Number Of Severe Hypoglycemic Events Research Articles

The Effectiveness of Telemedicine Solutions in Type 1 Diabetes Management: A Systematic Review and Meta-analysis.

Telemedicine holds a potential to strengthen self-management support outside health care settings in the everyday management of type 1 diabetes (T1D). However, existing effectiveness reviews are older or include a relatively narrow focus on specific definitions of telemedicine or included databases. To conduct a systematic review of the effectiveness of telemedicine solutions versus any comparator on diabetes-related outcomes among people with T1D. Studies including adults (≥18 years) with T1D published before October 14, 2020, were eligible. Primary outcome was glycated hemoglobin (HbA1c, %). The Cochrane Library, PubMed, EMBASE, and CINAHL were searched. Meta-analysis based on the mean difference in HbA1c% was used to pool effects. The Cochrane tool was applied to assess risk-of-bias, and the certainty of evidence was graded using the GRADE approach. A total of 22 studies were included (with 1615 participants). Treatment effect for HbA1c% favored telemedicine (mean difference of -0.26% [95% confidence interval:-0.37% to -0.15%]) with moderate effect certainty. Heterogeneity was moderate (I2 = 33.30%). Although not significant, secondary outcomes were all in favor of telemedicine except number of severe hypoglycemic events and diabetes knowledge, but the certainty of the evidence for those outcomes was all low or very low. Reducing average HbA1c% levels are important to combat the risk of diabetic complications and premature death. However, the evidence mostly consist of small studies with a relative short duration and the estimated pooled effect is smaller than could be expected from quality improvement strategies in general for diabetes management. CRD42020123565.

Risk of hypoglycaemia with insulin degludec versus insulin glargine U300 in insulin-treated patients with type 2 diabetes: the randomised, head-to-head CONCLUDE trial

Aims/hypothesisA head-to-head randomised trial was conducted to evaluate hypoglycaemia safety with insulin degludec 200 U/ml (degludec U200) and insulin glargine 300 U/ml (glargine U300) in individuals with type 2 diabetes treated with basal insulin.MethodsThis randomised (1:1), open-label, treat-to-target, multinational trial included individuals with type 2 diabetes, aged ≥18 years with HbA1c ≤80 mmol/mol (9.5%) and BMI ≤45 kg/m2. Participants were previously treated with basal insulin with or without oral glucose-lowering drugs (excluding insulin secretagogues) and had to fulfil at least one predefined criterion for hypoglycaemia risk. Both degludec U200 and glargine U300 were similarly titrated to a fasting blood glucose target of 4.0–5.0 mmol/l. Endpoints were assessed during a 36 week maintenance period and a total treatment period up to 88 weeks. There were three hypoglycaemia endpoints: (1) overall symptomatic hypoglycaemia (either severe, an event requiring third-party assistance, or confirmed by blood glucose [<3.1 mmol/l] with symptoms); (2) nocturnal symptomatic hypoglycaemia (severe or confirmed by blood glucose with symptoms, between 00:01 and 05:59 h); and (3) severe hypoglycaemia. The primary endpoint was the number of overall symptomatic hypoglycaemic events in the maintenance period. Secondary hypoglycaemia endpoints included the number of nocturnal symptomatic events and number of severe hypoglycaemic events during the maintenance period.ResultsOf the 1609 randomised participants, 733 of 805 (91.1%) in the degludec U200 arm and 734 of 804 (91.3%) in the glargine U300 arm completed the trial (87.3% and 87.8% completed on treatment, respectively). Baseline characteristics were comparable between the two treatment arms. For the primary endpoint, the rate of overall symptomatic hypoglycaemia was not significantly lower with degludec U200 vs glargine U300 (rate ratio [RR] 0.88 [95% CI 0.73, 1.06]). As there was no significant difference between treatments for the primary endpoint, the confirmatory testing procedure for superiority was stopped. The pre-specified confirmatory secondary hypoglycaemia endpoints were analysed using pre-specified statistical models but were now considered exploratory. These endpoints showed a lower rate of nocturnal symptomatic hypoglycaemia (RR 0.63 [95% CI 0.48, 0.84]) and severe hypoglycaemia (RR 0.20 [95% CI 0.07, 0.57]) with degludec U200 vs glargine U300.Conclusions/interpretationThere was no significant difference in the rate of overall symptomatic hypoglycaemia with degludec U200 vs glargine U300 in the maintenance period. The rates of nocturnal symptomatic and severe hypoglycaemia were nominally significantly lower with degludec U200 during the maintenance period compared with glargine U300.Trial registrationClinicalTrials.gov NCT03078478FundingThis trial was funded by Novo Nordisk (Bagsvaerd, Denmark)

Fasting insulin levels correlate with the frequency of hypoglycemic events in people with type 2 diabetes on treatment with sulfonylureas: A pilot study.

AIMS AND OBJECTIVES:We aimed to explore whether fasting insulin levels correlate with the risk of hypoglycemia in people with Type 2 diabetes (T2D) receiving sulfonylureas (SUs).MATERIALS AND METHODS:Our study included 58 individuals with T2D who had been on treatment with SUs, but not insulin, for more than 2 years. Confirmed hypoglycemic episodes during the past year were self-reported by the patients, and a potential relationship of hypoglycemic event frequency with fasting insulin levels was investigated.RESULTS:Fasting insulin concentrations were found to have a low positive and statistically significant correlation with the number of cases of mild hypoglycemia per year (ρ = 0.279/P = 0.034) and a moderately positive and statistically significant correlation with the number of severe hypoglycemic events per month (ρ = 0.349/P = 0.007) and per year (ρ = 0.39/P = 0.002).CONCLUSION:Our results suggest that fasting insulin levels might be a predictor of the risk of hypoglycemia in people with T2D on treatment with SUs.

A core outcomes set for clinical trials of interventions for young adults with type 1 diabetes: an international, multi-perspective Delphi consensus study

BackgroundAchieving consensus from a range of relevant stakeholders about an agreed set of core outcomes to be measured and reported as a minimum in clinical trials has the potential to enhance evidence synthesis and make findings more relevant and applicable. Intervention research to improve outcomes for young adults with type 1 diabetes (T1DM) is hampered by inconsistent use of outcome measures. This population frequently struggles to manage their condition and reports suboptimal clinical outcomes. Our aim was to conduct an international, e-Delphi consensus study to identify a core outcome set (COS) that key stakeholders (young adults with T1DM, diabetes health professionals, diabetes researchers and diabetes policy makers) consider as essential outcomes for future intervention research.MethodsUsing a list of 87 outcomes generated from a published systematic review, we administered two online surveys to a sample of international key stakeholders. Participants in the first survey (survey 1; n = 132) and the second survey (survey 2; n = 81) rated the importance of the outcomes. Survey 2 participants received information on total mean rating for each outcome and a reminder of their personal outcome ratings from Survey 1. Survey 2 results were discussed at a consensus meeting and participants (n = 12: three young adults with T1DM, four diabetes health professionals, four diabetes researchers and one diabetes policy maker) voted on outcomes. Final core outcomes were included provided that 70% of consensus group participants voted for their inclusion.ResultsEight core outcomes were agreed for inclusion in the final COS: measures of diabetes-related stress; diabetes-related quality of life; number of severe hypoglycaemic events; self-management behaviour; number of instances of diabetic ketoacidosis (DKA); objectively measured glycated haemoglobin (HbA1C); level of clinic engagement; and perceived level of control over diabetes.ConclusionsThis study is the first to identify a COS for inclusion in future intervention trials to improve outcomes for young adults with T1DM. Use of this COS will improve the quality of future research and increase opportunities for evidence synthesis. Future research is necessary to identify the most robust outcome measure instruments.

The relation between HbA1c and hypoglycemia revisited; a secondary analysis from an intervention trial in patients with type 1 diabetes and impaired awareness of hypoglycemia

AimsWe aimed to re-assess the previously shown but recently disputed association between HbA1c and severe hypoglycemia. Methods52 Patients with T1D and IAH participated in an earlier reported randomized, crossover trial with two 16-week intervention periods comparing continuous glucose monitoring (CGM) with self-monitoring of blood glucose (SMBG). In this previous study, time spent in normoglycemia (the primary outcome), was improved by 9.6% (p<0.0001). We performed post-hoc analyses using a zero-inflated Poisson regression model to assess the relationship between severe hypoglycemia and HbA1c, glucose variability and duration of diabetes. ResultsDuring SMBG use, HbA1c and the number of severe hypoglycemic events were negatively associated (OR 0.20 [95% CI 0.09 to 0.44]). During CGM use, this relationship showed an odds ratio of 0.65 (95% CI 0.42 to 1.01). There was no significant relationship between glucose variability or duration of diabetes and severe hypoglycemia. ConclusionsIn patients with T1D and IAH, treated with standard SMBG, a negative association exists between HbA1c and the number of severe hypoglycemic events. Thus, reaching target HbA1c values still comes with a higher risk of severe hypoglycemia. CGM weakens this association, suggesting CGM enables patients to reach their target HbA1c more safely.

Continuous glucose monitoring for patients with type 1 diabetes and impaired awareness of hypoglycaemia (IN CONTROL): a randomised, open-label, crossover trial

Patients with type 1 diabetes who have impaired awareness of hypoglycaemia have a three to six times increased risk of severe hypoglycaemia. We aimed to assess whether continuous glucose monitoring (CGM) improves glycaemia and prevents severe hypoglycaemia compared with self-monitoring of blood glucose (SMBG) in this high-risk population. We did a randomised, open-label, crossover trial (IN CONTROL) at two medical centres in the Netherlands. Eligible participants were patients diagnosed with type 1 diabetes according to American Diabetes Association criteria, aged 18-75 years, with impaired awareness of hypoglycaemia as confirmed by a Gold score of at least 4, and treated with either continuous subcutaneous insulin infusion or multiple daily insulin injections and doing at least three SMBG measurements per day. After screening, re-education about diabetes management, and a 6-week run-in phase (to obtain baseline CGM data), we randomly assigned patients (1:1) with a computer-generated allocation sequence (block size of four) to either 16 weeks of CGM followed by 12 weeks of washout and 16 weeks of SMBG, or 16 weeks of SMBG followed by 12 weeks of washout and 16 weeks of CGM (where the SMBG phase was the control). During the CGM phase, patients used a real-time CGM system consisting of a Paradigm Veo system with a MiniLink transmitter and an Enlite glucose sensor (Medtronic, CA, USA). During the SMBG phase, patients were equipped with a masked CGM device, consisting of an iPro 2 continuous glucose monitor and an Enlite glucose sensor, which does not display real-time glucose values. The number of SMBG measurements per day and SMBG systems were not standardised between patients, to mimic real-life conditions. During both intervention periods, patients attended follow-up visits at the centres each month and had telephone consultations 2 weeks after each visit inquiring about adverse events, episodes of hypoglycaemia, etc. The primary endpoint was the mean difference in percentage of time spent in normoglycaemia (4-10 mmol/L) over the total intervention periods, analysed on an intention-to-treat basis. Severe hypoglycaemia (requiring third party assistance) was a secondary endpoint. This trial is registered with ClinicalTrials.gov, number NCT01787903. Between March 4, 2013, and Feb 9, 2015, we recruited and randomly assigned 52 patients to either the CGM-SMBG sequence (n=26) or the SMBG-CGM sequence (n=26). The last patient visit was on March 21, 2016. Time spent in normoglycaemia was higher during CGM than during SMBG: 65·0% (95% CI 62·8-67·3) versus 55·4% (53·1-57·7; mean difference 9·6%, 95% CI 8·0-11·2; p<0·0001), with reductions in both time spent in hypoglycaemia (ie, blood glucose ≤3·9 mmol/L [6·8% vs 11·4%, mean difference 4·7%, 3·4-5·9; p<0·0001]) and time spent in hyperglycaemia (ie, blood glucose >10 mmol/L [28·2% vs 33·2%, mean difference 5·0%, 3·1-6·9; p<0·0001]). During CGM, the number of severe hypoglycaemic events was lower (14 events vs 34 events, p=0·033). Five serious adverse events other than severe hypoglycaemia occurred during the trial, but all were deemed unrelated to the trial intervention. Additionally, no mild to moderate adverse events were related to the trial intervention. CGM increased time spent in normoglycaemia and reduced severe hypoglycaemia in patients with type 1 diabetes and impaired awareness of hypoglycaemia, compared with SMBG. Our results support the concept of using CGM in this high-risk population. Eli Lilly and Sanofi.

Effect of insulin analogues on frequency of non-severe hypoglycaemia in patients with type 1 diabetes prone to severe hypoglycaemia: The HypoAna trial

AimInsulin analogues reduce the risk of hypoglycaemia compared with human insulin in patients with type 1 diabetes (T1D) and minor hypoglycaemia problems. The HypoAna trial showed that, in patients with recurrent severe hypoglycaemia, treatment based on insulin analogues reduces the risk of severe hypoglycaemia. The present study aims to assess whether this also applies to non-severe hypoglycaemia events during the day and at night. MethodsThis 2-year investigator-initiated multicentre, prospective, randomized, open, blinded endpoint (PROBE) trial involved patients with T1D and at least two episodes of severe hypoglycaemia during the previous year. Using a balanced crossover design, patients were randomized to basal–bolus therapy based on analogue (detemir/aspart) or human (NPH/regular) insulins. A total of 114 participants were included. Endpoints were the number of severe hypoglycaemic events and non-severe events, including documented symptomatic and asymptomatic episodes occurring during the day and at night (ClinicalTrials.gov number: NCT00346996). ResultsAnalogue-based treatment resulted in a 6% (2–10%; P=0.0025) overall relative risk reduction of non-severe hypoglycaemia. This was due to a 39% (32–46%; P<0.0001) reduction of non-severe nocturnal hypoglycaemia, seen for both symptomatic (48% [36–57%]; P<0.0001) and asymptomatic (28% [14–39%]; P=0.0004) nocturnal hypoglycaemia episodes. No clinically significant differences in hypoglycaemia occurrence were observed between the insulin regimens during the day. The time needed to treat one patient with insulin analogues to avoid one episode (TNT1) of non-severe nocturnal hypoglycaemia was approximately 3 months. ConclusionIn T1D patients prone to severe hypoglycaemia, treatment with analogue insulin reduced the risk of non-severe nocturnal hypoglycaemia compared with human insulin.

Sensor‐augmented pump therapy: review of new NICE diagnostic guidance

Sensor‐augmented pump therapy: review of new <scp>NICE</scp> diagnostic guidance

PHARMACEUTICAL CARE OF ADOLESCENTS WITH DIABETES MELLITUS TYPE 1: THE DIADEMA STUDY, A RANDOMIZED CONTROLLED TRIAL

BackgroundAdolescents with type 1 diabetes mellitus (T1DM) often show low adherence to complex insulin regimens, leading to poor glycemic control. The benefit of pharmaceutical care in adults with diabetes mellitus type 2 (T2DM) has been widely explored; however, evidence in adolescents with T1DM remains scarce.ObjectiveTo evaluate the impact of pharmaceutical care in adolescents with T1DM provided by a multidisciplinary team on multiple important clinical outcomes.SettingAt the outpatient Helios Paediatric Clinic and at the 12 regular community pharmacies of the study patients with 14 pharmacists in the Krefeld area, Germany, and at the University Pediatric Clinic with one pharmacist on-site in Sarajevo, Bosnia-Herzegovina.MethodsA randomized, controlled, prospective, multicenter study in 68 adolescents with T1DM. The intervention group received monthly structured pharmaceutical care delivered by pharmacists plus supplementary phone calls for 6 months. The control group received usual diabetic care. Data were collected at baseline and after 3 and 6 months. In addition, HbA1c was measured after 12 months.Main outcome measures The between-group difference in the change from baseline in glycosylated hemoglobin (HbA1c), the number of severe hypoglycemic events in both groups, and patient well-being in the intervention group.ResultsThe improvement from baseline in HbA1c was significantly greater in the intervention group than in the control group after 6 months (change from baseline −0.54 vs. +0.32%, p=0.0075), even after adjustment for country-specific variables (p=0.0078). However, the effect was more pronounced after only 3 months (−1.09 vs. +0.23%, p=0.00002). There was no significant between-group difference in the number of severe hypoglycemia events. After 6 months, the well-being according to the WHO-5 index in the intervention group increased significantly from 52.8% to 63.3%. After 12 months the mean total HbA1c remained significantly reduced in the intervention compared to the control group (8.6% vs. 9.5%, p=0.0184).ConclusionThe improved outcomes seen in this study provide new evidence that pharmaceutical care adds value to the management of T1DM in adolescents. However, the optimal methods of achieving sustained long-term improvements in this specific patient population require further study.

Pharmaceutical care of adolescents with diabetes mellitus type 1: the DIADEMA study, a randomized controlled trial.

Physiological and psychological changes during puberty and a low adherence to complex treatment regimens often result in poor glycemic control in adolescents with type 1 diabetes mellitus (T1DM). The benefit of pharmaceutical care in adults with diabetes mellitus type 2 has been explored; however, evidence in adolescents with T1DM is scarce. To evaluate the impact of pharmaceutical care in adolescents with T1DM provided by pharmacists, in collaboration with physicians and diabetes educators on important clinical outcomes (e.g., HbA1c and severe hypoglycemia) At the outpatient Helios Paediatric Clinic and at the 12 regular community pharmacies of the study patients with 14 pharmacists in the Krefeld area, Germany, and at the University Pediatric Clinic with one clinical pharmacist on-site in Sarajevo, Bosnia-Herzegovina. A randomized, controlled, prospective, multicenter study in 68 adolescents with T1DM. The intervention group received monthly structured pharmaceutical care visits delivered by pharmacists plus supplementary visits and phone calls on an as needed basis, for 6 months. The control group received usual diabetic care. Data were collected at baseline and after 3 and 6 months. The between-group difference in the change from baseline in glycosylated hemoglobin (HbA1c) and the number of severe hypoglycemic events in both groups. The improvement from baseline in HbA1c was significantly greater in the intervention group than in the control group after 6 months (change from baseline -0.54 vs. +0.32%, p = 0.0075), even after adjustment for country-specific variables (p = 0.0078). However, the effect was more pronounced after only 3 months (-1.09 vs. +0.23%, p = 0.00002). There was no significant between-group difference in the number of severe hypoglycemia events. (p = 0.1276). This study suggests that multidisciplinary PhC may add value in the management of T1DM in adolescents with inadequate glycemic control. However, the optimal methods on how to achieve sustained, long-term improvements in this challenging population require further study.

Does treatment with an insulin pump improve glycaemic control in children and adolescents with type 1 diabetes? A retrospective case-control study

To investigate long-term effects on glycaemic control, ketoacidosis, serious hypoglycaemic events, insulin requirements, and body mass index standard deviation scores (BMI-SDS) in children and adolescents with type 1 diabetes starting on continuous subcutaneous insulin infusion (CSII) compared with children and adolescents treated with multiple daily injections (MDI). This retrospective case-control study compares 216 patients starting CSII with a control group on MDI (n = 215), matched for glycated hemoglobin (HbA1c), sex, and age during a 2-yr period. Variables collected were gender, age, HbA1c, insulin requirement, BMI, BMI-SDS, ketoacidosis, and serious hypoglycaemic events. In the CSII group there was an improvement in HbA1c after 6 and 12 months compared with the MDI group. For boys and girls separately the same effect was detected after 6 months, but only for boys after 12 months. The incidence of ketoacidosis was higher in the CSII group compared with the MDI group (2.8 vs. 0.5/100 person-yr). The incidences of severe hypoglycaemic episodes per 100 person-yr were three in the CSII group and six in the MDI group (p < 0.05). After 6, 12, and 24 months, the insulin requirement was higher in the MDI group. This study shows that treatment with CSII resulted in an improvement in HbA1c levels up to 1 yr and decreased the number of severe hypoglycaemic events, but the frequency of ketoacidosis increased. The major challenge is to identify methods to maintain the HbA1c improvement, especially among older children and teenagers, and reduce the frequency of ketoacidosis.

DB2 Economic Consequences of Severe Hypoglycaemia – Preliminary Findings from Five Central European Countries

Severe hypoglycaemic events (SHEs) are most commonly defined as symptomatic, severe hypoglycaemia in which a patient needs either assistance from another individual or professional medical care. SHEs impose a substantial economic burden on health care systems. The aim of our analysis is to assess the total number and corresponding costs (both direct and indirect) of SHEs in either type 1 or 2 diabetes in five Central European countries in a unified approach in order to compare results and main drivers of differences. SHEs were further divided into low (only help provided on-site by a non-medical professional), medium (emergency care or consultation by a physician or other medical professional) and high (admission to hospital) resource consumption episodes. Data on unit costs and resource use for low, medium and high resource consumption SHEs were collected for each country based on published literature and expert opinions. The risks of SHEs were determined separately for individual groups of anti-diabetic drugs used in monotherapy or in a combined treatment. Subsequently the economic model was developed to combine epidemiological data and drug use patterns for Czech Republic, Croatia, Hungary, Poland and Slovenia, to estimate the number of SHEs and resulting indirect and direct costs from payer's perspective in each of the participating countries. Low resource consumption SHEs were rarely associated with resources used that were covered by public payers. Medium resource consumption SHEs contributed most to total direct costs. Hospital admissions directly associated with SHEs although not common, present a considerable expense to the health care system. The total number and corresponding costs of SHEs were different for participating countries as a consequence of diverse unit medical costs and sulphonylureas use. Our preliminary estimates for Central European countries suggested substantial economic burden associated with SHE and large differences between the countries.

A Retrospective Cohort Study of a Nurse-Driven Computerized Insulin Infusion Program Versus a Paper-Based Protocol in Critically Ill Patients

There is variability in the extent of outcome achievement between computerized insulin infusion programs (CIIPs) and paper-based protocols (PBPs). This reported variability may be improved by intensive CIIP training prior to implementation. The objective was to evaluate the impact of a CIIP following intensive nurse training versus a PBP in a critical care setting. A retrospective cohort study was performed on patients admitted to a mixed intensive care unit comparing glucose control between the CIIP following intensive training and a PBP. Consecutive patients on each protocol were assessed to obtain glucose concentrations and outcomes. The primary measure was the percentage of blood glucose values within target range (90-130 mg/dL). Patient glucose values were pooled and assessed using the χ(2) test for independence. In total, 61 patients with 5,495 glucose tests were included in the PBP group, and 51 patients with 5,645 glucose tests in the CIIP group. A greater percentage of glucose tests was within target range in the CIIP group (68.4% vs. 36.5%, P<0.001). In the CIIP group, time-to-target (median [interquartile range] 5 [3-8] h vs. 7 [4-20] h, P=0.02) and severe hypoglycemic events were reduced (26 vs. 6, P<0.0001). The nurse-driven CIIP led to a higher percentage of glucose values within target range, faster achievement of target glucose values, and a reduction in the number of severe hypoglycemic events. This improved outcome achievement compared with previous reports may be associated with intensive user training.

Use of Continuous Glucose Monitoring System in the Management of Severe Hypoglycemia

Severe hypoglycemia can have a dramatic impact on daily life for people with diabetes. Hypoglycemia is quantifiable by the HYPO-Score derived from the frequency of severe hypoglycemia over a year and a component based on 4 weeks of glucose records. The latter gives a modified HYPO-Score as a short-term measure of hypoglycemia. We used a continuous glucose monitoring system (CGMS) in patients with severe hypoglycemia to assess if we could decrease hypoglycemia as measured by the modified HYPO-Score. Sixteen type 1 diabetes subjects, 52.0 +/- 2.3 years old with a diabetes duration of 29.4 +/- 2.8 years having problematic hypoglycemia were enrolled. All used multiple daily insulin injections, and the glycosylated hemoglobin level was 8.4 +/- 0.3%. After a month of gathering hypoglycemia information for baseline modified HYPO-Score, subjects wore the CGMS for 2 months, and a modified HYPO-Score was repeated. To assess long-term benefit, CGMS was then discontinued for 3 months, and a final modified HYPO-Score was determined. The modified HYPO-Score decreased from 857 +/- 184 to 444 +/- 92 (P = 0.055) (intention-to-treat basis). Further analysis of the modified HYPO-Score when the CGMS was actually functioning showed it decreased from 857 +/- 184 to 366 +/- 86 (P = 0.023). Severe hypoglycemia episodes dropped from 16 at baseline to three when wearing the CGMS. The number of hypoglycemia episodes <3.0 mmol/L dropped from 8.6 +/- 1.5 to 4.7 +/- 0.9 (P = 0.01). Subjects expressed less fear of hypoglycemia with CGMS. In 11 who completed modified Final Month HYPO-Scores, the number of severe hypoglycemic events rose to six. At study end, 13 of 16 subjects elected to continue using the CGMS. When the CGMS was worn and functioning there was a significant decrease in the modified HYPO-Score and number of hypoglycemic values <3.0 mmol/L.

Should You Settle for a Surrogate?

Aman, et al, looked at various outcomes of diabetes, including diabetes-specific quality of life issues, psychological well-being, and health perception, along with measurements of diabetes control such as number of severe hypoglycemic events and diabetic ketoacidosis as well as hemoglobin A1c (HbA1c) measurements.All of these outcomes, with the exception of HbA1c, are outcomes that patients can appreciate directly; that is, they are patient-relevant. HbA1c concentration, in contrast, is not an element that patients feel.However, much evidence suggests it is tied to eventual patient-relevant outcomes, such as vision loss and kidney disease. HbA1c is a surrogate outcome, a substitute (usually physiologic, laboratory, or imaging) measurement that can infer long-term, patient-relevant outcomes. The utility of a surrogate outcome depends on how closely tied it is to patient-relevant outcomes.As Dr. Varma points out in his commentary, a single measurement of HbA1c may not reflect the degree of long-term diabetes control. That is an inherent weakness of any cross-sectional study: it provides a snapshot of a single point in time.In the Aman study, physical activity was positively associated with beneficial patient-relevant outcomes, but there was no association found with HbA1c or frequency of hypoglycemia or ketoacidosis.Why use surrogate markers at all? First, many disease outcomes take years to unfold. Think of waiting 30 years to accumulate the outcome evidence required to license a new drug for a chronic disease. This would be untenable, and surrogate outcomes often provide a more rapid outcome assessment.The degree to which the surrogate outcomes predict the patient-relevant outcomes is essential in interpreting study results. Second, surrogate markers can provide some insight into individual patient progress on therapy.One of the most difficult elements of evidence-based practice is translating results of studies of groups of patients to the individual patient. Surrogate markers often lend support that the patient is responding in a manner similar to those enrolled in clinical trials.Type 1 diabetes mellitus is a complex disorder with interplay of many psychologic and physiologic variables, particularly in adolescents. HbA1c is one surrogate marker that can be monitored, but like most surrogate markers, it doesn’t tell the whole story.

Youth insulin treatment and severe hypoglycemia risk. Medico-legal implications

Tight control of insulin treatment' results, in terms of hypo- or hyper-glycemia, is difficult to maintain in small children, because hypoglycemia may impair normal brain development which is not complete. Because pre-adolescents appear to be relatively protected from micro-vascular complications, the need for tight control might be less than in post-pubertal subjects. The danger of hypoglycemia is greater in infants and children because food intake, activity and adherance to treatment schedules are less predictable than in adults. Initially, we noticed an association between: increased number of injection, tight control and the occurence of hypoglycemia. We assess the effects of intensive, flexible insulin treatment with insulin analogues, after 3 months and 12 months, by measuring different parameters, including HbA1c and the number of severe hypoglycemic events (80 patients were enrolled.). After one year of intensive treatment with anlaogues of insuline, the number of severe hypoglycemic events decreased, combined with an intensified education. Because hypoglycemia is commonly seen in situations of medication error, homicide attempt and suicide attempt, sudden death, trafic accidents, strange behavior or aggressive status, memories black-outs etc., all incidents with great significance for forensic medicine, demonstration of it becomes a relevant objective. Physicians of children with diabetes should be aware of these consequences and a clinical judgment will be required in treatment options

Does family cohesiveness and parental alexithymia predict glycaemic control in children and adolescents with diabetes?

Aim Several studies indicate that family functioning and parental expressiveness can influence children's glycaemic control. However, previous studies have had contradictory findings. Furthermore, no previous work has simultaneously explored the mother's and father's perception of family cohesiveness together with maternal and paternal alexithymia in relation to a child's diabetic control. In this study, we examined whether the parental perception of family cohesion and the parents’ degree of alexithymia could predict their child's or adolescent's glycaemic control (severe hypoglycaemia, hospitalizations for hyperglycaemia and HbA 1c) after adjusting for demographic variables. Methods The study included 45 Belgian families with at least one type 1 diabetic child aged six to 18 years (25 girls and 20 boys). Parents completed demographic questionnaires about themselves and their children. Information on type 1 diabetes in their child and the family-medical history were also collected. The number of severe-hypoglycaemic events and hospitalizations for hyperglycaemia were documented for the last 12 months, as were HbA 1c levels over the last 16 months. Finally, family cohesiveness (FACES-III) and parental alexithymia (TAS-20) were assessed. Results Hierarchical regression analyses showed that the perception of family cohesion by mothers ( P < 0.05) was a predictor of the number of severe hypoglycaemic events in the last 12 months. Parents’ demographic variables (marital and professional status, P < 0.001) and maternal alexithymia ( P < 0.05) were found to be predictors of the number of hospitalizations for hyperglycaemia in the last 12 months. As for HbA 1c, only two parental demographic variables were significant predictors (marital and professional status, P < 0.01 and P < 0.05, respectively). Conclusion The maternal perception of family cohesiveness and maternal alexithymia predict on glycaemic control in children and adolescents with diabetes.

Integrity of cerebral white matter in type 1 diabetes. Reply to Wessels AM [letter

To the Editor: We appreciate the valuable comments of Dr Wessels [1] on our recent article in Diabetologia [2]. We specifically sought to study the impact of white matter hyperintensities (WMHs) on brain structure in relatively young patients (age 32±4 years) with diabetes of long duration (20±4 years) (mean ± SD). As Wessels noted, our large sample of patients did not differ from non-diabetic controls in terms of severity of white matter lesions. Indeed, our results are similar to those of Brands et al. [3], who studied cognition and WMHs in older type 1 diabetic adults with disease of longer duration associated with more complications. Taken together, these studies suggest that the incidence of WMHs in type 1 diabetes is not likely to be high. Using voxel-based morphometry, we have also found that, compared with non-diabetic controls, patients with type 1 diabetes had lower grey matter density and this was associated with both higher HbA1c levels and an increased number of severe hypoglycaemic events [4]. This finding suggests that more sensitive measures of brain structure would reveal changes induced by type 1 diabetes. Wessels notes that type 1 diabetes leads to changes in cognition, which may be mediated by hyperglycaemia, hypoglycaemia and/or vascular disease. The literature on these points is far from conclusive. We observed only small differences in cognition when comparing type 1 diabetic patients to non-diabetic controls [2]. Our results are consistent with a meta-analysis that found modest effects of type 1 diabetes on cognition, characterised by slowing of mental processing and diminished mental flexibility [5]. Furthermore, our cognitive data were consistent with recent results from an 18 year longitudinal study of type 1 diabetic patients enrolled in the Diabetes Control and Complications Trial [6], which found only minimal changes in psychomotor efficiency and motor speed over time among those with the highest HbA1c levels. Wessels’ suggestion that we examine our WMH findings in relation to total white matter volume measurements in patients with and without retinopathy is of interest and would be a useful complementary design. Our goal is to utilise multiple methods of assessing the grey and white matter compartments of the brain, to develop a more precise understanding of the ‘signature’ of type 1 diabetes. Diabetologia (2008) 51:1556–1557 DOI 10.1007/s00125-008-1056-2

Treatment of Danish adolescent diabetic patients with CSII - a matched study to MDI

To compare two intensified insulin therapy regimens - continuous subcutaneous insulin infusion (CSII) against multiple daily insulin injection (MDI) - in Danish adolescents examined in a prospective, matched controlled study design. Thirty type 1 diabetic adolescents at CSII and 26 matched MDI controls were included in this open intention-to-treat study. Actrapid was used in both groups. Before study entry, all participants followed a brush-up course in order to minimize study effect. At each visit, the following parameters were recorded: hemoglobin A1c (HbA1c), insulin dose, weight, number of hypoglycemic and diabetic ketoacidosis (DKA) events, and the time resources used. At entry and exit of the study, diet registration and validated quality-of-life (QoL) questionnaires were filled by the participants. A non-significant decline in HbA1c was seen in both groups (p = 0.468); HbA1c decreased from 9.5 to 8.9% and from 9.7 to 9.5% in the CSII and MDI group, respectively. The insulin dose and the number of severe hypoglycemic events per patient were lower (non-significant) in the CSII group. Both groups showed increased body mass index - highest in the CSII group - and mild to moderate DKA episodes were only seen among CSII users. No differences could be demonstrated within the QoL or diet registrations. CSII treatment is beneficial as an intensified insulin therapy for selected type 1 diabetic patients and both MDI and CSII can be offered by the professional diabetes team to better tailor therapy. In future, there is a strong need to identify the characteristics of responders to CSII treatment in order to increase the efficacy and safety of CSII treatment.

The Impact of the Diabetes Control and Complications Trial and Humalog Insulin on Glycohemoglobin Levels and Severe Hypoglycemia in Type 1 Diabetes

This study was performed to determine the effects of the Diabetes Control and Complications Trial (DCCT) report in 1993 and the introduction of Lispro (Humalog) insulin in 1996 on glycemic control and on the number of severe hypoglycemic episodes in type 1 diabetic patients of various ages. Diabetes care parameters and HbA1c data from 884 subjects with type 1 diabetes were entered into our database at the time of clinic visits from 1993 through 1998. In addition, a questionnaire was sent to all patients to validate the number of insulin injections per day, the incidence of severe hypoglycemic episodes (as defined by the DCCT), and the use of Humalog insulin. Data were divided into four age-groups: < 5, 5-12, 13-18, and > 18 years of age. Longitudinal HbA1c levels declined significantly after the DCCT report in 1993-1996 (P < 0.001), but the number of severe hypoglycemic events increased (P < 0.001). A second decline in HbA1c levels was observed after the introduction of Humalog insulin in 1996 (P < 0.001). However, severe hypoglycemic episodes did not change (P = 0.26). Administration of Humalog resulted in an additional reduction in HbA1c levels beyond the reduction in HbA1c values after the DCCT report. In contrast to the increase in severe hypoglycemic events after the DCCT results, the number of severe hypoglycemic episodes did not increase after the introduction of Humalog, despite a further decrease in HbA1c values.