Restoration of Self-Awareness of Hypoglycemia in Adults With Long-Standing Type 1 Diabetes Hypoglycemia anticipation, awareness and treatment training (HAATT) reduces occurrence of severe hypoglycemia among adults with type 1 diabetes mellitus A Psychoeducational Program to Restore Hypoglycemia Awareness: The DAFNE-HART Pilot Study Impaired hypoglycaemia awareness and employment in people with Type 1 diabetes. Recovery of Hypoglycemia Awareness in Long-standing Type 1 Diabetes: A Multicenter 2 × 2 Factorial Randomized Controlled Trial Comparing Insulin Pump With Multiple Daily Injections and Continuous With Conventional Glucose Self-monitoring (HypoCOMPaSS) Evaluation of a self-awareness intervention for adults with type 1 diabetes and hypoglycemia unawareness. Frequency of Severe Hypoglycemia in Patients With Type I Diabetes With Impaired Awareness of Hypoglycemia Severe sulfonylurea-induced hypoglycemia: a problem of uncritical prescription and deficiencies of diabetes care in geriatric patients Effectiveness of educational interventions to promote oral hypoglycaemic adherence in adults with Type 2 diabetes: a systematic review Intensified insulin therapy and the risk of severe hypoglycaemia Effects of intensive diabetes therapy on neuropsychological function in adults in the Diabetes Control and Complications Trial. Phase 3 Trial of Transplantation of Human Islets in Type 1 Diabetes Complicated by Severe Hypoglycemia Effect of Automated Bio-Behavioral Feedback on the Control of Type 1 Diabetes A randomized pilot study in Type 1 diabetes complicated by severe hypoglycaemia, comparing rigorous hypoglycaemia avoidance with insulin analogue therapy, CSII or education alone. Pharmaceutical care of adolescents with diabetes mellitus type 1: the DIADEMA study, a randomized controlled trial Reducing acute adverse outcomes in youths with type 1 diabetes: a randomized, controlled trial. Evaluation of a treatment and teaching refresher programme for the optimization of intensified insulin therapy in type 1 diabetes.
OBJECTIVE Impaired awareness of hypoglycemia ( IAH ) and defective counterregulation significantly increase severe hypoglycemia risk in type 1 diabetes ( T1D ) . We evaluated restoration of IAH/defective counterregulation by a treatment strategy targeted at hypoglycemia avoidance in adults with T1D with IAH ( Gold score ≥4 ) participating in the U.K.-based multicenter HypoCOMPaSS r and omized controlled trial . RESEARCH DESIGN AND METHODS Eighteen subjects with T1D and IAH ( mean ± SD age 50 ± 9 years , T1D duration 35 ± 10 years , HbA1c 8.1 ± 1.0 % [ 65 ± 10.9 mmol/mol ] ) underwent stepped hyperinsulinemic-hypoglycemic clamp studies before and after a 6-month intervention . The intervention comprised the HypoCOMPaSS education tool in all and r and omized allocation , in a 2 × 2 factorial study design , to multiple daily insulin analog injections or continuous subcutaneous insulin infusion therapy and conventional glucose monitoring or real-time continuous glucose monitoring  . Symptoms , cognitive function , and counterregulatory hormones were measured at each glucose plateau ( 5.0 , 3.8 , 3.4 , 2.8 , and 2.4 mmol/L ) , with each step lasting 40 min with subjects kept blinded to their actual glucose value throughout clamp studies . RESULTS After intervention , glucose concentrations at which subjects first felt hypoglycemic increased ( mean ± SE from 2.6 ± 0.1 to 3.1 ± 0.2 mmol/L , P = 0.02 ) , and symptom and plasma metanephrine responses to hypoglycemia were higher ( median area under curve for symptoms , 580 [ interquartile range { IQR } 420–780 ] vs. 710 [ 460–1,260 ] , P = 0.02 ; metanephrine , 2,412 [ −3,026 to 7,279 ] vs. 5,180 [ −771 to 11,513 ] , P = 0.01 ) . Glycemic threshold for deterioration of cognitive function measured by four-choice reaction time was unchanged , while the color-word Stroop test showed a degree of adaptation . CONCLUSIONS Even in long-st and ing T1D , IAH and defective counterregulation may be improved by a clinical strategy aim ed at hypoglycemia avoidance Severe hypoglycemia ( SH ) can be a significant problem for patients around the world with Type 1 Diabetes Mellitus ( T1DM ) . To avoid SH , patients need to better manage , and reduce the occurrence of , preceding mild hypoglycemia . Hypoglycemia Anticipation , Awareness and Treatment Training ( HAATT ) , developed in the United States specifically to address such issues , was evaluated at short- and long-term follow-up in a medically , economically and culturally different setting ; Bulgaria . Sixty adults with T1DM and a history of recurrent SH ( 20 each from Sofia , Russe , and Varna , Bulgaria ) were r and omized to Self-Monitoring of Blood Glucose ( SMBG ) or SMBG+ HAATT . For 6 months before and 1 to 6 and 13 to 18 months after intervention , participants recorded occurrence of moderate , severe , and nocturnal hypoglycemia . For 1-month pre- and post-intervention , participants completed daily diaries concerning their diabetes management . Relative to SMBG , HAATT produced significant improvement in occurrence of low BG , moderate , severe , and nocturnal hypoglycemia , and detection and treatment of low BG ( p values < .05 to < .001 ) , with no compromise in metabolic control . At long-term follow-up , HAATT participants continued to have significantly fewer episodes of moderate and severe hypoglycemia . These findings suggest that a structured , specialized psycho-educational treatment program ( HAATT ) can be highly effective in managing hypoglycemia OBJECTIVE To develop and pilot a novel intervention addressing motivational and cognitive barriers to avoiding hypoglycemia in people with type 1 diabetes and persistent impaired awareness of hypoglycemia ( IAH ) despite training in flexible insulin therapy . RESEARCH DESIGN AND METHODS A 6-week intervention using motivational interviewing and cognitive behavioral techniques was design ed . Diabetes educators were trained and supported in its delivery to 23 people with IAH ( Gold score ≥4 ) . RESULTS Twelve months postcourse , hypoglycemia awareness had improved ( P < 0.001 ) . Median ( range ) rates of severe hypoglycemia ( SH ) fell from 3 ( 0–104 ) to 0 ( 0–3 ) per person per year ( P < 0.0001 ) and moderate from 14 ( 0–100 ) to 0 ( 0–18 ) per person per 6 weeks ( P < 0.001 ) . Worry and behavior around hyperglycemia improved . HbA1c was unchanged . CONCLUSIONS A pilot intervention targeting motivation and cognitions around hypoglycemia engaged patients with resistant IAH and recurrent SH and was associated with significant improvement , supporting the hypothesis that these factors underpin problematic hypoglycemia BACKGROUND Impaired awareness of hypoglycaemia ( IAH ) is common in adults with Type 1 diabetes mellitus ( T1DM ) and is a major risk factor for severe hypoglycaemia . Little is known about its effect on employment status . AIMS To examine the effect that IAH has on the employment status or employability of people with T1DM . METHODS A r and omly selected cohort of adults of employment age with T1DM completed a question naire detailing the history of their diabetes , their occupational history ( including job and industry type ) and assessing both their hypoglycaemia awareness status and whether in their view their ability to obtain or retain employment had been adversely affected by having diabetes . RESULTS A total of 252 patients participated , with the following characteristics : 135 males , mean HbA1c 8.5 % [ st and ard deviation ( SD ) 1.4 ] , mean age 43.3 years ( SD 13.2 ) , mean duration of diabetes 21.3 years ( SD 12.8 ) and prevalence of IAH 23.4 % . The employment rate was comparable between those with preserved awareness ( 73 % ) and the IAH group ( 66 % ) ( not significant ) . People with IAH were older ( P < 0.05 ) and also more commonly felt that having diabetes affected their ability to work ( P < 0.05 ) . CONCLUSIONS This study is the first to demonstrate that those with T1DM and IAH remain as economically active as those with normal awareness of hypoglycaemia , although subjects with IAH were significantly more likely to feel that having diabetes had adversely affected their capacity for employment OBJECTIVE To determine whether impaired awareness of hypoglycemia ( IAH ) can be improved and severe hypoglycemia ( SH ) prevented in type 1 diabetes , we compared an insulin pump ( continuous subcutaneous insulin infusion [ CSII ] ) with multiple daily injections ( MDIs ) and adjuvant real-time continuous glucose monitoring ( RT ) with conventional self-monitoring of blood glucose ( SMBG ) . RESEARCH DESIGN AND METHODS A 24-week 2 × 2 factorial r and omized controlled trial in adults with type 1 diabetes and IAH was conducted . All received comparable education , support , and congruent therapeutic targets aim ed at rigorous avoidance of biochemical hypoglycemia without relaxing overall control . Primary end point was between-intervention difference in 24-week hypoglycemia awareness ( Gold score ) . RESULTS A total of 96 participants ( mean diabetes duration 29 years ) were r and omized . Overall , biochemical hypoglycemia ( ≤3.0 mmol/L ) decreased ( 53 ± 63 to 24 ± 56 min/24 h ; P = 0.004 [ t test ] ) without deterioration in HbA1c . Hypoglycemia awareness improved ( 5.1 ± 1.1 to 4.1 ± 1.6 ; P = 0.0001 [ t test ] ) with decreased SH ( 8.9 ± 13.4 to 0.8 ± 1.8 episodes/patient-year ; P = 0.0001 [ t test ] ) . At 24 weeks , there was no significant difference in awareness comparing CSII with MDI ( 4.1 ± 1.6 vs. 4.2 ± 1.7 ; difference 0.1 ; 95 % CI −0.6 to 0.8 ) and RT with SMBG ( 4.3 ± 1.6 vs. 4.0 ± 1.7 ; difference −0.3 ; 95 % CI −1.0 to 0.4 ) . Between-group analyses demonstrated comparable reductions in SH , fear of hypoglycemia , and insulin doses with equivalent HbA1c . Treatment satisfaction was higher with CSII than MDI ( 32 ± 3 vs. 29 ± 6 ; P = 0.0003 [ t test ] ) , but comparable with SMBG and RT ( 30 ± 5 vs. 30 ± 5 ; P = 0.79 [ t test ] ) . CONCLUSIONS Hypoglycemia awareness can be improved and recurrent SH prevented in long-st and ing type 1 diabetes without relaxing HbA1c . Similar biomedical outcomes can be attained with conventional MDI and SMBG regimens compared with CSII/RT , although satisfaction was higher with CSII The purpose of this prospect i ve before- and -after study was to determine whether there are psychosocial and physical benefits of a self-awareness intervention for adults with type 1 diabetes and hypoglycemia unawareness ( HU ) . A total of 29 adults participated in the self-awareness intervention of 8 sessions , each lasting 3 hours . Psychosocial ( integration , diabetes quality of life ) and physical ( number of body cues , HU-related events , HbA1c ) measures were taken at baseline and at 6 , 12 , and 18 months post-intervention . Post-intervention the participants detected more cues of euglycemia and hypoglycemia and experienced significant increases in integration and metabolic control ( HbA1c ) . The number of HU-related events was not decreased and diabetes quality -of-life results were unstable . A self-awareness intervention can have physical and psychosocial benefits and has implication s for diabetes education . This intervention needs to be tested in a multi-centre r and omized control trial OBJECTIVE To determine the frequency of hypoglycemia in patients with type I diabetes and impaired awareness of hypoglycemia by prospect i ve assessment . RESEARCH DESIGN AND METHODS A prospect i ve study was undertaken for 12 months in 60 patients with type I diabetes : 29 had impaired awareness of hypoglycemia and 31 retained normal awareness of hypoglycemia . The two groups of patients were matched for age , age at onset of diabetes , duration of diabetes , and glycemic control . Episodes of severe hypoglycemia were recorded within 24 h of the event and verified where possible by witnesses . RESULTS During the 12 months , 19 ( 66 % ) of the patients with impaired awareness had one or more episodes of severe hypoglycemia with an overall incidence of 2.8 episodes · patient–1 · year–1 . By comparison , 8 ( 26 % ) of the patients with normal awareness experienced severe hypoglycemia ( P < 0.01 ) with an annual incidence of 0.5 episode · patient–1 · year–1 ( P < 0.001 ) . Severe hypoglycemia occurred at different times of the day in the two groups : patients with impaired awareness experienced a greater proportion of episodes during the evening ( P = 0.03 ) , and patients with normal awareness experienced a greater proportion in the early morning ( P = 0.05 ) . An assessment of fear of hypoglycemia revealed that patients with impaired awareness of hypoglycemia worried more about hypoglycemia than did patients with normal awareness ( P = 0.008 ) , but did not modify their behavior accordingly . CONCLUSIONS This prospect i ve evaluation demonstrated that impaired awareness of hypoglycemia predisposes to a sixfold increase in the frequency of severe hypoglycemia , much of which occurred at home during waking hours Objective : Severe sulfonylurea-induced hypoglycemia ( SH ) remains a life-threatening and under-reported condition . We investigated the incidence of SH and clinical characteristics of patients with type 2 diabetes mellitus ( T2DM ) to demonstrate typical risk constellations . Methods : In a prospect i ve population -based observational study , all consecutive cases of SH in the period 2000 – 2009 in a German area with 200,000 inhabitants were registered .  Severe hypoglycemia was defined as a symptomatic event requiring treatment with intravenous glucose and was confirmed by a blood glucose measurement of < 50 mg/dl . Results : A mean incidence of seven episodes of SH per year and 100,000 inhabitants was registered . The 139 hypoglycemic individuals had been treated with glimepiride ( n = 98 ) , glibenclamide ( n = 40 ) or gliquidone ( n = 1 ) . No preparation showed a constant dose – effect relationship , SH occurring within a wide dose range . The patients were characterized as follows : age 77.5 ± 9.4 years , duration of diabetes 11 ± 7 years , body mass index 26.3 ± 4.9 kg/m2 , HbA1c 6.6 ± 1.3 % , creatinine clearance 46 ± 24 ml/min with renal insufficiency in 73 % and co-medication 7 ± 3 drugs . Two-thirds of all subjects lived independently at home whereas a third were cared for by a home nursing service or received care in nursing homes . In all , 30 % had participated in diabetes education programs . In 31 % , systematic blood glucose monitoring was performed . Conclusions : Uncritical prescription of sulfonylureas neglecting crucial contraindications – particularly renal insufficiency – and deficiencies of diabetes care contributed substantially to the risk of SH in the mainly geriatric patients . There is a need for alternative therapeutic concepts that minimize the risk of hypoglycemia in geriatric patients with T2DM Executive summary Background As a chronic condition , the prevalence of Type 2 diabetes is increasing worldwide and adherence to oral medications , an essential component of self‐management , has been shown to improve glycaemic control . However compliance with oral medication adherence remains poor . Educating people with Type 2 diabetes is an important strategy to enhance self‐management ability , including medication‐taking behaviour . Objectives The overall objective of the review was to determine the effectiveness of educational interventions to promote oral hypoglycaemic adherence in adults with Type 2 diabetes . Inclusion criteria Types of participants Studies involving adults over 18 years old with Type 2 diabetes , with or without co‐morbidities , currently taking oral hypoglycaemic medication without insulin treatment , and with aglycated haemoglobin ( HbA1c ) > 7.0 % prior to the intervention were considered . Aglycated haemoglobin ( HbA1c ) concentration of less than 7.0 % , is important in order to delay or prevent diabetes‐related complications . Participants could be from the primary , tertiary or acute care setting . Types of intervention The review focused on various forms of educational interventions delivered by healthcare professionals aim ed at improving participants ’ knowledge . Types of outcomes The review evaluated outcomes measuring oral hypoglycaemic adherence including HbA1c , fasting blood glucose levels and other relevant indicators . Types of studies Studies that were r and omized controlled trials ( RCTs ) or case‐control studies were considered . Search strategy A three‐stage search strategy was employed . Papers in English and between the years 1990‐2009 were search ed in the following data bases : CINAHL , Medline , Mosby 's Nursing Consult , PsycINFO , PubMed , ScienceDirect , Scopus , TRIP and Web of Science . Full text was retrieved when the titles and abstract s of studies fulfilled the inclusion criteria . Method ological quality Full papers were assessed for method ological quality independently by two review ers using critical appraisal checklists from the Joanna Briggs Institute ( JBI ) . A third review er was consulted whenever there were disagreements between the two review ers . Data collection / extraction Details of each study included in the review were extracted using st and ardized data extraction forms developed by JBI . Extraction was conducted independently by two review ers . Data synthesis Meta‐ analysis was not possible due to method ological and statistical heterogeneity of the included studies . Hence study findings are presented in narrative form . Results Seven studies included in the final review consisted of seven RCTs . Five studies concluded that the educational intervention was effective in promoting oral hypoglycaemic adherence compared to usual care . These included pharmacist‐led interventions , individual diabetes education provided by nurses and diabetes group education based on a self‐management approach . Similarities among these interventions were provision of information on oral hypoglycaemic medication and the need for regular education sessions . However , small sample s in some studies limited generalization of results . Conclusions Implication s for practice Increased knowledge of oral hypoglycaemic issues and reinforcement of the importance of medication adherence were useful in promoting adherence . Regular education sessions allow individuals to reinforce information and educators to identify barriers to medication adherence . Educational interventions focusing on self‐management strategies appear more likely to achieve positive outcomes . Implication s for research Further trials involving larger sample s and population s with poor glycaemic control are needed . The effects of educational interventions , influence of additional take‐home written material , the optimal interval length of follow‐up and duration of education sessions , and specific processes of individual or group education which have been identified as effective need further exploration Summary The objectives of the present analyses were to assess the association between HbA1 c levels and severe hypoglycaemia ( SH , treatment with glucose i. v. or glucagon injection ) and to identify predictors of SH in a prospect i ve multicentre trial . The study population consisted of 636 insulin-dependent diabetic patients who had participated in a structured 5-day in-patient group treatment and teaching programme for intensification of insulin therapy ( ITTP ) in one of 10 hospitals and who were re-examined after 1 , 2 , 3 , and 6 years including assessment of demographic , disease and treatment related parameters , diabetes-related knowledge , behaviour , and emotional coping . At baseline , age ( mean ± SD ) was 27 ± 7 years , diabetes duration 9 ± 7 years and HbA1 c 8.3 ± 1.9 % . During the 6-year follow-up , the mean HbA1 c value improved to 7.6 % , and in patients with a diabetes duration of more than 1 year at entry into the study ( n = 538 ) the incidence of SH decreased from 0.28 cases/patient/year during the year preceding the ITTP to 0.17 cases/patient/year . The patient group was divided into decile groups according to mean follow-up HbA1 c values . In each group more than 230 patient years could be analysed . Groups with mean HbA1 c values of 5.7 , 7.0 , 7.4 , 7.7 and 8.9 % had comparable risks of SH ( 0.15–0.19 cases/patient/year ) . In a logistic regression analysis , mean HbA1 c during follow-up , a history of SH during the year preceding the ITTP , C-peptide level , emotional coping , carrying emergency carbohydrates ( as assessed at the 1-year follow-up ) , and age at onset of diabetes were significant independent predictors of SH . The incidence of SH between centres varied between 0.05 and 0.27 cases/patient/year . In conclusion , in the present analyses no linear or exponential relationship between HbA1 c and severe hypoglycaemia could be identified by using simple group comparisons . Applying complex regression analyses , various patient-related predictors of severe hypoglycaemia were identified . [ Diabetologia ( 1997 ) 40 : 926–932 Intensive therapy for insulin-dependent diabetes mellitus ( IDDM ) delays the onset and slows the progression of long-term complications , including diabetic retinopathy , nephropathy , and neuropathy [ 1 ] . However , the implementation of this regimen increases the risk for severe hypoglycemia [ 2 , 3 ] . Severe hypoglycemia is particularly problematic because of its potential influence on the integrity of the central nervous system . Not only is severe hypoglycemia associated with a transient reduction in cognitive function that adversely affects activities of daily living , including driving [ 4 , 5 ] , but , if left untreated , it may also lead to clinical ly significant brain damage [ 6 - 8 ] . Although animal studies have provided the most compelling evidence for hypoglycemia-induced brain dysfunction [ 9 ] , investigators of several recent cross-sectional studies have concluded that five or more episodes of severe hypoglycemia may be associated with mild cognitive impairment , as measured by performance on neuropsychological tests [ 10 , 11 ] . To date , only one group of investigators has directly assessed the long-term effects of intensive diabetes therapy on cognitive functioning . Reichard and associates [ 12 ] examined 5-year follow-up data from 96 patients participating in the Stockholm Diabetes Intervention Study ( SDIS ) . In this clinical trial , intensive diabetes therapy ( 3 to 4 injections/d ) was compared with conventional treatment ( 1 to 2 injections/d ) . Despite the significantly higher occurrence of severe hypoglycemia in the intensive therapy group ( 77 % compared with 56 % ) , the 52 patients in that group did no worse on neuropsychological measures than the 44 patients in the st and ard treatment group . These negative findings remain controversial . Deary and associates [ 13 ] have suggested that the failure of Reichard and colleagues [ 12 ] to find meaningful between-group differences may have been a consequence of the study 's small sample size and result ant low statistical power , the unusually high incidence of hypoglycemia in the st and ard treatment group , and the use of a test battery that might have been insensitive to early changes in cognitive functioning . Each of these potential problems has been obviated in the Diabetes Control and Complications Trial ( DCCT ) . For 9 years , 1441 adolescents and adults with IDDM were followed at 29 clinical centers in the United States and Canada . Half the patients were r and omly assigned to receive intensive diabetes therapy , the other half to receive conventional treatment . Throughout the study , the risk for severe hypoglycemia was found to be approximately three times higher in the intensive treatment group than in the conventional treatment group [ 1 ] . The neuropsychological status of each patient was evaluated on two to five occasions ( at baseline ; years 2 , 5 , and 7 ; and study end ) by using an extensive battery of well-known neuropsychological tests selected for their sensitivity for neurocognitive deficits associated with hypoglycemia [ 14 ] . The analyses were done to answer two questions : 1 ) Did intensive therapy differentially affect neuropsychological functioning ? and 2 ) Was the number of episodes of severe hypoglycemia related to the degree of neuropsychological impairment ? Methods Study Sample Patients recruited for the DCCT were 13 to 39 years of age , had had IDDM for 1 to 15 years , and were in generally good health [ 1 ] . Exclusion criteria were advanced retinopathy , nephropathy , or neuropathy ; a history of drug or alcohol abuse ; psychotic episodes ; eating disorders ; epilepsy ; recurrent episodes of ketoacidosis ; and recurrent episodes of coma or seizure due to hypoglycemia . In the first 278 r and omly assigned patients followed for 12 months , a history of severe hypoglycemia was identified as a risk factor for severe hypoglycemia [ 15 ] . Potential volunteers were subsequently excluded if they had had more than two episodes of hypoglycemic seizure or coma in the previous 2 years . The demographic and clinical characteristics of the 1441 patients are listed in Table 1 . Table 1 . Demographic and Clinical Characteristics of Patients at Study Entry * Extent of Follow-up The entire cohort of 1441 patients was followed for 3.5 to 9 years ( mean , 6.5 years ) , yielding approximately 9300 patient-years of observation . Two hundred sixty-eight patients ( 19 % of the total cohort ) were studied for 9 years , and 1088 ( 76 % ) were studied for 5 years . Almost all patients ( 99.7 % ) were followed for at least 3 years . Final follow-up study data were collected on 1422 patients ( 99 % of the total cohort ) . Of the 19 patients who did not complete the study , 8 dropped out and 11 died . More than 95 % of expected visits were held over the 9-year study period , and 98 % of the expected neuropsychological protocol s were completed . Adherence to Assigned Treatment We r and omly assigned 711 patients to receive intensive treatment , which consisted of insulin administered three or more times per day by injection or by continuous subcutaneous infusion with an external pump .  Blood glucose levels were monitored four or more times per day , and the results , coupled with anticipated meal content and exercise , were used to adjust the insulin dose . Treatment goals were prepr and ial blood glucose levels between 3.89 and 6.66 mmol/L , postpr and ial blood glucose levels less than 9.99 mmol/L , a weekly 0300 h measurement greater than 3.61 mmol/L , a monthly measured glycosylated hemoglobin ( HbA1c ) level within the nondiabetic range ( < 6.05 % ) , and avoidance of severe hypoglycemia . Conventional therapy  ( 730 patients ) consisted of one or two daily insulin injections ; the goal was freedom from symptoms of hyperglycemia and frequent or severe hypoglycemia . The intensive and conventional treatment groups maintained a separation of median HbA1c level of about 2 percentage points throughout the follow-up period ( 7.1 % compared with 9.0 % ; P < 0.001 ) [ 1 ] . Patients '  adherence to r and omly assigned treatment was high ; more than 97 % of study time was spent receiving the assigned therapy [ 1 ] . Definition and Frequency of Severe Hypoglycemia All episodes of severe hypoglycemia were reported to the Coordinating Center as soon as possible after their occurrence . Severe hypoglycemic episodes were defined as those in which the patient had incapacity sufficient to require the assistance of another person . In addition , the definition of severe hypoglycemia required that 1 ) the blood glucose level was measured and found to be less than 2.78 mmol/L or 2 ) the clinical manifestations were reversed by the administration of oral carbohydrate , subcutaneous glucagon , or intravenous glucose . Approximately one third of severe hypoglycemic episodes involved coma , seizure , or suspected seizure . In the intensive treatment group , 61 severe hypoglycemic episodes occurred per 100 patient-years compared with 19 episodes per 100 patient-years in the conventional treatment group ( relative risk , 3.28 [ 95 % CI , 2.65 to 4.05 ] ; P < 0.001 ) [ 16 ] . In the intensive treatment group , 16 severe hypoglycemic episodes involving coma , seizure , or suspected seizure occurred per 100 patient-years compared with 5 such episodes in the conventional treatment group ( relative risk , 3.02 [ CI , 2.36 to 3.86 ] ; P < 0.001 ) [ 16 ] . Neuropsychological Test Protocol Neuropsychological testing was done by trained personnel at baseline ; years 2 , 5 , and 7 ; and study end . The Central Neuropsychological Coding Unit trained and certified the personnel at the clinical centers . Results from the final assessment were assigned to the closest year of expected scheduled neuropsychological evaluation , up to year 9 . The test protocol , which required 4 to 5 hours to complete , included the Wechsler Adult Intelligence Scale [ 17 ] for patients 16 years of age or older ; the Wechsler Intelligence Scale for Children , Revised [ 18 ] , for patients younger than 16 years of age ; four subtests ( category test , tactual performance test , trail making test , and finger tapping test )  from the Halstead-Reitan Neuropsychological Battery [ 19 ] ; the digit vigilance subtest from the Lafayette Clinic Repeatable Battery [ 20 ] ; the  logical memory and visual reproduction subtests  from the Wechsler Memory Scale [ 21 ] ; the  arithmetic subtest  from the Wide Range Achievement Test [ 22 ] ; the  Grooved Pegboard Test  [ 23 ] ; the  Verbal Fluency Test  [ 24 ] ; and several additional specialized measures ( Symbol Digit Learning Test , Four-Word Short-Term Memory Test , Embedded Figures Test )  [ 25 ] . Tests were administered in a fixed order , with rest breaks scheduled at 45- to 60-minute intervals . The same battery of tests was administered at each evaluation . Capillary blood glucose levels were monitored to rule out the presence of hypoglycemia during testing . The tests were scored by technicians at the Central Neuropsychological Coding Unit who were masked to treatment assignments . These results were sent to the Coordinating Center , where the data were entered , verified , and edited for out-of-range values and other errors . Outcome Measurements Clinical ly Rated Neuropsychological Worsening We had initially planned that all neuropsychological test protocol s would be rated by a team of expert clinicians to determine the presence of a clinical ly significant change in functioning between baseline and re assessment as part of a program to monitor safety . However , during the feasibility phase , we found that the neuropsychological tests could not be rated quickly enough to meet safety needs . We therefore developed a computer-based screening algorithm to identify patients with a high probability of neuropsychological worsening [ 26 ] . Protocol s so identified were review ed by two expert clinical neuropsychologists who independently rated each protocol for change from baseline . If a protocol was rated as significantly worsening since baseline , the local center was notified so that additional neurologic or psychological studies could be done and the patient could be more closely monitored . This screening process was OBJECTIVE Impaired awareness of hypoglycemia ( IAH ) and severe hypoglycemic events ( SHEs ) cause substantial morbidity and mortality in patients with type 1 diabetes ( T1D ) . Current therapies are effective in preventing SHEs in 50–80 % of patients with IAH and SHEs , leaving a substantial number of patients at risk . We evaluated the effectiveness and safety of a st and ardized human pancreatic islet product in subjects in whom IAH and SHEs persisted despite medical treatment . RESEARCH DESIGN AND METHODS This multicenter , single-arm , phase 3 study of the investigational product purified human pancreatic islets ( PHPI ) was conducted at eight centers in North America . Forty-eight adults with T1D for > 5 years , absent stimulated C-peptide , and documented IAH and SHEs despite expert care were enrolled . Each received immunosuppression and one or more transplants of PHPI , manufactured on-site under good manufacturing practice conditions using a common batch record and st and ardized lot release criteria and test methods . The primary end point was the achievement of HbA1c < 7.0 % ( 53 mmol/mol ) at day 365 and freedom from SHEs from day 28 to day 365 after the first transplant . RESULTS The primary end point was successfully met by 87.5 % of subjects at 1 year and by 71 % at 2 years . The median HbA1c level was 5.6 % ( 38 mmol/mol ) at both 1 and 2 years . Hypoglycemia awareness was restored , with highly significant improvements in Clarke and HYPO scores ( P > 0.0001 ) . No study -related deaths or disabilities occurred . Five of the enrollees ( 10.4 % ) experienced bleeds requiring transfusions ( corresponding to 5 of 75 procedures ) , and two enrollees ( 4.1 % ) had infections attributed to immunosuppression . Glomerular filtration rate decreased significantly on immunosuppression , and donor-specific antibodies developed in two patients . CONCLUSIONS Transplanted PHPI provided glycemic control , restoration of hypoglycemia awareness , and protection from SHEs in subjects with intractable IAH and SHEs . Safety events occurred related to the infusion procedure and immunosuppression , including bleeding and decreased renal function .  Islet transplantation should be considered for patients with T1D and IAH in whom other , less invasive current treatments have been ineffective in preventing SHEs OBJECTIVE To test the effect of an automated system providing real-time estimates of HbA1c , glucose variability , and risk for hypoglycemia . RESEARCH DESIGN AND METHODS For 1 year , 120 adults with type 1 diabetes ( 69 female/51 male , age = 39.1 [ 14.3 ] years , duration of diabetes 20.3 [ 12.9 ] years , HbA1c = 8.0 [ 1.5 ] ) , performed self-monitoring of blood glucose ( SMBG ) and received feedback at three increasingly complex levels , each continuing for 3 months : level 1—routine SMBG ; level 2—adding estimated HbA1c , hypoglycemia risk , and glucose variability ; and level 3—adding estimates of symptoms potentially related to hypoglycemia . The subjects were r and omized to feedback sequences of either levels 1 - 2 - 3 or levels 2 - 3 - 1 . HbA1c , symptomatic hypoglycemia , and blood glucose awareness were evaluated at baseline and at the end of each level . RESULTS For all subjects , HbA1c was reduced from 8.0 to 7.6 from baseline to the end of study ( P = 0.001 ) . This effect was confined to subjects with baseline HbA1c > 8.0 ( from 9.3 to 8.5 , P < 0.001 ) . Incidence of symptomatic moderate/severe hypoglycemia was reduced from 5.72 to 3.74 episodes/person/month ( P = 0.019 ) , more prominently for subjects with a history of severe hypoglycemia ( from 7.20 to 4.00 episodes , P = 0.008 ) and for those who were hypoglycemia unaware ( from 6.44 to 3.71 episodes , P = 0.045 ) . The subjects ’ ratings of the feedback were positive , with up to 89 % approval of the provided features . CONCLUSIONS Feedback of SMBG data and summary SMBG-based measures result ed in improvement in average glycemic control and reduction in moderate/severe hypoglycemia . These effects were most prominent in subjects who were at highest risk at the baseline AIM To determine potential for amelioration of recurrent severe hypoglycaemia without worsening in overall control in individuals with long-st and ing Type 1 diabetes ( T1DM ) . METHODS Twenty-one people with T1DM characterized by altered hypoglycaemia awareness and debilitating severe hypoglycaemia were r and omized in a pilot 24-week prospect i ve study to optimized analogue therapy ( ANALOGUE ; lispro/glargine ) ; continuous subcutaneous insulin infusion therapy ( CSII ; lispro ) ; or re-education with relaxation of blood glucose targets on existing conventional insulin regimen ( EDUCATION ) .  Glycaemic profiles and duration of biochemical hypoglycaemia were measured by continuous subcutaneous glucose monitoring and self-monitored blood glucose . RESULTS Further severe hypoglycaemia was prevented in five participants ( 71 % ) in each group ( P = 0.06 ) . Incidence of severe hypoglycaemia was : 0.6 ( ANALOGUE ) , 0.9 ( CSII ) , and 3.7 ( EDUCATION ) episodes per patient year . Restoration of hypoglycaemia awareness was confirmed by vali date d question naire in three ( 43 % ) ANALOGUE , four ( 57 % ) CSII and five ( 71 % ) EDUCATION patients . Glycated haemoglobin ( HbA1c ) was significantly improved in the ANALOGUE group between weeks 0 and 24 ( 8.6 + /- 1.1 vs. 7.6 + /- 0.8 % ; P = 0.04 for change ) . Non-significant improvement was seen in the CSII group ( 8.5 + /- 1.9 vs. 7.4 + /- 1.0 % ; P = 0.06 ) . No change in HbA1c was seen in the EDUCATION group ( 8.5 + /- 1.1 vs. 8.3 + /- 1.0 % ; P = 0.54 ) . There were no episodes of diabetic ketoacidosis or any other adverse events in any group . CONCLUSIONS In this pilot r and omized trial comparing optimized ANALOGUE , CSII or EDUCATION alone in unselected individuals with recurrent severe hypoglycaemia , we show potential for restoring hypoglycaemia awareness and preventing further severe hypoglycaemia with concomitant improvement in glycaemic control in ANALOGUE and CSII groups Abstract Background 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 . Objective 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 ) Setting : 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 . Methods A r and omized , controlled , prospect i ve , 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 . Main outcome measures : The between-group difference in the change from baseline in glycosylated hemoglobin ( HbA1c ) and the number of severe hypoglycemic events in both groups . Results 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 ) . Conclusion 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 OBJECTIVE Both acute and chronic complications of diabetes account for a disproportionate percentage of US health care expenditures . Despite improvements in diabetes care , the incidence of adverse events in children with type 1 diabetes remains high , particularly for youths with poor glycemic control . Cost-effective intervention programs design ed to reduce complications are needed . This study evaluated a low-intensity , nonmedical intervention using a case manager ( called a " Care Ambassador " ) , with and without the supplementation of psychoeducational modules , design ed to monitor and encourage routine diabetes care visits to reduce short-term adverse outcomes and improve glycemic control in youths with type 1 diabetes . METHODS We performed a 2-year prospect i ve , r and omized clinical trial in 299 youths with type 1 diabetes , aged 7 to 16 years , comparing 3 treatment programs ( Care Ambassador [ CA ] , Care Ambassador plus psychoeducational modules [ CA+ ] , and st and ard multidisciplinary diabetes care [ SC ] ) . The study was conducted in a large metropolitan US city from April 1997 through April 2000 .  Number of medical visits , frequency of hypoglycemic events , hospital/emergency department ( ED ) utilization , and glycosylated hemoglobin A1c were assessed during follow-up . RESULTS During the 2-year study period , both the CA and CA+ groups had significantly more routine visits ( mean [ st and ard deviation ] : 7.3 [ 2.06 ] and 7.5 [ 2.02 ] , respectively ) compared with the SC group ( 5.4 [ 2.62 ] ) . The CA+ intervention group had significantly reduced rates of short-term adverse outcomes compared with the other 2 groups ; 25 % fewer total hypoglycemic events , 60 % fewer severe hypoglycemic events , and 40 % fewer hospitalizations and ED visits . " High-risk " youths in the CA+ group ( baseline glycosylated hemoglobin A1c > or = 8.7 % ) were 3.4-fold ( 1.57 - 7.41 ) more likely to improve their glycemic control compared with those at high risk in the other 2 groups . CONCLUSIONS For youths with type 1 diabetes , the CA and CA+ interventions increased visit frequency . Youths in the CA+ intervention had reduced rates of hypoglycemia and hospital/ED utilization with estimated annual cost savings of 80 000 dollars to 90 000 dollars . The CA+ intervention compared with the other 2 groups improved glycemic control in " high-risk " youths . Nonmedical case management incorporating psychoeducational modules seems to be a cost-effective approach to improving outcomes in youths with diabetes OBJECTIVE Evaluation of an ambulatory diabetes teaching and treatment refresher programme ( DTTP ) for the optimization of intensified insulin therapy in patients with type 1 diabetes ( refresher course ) . METHODS 85 out patients took part in this prospect i ve multicentre trial . Metabolic and psychosocial data were analyzed at baseline ( V1 ) , 6 weeks ( V2 ) and 12 months after DTTP ( V3 ) . RESULTS In patients with baseline HbA1c>7 % ( 88 % ) , HbA1c decreased by 0.36 % ( p=0.004 ) . The percentage of patients with HbA1c≤7 % increased from 21.3 to 34.9 % and with HbA1c above 10 % decreased from 6.6 to 1.6 % at V3 . The incidence of hypoglycaemia decreased significantly : non severe hypoglycaemia from 3.31 to 1.39 episodes/pat/week ( p=0.001 ) and severe hypoglycaemia from 0.16 to 0.03 episodes/pat/year ( p=0.02 ) . The treatment satisfaction increased by + 10 of maximal ±18 points . The negative influence of diabetes on quality of life decreased from -1.93 to -1.69 points ( p=0.031 ) . CONCLUSION In a group of patients with moderately controlled diabetes type 1 who were already treated with intensified insulin therapy , metabolic control , treatment satisfaction and quality of life were improved after participation in an ambulatory DTTP without increasing insulin dosage , number of injections or insulin species . PRACTICE IMPLICATION S This DTTP is effective for the optimization of intensified insulin therapy
These were able to reduce SH and improve glycemic control , with greater benefit from the latter two techniques in improving IAH .
Technological interventions ( insulin pump therapy , continuous glucose monitoring , and sensor-augmented pump ) reduced SH , improved glycemic control , and restored awareness when used in combination with structured education and frequent contact .
This review provides evidence for the effectiveness of a stepped-care approach in the management of patients with IAH  , initially with structured diabetes education in flexible insulin therapy , which may incorporate psychotherapeutic and behavioral therapies , progressing to diabetes technology , incorporating sensors and insulin pumps , in those with persisting need
OBJECTIVE Impaired awareness of hypoglycemia ( IAH ) increases the risk of severe hypoglycemia ( SH ) sixfold and affects 30 % of adults with type 1 diabetes ( T1D ) .
This systematic review and meta- analysis looks at the educational , technological , and pharmacological interventions aim ed at restoring hypoglycemia awareness ( HA ) in adults with T1D .