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1.  Phase II study of tight glycaemic control in COPD patients with exacerbations admitted to the acute medical unit 
BMJ Open  2011;1(1):e000210.
Hyperglycaemia is associated with poor outcomes from exacerbations of chronic obstructive pulmonary disease (COPD). Glycaemic control could improve outcomes by reducing infection, inflammation and myopathy. Most patients with COPD are managed on the acute medical unit (AMU) outside intensive care (ICU).
To determine the feasibility, safety and efficacy of tight glycaemic control in patients on an AMU.
Prospective, non-randomised, phase II, single-arm study of tight glycaemic control in COPD patients with acute exacerbations and hyperglycaemia admitted to the AMU. Participants received intravenous, then subcutaneous, insulin to control blood glucose to 4.4–6.5 mmol/l. Tight glycaemic control was evaluated: feasibility, protocol adherence; acceptability, patient questionnaire; safety, frequency of hypoglycaemia (capillary blood glucose (CBG) <2.2 mmol/l and 2.2–3.3 mmol/l); efficacy, median CBG, fasting CBG, proportion of measurements/time in target range, glycaemic variability. Results were compared with 25 published ICU studies.
20 patients (10 females, age 71±9 years; forced expiratory volume in 1 s: 41±16% predicted) were recruited. Tight glycaemic control was feasible (78% CBG measurements and 89% of insulin-dose adjustments were adherent to protocol) and acceptable to patients. 0.2% CBG measurements were <2.2 mmol/l and 4.1% measurements 2.2–3.3 mmol/l. The study CBG and proportion of measurements/time in target range were similar to that of ICU studies, whereas the fasting CBG was lower, and the glycaemic variability was greater.
Tight glycaemic control is feasible and has similar safety and efficacy on AMU to ICU. However, as more recent ICU studies have shown no benefit and possible harm from tight glycaemic control, alternative strategies for blood glucose control in COPD exacerbations should now be explored.
Trial registration number
ISRCTN: 42412334. NCT00764556.
Article summary
Article focus
Hyperglycaemia is associated with poor outcomes from acute chronic obstructive pulmonary disease (COPD) exacerbations requiring hospital admission.
It is not known whether glycaemic control can improve COPD exacerbation outcomes.
The aim of this phase II study was to determine the feasibility, safety and efficacy of tight glycaemic control with insulin in COPD patients with exacerbations on acute medical wards, towards testing this intervention in a randomised controlled trial.
Key messages
Tight glycaemic control with insulin was feasible and acceptable to patients in a general ward setting.
The efficacy and safety of tight glycaemic control were similar in COPD patients on acute medical wards to that achieved in intensive care settings, with improved glycaemic control but increased hypoglycaemia and glycaemic variability.
Strengths and limitations of this study
This study was conducted when tight glycaemic control was standard practice in intensive care units (ICUs), following the publication of two single-centre studies demonstrating reduced morbidity and mortality compared with conventional glycaemic control.
More recent ICU studies have shown no benefit and possible harm from tight glycaemic control.
In this context, our finding that tight glycaemic control in the acute medical unit has a similar safety and efficacy to ICU protocols indicates that we should explore alternative strategies for blood glucose control in COPD exacerbations.
PMCID: PMC3191583  PMID: 22021788
Hyperglycaemia; insulin; hypoglycaemia; glycaemic variability; COPD; acute medical unit; Chronic airways disease; clinical pharmacology; medical education and training; respiratory infections; cystic fibrosis; other metabolic; iron; porphyria
2.  Glucose control in intensive care: usability, efficacy and safety of Space GlucoseControl in two medical European intensive care units 
The Space GlucoseControl system (SGC) is a nurse-driven, computer-assisted device for glycemic control combining infusion pumps with the enhanced Model Predictive Control algorithm (B. Braun, Melsungen, Germany). We aimed to investigate the performance of the SGC in medical critically ill patients.
Two open clinical investigations in tertiary centers in Graz, Austria and Zurich, Switzerland were performed. Efficacy was assessed by percentage of time within the target range (4.4-8.3 mmol/L; primary end point), mean blood glucose, and sampling interval. Safety was assessed by the number of hypoglycemic episodes (≤2.2 mmol/L) and the percentage of time spent below this cutoff level. Usability was analyzed with a standardized questionnaire given to involved nursing staff after the trial.
Forty medical critically ill patients (age, 62 ± 15 years; body mass index, 30.0 ± 8.9 kg/m2; APACHE II score, 24.8 ± 5.4; 27 males; 8 with diabetes) were included for a period of 6.5 ± 3.7 days (n = 20 in each center). The primary endpoint (time in target range 4.4 to 8.3 mmol/l) was reached in 88.3% ± 9.3 of the time and mean arterial blood glucose was 6.7 ± 0.4 mmol/l. The sampling interval was 2.2 ± 0.4 hours. The mean daily insulin dose was 87.2 ± 64.6 IU. The adherence to the given insulin dose advice was high (98.2%). While the percentage of time spent in a moderately hypoglycemic range (2.2 to 3.3 mmol/L) was low (0.07 ± 0.26% of the time), one severe hypoglycemic episode (<2.2 mmol/L) occurred (2.5% of patients or 0.03% of glucose readings).
SGC is a safe and efficient method to control blood glucose in critically ill patients as assessed in two European medical intensive care units.
PMCID: PMC4118658  PMID: 25074071
Tight glycemic control; Critical illness; Critically ill patients; Protocol; Computer-assisted glycemic control; Insulin infusion protocol; Glucose control in intensive care
3.  Towards a feasible algorithm for tight glycaemic control in critically ill patients: a systematic review of the literature 
Critical Care  2006;10(1):R19.
Tight glycaemic control is an important issue in the management of intensive care unit (ICU) patients. The glycaemic goals described by Van Den Berghe and colleagues in their landmark study of intensive insulin therapy appear difficult to achieve in a real life ICU setting. Most clinicians and nurses are concerned about a potentially increased frequency of severe hypoglycaemic episodes with more stringent glycaemic control. One of the steps we took before we implemented a glucose regulation protocol was to review published trials employing insulin/glucose algorithms in critically ill patients.
We conducted a search of the PubMed, Embase and Cochrane databases using the following terms: 'glucose', 'insulin', 'protocol', 'algorithm', 'nomogram', 'scheme', 'critically ill' and 'intensive care'. Our search was limited to clinical trials conducted in humans. The aim of the papers selected was required to be glycaemic control in critically ill patients; the blood glucose target was required to be 10 mmol/l or under (or use of a protocol that resulted in a mean blood glucose = 10 mmol/l). The studies were categorized according to patient type, desired range of blood glucose values, method of insulin administration, frequency of blood glucose control, time taken to achieve the desired range for glucose, proportion of patients with glucose in the desired range, mean blood glucose and frequency of hypoglycaemic episodes.
A total of twenty-four reports satisfied our inclusion criteria. Most recent studies (nine) were conducted in an ICU; nine others were conducted in a perioperative setting and six were conducted in patients with acute myocardial infarction or stroke. Studies conducted before 2001 did not include normoglycaemia among their aims, which changed after publication of the study by Van Den Berghe and coworkers in 2001; glycaemic goals became tighter, with a target range between 4 and 8 mmol/l in most studies.
Studies using a dynamic scale protocol combining a tight glucose target and the last two blood glucose values to determine the insulin infusion rate yielded the best results in terms of glycaemic control and reported low frequencies of hypoglycaemic episodes.
PMCID: PMC1550808  PMID: 16469124
4.  Glycaemic control in Australia and New Zealand before and after the NICE-SUGAR trial: a translational study 
Critical Care  2013;17(5):R215.
There is no information on the uptake of Intensive Insulin Therapy (IIT) before the Normoglycemia in Intensive Care Evaluation and Surviving Using Glucose Algorithm Regulation (NICE-SUGAR) trial in Australia and New Zealand (ANZ) and on the bi-national response to the trial, yet such data would provide important information on the evolution of ANZ practice in this field. We aimed to study ANZ glycaemic control before and after the publication of the results of the NICE-SUGAR trial.
We analysed glucose control in critically ill patients across Australia and New Zealand during a two-year period before and after the publication of the NICE-SUGAR study. We used the mean first day glucose (Glu1) (a validated surrogate of ICU glucose control) to define practice. The implementation of an IIT protocol was presumed if the median of Glu1 measurements was <6.44 mmol/L for a given ICU. Hypoglycaemia was categorised as severe (glucose ≤2.2 mmol/L) or moderate (glucose ≤3.9 mmol/L).
We studied 49 ICUs and 176,505 patients. No ICU practiced IIT before or after NICE-SUGAR. Overall, Glu1 increased from 7.96 (2.95) mmol/L to 8.03 (2.92) mmol/L (P <0.0001) after NICE-SUGAR. Similar increases were noted in all patient subgroups studied (surgical, medical, insulin dependent diabetes mellitus, ICU stay >48/<48 hours). The rate of severe and moderate hypoglycaemia before and after NICE-SUGAR study were 0.59% vs. 0.55% (P =0.33) and 6.62% vs. 5.68% (P <0.0001), respectively. Both crude and adjusted mortalities declined over the study period.
IIT had not been adopted in ANZ before the NICE-SUGAR study and glycaemic control corresponded to that delivered in the control arm of NICE-SUGAR trial. There were only minor changes in practice after the trial toward looser glycaemic control. The rate of moderate hypoglycaemia and mortality decreased along with such changes.
PMCID: PMC4056083  PMID: 24088368
5.  Tight glycaemic control: a prospective observational study of a computerised decision-supported intensive insulin therapy protocol 
Critical Care  2007;11(4):R75.
A single centre has reported that implementation of an intensive insulin protocol, aiming for tight glycaemic control (blood glucose 4.4 to 6.1 mmol/l), resulted in significant reduction in mortality in longer stay medical and surgical critically ill patients. Our aim was to determine the degree to which tight glycaemic control can be maintained using an intensive insulin therapy protocol with computerized decision support and to identify factors that may be associated with the degree of control.
At a general adult 22-bed intensive care unit, we implemented an intensive insulin therapy protocol in mechanically ventilated patients, aiming for a target glucose range of 4.4 to 6.1 mmol/l. The protocol was integrated into the computerized information management system by way of a decision support program. The time spent in each predefined blood glucose band was estimated, assuming a linear trend between measurements.
Fifty consecutive patients were investigated, involving analysis of 7,209 blood glucose samples, over 9,214 hours. The target tight glycaemic control band (4.4 to 6.1 mmol/l) was achieved for a median of 23.1% of the time that patients were receiving intensive insulin therapy. Nearly half of the time (median 48.5%), blood glucose was within the band 6.2 to 7.99 mmol/l. Univariate analysis revealed that body mass index (BMI), Acute Physiology and Chronic Health Evaluation (APACHE) II score and previous diabetes each explained approximately 10% of the variability in tight glycaemic control. BMI and APACHE II score explained most (27%) of the variability in tight glycaemic control in the multivariate analysis, after adjusting for age and previous diabetes.
Use of the computerized decision supported intensive insulin therapy protocol did result in achievement of tight glycaemic control for a substantial percentage of each patient's stay, although it did deliver 'normoglycaemia' (4.4 to about 8 mmol/l) for nearly 75% of the time. Tight glycaemic control was difficult to achieve in critically ill patients using this protocol. More sophisticated methods such as continuous blood glucose monitoring with automated insulin and glucose infusion adjustment may be a more effective way to achieve tight glycaemic control. Glycaemia in patients with high BMI and APACHE II scores may be more difficult to control using intensive insulin therapy protocols. Trial registration number 05/Q0505/1.
PMCID: PMC2206495  PMID: 17623086
6.  The effects of baseline characteristics, glycaemia treatment approach, and glycated haemoglobin concentration on the risk of severe hypoglycaemia: post hoc epidemiological analysis of the ACCORD study 
Objectives To investigate potential determinants of severe hypoglycaemia, including baseline characteristics, in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial and the association of severe hypoglycaemia with levels of glycated haemoglobin (haemoglobin A1C) achieved during therapy.
Design Post hoc epidemiological analysis of a double 2×2 factorial, randomised, controlled trial.
Setting Diabetes clinics, research clinics, and primary care clinics.
Participants 10 209 of the 10 251 participants enrolled in the ACCORD study with type 2 diabetes, a haemoglobin A1C concentration of 7.5% or more during screening, and aged 40-79 years with established cardiovascular disease or 55-79 years with evidence of significant atherosclerosis, albuminuria, left ventricular hypertrophy, or two or more additional risk factors for cardiovascular disease (dyslipidaemia, hypertension, current smoker, or obese).
Interventions Intensive (haemoglobin A1C <6.0%) or standard (haemoglobin A1C 7.0-7.9%) glucose control.
Main outcome measures Severe hypoglycaemia was defined as episodes of “low blood glucose” requiring the assistance of another person and documentation of either a plasma glucose less than 2.8 mmol/l (<50 mg/dl) or symptoms that promptly resolved with oral carbohydrate, intravenous glucose, or glucagon.
Results The annual incidence of hypoglycaemia was 3.14% in the intensive treatment group and 1.03% in the standard glycaemia group. We found significantly increased risks for hypoglycaemia among women (P=0.0300), African-Americans (P<0.0001 compared with non-Hispanic whites), those with less than a high school education (P<0.0500 compared with college graduates), aged participants (P<0.0001 per 1 year increase), and those who used insulin at trial entry (P<0.0001). For every 1% unit decline in the haemoglobin A1C concentration from baseline to 4 month visit, there was a 28% (95% CI 19% to 37%) and 14% (4% to 23%) reduced risk of hypoglycaemia requiring medical assistance in the standard and intensive groups, respectively. In both treatment groups, the risk of hypoglycaemia requiring medical assistance increased with each 1% unit increment in the average updated haemoglobin A1C concentration (standard arm: hazard ratio 1.76, 95% CI 1.50 to 2.06; intensive arm: hazard ratio 1.15, 95% CI 1.02 to 1.21).
Conclusions A greater drop in haemoglobin A1C concentration from baseline to the 4 month visit was not associated with an increased risk for hypoglycaemia. Patients with poorer glycaemic control had a greater risk of hypoglycaemia, irrespective of treatment group. Identification of baseline subgroups with increased risk for severe hypoglycaemia can provide guidance to clinicians attempting to modify patient therapy on the basis of individual risk.
Trial registration number NCT00000620.
PMCID: PMC2803743  PMID: 20061360
7.  Implementation and evaluation of the SPRINT protocol for tight glycaemic control in critically ill patients: a clinical practice change 
Critical Care  2008;12(2):R49.
Stress-induced hyperglycaemia is prevalent in critical care. Control of blood glucose levels to within a 4.4 to 6.1 mmol/L range or below 7.75 mmol/L can reduce mortality and improve clinical outcomes. The Specialised Relative Insulin Nutrition Tables (SPRINT) protocol is a simple wheel-based system that modulates insulin and nutritional inputs for tight glycaemic control.
SPRINT was implemented as a clinical practice change in a general intensive care unit (ICU). The objective of this study was to measure the effect of the SPRINT protocol on glycaemic control and mortality compared with previous ICU control methods. Glycaemic control and mortality outcomes for 371 SPRINT patients with a median Acute Physiology And Chronic Health Evaluation (APACHE) II score of 18 (interquartile range [IQR] 15 to 24) are compared with a 413-patient retrospective cohort with a median APACHE II score of 18 (IQR 15 to 23).
Overall, 53.9% of all measurements were in the 4.4 to 6.1 mmol/L band. Blood glucose concentrations were found to be log-normal and thus log-normal statistics are used throughout to describe the data. The average log-normal glycaemia was 6.0 mmol/L (standard deviation 1.5 mmol/L). Only 9.0% of all measurements were below 4.4 mmol/L, with 3.8% below 4 mmol/L and 0.1% of measurements below 2.2 mmol/L. On SPRINT, 80% more measurements were in the 4.4 to 6.1 mmol/L band and standard deviation of blood glucose was 38% lower compared with the retrospective control. The range and peak of blood glucose were not correlated with mortality for SPRINT patients (P >0.30). For ICU length of stay (LoS) of greater than or equal to 3 days, hospital mortality was reduced from 34.1% to 25.4% (-26%) (P = 0.05). For ICU LoS of greater than or equal to 4 days, hospital mortality was reduced from 34.3% to 23.5% (-32%) (P = 0.02). For ICU LoS of greater than or equal to 5 days, hospital mortality was reduced from 31.9% to 20.6% (-35%) (P = 0.02). ICU mortality was also reduced but the P value was less than 0.13 for ICU LoS of greater than or equal to 4 and 5 days.
SPRINT achieved a high level of glycaemic control on a severely ill critical cohort population. Reductions in mortality were observed compared with a retrospective hyperglycaemic cohort. Range and peak blood glucose metrics were no longer correlated with mortality outcome under SPRINT.
PMCID: PMC2447603  PMID: 18412978
8.  Diabetes: glycaemic control in type 2 
BMJ Clinical Evidence  2008;2008:0609.
Diabetes mellitus is now seen as a progressive disorder of glucose metabolism, affecting about 5% of the population worldwide, over 85% of whom have type 2 diabetes. Type 2 diabetes may occur with obesity, hypertension and dyslipidaemia (the metabolic syndrome), which are powerful predictors of CVD. Blood glucose levels rise progressively over time in people with type 2 diabetes regardless of treatment, causing microvascular and macrovascular complications.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of interventions in adults with type 2 diabetes? We searched: Medline, Embase, The Cochrane Library and other important databases up to October 2006 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
We found 69 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
In this systematic review we present information relating to the effectiveness and safety of the following interventions: combined oral drug treatment, diet, education, insulin (continuous subcutaneous infusion), insulin, intensive treatment programmes, meglitinides (nateglinide, repaglinide), metformin, monotherapy, blood glucose self-monitoring (different frequencies), and sulphonylureas (newer or older).
Key Points
Diabetes mellitus is now seen as a progressive disorder of glucose metabolism; it affects about 5% of the population worldwide, over 85% of whom have type 2 diabetes. Type 2 diabetes is often associated with obesity, hypertension, and dyslipidaemia (the metabolic syndrome), which are powerful predictors of CVD.Type 2 diabetes is a disease in which glucose levels rise over time, with or without treatment and irrespective of the type of treatment given. This rise may lead to microvascular and macrovascular complications.
Most people with type 2 diabetes will eventually need treatment with oral hypoglycaemic agents. Metformin reduces glycated haemoglobin by 1−2% and reduces mortality compared with diet alone, without increasing weight, but it can cause hypoglycaemia compared with placebo. Sulphonylureas reduce HbA1c by 1−2% compared with diet alone. Older sulphonylureas can cause weight gain and hypoglycaemia, but the risk of these adverse effects may be lower with newer-generation sulphonylureas. Meglitinides (nateglinide, repaglinide) may reduce HbA1c by 0.4-0.9% compared with placebo, but may cause hypoglycaemia. Combined oral drug treatment may reduce HbA1c levels more than monotherapy, but increases the risk of hypoglycaemia. Insulin is no more effective than sulphonylureas in improving glucose control in people with newly diagnosed type 2 diabetes, and is associated with a higher rate of major hypoglycaemic episodes, and with weight gain.
Individual or group intensive educational programmes may reduce HbA1c compared with usual care, although studies have been of poor quality.
Insulin improves glycaemic control in people with inadequate control of HbA1c from oral drug treatment, but is associated with weight gain, and an increased risk of hypoglycaemia. Adding metformin to insulin improves glucose control compared with insulin alone, but increases gastrointestinal adverse effects. However, the combination may cause less weight gain than insulin alone.
Monitoring of blood glucose levels has not been shown to improve glycaemic control in people not being treated with insulin.
Diet may be less effective than metformin or sulphonylureas in improving glucose control, although sulphonylureas were associated with higher rates of hypoglycaemia. However, there is consensus that weight reduction in people with type 2 diabetes can improve glycaemic control, as well as conferring other health benefits.
PMCID: PMC2907982  PMID: 19450326
9.  The effect of diabetes mellitus on the association between measures of glycaemic control and ICU mortality: a retrospective cohort study 
Critical Care  2013;17(2):R52.
In critical illness, four measures of glycaemic control are associated with ICU mortality: mean glucose concentration, glucose variability, the incidence of hypoglycaemia (≤ 2.2 mmol/l) or low glucose (2.3 to 4.7 mmol/l). Underlying diabetes mellitus (DM) might affect these associations. Our objective was to study whether the association between these measures of glycaemic control and ICU mortality differs between patients without and with DM and to explore the cutoff value for detrimental low glucose in both cohorts.
This retrospective database cohort study included patients admitted between January 2004 and June 2011 to a 24-bed medical/surgical ICU in a teaching hospital. We analysed glucose and outcome data from 10,320 patients: 8,682 without DM and 1,638 with DM. The cohorts were subdivided into quintiles of mean glucose and quartiles of glucose variability. Multivariable regression models were used to examine the independent association between the four measures of glycaemic control and ICU mortality, and for defining the cutoff value for detrimental low glucose.
Regarding mean glucose, a U-shaped relation was observed in the non-DM cohort with an increased ICU mortality in the lowest and highest glucose quintiles (odds ratio = 1.4 and 1.8, P < 0.001). No clear pattern was found in the DM cohort. Glucose variability was related to ICU mortality only in the non-DM cohort, with highest ICU mortality in the upper variability quartile (odds ratio = 1.7, P < 0.001). Hypoglycaemia was associated with ICU mortality in both cohorts (odds ratio non-DM = 2.5, P < 0.001; odds ratio DM = 4.2, P = 0.001), while low-glucose concentrations up to 4.9 mmol/l were associated with an increased risk of ICU mortality in the non-DM cohort and up to 3.5 mmol/l in the DM cohort.
Mean glucose and high glucose variability are related to ICU mortality in the non-DM cohort but not in the DM cohort. Hypoglycaemia (≤ 2.2 mmol/l) was associated with ICU mortality in both. The cutoff value for detrimental low glucose is higher in the non-DM cohort (4.9 mmol/l) than in the DM cohort (3.5 mmol/l). While hypoglycaemia (≤ 2.2 mmol/l) should be avoided in both groups, DM patients seem to tolerate a wider glucose range than non-DM patients.
PMCID: PMC3733428  PMID: 23510051
10.  Reducing the impact of insulin sensitivity variability on glycaemic outcomes using separate stochastic models within the STAR glycaemic protocol 
The metabolism of critically ill patients evolves dynamically over time. Post critical insult, levels of counter-regulatory hormones are significantly elevated, but decrease rapidly over the first 12–48 hours in the intensive care unit (ICU). These hormones have a direct physiological impact on insulin sensitivity (SI). Understanding the variability of SI is important for safely managing glycaemic levels and understanding the evolution of patient condition. The objective of this study is to assess the evolution of SI over the first two days of ICU stay, and using this data, propose a separate stochastic model to reduce the impact of SI variability during glycaemic control using the STAR glycaemic control protocol.
The value of SI was identified hourly for each patient using a validated physiological model. Variability of SI was then calculated as the hour-to-hour percentage change in SI. SI was examined using 6 hour blocks of SI to display trends while mitigating the effects of noise. To reduce the impact of SI variability on achieving glycaemic control a new stochastic model for the most variable period, 0–18 hours, was generated. Virtual simulations were conducted using an existing glycaemic control protocol (STAR) to investigate the clinical impact of using this separate stochastic model during this period of increased metabolic variability.
For the first 18 hours, over 80% of all SI values were less than 0.5 × 10-3 L/mU.min, compared to 65% for >18 hours. Using the new stochastic model for the first 18 hours of ICU stay reduced the number of hypoglycaemic measurements during virtual trials. For time spent below 4.4, 4.0, and 3.0 mmol/L absolute reductions of 1.1%, 0.8% and 0.1% were achieved, respectively. No severe hypoglycaemic events (BG < 2.2 mmol/L) occurred for either case.
SI levels increase significantly, while variability decreases during the first 18 hours of a patients stay in ICU. Virtual trials, using a separate stochastic model for this period, demonstrated a reduction in variability and hypoglycaemia during the first 18 hours without adversely affecting the overall level of control. Thus, use of multiple models can reduce the impact of SI variability during model-based glycaemic control.
PMCID: PMC4013832  PMID: 24739335
Insulin sensitivity; Intensive care; Glycaemia; Model-based control
11.  Clinical review: Strict or loose glycemic control in critically ill patients - implementing best available evidence from randomized controlled trials 
Critical Care  2010;14(3):223.
Glycemic control aiming at normoglycemia, frequently referred to as 'strict glycemic control' (SGC), decreased mortality and morbidity of adult critically ill patients in two randomized controlled trials (RCTs). Five successive RCTs, however, failed to show benefit of SGC with one trial even reporting an unexpected higher mortality. Consequently, enthusiasm for the implementation of SGC has declined, hampering translation of SGC into daily ICU practice. In this manuscript we attempt to explain the variances in outcomes of the RCTs of SGC, and point out other limitations of the current literature on glycemic control in ICU patients. There are several alternative explanations for why the five negative RCTs showed no beneficial effects of SGC, apart from the possibility that SGC may indeed not benefit ICU patients. These include, but are not restricted to, variability in the performance of SGC, differences among trial designs, changes in standard of care, differences in timing (that is, initiation) of SGC, and the convergence between the intervention groups and control groups with respect to achieved blood glucose levels in the successive RCTs. Additional factors that may hamper translation of SGC into daily ICU practice include the feared risk of severe hypoglycemia, additional labor associated with SGC, and uncertainties about who the primarily responsible caregiver should be for the implementation of SGC.
PMCID: PMC2911685  PMID: 20550725
12.  Optimal blood glucose control in severely burned patients: a long way to go, but one step closer 
Critical Care  2013;17(5):1005.
Over the past years there has been a significant decrease in mortality and morbidity in patients suffering from severe burns due to improved burn wound management and approaches in critical care. Survival is no longer the exception, but unfortunately death still occurs. One of the key elements concerning state-of-the-art burn care is blood glucose control and insulin therapy; it is well known that burn-induced hyperglycaemia is associated with adverse clinical outcomes. However, controversy for insulin therapy and tight glycaemic control in critically ill and burn patients exists. The increased incidence of hypoglycaemia is the dominant argument against this treatment, because hypoglycaemia is also associated with an increased risk for death in critically ill patients. Taking all current data together, insulin therapy appears both a friend and a foe in the treatment of ICU patients. In order to overcome the limits of tight glycaemic control resulting from hypoglycaemic episodes, current efforts have been directed towards the development of protocols allowing for implementation of clinically feasible and safe guidelines. Among the strategies addressing this problem are closed loop techniques, which are supported by studies demonstrating their capability of exerting tight glycaemic control without the risk of developing hypoglycaemic episodes. Although closed loop techniques have become readily available, we require further evidence to ensure their safety in various ICU environments, notably in ICUs dealing with burn patients. Nonetheless, it is important to emphasise that glycaemic control and adequate insulin therapy are crucial factors for the final outcome (survival) and require our attention.
PMCID: PMC4056980  PMID: 24107553
13.  Twice daily versus four times daily insulin dose regimens for diabetes in pregnancy: randomised controlled trial 
BMJ : British Medical Journal  1999;319(7219):1223-1227.
To compare perinatal outcome and glycaemic control in two groups of pregnant diabetic patients receiving two insulin regimens.
Randomised controlled open label study.
University affiliated hospital, Israel.
138 patients with gestational diabetes mellitus and 58 patients with pregestational diabetes mellitus received insulin four times daily, and 136 patients with gestational diabetes and 60 patients with pregestational diabetes received insulin twice daily.
Three doses of regular insulin before meals and an intermediate insulin dose before bedtime (four times daily regimen), and a combination of regular and intermediate insulin in the morning and evening (twice daily regimen).
Main outcome measures
Maternal glycaemic control and perinatal outcome.
Mean daily insulin concentration before birth was higher in the women receiving insulin four times daily compared with twice daily: by 22 units (95% confidence interval 12 to 32) in patients with gestational diabetes and by 28 units (15 to 41) in patients with pregestational diabetes. Glycaemic control was better with the four times daily regimen than with the twice daily regimen: in patients with gestational diabetes mean blood glucose concentrations decreased by 0.19 mmol/l (0.13 to 0.25), HbA1c by 0.3% (0.2% to 0.4%), and fructosamine by 41 μmol/l (37 to 45), and adequate glycaemic control (mean blood glucose concentration <5.8 mmol/l) was achieved in 17% (8% to 26%) more women; in patients with pregestational diabetes mean blood glucose concentration decreased by 0.44 mmol/l (0.28 to 0.60), HbA1c by 0.5% (0.2% to 0.8%), and fructosamine by 51 μmol/l (45 to 57), and adequate glycaemic control was achieved in 31% (15% to 47%) more women. Maternal severe hypoglycaemic events, caesarean section, preterm birth, macrosomia, and low Apgar scores were similar in both dose groups. In women with gestational diabetes the four times daily regimen resulted in a lower rate of overall neonatal morbidity than the twice daily regimen (relative risk 0.59, 0.38 to 0.92), and the relative risk for hyperbilirubinaemia and hypoglycaemia was lower (0.51, 0.29 to 0.91 and 0.12, 0.02 to 0.97 respectively). The relative risk of hypoglycaemia in newborn infants to mothers with pregestational diabetes was 0.17 (0.04 to 0.74).
Giving insulin four times rather than twice daily in pregnancy improved glycaemic control and perinatal outcome without further risking the mother.
Key messagesImproving maternal glycaemic control during pregnancy is the key to better perinatal outcomeIn pregnant diabetic women insulin four times daily achieved better glycaemic control and lower rate of perinatal complications (hypoglycaemia, hyperbilirubinaemia) than insulin twice dailyBetter glycaemic control resulted from a larger total daily insulin doseThe intensified regimen did not lead to higher rate of severe maternal hypoglycaemia
PMCID: PMC28269  PMID: 10550081
14.  Influence of human insulin on symptoms and awareness of hypoglycaemia: a randomised double blind crossover trial. 
BMJ : British Medical Journal  1991;303(6803):622-626.
OBJECTIVE--To investigate the apparent increased risk of severe hypoglycaemia associated with use of human insulin by comparing the pattern of symptoms of hypoglycaemia with human insulin and porcine insulin. DESIGN--Randomised controlled double blind crossover trial of treatment with human insulin and porcine insulin, with two treatment periods of six weeks. SETTING--Diabetes outpatient department of a university teaching hospital in Berne, Switzerland. PATIENTS--44 patients (25 men, 19 women) aged 14 to 60 years, with insulin dependent diabetes mellitus. All patients met the following criteria: receiving treatment with fast acting soluble insulin and long acting protamine insulin; performing multiple daily fingerstick blood glucose self measurements; and had stable glycaemic control with about one mild hypoglycaemic episode a week during the preceding two months. INTERVENTION--Patients were randomised to receive either human or porcine insulin for six weeks and were then changed over to the other type of insulin for a further six weeks. MAIN OUTCOME MEASURE--Questionnaire recording "autonomic" and "neuroglycopenic" symptoms that occurred during hypoglycaemic episodes confirmed by a blood glucose concentration less than or equal to 2.8 mmol/l. RESULTS--Insulin doses and blood glucose, glycated haemoglobin A1c, and fructosamine concentrations were similar during the two treatment periods. 493 questionnaires on hypoglycaemia (234 during treatment with human insulin and 259 during treatment with porcine insulin) were analysed. With human insulin patients were more likely to report lack of concentration (52% v 35%, p = 0.0003) and restlessness (53% v 45%, p = 0.004) and less likely to report hunger (33% v 42%, p = 0.016) than during treatment with porcine insulin. The difference in the pattern of symptoms during the two treatments was similar to that between the 12 patients with a history of recurrent hypoglycaemic coma and the 32 patients without such a history. CONCLUSIONS--The pattern of symptoms associated with human insulin could impair patients' ability to take appropriate steps to avoid severe hypoglycaemia. Caution should be exercised when transferring patients from animal insulin to human insulin, and a large scale randomised trial of the two types of insulin may be justified.
PMCID: PMC1671054  PMID: 1932903
15.  Double blind clinical and laboratory study of hypoglycaemia with human and porcine insulin in diabetic patients reporting hypoglycaemia unawareness after transferring to human insulin. 
BMJ : British Medical Journal  1993;306(6871):167-171.
OBJECTIVES--To compare awareness of hypoglycaemia and physiological responses to hypoglycaemia with human and porcine insulin in diabetic patients who reported loss of hypoglycaemia awareness after transferring to human insulin. DESIGN--Double blind randomised crossover study of clinical experience and physiological responses during slow fall hypoglycaemic clamping with porcine and human insulin. SETTING--Clinical investigation unit of teaching hospital recruiting from diabetes clinics of five teaching hospitals and one district general hospital. SUBJECTS--17 patients with insulin dependent diabetes mellitus of more than five years' duration who had reported altered hypoglycaemia awareness within three months of transferring to human insulin. MAIN OUTCOME MEASURES--Glycaemic control and frequency of hypoglycaemic episodes during two months' treatment with each insulin. Glucose thresholds for physiological and symptomatic responses during clamping. RESULTS--Glycaemic control did not change with either insulin. 136 hypoglycaemic episodes (eight severe) were reported with human insulin and 149 (nine severe) with porcine insulin (95% confidence interval -4 to 2.5, p = 0.63). 20 episodes of biochemical hypoglycaemia occurred with human insulin versus 18 with porcine insulin (-0.8 to 1, p = 0.78). During controlled hypoglycaemia the mean adrenaline response was 138 nmol/l/240 min for both insulins; neurohormonal responses were triggered at 3.0 (SE 0.2) versus 3.1 (0.2) mmol/l of glucose for adrenaline and 2.5 (0.1) versus 2.5 (0.1) mmol/l for subjective awareness. CONCLUSIONS--These data suggest that human insulin per se does not affect the presentation of hypoglycaemia or the neurohumoral, symptomatic, and cognitive function responses to hypoglycaemia in insulin dependent diabetic patients with a history of hypoglycaemia unawareness.
PMCID: PMC1676615  PMID: 8443479
16.  Implementation and evaluation of a nurse-centered computerized potassium regulation protocol in the intensive care unit - a before and after analysis 
Potassium disorders can cause major complications and must be avoided in critically ill patients. Regulation of potassium in the intensive care unit (ICU) requires potassium administration with frequent blood potassium measurements and subsequent adjustments of the amount of potassium administrated. The use of a potassium replacement protocol can improve potassium regulation. For safety and efficiency, computerized protocols appear to be superior over paper protocols. The aim of this study was to evaluate if a computerized potassium regulation protocol in the ICU improved potassium regulation.
In our surgical ICU (12 beds) and cardiothoracic ICU (14 beds) at a tertiary academic center, we implemented a nurse-centered computerized potassium protocol integrated with the pre-existent glucose control program called GRIP (Glucose Regulation in Intensive Care patients). Before implementation of the computerized protocol, potassium replacement was physician-driven. Potassium was delivered continuously either by central venous catheter or by gastric, duodenal or jejunal tube. After every potassium measurement, nurses received a recommendation for the potassium administration rate and the time to the next measurement. In this before-after study we evaluated potassium regulation with GRIP. The attitude of the nursing staff towards potassium regulation with computer support was measured with questionnaires.
The patient cohort consisted of 775 patients before and 1435 after the implementation of computerized potassium control. The number of patients with hypokalemia (<3.5 mmol/L) and hyperkalemia (>5.0 mmol/L) were recorded, as well as the time course of potassium levels after ICU admission. The incidence of hypokalemia and hyperkalemia was calculated. Median potassium-levels were similar in both study periods, but the level of potassium control improved: the incidence of hypokalemia decreased from 2.4% to 1.7% (P < 0.001) and hyperkalemia from 7.4% to 4.8% (P < 0.001). Nurses indicated that they considered computerized potassium control an improvement over previous practice.
Computerized potassium control, integrated with the nurse-centered GRIP program for glucose regulation, is effective and reduces the prevalence of hypo- and hyperkalemia in the ICU compared with physician-driven potassium regulation.
PMCID: PMC2826292  PMID: 20100342
17.  Strict glycaemic control in patients hospitalised in a mixed medical and surgical intensive care unit: a randomised clinical trial 
Critical Care  2008;12(5):R120.
Critically ill patients can develop hyperglycaemia even if they do not have diabetes. Intensive insulin therapy decreases morbidity and mortality rates in patients in a surgical intensive care unit (ICU) and decreases morbidity in patients in a medical ICU. The effect of this therapy on patients in a mixed medical/surgical ICU is unknown. Our goal was to assess whether the effect of intensive insulin therapy, compared with standard therapy, decreases morbidity and mortality in patients hospitalised in a mixed ICU.
This is a prospective, randomised, non-blinded, single-centre clinical trial in a medical/surgical ICU. Patients were randomly assigned to receive either intensive insulin therapy to maintain glucose levels between 80 and 110 mg/dl (4.4 to 6.1 mmol/l) or standard insulin therapy to maintain glucose levels between 180 and 200 mg/dl (10 and 11.1 mmol/l). The primary end point was mortality at 28 days.
Over a period of 30 months, 504 patients were enrolled. The 28-day mortality rate was 32.4% (81 of 250) in the standard insulin therapy group and 36.6% (93 of 254) in the intensive insulin therapy group (Relative Risk [RR]: 1.1; 95% confidence interval [CI]: 0.85 to 1.42). The ICU mortality in the standard insulin therapy group was 31.2% (78 of 250) and 33.1% (84 of 254) in the intensive insulin therapy group (RR: 1.06; 95%CI: 0.82 to 1.36). There was no statistically significant reduction in the rate of ICU-acquired infections: 33.2% in the standard insulin therapy group compared with 27.17% in the intensive insulin therapy group (RR: 0.82; 95%CI: 0.63 to 1.07). The rate of hypoglycaemia (≤ 40 mg/dl) was 1.7% in the standard insulin therapy group and 8.5% in the intensive insulin therapy group (RR: 5.04; 95% CI: 1.20 to 21.12).
IIT used to maintain glucose levels within normal limits did not reduce morbidity or mortality of patients admitted to a mixed medical/surgical ICU. Furthermore, this therapy increased the risk of hypoglycaemia.
Trial Registration Identifiers: 4374-04-13031; 094-2 in 000966421
PMCID: PMC2592751  PMID: 18799004
18.  Impact of improved glycaemic control on rates of hypoglycaemia in insulin dependent diabetes mellitus 
Archives of Disease in Childhood  1998;78(2):111-115.
Increased emphasis on strict glycaemic control of insulin dependent diabetes mellitus (IDDM) in young patients may be expected to cause increases in rates of significant hypoglycaemia. To evaluate whether this is the case for a large population based sample of IDDM children and adolescents rates of severe (coma, convulsion) and moderate (requiring assistance for treatment) hypoglycaemia were studied prospectively over a four year period.
 A total of 709 patients were studied yielding 2027 patient years of data (mean (SD) age: 12.3 (4.4); range 0-18 years, duration IDDM: 4.9 (3.8) years). Details of hypoglycaemia were recorded at clinic visits every three months when glycated haemoglobin (HbA1c) was also measured.
Overall the incidence of severe hypoglycaemia was 7.8 and moderate was 15.4 episodes/100 patient years. Over the four years mean (SD) clinic HbA1c steadily fell from 10.2 (1.6)% in 1992to 8.8 (1.5)% in 1995. In parallel with this there was a dramatic increase in the rate of hypoglycaemia, especially in the fourth year of the study, when severe hypoglycaemia increased from 4.8to 15.6 episodes/100 patient years. This increase was particularly marked in younger children (<6 years) in whom severe hypoglycaemia increased from 14.9 to 42.1 episodes/100 patient years in 1995.
It is concluded that attempts to achieve improved metabolic control must be accompanied by efforts to minimise the effects of significant hypoglycaemia, particularly in the younger age group.

PMCID: PMC1717459  PMID: 9579150
19.  Conventional insulin vs insulin infusion therapy in acute coronary syndrome diabetic patients 
World Journal of Diabetes  2014;5(4):562-568.
AIM: To evaluate the impact on glucose variability (GLUCV) of an nurse-implemented insulin infusion protocol when compared with a conventional insulin treatment during the day-to-day clinical activity.
METHODS: We enrolled 44 type 2 diabetic patients (n = 32 males; n = 12 females) with acute coronary syndrome (ACS) and randomy assigned to standard a subcutaneous insulin treatment (n = 23) or a nurse-implemented continuous intravenous insulin infusion protocol (n = 21). We utilized some parameters of GLUCV representing well-known surrogate markers of prognosis, i.e., glucose standard deviation (SD), the mean daily δ glucose (mean of daily difference between maximum and minimum glucose), and the coefficient of variation (CV) of glucose, expressed as percent glucose (SD)/glucose (mean).
RESULTS: At the admission, first fasting blood glucose, pharmacological treatments (insulin and/or anti-diabetic drugs) prior to entering the study and basal glycated hemoglobin (HbA1c) were observed in the two groups treated with subcutaneous or intravenous insulin infusion, respectively. When compared with patients submitted to standard therapy, insulin-infused patients showed both increased first 24-h (median 6.9 mmol/L vs 5.7 mmol/L P < 0.045) and overall hospitalization δ glucose (median 10.9 mmol/L vs 9.3 mmol/L, P < 0.028), with a tendency to a significant increase in first 24-h glycaemic CV (23.1% vs 19.6%, P < 0.053). Severe hypoglycaemia was rare (14.3%), and it was observed only in 3 patients receiving insulin infusion therapy. HbA1c values measured during hospitalization and 3 mo after discharge did not differ in the two groups of treatment.
CONCLUSION: Our pilot data suggest that no real benefit in terms of GLUCV is observed when routinely managing blood glucose by insulin infusion therapy in type 2 diabetic ACS hospitalized patients in respect to conventional insulin treatment
PMCID: PMC4127591  PMID: 25126402
Glycaemic management; Intensive insulin therapy; Conventional insulin treatment; Acute coronay syndrome; Glucose variability
20.  The impact of the severity of sepsis on the risk of hypoglycaemia and glycaemic variability 
Critical Care  2008;12(5):R129.
The purpose of this study was to assess the relation between glycaemic control and the severity of sepsis in a cohort of patients treated with intensive insulin therapy (IIT).
In a prospective, observational study, all patients in the intensive care unit (ICU) (n = 191) with sepsis, severe sepsis or septic shock were treated with IIT (target blood glucose (BG) level 80 to 140 mg/dl instead of strict normoglycaemia). BG values were analysed by calculating mean values, rate of BG values within different ranges, rate of patients experiencing BG values within different levels and standard deviation (SD) of BG values as an index of glycaemic variability.
The number of patients with hypoglycaemia and hyperglycaemia was highly dependent on the severity of sepsis (critical hypoglycaemia ≤ 40 mg/dl: sepsis: 2.1%, severe sepsis: 6.0%, septic shock: 11.5%, p = 0.1497; hyperglycaemia: >140 mg/dl: sepsis: 76.6%, severe sepsis: 88.0%, septic shock: 100%, p = 0.0006; >179 mg/dl: sepsis: 55.3%, severe sepsis: 73.5%, septic shock: 88.5%, p = 0.0005; >240 mg/dl: sepsis: 17.0%, severe sepsis: 48.2%, septic shock: 45.9%, p = 0.0011). Multivariate analyses showed a significant association of SD levels with critical hypoglycaemia especially for patients in septic shock (p = 0.0197). In addition, SD levels above 20 mg/dl were associated with a significantly higher mortality rate relative to those with SD levels below 20 mg/dl (24% versus 2.5%, p = 0.0195).
Patients with severe sepsis and septic shock who were given IIT had a high risk of hypoglycaemia and hyperglycaemia. Among these patients even with a higher target BG level, IIT mandates an increased awareness of the occurrence of critical hypoglycaemia, which is related to the severity of the septic episode.
PMCID: PMC2592768  PMID: 18939991
21.  Peri-operative glycaemic control regimens for preventing surgical site infections in adults 
Surgical site infections (SSIs) are associated with significant morbidity, mortality, and resource utilization and are potentially preventable. Peri-operative hyperglycaemia has been associated with increased SSIs and previous recommendations have been to treat glucose levels above 200 mg/dL. However, recent studies have questioned the optimal glycaemic control regimen to prevent SSIs. Whether the benefits of strict or intensive glycaemic control with insulin infusion as compared to conventional management outweigh the risks remains controversial.
To summarise the evidence for the impact of glycaemic control in the peri-operative period on the incidence of surgical site infections, hypoglycaemia, level of glycaemic control, all-cause and infection-related mortality, and hospital length of stay and to investigate for differences of effect between different levels of glycaemic control.
Search strategy
A search strategy was developed to search the following databases: Cochrane Wounds Group Specialised Register (searched 25 March 2009), The Cochrane Central Register of Controlled Trials, The Cochrane Library 2009, Issue 1; Ovid MEDLINE (1950 to March Week 2 2009); Ovid EMBASE (1980 to 2009 Week 12) and EBSCO CINAHL (1982 to March Week 3 2009). The search was not limited by language or publication status.
Selection criteria
Randomised controlled trials (RCTs) were eligible for inclusion if they evaluated two (or more) glycaemic control regimens in the peri-operative period (within one week pre-, intra-, and/or post-operative) and reported surgical site infections as an outcome.
Data collection and analysis
The standard method for conducting a systematic review in accordance with the Cochrane Wounds Group was used. Two review authors independently reviewed the results from the database searches and identified relevant studies. Two review authors extracted study data and outcomes from each study and reviewed each study for methodological quality. Any disagreement was resolved by discussion or by referral to a third review author.
Main results
Five RCTs met the pre-specified inclusion criteria for this review. No trials evaluated strict glycaemic control in the immediate pre-operative period or outside the intensive care unit. Due to heterogeneity in patient populations, peri-operative period, glycaemic target, route of insulin administration, and definitions of outcome measures, combination of the results of the five included trials into a meta-analysis was not appropriate. The methodological quality of the trials was variable. In terms of outcomes, only one trial demonstrated a significant reduction in SSIs with strict glycaemic control, but the quality of this trial was difficult to assess as a result of poor reporting; furthermore the baseline rate of SSIs was high (30%). The other trials were either underpowered to detect a difference in SSIs, due to a low baseline rate (less than or equal to 5%), or did not report SSIs as a single outcome but as part of a composite. Of the three trials reporting hypoglycaemia (which was not consistently defined) all had a higher rate in the strict glycaemic control group but none attributed significant morbidity to the hypoglycaemia. Adequacy of glucose control between groups was measured differently among studies. Studies could not be compared due to differences in target ranges, and were susceptible to measurement bias due to differences in frequency of measurement and lack of blinding by the providers following the glycaemic protocols. Infection-related mortality was not reported in any of the trials, and no trials demonstrated a significant difference in all-cause mortality. Length of hospital stay was significantly reduced in the strict glycaemic control groups in only one trial.
PMCID: PMC2893384  PMID: 19588404
Hyperglycemia [complications; *prevention & control]; Hypoglycemic Agents [therapeutic use]; Insulin [therapeutic use]; Intraoperative Complications [prevention & control]; Perioperative Care; Postoperative Complications [prevention & control]; Randomized Controlled Trials as Topic; Surgical Wound Infection [etiology; *prevention & control]; Adult; Humans
22.  Patients with type 2 diabetes inadequately controlled on premixed insulin: effect of initiating insulin glargine plus oral antidiabetic agents on glycaemic control in daily practice* 
Premixed insulin regimens are commonly used for type 2 diabetes mellitus (T2DM) patients. However, there is limited information regarding next-step therapy options in cases where premixed insulin does not provide adequate glycaemic control. This 12-week observational study of everyday clinical practice evaluated the efficacy and safety of insulin glargine (glargine) plus oral antidiabetic drugs (OADs) in T2DM patients previously treated with premixed insulin.
Type 2 diabetes mellitus patients taking premixed insulin were identified from German clinics and were eligible to switch to glargine plus OADs at the physicians’ and patients’ discretion, as part of routine clinical practice. The study design and conduct was in accordance with German regulations. Fasting blood glucose (FBG), 2-h postprandial blood glucose (PPBG) and glycosylated haemoglobin (HbA1c) were measured at the start and after a 12-week observation period.
A total of 5045 patients were followed-up and received glargine plus OADs. FBG [start to end-point: 9.9 ± 2.7 to 6.9 ± 1.5 mmol/l (178 ± 48 to 124 ± 26 mg/dl); p ≤ 0.001], 2-h PPBG [10.8 ± 2.8 to 7.8 ± 1.5 mmol/l (195 ± 50 to 140 ± 27 mg/dl)] and HbA1c (8.3 ± 1.2 to 7.2 ± 0.8%; p ≤ 0.001) improved significantly from start to end-point, respectively. A total of 48.9%, 38.4% and 73.9% of patients had FBG < 6.7 mmol/l (< 120 mg/dl), 2-h PPBG < 7.2 mmol/l (< 130 mg/dl) or HbA1c < 7.5%, respectively, after 12 weeks. Significant reductions in body weight were observed between the start and end of the observation period. A total of 71 adverse events were reported by 38 patients. Hypoglycaemia was the most common event (n = 16).
This observational study shows that, in T2DM patients inadequately controlled with premixed insulin, switching therapy to glargine plus OADs is associated with significant improvements in FBG and HbA1c, and is well tolerated in everyday clinical practice. Further intensification of insulin therapy, perhaps by adding one or more injections of prandial insulin, would help provide further improvements in glycaemic control in these patients.
What's knownPharmacological therapy of type 2 diabetes mellitus typically starts with oral agents, including metformin or sulfonylurea. However, the natural progression of type 2 diabetes mellitus means that combination therapy is often required. One option to starting insulin therapy is the addition of a ‘basal’ insulin to help manage fasting blood glucose.What's newPremixed insulin is used by approximately 40% of patients with type 2 diabetes mellitus, but for many people, premixed insulin provides inadequate glycaemic control. In this observational study of everyday clinical practice, transferring from premixed insulin to insulin glargine was associated with significant improvements in HbA1c and fasting blood glucose. Thus, the switch to insulin glargine offers an alternative treatment option for patients with inadequate glycaemic control on premixed insulin.
PMCID: PMC2228388  PMID: 17997807
23.  Design and implementation of GRIP: a computerized glucose control system at a surgical intensive care unit 
Tight glucose control by intensive insulin therapy has become a key part of critical care and is an important field of study in acute coronary care. A balance has to be found between frequency of measurements and the risk of hypoglycemia. Current nurse-driven protocols are paper-based and, therefore, rely on simple rules. For safety and efficiency a computer decision support system that employs complex logic may be superior to paper protocols.
We designed and implemented GRIP, a stand-alone Java computer program. Our implementation of GRIP will be released as free software. Blood glucose values measured by a point-of-care analyzer were automatically retrieved from the central laboratory database. Additional clinical information was asked from the nurse and the program subsequently advised a new insulin pump rate and glucose sampling interval.
Implementation of the computer program was uneventful and successful. GRIP treated 179 patients for a total of 957 patient-days. Severe hypoglycemia (< 2.2 mmol/L) only occurred once due to human error. With a median (IQR) of 4.9 (4.2 – 6.2) glucose measurements per day the median percentage of time in which glucose fell in the target range was 78%. Nurses rated the program as easy to work with and as an improvement over the preceding paper protocol. They reported no increase in time spent on glucose control.
A computer driven protocol is a safe and effective means of glucose control at a surgical ICU. Future improvements in the recommendation algorithm may further improve safety and efficiency.
PMCID: PMC1334184  PMID: 16359559
24.  Efficacy and safety of insulin degludec given as part of basal–bolus treatment with mealtime insulin aspart in type 1 diabetes: a 26-week randomized, open-label, treat-to-target non-inferiority trial 
Diabetes, Obesity & Metabolism  2014;16(10):922-930.
The efficacy and safety of insulin degludec (IDeg) was compared with insulin detemir (IDet), both administered once daily (OD) as basal treatment in participants with type 1 diabetes mellitus (T1DM). The primary outcome was non-inferiority of IDeg to IDet in glycated haemoglobin (HbA1c) reduction after 26 weeks.
This multinational, 26-week, controlled, open-label, parallel-group trial randomized adults with T1DM to IDeg or IDet as OD basal insulin treatment combined with mealtime bolus insulin aspart (IAsp). Participants with T1DM treated with any basal–bolus insulin regimen for ≥12 months prior to the trial, a mean HbA1c ≤ 10.0% (85.8 mmol/mol) and body mass index (BMI) ≤35.0 kg/m2 at screening participated in the trial (IDeg: N = 302; IDet: N = 153).
After 26 weeks, HbA1c decreased 0.73% (8.0 mmol/mol) (IDeg) and 0.65% (7.1 mmol/mol) (IDet) [estimated treatment difference (ETD) IDeg–IDet: −0.09% (−0.23; 0.05)95%CI (−10.0 mmol/mol [−2.6; 0.6]95% CI); confirming non-inferiority]. Mean fasting plasma glucose improved in both groups, and was lower with IDeg than IDet [ETD IDeg–IDet: −1.66 mmol/l (−2.37; −0.95)95% CI, p < 0.0001]. The rate of confirmed hypoglycaemia was similar with IDeg and IDet [45.83 vs. 45.69 episodes per patient-year of exposure (PYE); estimated rate ratio (RR) IDeg/IDet: 0.98 (0.80; 1.20)95% CI, p = 0.86]. The rate of nocturnal confirmed hypoglycaemia was lower with IDeg than IDet [4.14 vs. 5.93 episodes per PYE; RR IDeg/IDet: 0.66 (0.49; 0.88)95% CI, p = 0.0049]. Adverse event profiles were similar between groups.
IDeg administered OD in basal–bolus therapy effectively improved long-term glycaemic control in participants with T1DM with a lower risk of nocturnal confirmed hypoglycaemia than IDet.
PMCID: PMC4237553  PMID: 24702700
glycaemic control; hypoglycaemia; insulin aspart; insulin degludec; insulin detemir; insulin therapy; type 1 diabetes mellitus
25.  Clinical study of treatment switching from premixed insulin to basal insulin combined with oral hypoglycemic drugs in patients with type 2 diabetes 
Premixed insulin regimens are commonly used for the treatment of patients with type-2 diabetes mellitus (T2DM). However, limited data are available regarding next-step therapy options in cases where premixed insulin fails to provide adequate glycemic control. This 20-week observational study of everyday clinical practice evaluated the efficacy, safety and treatment satisfaction of insulin glargine plus oral anti-diabetic drugs (OADs) in T2DM patients previously treated with premixed insulin.
In this open-label, single-arm, 20-week study, 70 subjects with T2DM inadequately controlled with premixed insulin were switched to insulin glargine plus OADs. Changes in glycaemic control, incidence of hypoglycaemia, treatment satisfaction using the Diabetes Treatment Satisfaction Questionnaire (DTSQ), serum superoxide dismutase (SOD), and serum 8-iso-prostaglandin (8-iso-PG) were evaluated at the start and the end of the study.
Over the 20 week treatment period, mean (±SD) HbA1c levels decreased from 8.28 ± 1.24% to 6.83 ± 1.09%, mean (±SD) FBG levels decreased from 7.64 ± 1.36 mmol/L to 5.57 ± 1.21 mmol/L, and 2 h PBG levels decreased from 12.07 ± 1.17 mmol/L to 8.94 ± 1.56 mmol/L, all P < 0.001. A total of 3 symptomatic hypoglycemic episodes were reported. No significant reductions in body weight were observed. The mean daily dose of insulin decreased by 14 U between week 0 (30.20 ± 9.93 U) and week 20 (16.38 ± 5.15 U). The total treatment satisfaction score showed a significant increase from study baseline to end point. Significant increases in SOD(90.00 ± 16.62 to 108.81 ± 27.02 u/ml, P < 0.01) and reductions in 8-iso-PG(2.15 ± 0.61 to 1.64 ± 0.42 pg/ml, P < 0.05) were observed between the start and end of the observation period. There were significant differences in baseline HbA1c, duration of diabetes, and baseline postprandial C-peptide between the A1c ≤ 6.5% group and the A1c > 7.0% group [HbA1c: 7.25% ± 1.02% vs. 9.32% ± 1.23%; duration: 7.84 ± 1.02 vs. 13.96 ± 1.35 years; postprandial C-peptide: 4.83 ± 2.11 vs 2.54 ± 0.87 nmol/L, all P < 0.05].
The observational study shows that, in T2DM patients inadequately controlled with premixed insulin, switching therapy to glargine plus OADs is associated with significant improvements in glycaemic control and treatment satisfaction, and is with low incidence of hypoglycemia. Baseline postprandial C-peptide, HbA1c, and duration of diabetes are the key factors closely related to efficacy of this treatment regimen.
PMCID: PMC3984683  PMID: 24620742
Type 2 diabetes mellitus; Glargine; Premixed insulin; Oxidative stress

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