Skin Advanced Glycation End Product Accumulation Is Poorly Reflected by Glycemic Control in Type 2 Diabetic Patients (ZODIAC-9)

Background

Glycemic memory can be reflected by tissue accumulation of advanced glycation end products (AGEs). In type 1 diabetes mellitus (T1DM) patients, hemoglobin A1c (HbA1c) levels over various time periods poorly predicted the accumulation of different AGEs in skin biopsies. Our aim was to investigate whether HbA1c assessments can predict the change in skin AGEs during time in type 2 diabetes mellitus (T2DM).

Methods

We included 452 T2DM patients participating in a shared-care setting, who are screened annually for HbA1c and diabetic complications. Baseline and follow-up levels of skin AGEs were assessed with a validated noninvasive autofluorescence (AF) method, which is based on the fluorescence characteristics of certain AGEs.

Results

Our study population had a mean age of 65 years and 54% were female. After a mean follow-up duration of 3.3 years, linear regression analyses showed weak relationships among different assessments of HbA1c (baseline, maximum, mean, and variance of HbA1c) and skin AF at follow-up. Baseline skin AF and age were predictors of skin AF at follow-up, but diabetes duration, smoking, and creatinine were of less or no predictive value for skin AF at follow-up.

Conclusions

In our T2DM population, integrated HbA1c assessments over years poorly predict the change in skin AGE level measured by skin AF. These findings agree with results in patients with T1DM. This suggests either the need for longer exposure to glucose disturbances to change tissue AGEs or other mechanisms, such as oxidative stress, leading to AGE accumulation.     

Insulin doses before and one year after pump start: children have a reversed dawn phenomenon

Objective

We aimed to investigate the basal rate and bolus doses in children and adolescents at the start of insulin pump therapy and after 1 year of use.

Patients and Methods

Case records from 29 children and adolescents were examined. All pumps were started with rapid-acting insulin (Humalog). Patients were aged 13.1 ± 3.9 years, with a diabetes duration of 5.4 ± 4.1 years at pump start. Sixteen pumps were started for high hemoglobin A1c (HbA1c; >8.8%, 73 mmol/mol) and 13 for other reasons.

Results

Basal rates declined in both groups by 20% at 3 days after pump start. The bolus doses were reduced by 25–30% when the indication was high HbA1c and by 15% in the others. After 1 year, there was a significant difference in the basal rate between age groups. The 3–9-year-old age group had higher basal rates during the late evening (10:00 PM–12:00 AM), while the 15–21-year-old age group had higher basal rates in the early morning (3:00 AM–7:00 AM).

Conclusions

Insulin doses are reduced considerably when starting with a pump in pediatric practice. Younger children needed higher basal rates late in the evening (reversed dawn phenomenon), while older teenagers seem to need an increase in the morning, which may correspond to a true dawn phenomenon.     

Association of Self-Monitoring of Blood Glucose Use on Glycated Hemoglobin and Weight in Newly Diagnosed,Insulin-Na?ve Adult Patients with Type 2 Diabetes

Background

Clinical trials have shown that self-monitoring of blood glucose (SMBG) combined with patient education and medication titration can lead to improved glycated hemoglobin (HbA1c) and reduced weight in recently diagnosed non-insulin-treated type 2 diabetes mellitus (T2DM) patients. This retrospective matched cohort study assessed the association of SMBG with achieving long-term clinical outcomes in these patients in a real-world clinical setting.

Methods

Using electronic medical records (2008–2011), we selected a population of adult patients recently diagnosed with T2DM not receiving insulin who were SMBG users and a population of non-SMBG controls with similar demographic and clinical characteristics using propensity score matching. The main study outcomes compared between the two groups were time to achieve (1) HbA1c <7% for patients with baseline HbA1c ≥7% and (2) a ≥5% reduction in weight from baseline.

Results

Of the 589 patients identified in each group, 113 in each group had a baseline HbA1c ≥7% (mean, 8.2%). The SMBG users were more likely to achieve an HbA1c <7% (12 months: 58.4% versus 38.9%, p = .0037; 36 months: 84.0% versus 70.0%, p = .0013) and to do so faster (median, 6.5 versus 20.5 months; log-rank p = . 0016). Self-monitoring of blood glucose was associated with faster weight reduction (median time to achieve a ≥5% reduction, 23.5 versus 35.9 months for SMBG and non-SMBG, respectively; log-rank p = .0005).

Conclusions

In newly diagnosed T2DM insulin-naïve patients, SMBG users had an improved rate of achieving long-term glycemic control and weight loss in a real-world clinical setting.     

A Single-Center, Open, Comparative Study of the Effect of Using Self-Monitoring of Blood Glucose to Guide Therapy on Preclinical Atherosclerotic Markers in Type 2 Diabetic Subjects

Background

The aim of our study was to determine the effect of treatment based on preprandial and postprandial self-monitoring of blood glucose (SMBG) on the progression of carotid intima-medial thickness (CIMT) in noninsulin-treated type 2 diabetes mellitus (T2DM) subjects.

Methods

In this 18-month prospective trial, we recruited subjects 18–70 years of age, treated with metformin and sulfonylurea, with a standardized hemoglobin A1c (HbA1c) level ≤9.0%. Subjects were randomized to use of fasting/preprandial (FP) SMBG results to adjust evening medication or use of postprandial (PP) SMBG results to adjust morning medication. The primary end point was change in CIMT; change in HbA1c was a secondary end point.

Results

Of the 300 subjects randomized, 280 (140 in each group) completed all biochemical tests and CIMT analysis. Carotid intima-medial thickness was reduced significantly in PP subjects from 0.78 (±0.15) mm to 0.73 (±0.14) mm (p < 0.005), but no significant CIMT reduction was seen in FP subjects. A significant reduction in HbA1c was also seen in the PP group (p < 0.005) but not in the FP group 1 (p = 0.165). Significant improvements in body mass index (p = 0.038), waist circumference (p < 0.001), systolic blood pressure (p = 0.008), and serum cholesterol (p = 0.02) were also seen in PP subjects but not in FP subjects.

Conclusion

Use of postprandial SMBG data to adjust therapy was associated with a significant regression of carotid intima-medial thickening and a reduction in HbA1c in T2DM, whereas no significant improvement in these parameters was seen in subjects who used fasting/preprandial SMBG data for therapy adjustment.     

Pancreatic polypeptide administration enhances insulin sensitivity and reduces the insulin requirement of patients on insulin pump therapy

Introduction

The effects of pancreatic polypeptide (PP) infusion were examined in patients on insulin pump therapy to determine whether PP administration can reduce insulin requirements in patients with type 1 diabetes mellitus (T1DM) or type 3c diabetes mellitus (T3cDM; pancreatogenic).

Methods

Ten subjects with long-standing T1DM (n = 7) or T3cDM (n = 3) on insulin pump treatment received a 72 h subcutaneous infusion of 2 pmol/kg/min bovine PP or saline by portable infusion pump in a single-blinded, randomized, crossover design.

Results

Pancreatic polypeptide infusion raised plasma PP levels to 450–700 pmol/liter. Daily insulin infusion requirements (I) fell from 48 ± 6.9 to 40 ± 7.5 U on day 2 (p < .05) and from 46 ± 7.7 to 37 ± 6.6 U on day 3 (p < .05) of PP infusion compared with saline. Corrected for average blood glucose concentration (G), I/G fell in 10/10 subjects during the second 24 h period and in 7/10 subjects during the third 24 h period; sensitivity to insulin, calculated as 1/(I/G), increased 45% ± 12% on day 2 (p < .01) and 34% ± 14% on day 3 (p < .05) of PP infusion. Pancreatic polypeptide responses to a test meal were compared with the change in insulin infusion requirements in 5 subjects; the reduction in insulin requirements seen during PP infusion correlated with the degree of baseline PP deficiency (p < .002).

Conclusions

A concurrent subcutaneous infusion of PP enhances insulin sensitivity and reduces insulin requirements in patients with long-standing T1DM and T3cDM on insulin pump therapy. The benefit of PP infusion correlated with the degree of PP deficiency.     

Resource Consumption and Costs of Treatment in Patients with Type 1 Diabetes under Intensified Conventional Therapy under German Real-Life Conditions

Introduction:

The aim of this study was to compare, from the perspective of the statutory health insurance, resource consumption and the associated adjusted treatment costs of intensified conventional therapy (ICT) with long-acting insulins in patients with type 1 diabetes mellitus (T1DM).

Methods:

We identified patients with T1DM who started ICT with either insulin glargine or neutral protamine Hagedorn (NPH) insulin between July 2000 and February 2008 using a representative German database (IMS® Disease Analyzer). The variables age, gender, insurance status, diabetes duration, hemoglobin A1c level, body mass index, and geographic region and specialization of practice were collected. Resource consumption was evaluated over a time period of 12 months and included the quantities of applied basal and bolus insulin, blood glucose test strips, lancets and needles, physician visits (general practitioner, specialist), hospitalization, and antihypoglycemic therapy (intravenous glucose/glucagon).

Results:

A total of 2297 patients with T1DM were included; 1079 received ICT with insulin glargine and 1218 with NPH insulin. After adjustment, annual cost savings in favor of insulin glargine amounted to €423.94 compared with NPH insulin (p = .3019).

Discussion:

The adjusted results show that an ICT with insulin glargine results in lower annual costs than ICT with NPH insulin (this difference was not statistically significant). However, in the context of glucose-lowering effect and a lower hypoglycemia rate, insulin glargine is preferred to NPH insulin for patients with T1DM undergoing ICT.     

How Much Do Forgotten Insulin Injections Matter to Hemoglobin A1c in People with Diabetes? A Simulation Study

Background

Forgotten or omitted insulin injections are an important contributing factor to poor glycemic control in people with type 1 diabetes. This study uses mathematical modeling and examines the impact on hemoglobin A1c (HbA1c) levels if insulin injections are forgotten. The simulation concerns people with type 1 diabetes on intensive insulin therapy.

Methods

Five sets of blood glucose profiles with and without a forgotten injection were obtained. The difference to HbA1c was calculated using an HbA1c estimator on the profiles and was multiplied by the frequency of forgotten events. A frequency of 2.1 forgotten injections per week was found in the literature.

Results

Calculations showed that forgetting 2.1 meal-related injections per week would lead to an increase in HbA1c of at least 0.3–0.4% points, and similarly 0.2–0.3% points related to forgotten injections of the long-acting insulin. In case of even more pronounced nonadherence (e.g., if 39% of all injections are forgotten) there is a possible increase of HbA1c of 1.8% points.

Conclusions

The magnitude of the possible improvement in HbA1c agrees well with other studies in the relation between adherence and HbA1c levels. The estimated numbers suggest that missing injections are an important reason for suboptimal treatment.     

Identifying type 1 and type 2 diabetic cases using administrative data: a tree-structured model

Background:

To date, few administrative diabetes mellitus (DM) registries have distinguished type 1 diabetes mellitus (T1DM) from type 2 diabetes mellitus (T2DM).

Objective:

Using a classification tree model, a prediction rule was developed to distinguish T1DM from T2DM in a large administrative database.

Methods:

The Medical Archival Retrieval System at the University of Pittsburgh Medical Center included administrative and clinical data from January 1, 2000, through September 30, 2009, for 209,647 DM patients aged ≥18 years. Probable cases (8,173 T1DM and 125,111 T2DM) were identified by applying clinical criteria to administrative data. Nonparametric classification tree models were fit using TIBCO Spotfire S+ 8.1 (TIBCO Software), with model size based on 10-fold cross validation. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of T1DM were estimated.

Results:

The main predictors that distinguished T1DM from T2DM are age <40 years; International Classification of Disease, 9th revision, codes of T1DM or T2DM diagnosis; inpatient oral hypoglycemic agent use; inpatient insulin use; and episode(s) of diabetic ketoacidosis diagnosis. Compared with a complex clinical algorithm, the tree-structured model to predict T1DM had 92.8% sensitivity, 99.3% specificity, 89.5% PPV, and 99.5% NPV.

Conclusion:

The preliminary predictive rule appears to be promising. Being able to distinguish between DM subtypes in administrative databases will allow large-scale subtype-specific analyses of medical care costs, morbidity, and mortality.     

Impact of Islet Transplantation on Glycemic Control as Evidenced by a Continuous Glucose Monitoring System

Background

This study evaluated the effects of islet allotransplantation (ITx) on metabolic control utilizing a continuous glucose monitoring system (CGMS) and assessed its effectiveness as an indicator and predictor of graft dysfunction (GD).

Methods

Glycemic control was assessed in 25 patients with type 1 diabetes mellitus (T1DM); 12 ITx recipients and 13 controls. Mean interstitial glucose, standard deviation (SD), glucose variability, and percentage of time in hyperglycemia (%GT >140 mg/dl), hypoglycemia (%GT <54 mg/dl), and normoglycemia (%GT 54–140 mg/dl) were measured in 72-hour time periods from CGMS recordings in the control group at baseline and in the ITx group at 3, 6, 9, 12, 15, and 18 months after ITx completion and were analyzed as predictors and indicators of GD. Hemoglobin A1c (HbA1c), 90-minute glucose after a mixed meal tolerance test, fasting C-peptide/glucose ratio, and insulin requirements were followed.

Results

Compared to the control group, the percentage of time in hypoglycemia was significantly lower in the ITx group at all time points; time in normoglycemia was increased at all times except at 15 months; and time in hyperglycemia was significantly lower at 6, 9, 12, and 18 months. Mean glucose and glucose variability were significantly lower in the ITx group at all times except at 3 and 15 months, whereas HbA1c and 90-minute glucose were significantly lower in the ITx group at all time points. Mean glucose, SD, glucose variability, and %GT >140 mg/dl were significant as indicators but not as predictors of GD.

Conclusions

The CGMS demonstrated the benefits of ITx in T1DM, with improvements in glycemic control apparent up to 18 months after transplant. CGMS measures were found to be indicators of GD.     

Short and Long-Term Outcomes of Diabetes Mellitus in Patients with Autoimmune Pancreatitis after Steroid Therapy

Background/Aims

Autoimmune pancreatitis (AIP) is frequently associated with diabetes mellitus (DM). This study evaluated the effect of steroid therapy on the course of DM in AIP.

Methods

Glucose tolerance was examined in 69 patients with AIP. DM onset was classified as either a simultaneous onset with AIP or an exacerbation of pre-existing DM. Based on the changes in the HbA1c levels and insulin dose, the responses of DM to steroids were classified as improved, no change, or worsened.

Results

Thirty (46%) patients were diagnosed as having DM (simultaneous onset, n=17; pre-existing, n=13). Three months after starting the steroid treatment, the DM improved in 13 (54%) of 24 DM patients. The DM improved in 55%, had no change in 36%, and worsened in 9% of the 11 simultaneous onset DM patients, and it improved in 54%, had no change in 31%, and worsened in 15% of the 13 pre-existing DM patients. At approximately 3 years after starting the steroid treatment, the DM improved in 10 (63%) of 16 patients. The pancreatic exocrine function improved in parallel with the changes in the DM in seven patients.

Conclusions

Because approximately 60% of DM associated with AIP is responsive to steroids in the short- and long-terms, marked DM associated with AIP appears to be an indication for steroid therapy.     

Efficacy of continuous glucose monitoring in improving glycemic control and reducing hypoglycemia: a systematic review and meta-analysis of randomized trials

Objective

We conducted a systematic review and meta-analysis to assess the efficacy of continuous glucose monitoring (CGM) in improving glycemic control and reducing hypoglycemia compared to self-monitored blood glucose (SMBG).

Methods

We searched MEDLINE, EMBASE, Cochrane Central, Web of Science, and Scopus for randomized trials of adults and children with type 1 or type 2 diabetes mellitus (T1DM or T2DM). Pairs of reviewers independently selected studies, assessed methodological quality, and extracted data. Meta-analytic estimates of treatment effects were generated using a random-effects model.

Results

Nineteen trials were eligible and provided data for meta-analysis. Overall, CGM was associated with a significant reduction in mean hemoglobin A1c [HbA1c; weighted mean difference (WMD) of -0.27% (95% confidence interval [CI] -0.44 to -0.10)]. This was true for adults with T1DM as well as T2DM [WMD -0.50% (95% CI -0.69 to -0.30) and -0.70 (95% CI, -1.14 to -0.27), respectively]. No significant effect was noted in children and adolescents. There was no significant difference in HbA1c reduction between studies of real-time versus non-realtime devices (WMD -0.22%, 95% CI, -0.59 to 0.15 versus -0.30%, 95% CI, -0.49 to -0.10; p for interaction 0.71). The quality of evidence was moderate due to imprecision, suggesting increased risk for bias. Data for the incidence of severe or nocturnal hypoglycemia were sparse and imprecise. In studies that reported patient satisfaction, users felt confident about the device and gave positive reviews.

Conclusion

Continuous glucose monitoring seems to help improve glycemic control in adults with T1DM and T2DM. The effect on hypoglycemia incidence is imprecise and unclear. Larger trials with longer follow-up are needed to assess the efficacy of CGM in reducing patient-important complications without significantly increasing the burden of care for patients with diabetes.     

Trend analyses of insulin delivery systems in the United States

Background

Despite potential advantages in insulin pen delivery systems (IPDSs), the percentage of patients using an IPDS is relatively low in the United States.

Objective

Our aim was to investigate the trend of initiating IPDSs among patients with type 2 diabetes mellitus (T2DM) who newly initiated insulin therapy.

Methods

A retrospective analysis was conducted using a U.S. database from January 1, 2004, to December 31, 2008. Patients with T2DM who initiated a new insulin type and delivery system were included. The Cochran–Armitage test was used to assess the significance of the trend of initiating an insulin delivery system, including vial/syringe, IPDS overall, reusable pen delivery systems (RPDSs), and prefilled pen delivery systems (PPDSs). Different types of insulin (e.g., basal analog, prandial analog) were examined separately.

Results

Patients initiating an IPDS increased from 10.6% in 2004 to 48.5% in 2008 (p < .001), most notably in basal analog and prandial analog insulin therapies. Although the percentage of patients using a PPDS increased by 36.2 percentage points (from 9.2% in 2004 to 45.4% in 2008; p < .001), use of a RPDS increased only by 1.7 percentage points (from 1.4% in 2004 to 3.1% in 2008; p < .001).

Conclusion

There was an overall increase in the use of IPDSs in the United States among patients with T2DM who newly initiated insulin from July 1, 2004, to December 31, 2008. This increase was driven by the use of PPDSs for basal analog and prandial analog insulin therapies. Despite the increasing use of IPDS over time, approximately 50% of patients still initiated insulin using a vial/syringe in 2008.     

Health-Related Quality of Life and Metabolic Control in Children and Adolescents with Type 1 Diabetes Mellitus

Objective:

The burdens imposed on a child and his/her parents by a diagnosis of type 1 diabetes mellitus (T1DM) adversely affect their health-related quality of life (HRQoL). HRQoL is important for prognosis and is related to metabolic control. To evaluate the HRQoL of Turkish children and adolescents with T1DM and to assess the correlation of HRQoL subscales (including physical and psychosocial health) with metabolic control, and particularly with hypo- and hyperglycaemic episodes.

Methods:

This cross-sectional study included 70 participants with T1DM aged between 8 and 18 years (study group) and 72 healthy controls who were matched to the study group in terms of age, gender, and sociodemographic characteristics (control group), and their parents. HRQoL was determined by the Pediatric Quality of Life Inventory. As an indicator of metabolic control, the most recent hemoglobin A1c (HbA1c) levels were obtained and the number of hypo- and hyperglycaemic episodes over the past one month were checked.

Results:

The study group had similar HRQoL scores for children’s self-reports and parents’ proxy-reports to the control group apart from a decreasing psychosocial health score for parents’ proxy-reports in the study group. Although HbA1c level was not related to HRQoL scores, lower number of hypo- and hyperglycaemic episodes were associated with an increase in psychosocial health scores and physical health scores as well as an increase in the total score for parents’ proxy-reports.

Conclusion:

Although there was no correlation between metabolic control and HRQoL in children’s self-reports, the improving HRQoL levels in parents’ proxy-reports were associated with good metabolic control.     

Effects of a structured self-monitoring of blood glucose method on patient self-management behavior and metabolic outcomes in type 2 diabetes mellitus

Background

The purpose of this study was to evaluate the effect of structured self-monitoring of blood glucose (SMBG) on patient self-management behavior and metabolic outcomes in patients with type 2 diabetes mellitus (T2DM).

Methods

From January to June 2009, 30 patients with basic diabetes education were followed for a period of 90 days. To provide assessment of glycemic control and frequency of dysglycemia, patients, underwent 3 consecutive days of seven-point SMBG during each month for 3 consecutive months, using the ACCU-CHEK 360° View tool. Glucose profiles of the first and third month were used for comparison.

Results

Hemoglobin A1c (HbA1c) improved significantly during the 90-day period in all patients [confidence interval (CI) 95%, 0.32–1.64%, p < .05] and those with poor metabolic control (group B; CI 95%, 0.86–2.64%, p < .05). Mean blood glucose (MBG) values decreased significantly in group B (CI 95%, 0.56–24.78 mg/dl, p < .05) and all cases (CI 95%, 1.61–19.73 mg/dl, p < .05). Meanwhile, there was an average decrease of 15.7 mg/dl in fasting blood sugar (FBS) levels in the whole subjects. Mean postprandial blood glucose levels (MPP) decreased by 19.3 and 11.3 mg/dl in group B and in all cases, respectively. However, there were no significant changes in HbA1c, MBG, FBS, and MPP in people with good metabolic control.

Conclusion

A structured SMBG program improves HbA1c, FBS, MPP, and MBG in people with poorly controlled diabetes. This improvement shows the importance of patient self-management behavior on metabolic outcomes in T2DM.     

Elevated Hemoglobin A1c Levels Are Associated with Worse Survival in Advanced Pancreatic Cancer Patients with Diabetes

Background/Aims

Pre-existing diabetes mellitus (DM) has been identified as an adverse prognostic variable associated with increased mortality in various cancers. Although DM and hyperglycemia are considered risk factors for pancreatic cancer (PC), antidiabetic treatments for patients with advanced PC have been overlooked. This study aimed to evaluate the impact of hemoglobin A1c (HbA1c) levels on PC survival.

Methods

We retrospectively reviewed the medical records of first-diagnosed patients with advanced PC who were admitted to Konkuk University Medical Center from 2005 to 2011.

Results

A total of 127 patients were enrolled, and there were 111 deaths (87.4%) within the 7-year observational period. The most common etiology was disease progression (n=108). DM before PC diagnosis was observed in 65 patients (51.1%), including 28 patients with new-onset DM. The overall median survival times in patients with and without DM were 198 and 263 days, respectively (p=0.091). Survival time according to HbA1c was significantly different between the <7.0% and ≥7.0% groups (362 and 144 days, respectively; p=0.038). In the HbA1c ≥7.0% group, the median overall survival time was 273 days for the metformin group and 145 days for the nonmetformin oral agent group; however, there was no significant difference between the two groups (p=0.058).

Conclusions

A high HbA1c level may be associated with worse survival in patients with advanced PC with DM. Antidiabetic treatment, metformin in particular, was associated with an improved outcome.     

Gastric Electrical Stimulation with the TANTALUS? System in Obese Type 2 Diabetes Patients: Effect on Weight and Glycemic Control

Background

The TANTALUS^® System is an investigational device that consists of an implantable pulse generator connected to gastric electrodes. The system is designed to automatically detect when eating starts and only then deliver sessions of gastric electrical stimulation (GES) with electrical pulses that are synchronized to the intrinsic antral slow waves. We report the effect of this type of GES on weight loss and glucose control in overweight/obese subjects with type 2 diabetes mellitus (T2DM). This study was conducted under a Food and Drug Administration/Institutional Review Board-approved investigational device exemption.

Method

Fourteen obese T2DM subjects on oral antidiabetes medication were enrolled and implanted laparoscopically with the TANTALUS System (body mass index 39 ± 1 kg/m², hemoglobin A1c [HbA1c] 8.5 ± 0.2%).Gastric electrical stimulation was initiated four weeks after implantation. Weight, HbA1c, fasting blood glucose, blood pressure, and lipid levels were assessed during the study period.

Results

Eleven subjects reached the 6-month treatment period endpoint. Gastric electrical stimulation was well tolerated by all subjects. In those patients completing 6 months of therapy, HbA1c was reduced significantly from 8.5 ± 0.7% to 7.6 ± 1%, p < .01. Weight was also significantly reduced from 107.7 ± 21.1 to 102.4 ± 20.5 kg, p < .01. The improvement in glucose control did not correlate with weight loss (R² = 0.05, p = .44). A significant improvement was noted in blood pressure, triglycerides, and cholesterol (low-density lipoprotein only).

Conclusions

Short-term therapy with the TANTALUS System improves glucose control, induces weight loss, and improves blood pressure and lipids in obese T2DM subjects on oral antidiabetes therapy.     

A stepwise approach toward closed-loop blood glucose control for intensive care unit patients: results from a feasibility study in type 1 diabetic subjects using vascular microdialysis with infrared spectrometry and a model predictive control algorithm

Background

Glycemic control can reduce the mortality and morbidity of intensive care patients. The CLINICIP (closed-loop insulin infusion for critically ill patients) project aimed to develop a closed-loop control system for this patient group. Following a stepwise approach, we combined three independently tested subparts to form a semiautomatic closed-loop system and evaluated it with respect to safety and performance aspects by testing it in subjects with type 1 diabetes mellitus (T1DM) in a first feasibility trial.

Methods

Vascular microdialysis, a multianalyte infrared spectroscopic glucose sensor, and a standard insulin infusion pump controlled by an adaptive model predictive control (MPC) algorithm were combined to form a closed-loop device, which was evaluated in four T1DM subjects during 30-hour feasibility studies. The aim was to maintain blood glucose concentration in the target range between 80 and 110 mg/dl.

Results

Mean plasma glucose concentration was 110.5 ± 29.7 mg/dl. The MPC managed to establish normoglycemia within 105 ± 78 minutes after trial start and managed to maintain glucose concentration within the target range for 47% of the time. The hyperglycemic index averaged to 11.9 ± 5.3 mg/dl.

Conclusion

Data of the feasibility trial illustrate the device being effective in controlling glycemia in T1DM subjects. However, the monitoring part of the loop must be improved with respect to accuracy and precision before testing the system in the target population.     

The effect of real-time continuous glucose monitoring on glycemic control in patients with type 2 diabetes mellitus

Background:

Real-time continuous glucose monitoring (RT-CGM) improves hemoglobin A1c (A1C) and hypoglycemia in people with type 1 diabetes mellitus and those with type 2 diabetes mellitus (T2DM) on prandial insulin; however, it has not been tested in people with T2DM not taking prandial insulin. We evaluated the utility of RT-CGM in people with T2DM on a variety of treatment modalities except prandial insulin.

Methods:

We conducted a prospective, 52-week, two-arm, randomized trial comparing RT-CGM (n = 50) versus self-monitoring of blood glucose (SMBG) (n = 50) in people with T2DM not taking prandial insulin. Real-time continuous glucose monitoring was used for four 2-week cycles (2 weeks on/1 week off). All patients were managed by their usual provider. This article reports on changes in A1C 0–12 weeks.

Results:

Mean (±standard deviation) decline in A1C at 12 weeks was 1.0% (±1.1%) in the RT-CGM group and 0.5% (±0.8%) in the SMBG group (p = .006). There were no group differences in the net change in number or dosage of hypoglycemic medications. Those who used the RT-CGM for ≥48 days (per protocol) reduced their A1C by 1.2% (±1.1%) versus 0.6% (±1.1%) in those who used it <48 days (p = .003). Multiple regression analyses statistically adjusting for baseline A1C, an indicator for usage, and known confounders confirmed the observed differences between treatment groups were robust (p = .009). There was no improvement in weight or blood pressure.

Conclusions:

Real-time continuous glucose monitoring significantly improves A1C compared with SMBG in patients with T2DM not taking prandial insulin. This technology might benefit a wider population of people with diabetes than previously thought.     

The DURABLE Trial Study Design: Comparing the Safety, Efficacy, and Durability of Insulin Glargine to Insulin Lispro Mix 75/25 Added to Oral Antihyperglycemic Agents in Patients with Type 2 Diabetes

Background

While studies have compared the safety and efficacy of starter insulin regimens in type 2 diabetes, none have evaluated regimen durability (length of time a patient can maintain glycemic control) or the safety and efficacy of subsequent intensification regimens in a large, multinational cohort.

Methods

The DURABLE (Assessing the DURAbility of Basal vs Lispro Mix 75/25 Insulin Efficacy) trial will compare the ability of glargine once daily vs lispro mix 75/25 (75% insulin lispro protamine suspension, 25% lispro) twice daily added to oral antihyperglycemic agents to achieve and maintain hemoglobin A1c (HbA1c) goals. This randomized, open label, parallel study will enroll over 2000 insulin-naïve patients with type 2 diabetes from 11 countries, ages 30 to 80, with HbA1c >7.0% on at least two oral antihyperglycemic agents. At the completion of the 6-month initiation phase, safety and efficacy of the two regimens will be compared. Patients who achieve an HbA1c ≤7.0% at 6 months will continue into the 24-month maintenance phase to evaluate durability.In a substudy, patients not achieving HbA1c ≤7.0% at 6 months may be randomized to one of two intensification comparisons: patients previously on glargine will receive lispro mix 75/25 twice daily or basal/bolus therapy (glargine + thrice-daily mealtime lispro) and patients previously on lispro mix 75/25 will receive lispro mix 50/50 (50% insulin lispro protamine suspension, 50% lispro) thrice daily or basal/bolus therapy.

Results

Upon completion, this trial will provide new information about starter insulin durability, defined as the length of time patients can maintain HbA1c control (HbA1c ≤7.0%, or >7.0% but with an increase of <0.4% from the most recent HbA1c ≤7.0%). Additionally, the study will provide comparative data on HbA1c, blood glucose profiles, 1,5-anhydroglucitol, hypoglycemic episodes, weight change, and insulin dose for starter insulin regimens following 6 and 24 months of treatment, as well as intensified insulin via the 6-month substudy.

Conclusion

This trial aims to broaden clinicians'' understanding of the ability of starter insulin and insulin intensification regimens to achieve and maintain glycemic control in patients with type 2 diabetes.     

Clinical Update on Optimal Prandial Insulin Dosing Using a Refined Run-to-Run Control Algorithm

Background

This article provides a clinical update using a novel run-to-run algorithm to optimize prandial insulin dosing based on sparse glucose measurements from the previous day''s meals. The objective was to use a refined run-to-run algorithm to calculate prandial insulin-to-carbohydrate ratios (I:CHO) for meals of variable carbohydrate content in subjects with type 1 diabetes (T1DM).

Method

The open-labeled, nonrandomized study took place over a 6-week period in a nonprofit research center. Nine subjects with T1DM using continuous subcutaneous insulin infusion participated. Basal insulin rates were optimized using continuous glucose monitoring, with a target fasting blood glucose of 90 mg/dl. Subjects monitored blood glucose concentration at the beginning of the meal and at 60 and 120 minutes after the start of the meal. They were instructed to start meals with blood glucose levels between 70 and 130 mg/dl. Subjects were contacted daily to collect data for the previous 24-hour period and to give them the physicianapproved, algorithm-derived I:CHO ratios for the next 24 hours. Subjects calculated the amount of the insulin bolus for each meal based on the corresponding I:CHO and their estimate of the meal''s carbohydrate content. One- and 2-hour postprandial glucose concentrations served as the main outcome measures.

Results

The mean 1-hour postprandial blood glucose level was 104 ± 19 mg/dl. The 2-hour postprandial levels (96.5 ± 18 mg/dl) approached the preprandial levels (90.1 ± 13 mg/dl).

Conclusions

Run-to-run algorithms are able to improve postprandial blood glucose levels in subjects with T1DM.