Frequency Of Severe Hypoglycemic Episodes Research Articles

264-OR: Characterizing the Distinct Glycemic Patterns Of Postbariatric Hypoglycemia (PBH)

While bariatric surgery can promote remission of type 2 diabetes (T2D), it can also result in severe hypoglycemia, termed post-bariatric hypoglycemia (PBH). Hypoglycemia is most often recognized after meals, but also can occur after activity or during mid-nocturnal hours and can yield unawareness and disabling neuroglycopenia. We used blinded CGM (Dexcom G4) to characterize glycemia, glycemic variability (GV), and severity and length of hypoglycemia in patients with PBH with prior roux-en-Y gastric bypass (PBH, n=40). We compared results to those of individuals with reactive hypoglycemia with no prior GI surgery (Hypo, no-GS, n=20) and to publicly available Dexcom G4 data from 3 additional groups: healthy controls (HC, n=38), prediabetes (Pre-DM, n=14), and T2D (n=5). Metrics were assessed over 24 hours as well as during daytime (6 AM to midnight) and nighttime (midnight to 6 AM) independently. Mean and median sensor glucose (SG) were similar for PBH and HC (mean: 99.8±18.6 vs. 96.9±10.2 mg/dL; median: 93.0±14.8 vs. 94.5±7.4 mg/dL, p>0.05 for both). By contrast, PBH had higher coefficient of variation (27.3±6.8 vs. 17.9±2.4%, p<0.0001) and a wider range and IQR of SG values (range: 154.5±50.4 vs. 112.0±26.7 mg/dL; IQR: 28.0±7.4 vs. 20.0±4.4, p<0.0001 for both). Nadir SG was lowest in PBH (42.5± 3.7 mg/dL vs. other groups, p<0.0001) with statistical significance vs. HC (49.0±11.9 mg/dL, p=0.0046). PBH had greater percentage of time with SG<70 mg/dL vs. HC (7.7±8.4 vs. 3.2±4.1%, p<0.002); these differences were greater at night (12.6±16.9 vs. 1.0±1.5%, p<0.0001). Also, the frequency of severe hypoglycemic episodes (<54 mg/dL, duration ≥ 15 minutes) per day was higher for PBH group vs. HC (0.5 vs. 0.1, p<0.002). In summary, patients with PBH experience higher GV and greater severity and frequency of hypoglycemia compared to HC, especially at night. Future studies should explore the potential of CGM technology in assisting PBH patients to recognize early hypoglycemia and prevent severe hypoglycemia. Disclosure D. Lee: None. J. Dreyfuss: None. C.M. Mulla: None. M. Patti: Consultant; Self; Fractyl Laboratories, Inc. Research Support; Self; Dexcom, Inc., Xeris Pharmaceuticals, Inc. Other Relationship; Self; Academy of Nutrition and Dietetics, American Diabetes Association, American Society of Metabolic and Bariatric Surgery, Endocrine Society, Insulet Corporation, King Abdullah International Medical Research Center, SUNY Downstate. Funding National Institutes of Health (R01DK121995); National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007260)

Metabolic control of insulin detemir in basal-bolus therapy: treat-to-target study in children and adolescents with type 1 diabetes†

To assess the efficacy and safety of insulin detemir administered once vs. twice daily in children and adolescents with type 1 diabetes mellitus. In this prospective, open-label, treat-to-target study, 37 patients [mean age 12.7 ± 3 yr; diabetes duration 4.2 ± 3 yr, hemoglobin A1c (HbA1c) 8.8 ± 0.8%] were scheduled to receive insulin detemir once daily before breakfast, with pre-meal insulin aspart, for 16-20 wk. Detemir dose titration algorithm was based on age-related target fasting blood glucose levels during 4-8 wk. Patients achieving target range continued on once-daily detemir (Group A) if up-titration could not be done due to hypoglycemia patients were switched to twice-daily detemir (Group B). Nineteen (51%) patients continued with once-daily detemir. HbA1c decreased significantly in both groups (A: -0.7%, p = 0.02; B: -0.8%, p = 0.004), without a significant difference between groups. The frequency of nocturnal hypoglycemic events/week decreased in both groups but a significant change was found only in Group A (10.9-2.7, p < 0.05 vs. 8.7-5.8, NS), with no change in frequency of severe hypoglycemic episodes in either group. No significant differences were found between and within groups for body mass index-standard deviation score, insulin requirement or treatment satisfaction. Group B patients were significantly younger than Group A patients (11.5 ± 2.3 vs.13.8 ± 3.2 yr, p = 0.01), with a higher percentage in active puberty (50 vs. 11%, p = 0.003). Since twice-daily determir showed no clinical advantage over once-daily detemir, it appears reasonable to commence all children on once-daily detemir, taking into consideration that younger children and those in active puberty may require twice-daily therapy (ClinicalTrials.gov number, NCT00542399).

Short-term continuous glucose monitoring: effects on glucose and treatment satisfaction in patients with type 1 diabetes mellitus; a randomized controlled trial

Objective: To assess whether 4 week's use of a continuous glucose monitoring (CGM) system improves glucose control, treatment satisfaction or health status, as compared to intensified conventional finger-prick measurements (ICFM) in patients with type 1 diabetes mellitus (DM1). Method: Thirty patients suffering from DM1 for more than three years and treated with either insulin pumps or multiple daily insulin injections, were included in a randomised controlled cross-over trial. They were Caucasians of both genders, between 18 and 50 years, and had moderately well controlled diabetes. The participants performed either ICFM or CGM for 4 weeks, followed by an 8 week's observation period. Thereafter they were crossed over to the opposite intervention. HbA(1c) , hypoglycaemic episodes, treatment satisfaction and health status were assessed at all meetings, although HbA(1c) was the primary endpoint. Results: At inclusion mean HbA(1c) was 7.8 ± 0.9 %. The mean change in HbA(1c) was -0.2 ± 0.1% and -0.2 ± 0.1% for the CGM and the ICFM periods, accordingly (p = 0.91). The mean changes in HbA(1c) during the combined treatment and observation periods were -0.1 ± 0.1% and -0.2 ± 0.1% for the CGM and the ICFM period, accordingly (p = 0.86). The frequency of severe hypoglycaemic episodes, treatment satisfaction and health status was also equal between the two interventions. No adverse events were observed.

Insulin analogues and severe hypoglycaemia in type 1 diabetes

IntroductionThe effect of insulin analogues on glycaemic control is well-documented, whereas the effect on avoidance of severe hypoglycaemia remains tentative. We studied the frequency of severe hypoglycaemia in unselected patients with type 1 diabetes treated with insulin analogues, human insulin, or mixed regimens. MethodsA questionnaire was posted from six Danish diabetes clinics to 6112 unselected patients with type 1 diabetes and filled in by 3861 patients (63.2%). Primary endpoint was number of episodes of severe hypoglycaemia in the preceding year. Mild hypoglycaemia was also reported. ResultsThe frequency of severe hypoglycaemic episodes per patient-year in patients receiving long-acting insulin analogues was 1.47±0.18 versus 1.09±0.10 in patients on long-acting human insulin (p=0.01). The frequency of severe hypoglycaemic episodes per patient-year was 1.09±0.11 in patients on short-acting insulin analogues versus 1.26±0.13 in patients on short-acting human insulin (p=0.15), which was statistically significant in an adjusted analysis. ConclusionsSevere hypoglycaemia is more frequent in patients with type 1 diabetes treated with long-acting insulin analogues. Confounding by indication may be involved. Clinical intervention trials using insulin analogues in patients prone to severe hypoglycaemia are highly needed.

Potential of education‐based insulin therapy for achievement of good metabolic control: a real‐life experience

Achievement of good metabolic control in Type 1 diabetes is a difficult task in routine diabetes care. Education-based flexible intensified insulin therapy has the potential to meet the therapeutic targets while limiting the risk for severe hypoglycaemia. We evaluated the metabolic control and the rate of severe hypoglycaemia in real-life clinical practice in a centre using flexible intensified insulin therapy as standard of care since 1990. Patients followed for Type 1 diabetes (n = 206) or those with other causes of absolute insulin deficiency (n = 17) in our outpatient clinic were analysed in a cross-sectional study. Mean age (± standard deviation) was 48.9 ± 15.7 years, with diabetes duration of 21.4 ± 14.4 years. Outcome measures were HbA(1c) and frequency of severe hypoglycaemia. Median HbA(1c) was 7.1% (54 mmol/mol) [interquartile range 6.6-7.8 (51-62 mmol/mol)]; a good or acceptable metabolic control with HbA(1c) < 7.0% (53 mmol/mol) or 7.5% (58 mmol/mol) was reached in 43.5 and 64.6% of the patients, respectively. The frequency of severe hypoglycaemic episodes was 15 per 100 patient years: 72.3% of the patients did not experience any such episodes during the past 5 years. Good or acceptable metabolic control is achievable in the majority of patients with Type 1 diabetes or other causes of absolute insulin deficiency in routine diabetes care while limiting the risk for severe hypoglycaemia.

Pancreatic islet transplantation

BackgroundNo formulation of exogenous insulin available to date has yet been able to mimic the physiological nictemeral rhythms of this hormone, and despite all engineering advancements, the theoretical proposal of developing a mechanical replacement for pancreatic β cell still has not been reached. Thus, the replacement of β cells through pancreas and pancreatic islet transplantation are the only concrete alternatives for re-establishing the endogenous insulin secretion in type 1 diabetic patients. Since only 1 to 1.5% of the pancreatic mass corresponds to endocrine tissue, pancreatic islets transplantation arises as a natural alternative. Data from the International Islet Transplant Registry (ITR) from 1983 to December 2000 document a total of 493 transplants performed around the world, with progressively worse rates of post-transplant insulin independence. In 2000, the "Edmonton Protocol" introduced several modifications to the transplantation procedure, such as the use of a steroid-free immunosuppression regimen and transplantation of a mean islet mass of 11,000 islet equivalents per kilogram, which significantly improved 1-year outcomes. Although the results of a 5-year follow-up in 65 patients demonstrated improvement in glycemic instability in a significant portion of them, only 7.5% of the patients have reached insulin independence, indicating the need of further advances in the preservation of the function of transplanted islet. In addition to the scarcity of organs available for transplantation, islets transplantation still faces major challenges, specially those related to cell loss during the process of islet isolation and the losses related to the graft site, apoptosis, allorejection, autoimmunity, and immunosuppression. The main strategies to optimize islet transplantation aim at improving all these aspects.ConclusionHuman islet transplantation should be regarded as an intervention that can decrease the frequency of severe hypoglycemic episodes and improve glycemic control in selected patient for whom benefits of 4-5 years duration would be very valuable. Its limitations, however, indicate that the procedure in its current format is not suitable for all patients with type 1 diabetes.

Outcome of pregnancy in type 1 diabetic patients treated with insulin lispro or regular insulin: an Italian experience

Some studies have shown that fetal outcome observed in patients using insulin lispro is much the same as in pregnant women using regular insulin. This study aims to analyze the Italian data emerging from a multinational, multicenter, retrospective study on mothers with type 1 diabetes mellitus before pregnancy, comparing those treated with insulin lispro for at least 3 months before and 3 months after conception with those treated with regular insulin. The data collected on pregnant women with diabetes attending 15 Italian centers from 1998 to 2001 included: HbA1c at conception and during the first and third trimesters, frequency of severe hypoglycemic episodes, spontaneous abortions, mode and time of delivery, fetal malformations and mortality. Seventy-two diabetic pregnancies treated with lispro and 298 treated with regular insulin were analyzed, revealing a trend towards fewer hypoglycemic episodes in the former, who also had a significantly greater reduction in HbA1c during the first trimester. The rate of congenital malformations was similar in the offspring of the two groups of women treated with insulin lispro or regular insulin. These findings suggest that insulin lispro could be useful for the treatment of hyperglycemia in type 1 diabetic pregnant women.

Fulminant type 1 diabetes as a high risk group for diabetic microangiopathy—a nationwide 5-year-study in Japan

The aim of the present study was to assess the development of microangiopathy in patients with fulminant type 1 diabetes, a novel subtype of type 1B diabetes. In a nationwide survey, we followed 41 patients with fulminant type 1 diabetes and 76 age- and sex-matched patients with type 1A diabetes for 5 years. The following data were recorded every 12 months after the onset of diabetes: seven-point blood glucose concentrations, HbA1c level, urinary albumin excretion, serum C-peptide level, blood pressure, daily dosages of insulin, frequency of severe hypoglycaemic episodes, and neurological and fundoscopic examination. The 5-year cumulative incidence of microangiopathy was 24.4% in fulminant type 1 diabetes and 2.6% in type 1A diabetes. In longitudinal studies using the Kaplan-Meier method, the cumulative incidence of each form of microangiopathy was significantly higher in fulminant type 1 diabetes than in type 1A diabetes; retinopathy was 9.8% vs 0% (p=0.014), nephropathy 12.2% vs 2.6% (p=0.015) and neuropathy 12.2% vs 1.3% (p=0.010), respectively. Mean HbA1c levels were similar in the fulminant and type 1A diabetes groups during the follow-up periods. However, the mean M-value, mean insulin dosages and the frequency of severe hypoglycaemic episodes were significantly higher, and the mean postprandial C-peptide level was significantly lower in the fulminant type 1 diabetes group. These data suggest that patients with fulminant type 1 diabetes are a high-risk subgroup for diabetic microangiopathy associated with the lack of endogenous insulin secretion from the onset of diabetes.

Predictors of fear of hypoglycemia in adolescents with type 1 diabetes and their parents

This study tested the hypothesis that both trait anxiety and hypoglycemic history contribute to fear of hypoglycemia (FOH) both in adolescents with type 1 diabetes mellitus (T1DM) and in their parents, and relationships between FOH and other variables including metabolic control, symptom perception, and use of insulin pump therapy. Thirty-nine parent-adolescent pairs completed questionnaires assessing background and clinical information, hypoglycemic episodes, FOH, and trait anxiety. Adolescent blood was also sampled for glycosylated hemoglobin A1c (HbA1c) measurement. In adolescents, both trait anxiety and frequency of severe hypoglycemic episodes were significant predictors of FOH, together accounting for almost 50% of the variance. Parental FOH was not predicted by their own trait anxiety or their child's hypoglycemic history but by whether they believed that their child carried emergency glucose. FOH was not related to metabolic control, although adolescents who experienced recent severe hypoglycemia (SH) with unconsciousness had significantly higher HbA1c. Parental trait anxiety significantly correlated with child trait anxiety, but parent-child levels of FOH were unrelated. Neither trait anxiety nor FOH related to reported symptoms, and FOH was not lower in parents with insulin pump therapy. Consistent with findings from adult patient populations, trait anxiety levels and recent experiences with hypoglycemia predict FOH in adolescents with T1DM. In parents, however, beliefs about their adolescents' ability to cope with hypoglycemic episodes predicted FOH. FOH in adolescents with T1DM and their parents is a complex construct influenced by multiple personality and situational and behavioral factors, and its impact on diabetes management remains unclear.

Towards a feasible algorithm for tight glycaemic control in critically ill patients: a systematic review of the literature

IntroductionTight glycaemic control is an important issue in the management of intensive care unit (ICU) patients. The glycaemic goals described by Van Den Berghe and colleagues in their landmark study of intensive insulin therapy appear difficult to achieve in a real life ICU setting. Most clinicians and nurses are concerned about a potentially increased frequency of severe hypoglycaemic episodes with more stringent glycaemic control. One of the steps we took before we implemented a glucose regulation protocol was to review published trials employing insulin/glucose algorithms in critically ill patients.MethodsWe conducted a search of the PubMed, Embase and Cochrane databases using the following terms: 'glucose', 'insulin', 'protocol', 'algorithm', 'nomogram', 'scheme', 'critically ill' and 'intensive care'. Our search was limited to clinical trials conducted in humans. The aim of the papers selected was required to be glycaemic control in critically ill patients; the blood glucose target was required to be 10 mmol/l or under (or use of a protocol that resulted in a mean blood glucose = 10 mmol/l). The studies were categorized according to patient type, desired range of blood glucose values, method of insulin administration, frequency of blood glucose control, time taken to achieve the desired range for glucose, proportion of patients with glucose in the desired range, mean blood glucose and frequency of hypoglycaemic episodes.ResultsA total of twenty-four reports satisfied our inclusion criteria. Most recent studies (nine) were conducted in an ICU; nine others were conducted in a perioperative setting and six were conducted in patients with acute myocardial infarction or stroke. Studies conducted before 2001 did not include normoglycaemia among their aims, which changed after publication of the study by Van Den Berghe and coworkers in 2001; glycaemic goals became tighter, with a target range between 4 and 8 mmol/l in most studies.ConclusionStudies using a dynamic scale protocol combining a tight glucose target and the last two blood glucose values to determine the insulin infusion rate yielded the best results in terms of glycaemic control and reported low frequencies of hypoglycaemic episodes.

Evaluation of the insulin application system Autopen 24®

In patients with insulin therapy, a simple to use, reliable and safe insulin application device is a prerequisite to achieve good glucose control, and for reducing and avoiding progression of secondary complications. Modern injection pen systems provide the patient with a high degree of flexibility and quality of life. However, the integration of further and appropriate therapeutic aids into a device can make a positive contribution to compliance and therapy satisfaction. In this multicentre, open, randomised, three-month, cross-over study, the new insulin application device Autopen 24® (designed for Sanofi-Aventis insulin cartridges) was evaluated in comparison to the established OptiPen® Pro device with regard to clinical efficacy (HbA1c, frequency of severe hypoglycaemic episodes) and patients' preference and acceptance in 40 patients (20 women, 20 men; 20 type 1, 20 type 2; age [mean±SD] 49.3±15.1 years; BMI 29.0±5.0 kg/m2). No differences were seen regarding HbA1c and hypoglycaemic episodes between the treatment groups. The Autopen 24 showed a high level of acceptance by patients in comparison to OptiPen Pro and was preferred by older patients with type 2 diabetes. In conclusion, Autopen 24 is a suitable alternative to other injection devices in patients with diabetes mellitus treated with Sanofi-Aventis insulin products. Copyright © 2005 John Wiley & Sons, Ltd.

Development of a New Fear of Hypoglycemia Scale: Preliminary Results

To provide preliminary psychometric data on the Children's Hypoglycemia Index (CHI), a new scale was designed to measure fear of hypoglycemia (FH) in children. One hundred and nine children with type 1 diabetes attending a diabetes summer camp completed the CHI, and 57 of these children completed the CHI 2 weeks later. All participants also completed the Children's Hypoglycemia Fear Survey (CHFS), the Revised Children's Manifest Anxiety Scale (RCMAS), and a Hypoglycemia History Form. Parents of the children also completed a Hypoglycemia History Form. The CHI demonstrated good factor structure, internal consistency, test-retest reliability, and criterion-related validity with established measures. Frequency of severe hypoglycemic episodes since diabetes diagnosis also predicted scores on the Situation- and General-Fear subscales of the CHI. The CHI demonstrated reliability and validity as a measurement of children's FH. The use of this measure offers important clinical and research implications.

Assessment of Therapy with Continuous Subcutaneous Insulin Infusion in an Academic Diabetes Clinic

To assess the results of continuous subcutaneous insulin infusion (CSII) therapy in patients with type 1 diabetes mellitus, especially relative to glycemic control and rate of discontinuation of insulin pump therapy. A retrospective review of the medical records of 107 patients with type 1 diabetes who were receiving CSII at the Diabetes Care Center at the University of Washington Medical Center was performed to evaluate clinical outcomes. All patients considering CSII therapy participated in a class to learn the details of insulin pump treatment. The mean age of our patient population was 36.0 +/- 10.4 years (mean value +/- standard deviation). The mean duration of diabetes at the initiation of insulin pump therapy was 17.0 +/- 9.1 years. The mean duration of CSII use was 36.1 +/- 25.5 months (median, 26.2 months). Insulin lispro was used by 89.7% of the patients. Six patients (5.6%) discontinued CSII therapy after a mean of 19.1 +/- 14.7 months for a variety of reasons. Despite no significant difference in home blood glucose monitoring (number of tests per day) before initiation of CSII, mean hemoglobin A1c levels decreased from 7.6% to 7.1% (P<0.0001), and the occurrence of severe hypoglycemic episodes decreased 73.8% (P = 0.0003). In our academic diabetes clinic with a formal insulin pump program, we noted a significant improvement in hemoglobin A1c values, a significant reduction in the frequency of severe hypoglycemic episodes, and a low rate of discontinuation of CSII. CSII therapy, when provided in conjunction with a standard educational program, should continue to be an important treatment option in appropriately selected patients with type 1 diabetes.

A Risk-Benefit Assessment of Conventional versus Intensive Insulin Therapy

Some retrospective nonrandomised or cross-sectional studies have shown that higher blood glucose levels are associated with more pronounced microvascular complications in patients with insulin-dependent diabetes mellitus (IDDM). The prospective randomised studies had, until recently, been less definitive. Intensified treatment, and thus lower blood glucose levels, has led to an initial worsening of retinopathy, but this tendency towards more advanced retinopathy has been transient. Albuminuria and manifest neuropathy have been retarded to some extent. Today, 2 long term randomised studies, the Stockholm study and the Diabetes Control and Complications Trial (DCCT), have proven that a lowering of mean blood glucose levels, measured as a lower glycosylated haemoglobin (HbA1c) value, retards or halts retinopathy, nephropathy and peripheral neuropathy. Intensified treatment, whether performed with multiple injections or insulin pumps, leads to some weight gain and a 3-fold increase in the frequency of severe hypoglycaemic episodes. Hypoglycaemia did not cause long term reduced cognitive function in either study, but was unpleasant to the patients. A great majority of patients in the Stockholm study stated that their well-being had increased while participating in the study. The Stockholm programme required 35 minutes extra per patient per month, and a physician and a nurse could tutor 400 patients. This would bring a significant reduction of serious complications and a gain in terms of patient discomfort and cost. A programme of intensified treatment for IDDM is generally indicated and is possible to carry out.

Recurrent severe hypoglycemia, intelligence, and speed of information processing

In a previous study, the cumulative effect of recurrent severe hypoglycemia on cognitive function was examined in 100 patients with insulin-treated diabetes and a significant correlation was observed between the frequency of severe hypoglycemic episodes and the difference between their current IQ and estimated premorbid IQ (Langan, Deary, Hepburn, & Frier, 1991). The study here extended this model for examination of the role of biological environmental influences on intelligence. Eighty-five of the original cohort of 100 patients were recalled and tested on Wechsler Performance IQ, a test of premorbid IQ, the Hick Reaction Time task, the Sternberg Memory Scan task and a test of Rapid Visual Information Processing (RVIP). The patients' frequency of severe hypoglycemia was assessed using a structured interview. Both IQ-decrement estimates and frequencies of severe hypoglycemia proved reliable after 18 months (correlations > .75) and the corrected correlation between these two variables was about .4. Therefore, repeated episodes of acute severe neuroglycopenia are associated with a lowering of IQ. Frequency of severe hypoglycemia was significantly related to Hick decision times and to response thresholds in the RVIP task. Factor analysis suggested that hypoglycemia affects decision or response-initiation processes rather than encoding, storage, comparison, or classification processes in short-term memory. Indices of these short-term memory processes were highly related to IQ-type test scores. This study also confirms, in a sample with a near-normal distribution of IQ, that measures of psychometric intelligence are significantly correlated with indices from elementary cognitive tests, especially RVIP task, which is based on signal-detection theory.

Severe hypoglycemia in diabetic patients: frequency, causes, prevention.

Over a 12-mo period, the frequency of severe hypoglycemic episodes was measured in a population of approximately 400 (50% type I) diabetic patients treated with insulin. There were 32 severe insulin reactions in 26 patients, a patient-yr incidence of 8%. The major precipitating causes were patients' errors (nine), and too much insulin or a wrong combination (six). In seven cases no cause could be found. For the group as a whole there was clear evidence of overtreatment as measured by insulin doses (0.89 +/- 0.43 U/kg/day versus 0.65 +/- 0.34 U/kg/day in a convenience group of 100 patients from the same diabetic population [P less than 0.05] ). Furthermore, 6-12 mo after the event the mean insulin dose had decreased from 0.82 +/- 0.25 to 0.69 +/- 0.27 U/kg/day in the subgroup of 20 hypoglycemic patients that could be followed (P less than 0.001). The mean HbAlc levels of the hypoglycemic group and the control group differed significantly (8.1 +/- 1.3% versus 8.7 +/- 1.7%, P less than 0.05). Six to 12 mo after the reaction, the mean HbAlc level in the follow-up subgroup rose from 8.1 +/- 1.3% to 9.1 +/- 1.1% (P less than 0.05). Patients' errors as a cause of the insulin reaction were not only the result of the patients' deficient knowledge but more often of lack of alertness and carelessness. We conclude that it is not possible to prevent all the severe hypoglycemic reactions in diabetic patients. However, besides avoiding overtreatment by the physician, teaching patients to respond more adequately to changing circumstances in daily life or to warning signs could also reduce the incidence of hypoglycemia.