Background Metformin is an oral anti-hyperglycemic agent that has been shown to reduce total mortality compared to other anti-hyperglycemic agents, in the treatment of type 2 diabetes mellitus. Metformin, however, is thought to increase the risk of lactic acidosis, and has been considered to be contraindicated in many chronic hypoxemic conditions that may be associated with lactic acidosis, such as cardiovascular, renal, hepatic and pulmonary disease, and advancing age. Objectives To assess the incidence of fatal and nonfatal lactic acidosis, and to evaluate blood lactate levels, for those on metformin treatment compared to placebo or non-metformin therapies. Search strategy A comprehensive search was performed of electronic databases to identify studies of metformin treatment. The search was augmented by scanning references of identified articles, and by contacting principal investigators. Selection criteria Prospective trials and observational cohort studies in patients with type 2 diabetes of least one month duration were included if they evaluated metformin, alone or in combination with other treatments, compared to placebo or any other glucose-lowering therapy. Data collection and analysis The incidence of fatal and nonfatal lactic acidosis was recorded as cases per patient-years, for metformin treatment and for non-metformin treatments. The upper limit for the true incidence of cases was calculated using Poisson statistics. In a second analysis lactate levels were measured as a net change from baseline or as mean treatment values (basal and stimulated by food or exercise) for treatment and comparison groups. The pooled results were recorded as a weighted mean difference (WMD) in mmol/L, using the fixed-effect model for continuous data. Main results Pooled data from 347 comparative trials and cohort studies revealed no cases of fatal or nonfatal lactic acidosis in 70,490 patient-years of metformin use or in 55,451 patients-years in the non-metformin group. Using Poisson statistics the upper limit for the true incidence of lactic acidosis per 100,000 patient-years was 4.3 cases in the metformin group and 5.4 cases in the non-metformin group. There was no difference in lactate levels, either as mean treatment levels or as a net change from baseline, for metformin compared to non-metformin therapies. Authors' conclusions There is no evidence from prospective comparative trials or from observational cohort studies that metformin is associated with an increased risk of lactic acidosis, or with increased levels of lactate, compared to other anti-hyperglycemic treatments.

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Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus

Background Despite increasing emphasis on the role of clinical decision-support systems (CDSSs) for improving care and reducing costs, evidence to support widespread use is lacking. Purpose To evaluate the effect of CDSSs on clinical outcomes, health care processes, workload and efficiency, patient satisfaction, cost, and provider use and implementation. Data sources MEDLINE, CINAHL, PsycINFO, and Web of Science through January 2011. Study selection Investigators independently screened reports to identify randomized trials published in English of electronic CDSSs that were implemented in clinical settings; used by providers to aid decision making at the point of care; and reported clinical, health care process, workload, relationship-centered, economic, or provider use outcomes. Data extraction Investigators extracted data about study design, participant characteristics, interventions, outcomes, and quality. Data synthesis 148 randomized, controlled trials were included. A total of 128 (86%) assessed health care process measures, 29 (20%) assessed clinical outcomes, and 22 (15%) measured costs. Both commercially and locally developed CDSSs improved health care process measures related to performing preventive services (n= 25; odds ratio [OR], 1.42 [95% CI, 1.27 to 1.58]), ordering clinical studies (n= 20; OR, 1.72 [CI, 1.47 to 2.00]), and prescribing therapies (n= 46; OR, 1.57 [CI, 1.35 to 1.82]). Few studies measured potential unintended consequences or adverse effects. Limitations Studies were heterogeneous in interventions, populations, settings, and outcomes. Publication bias and selective reporting cannot be excluded. Conclusion Both commercially and locally developed CDSSs are effective at improving health care process measures across diverse settings, but evidence for clinical, economic, workload, and efficiency outcomes remains sparse. This review expands knowledge in the field by demonstrating the benefits of CDSSs outside of experienced academic centers. Primary funding source Agency for Healthcare Research and Quality.

Effect of Clinical Decision-Support Systems: A Systematic Review

Protein aggregation is a common issue encountered during manufacture of biotherapeutics. It is possible to influence the amount of aggregate produced during the cell culture and purification process by carefully controlling the environment (eg, media components) and implementing appro-priate strategies to minimize the extent of aggregation. Steps to remove aggregates have been successfully used at a manufacturing scale. Care should be taken when developing a process to monitor the compatibility of the equipment and process with the protein to ensure that potential aggregation is minimized.

/pdf/protein-aggregation-and-bioprocessing-rssiny6wco.pdf

Protein aggregation and bioprocessing.

Evidence to support widespread use of clinical decision-support systems (CDSSs) is lacking. This review summarizes trials of CDSSs implemented in clinical settings to aid decision making at the poi...

Effect of Clinical Decision-Support Systems

ContextThere have been numerous reports of interventions designed to improve the care of patients with diabetes, but the effectiveness of such interventions is unclearObjectiveTo assess the impact on glycemic control of 11 distinct strategies for quality improvement (QI) in adults with type 2 diabetesData Sources and Study SelectionMEDLINE (1966-April 2006) and the Cochrane Collaboration's Effective Practice and Organisation of Care Group database, which covers multiple bibliographic databases Eligible studies included randomized or quasi-randomized controlled trials and controlled before-after studies that evaluated a QI intervention targeting some aspect of clinician behavior or organizational change and reported changes in glycosylated hemoglobin (HbA1c) valuesData ExtractionPostintervention difference in HbA1c values were estimated using a meta-regression model that included baseline glycemic control and other key intervention and study features as predictorsData SynthesisFifty randomized controlled trials, 3 quasi-randomized trials, and 13 controlled before-after trials met all inclusion criteria Across these 66 trials, interventions reduced HbA1c values by a mean of 042% (95% confidence interval [CI], 029%-054%) over a median of 13 months of follow-up Trials with fewer patients than the median for all included trials reported significantly greater effects than did larger trials (061% vs 027%, P = 004), strongly suggesting publication bias Trials with mean baseline HbA1c values of 80% or greater also reported significantly larger effects (054% vs 020%, P = 005) Adjusting for these effects, 2 of the 11 categories of QI strategies were associated with reductions in HbA1c values of at least 050%: team changes (067%; 95% CI, 043%-091%; n = 26 trials) and case management (052%; 95% CI, 031%-073%; n = 26 trials); these also represented the only 2 strategies conferring significant incremental reductions in HbA1c values Interventions involving team changes reduced values by 033% more (95% CI, 012%-054%; P = 004) than those without this strategy, and those involving case management reduced values by 022% more (95% CI, 000%-044%; P = 04) than those without case management Interventions in which nurse or pharmacist case managers could make medication adjustments without awaiting physician authorization reduced values by 080% (95% CI, 051%-110%), vs only 032% (95% CI, 014%-049%) for all other interventions (P = 002)ConclusionsMost QI strategies produced small to modest improvements in glycemic control Team changes and case management showed more robust improvements, especially for interventions in which case managers could adjust medications without awaiting physician approval Estimates of the effectiveness of other specific QI strategies may have been limited by difficulty in classifying complex interventions, insufficient numbers of studies, and publication bias

Effects of quality improvement strategies for type 2 diabetes on glycemic control: a meta-regression analysis.

Marked increase in plasma high-density-lipoprotein cholesterol after prolonged fasting during Ramadan.

Practicing physicians as well as diabetes specialists are confronted with the often-frustrating experience of dealing with patients with poorly controlled diabetes. It is not always obvious why these patients fail to improve. The aims of this study were two-fold: (a). to determine if the interdisciplinary approach offered by the Western Negev Mobile Clinic Diabetes Program (WNMDCP) is of benefit in patients with poorly controlled type 2 diabetes and (b). to more fully characterize patients refractory to treatment. Two primary-care clinics of the Western Negev were randomly selected as control and intervention. All patients from both clinics with hemoglobin (HbA(1C)) >or=10% (tested during June-July 2000) were studied for 6 months. Patients from the control clinic continued the usual treatment. Patients from the intervention clinic received the interdisciplinary approach offered by WNMCDP. The rate of improvement of diabetes control, measured as a decrease in HbA(1C) values of at least 0.5%, and compliance to treatment were determined. Overall, 48 of 258 patients in the intervention clinic and 34 of 179 patients in the control clinic met the inclusion criteria. At the 6-month follow-up, we observed significant improvements in plasma glucose (-1.5 mmol/l; p=0.003) and HbA(1C) (-1.8%; p=0.00001) in the intervention group but not in the control group. The compliance and response rates were 85% and 71% for the intervention group and 32% and 35% for the control group, respectively. Patients from the intervention clinic showed significant improvement in the endpoints compared to patients from the control clinic. More than 70% of patients with poorly controlled diabetes mellitus responded to the interdisciplinary treatment approach offered by WNMDCP. The group of non-responders comprised patients with poor compliance (15%) and those with serious concomitant diseases or limitations of mobility.

Multidisciplinary approach to patients with poorly controlled type 2 diabetes mellitus: a prospective, randomized study.

Background: Dyslipidemia remains underdiagnosed and under-treated in patients with coronary artery disease. The Computer-based Clinical Decision Support System provides an opportunity to close these gaps. Objectives: To study the impact of computerized intervention on secondary prevention of CAD. Methods: The CDSS was programmed to automatically detect patients with CAD and to evaluate the availability of an updated lipoprotein profile and treatment with lipid-lowering drugs. The program produced automatic computer-generated monitoring and treatment recommendations. Adjusted primary clinics were randomly assigned to intervention (n=56) or standard care arms (n=56). Reminders were mailed to the primary medical teams in the intervention arm every 4 months updating them with current lipid levels and recommendations for further treatment. Compliance and lipid levels were monitored. The study group comprised all patients with CAD who were alive at least 3 months after hospitalization. Results: Follow-up was available for 7448 patients (median 19.8 months, range 6-36 months). Overall, 51.7% of patients were adequately screened, and 55.7% of patients were compliant with treatment to lower lipid level. In patients with initial low density lipoprotein > 120 mg/dl, a significant decrease in LDL levels was observed in both arms, but was more pronounced in the intervention arm: 121.9 ± 34.2 vs. 124.3 ± 34.6 mg/dl (P< 0.02). A significantly lower rate of cardiac rehospitalizations was documented in patients who were adequately treated with lipid-lowering drugs, 37% vs. 40.9% (P< 0.001). Conclusions: This initial assessment of our data represent a real-world snapshot where physicians and CAD patients often do not adhere to clinical guidelines, presenting a major obstacle to implementing effective secondary prevention. Our automatic computerized reminders system substantially facilitates adherence to guide-Lines and supports wide-range implementation.

Computerized community cholesterol control (4C): meeting the challenge of secondary prevention.

SUMMARY



Aim To investigate the efficacy and safety of miglitol vs placebo in type 2 diabetic outpatients insufficiently controlled (HbA1c between 75 and 105%) with diet and metformin



Methods  Patients treated with diet and metformin (1500–2250 mg/day) were randomized to receive additional treatment with either miglitol or placebo for 32 weeks The dosages were force-titrated: 4 weeks at 25 mg miglitol tid, 12 weeks at 50 mg miglitol tid, and 16 weeks at 100 mg miglitol tid or matching placebo If the highest dosage could not be tolerated, patients could be down-titrated to 50 mg tid The primary efficacy criterion was the change in glycated haemoglobin (HbA1c) Secondary efficacy parameters included fasting and 1 h postprandial blood glucose, serum insulin, and fasting and 1 h postprandial triglyceride levels Safety and tolerability were evaluated by the incidence of adverse events and changes in vital signs or routine biochemical and haematological parameters



Results  One hundred and fifty-two patients were valid for the intent-to-treat (ITT) analysis There was a significant decrease in HbA1c on adding miglitol to metformin compared to adding placebo (miglitol treatment effect, − 021%; placebo treatment effect, + 022%; p = 0011) Postprandial blood glucose declined in both the miglitol/metformin and placebo/metformin groups with a statistically significant difference in favour of miglitol/metformin (end of treatment adjusted means 138 mmol/l for miglitol vs 158 mmol/l for placebo, p = 00007) Adverse events (AEs) were reported by only 8% more patients in the miglitol/metformin group than placebo/metformin No cases of hypoglycaemia were reported



Conclusions  Miglitol can safely and effectively be added to diet and metformin in patients whose type 2 diabetes is insufficiently controlled, and improves glycaemic control by significantly reducing HbA1c and postprandial blood glucose levels

Miglitol combined with metformin improves glycaemic control in type 2 diabetes.

OBJECTIVE To describe a case of severe DKA in an otherwise healthy pregnant woman. RESEARCH DESIGN AND METHODS We describe 2.5 yr of close follow-up of a Bedouin woman who was hospitalized for DKA while pregnant with her 11th child. Plasma glucose returned to normal levels immediately after delivery of a dead conceptus. Four months later, while normoglycemic, the patient became pregnant again. During the subsequent pregnancy, GDM was diagnosed at week 20 of gestation. Tight plasma glucose control was achieved with an insulin regimen, and the patient delivered a healthy girl at term. Plasma glucose again returned to normal and remained so to date, 18 mo postpartum. An OGTT and a euglycemic hyperinsulinemic clamp were performed between pregnancies; another OGTT was performed at week 14 of the last pregnancy. Plasma glucose, insulin, and C-peptide were measured in blood samples during these procedures. RESULTS We established beyond doubt that the patient developed GDM and returned to essentially normal glucose tolerance after her last (12th) delivery. During the 11th pregnancy, gestational diabetes was complicated by severe DKA. CONCLUSIONS GDM is a common abnormality of glucose metabolism during pregnancy, which affects fetal development and leads to peripartum complications. Our report stresses that under certain circumstances, gestational diabetes can be complicated by DKA and become life-threatening to the mother and fetus.

Maximo Maislos

Papers

Marked increase in plasma high-density-lipoprotein cholesterol after prolonged fasting during Ramadan.

Multidisciplinary approach to patients with poorly controlled type 2 diabetes mellitus: a prospective, randomized study.

Computerized community cholesterol control (4C): meeting the challenge of secondary prevention.

Miglitol combined with metformin improves glycaemic control in type 2 diabetes.

Diabetic ketoacidosis. A rare complication of gestational diabetes.