasma free insulin profiles were determined from 12: 00 am to 12: 30 pm on two separate test days, one month apart. Anti-insulin antibody (AIA) levels were measured on each test day. RESULTS: From test day 1 to test day 2, no difference was observed in morning fasting free insulin levels (m +/- SD): 9.7 +/- 5.4 mU/L versus 9.8 +/- 5.3 mU/L, insulin peak values: 19.1 +/- 17 mU/L versus 20.8 +/- 9.9 mU/L, time to peak: 40 +/- 15 versus 42.8 +/- 16 minutes or post-bolus area under the plasma free insulin curve (AUC): 40.7 +/- 29 mU/L.h versus 45.5 +/- 29 mU/L.h. The intrapatient coefficient of variation was 14.4 +/- 13% for insulin peaks and 16.9 +/- 9.2% for post-bolus AUC. A significant increase in AIA levels (m +/- SD) was observed from 16.5 +/- 18% on test day 1 to 28.1 +/- 28% on test day 2. CONCLUSIONS: The reproducibility of plasma free insulin profiles is highly satisfactory during insulin delivery by the IP route using an implanted device.

[History, accuracy and precision of SMBG devices]. / Technologie et fiabilité de l'autosurveillance glycémique: historique et état actuel.

Self-monitoring of blood glucose started only fifty years ago. Until then metabolic control was evaluated by means of qualitative urinary blood measure often of poor reliability. Reagent strips were the first semi quantitative tests to monitor blood glucose, and in the late seventies meters were launched on the market. Initially the use of such devices was intended for medical staff, but thanks to handiness improvement they became more and more adequate to patients and are now a necessary tool for self-blood glucose monitoring. The advanced technologies allow to develop photometric measurements but also more recently electrochemical one. In the nineties, improvements were made mainly in meters' miniaturisation, reduction of reaction time and reading, simplification of blood sampling and capillary blood laying. Although accuracy and precision concern was in the heart of considerations at the beginning of self-blood glucose monitoring, the recommendations of societies of diabetology came up in the late eighties. Now, the French drug agency: AFSSAPS asks for a control of meter before any launching on the market. According to recent publications very few meters meet reliability criteria set up by societies of diabetology in the late nineties. Finally because devices may be handled by numerous persons in hospitals, meters use as possible source of nosocomial infections have been recently questioned and is subject to very strict guidelines published by AFSSAPS.

Improved metabolic control in diabetic adolescents using the continuous glucose monitoring system (CGMS).

OBJECTIVE: To determine the utility of the continuous glucose monitoring system (CGMS) as an outpatient procedure to improve management of diabetes in adolescents. RESEARCH DESIGN AND METHODS: Twelve adolescents (mean age: 16.2 +/- 3 years) with poorly controlled type 1 diabetes (HbA(1c) > 8%) were included in this trial. Mean HbA(1c) during the previous year was 10.1 +/- 1.2%. Insulin treatment consisted of 2 or 3 daily injections in 10 cases and CSII in 2. At the beginning of the study, HbA(1c) was determined and low blood glucose index (LBGI) was calculated. Continuous glucose monitoring was performed for three days. After downloading and analyzing data, results were discussed with the patient and insulin treatment was adjusted. Two months later testing was repeated and all parameters were reassessed. RESULTS: Initial CGMS profiles demonstrated glycemic excursions unrecognized by capillary measurements in all twelve patients. Glycemia before and after meals varied from<60 mg/dL to > 200 mg/dL in 2 patients (2 episodes). Postprandial hyperglycemia exceeded 200 mg/dL in 10 patients (24 episodes). Prolonged overnight hyperglycemia was observed in 5 patients (7 episodes), dawn phenomenon in 4 patients (6 episodes) and nighttime hypoglycemia in 4 patients (4 episodes). A day-to-day reproducibility of glycemic profiles was observed in 8 patients. Then insulin treatment was adjusted according to CGMS data. Changes involved dose levels in 3 patients, insulin type in 7, number of injections, i.e. 3 instead of 2, in 5 or change from insulin injection to CSII in 1. Reassessment two months later demonstrated a significant reduction of glycemic excursions in 8 patients. HbA(1c) (m +/- SD) decreased from 10.3 +/- 2.1% to 8.75 +/- 1.06% (p<0.05). LBGI increased from 1.7 +/- 0.9 to 2.4 +/- 1.4 but the difference was not significant. CONCLUSIONS: Use of CGMS in diabetic adolescent outpatients achieved a significant improvement in metabolic control not only by providing accurate data for adjustment of insulin treatment but also by promoting patient communication and motivation.

[How should we use the short-acting insulin analog Lys-Pro in external continuous subcutaneous pumps?]. / Comment utiliser l'analogue de l'insuline Lys-Pro en perfusion sous-cutanée continue par pompe portable?

External pump treatment improves glycemic control, particularly thanks to the continuous basal rate. The pharmacokinetics of the short-acting insulin analog lispro allow a better control of post-prandial hyperglycemia than regular insulin. The use of the short-acting insulin analog in the pump improves HbA1c and blood glucose stability, without increasing the risk of hypoglycemia. Frequent blood glucose self-monitoring is required in order to optimize insulin adjustments, using the retro-active method. Systematic monitoring of urine ketones is also required, for an early detection of any interruption in insulin delivery. Under these conditions, this modality of intensified treatment seems very efficient.