Assessment of severity and frequency of self-reported hypoglycemia on quality of life in patients with type 2 diabetes treated with oral antihyperglycemic agents: A survey study

Background

Some oral antihyperglycemic agents may increase risk of hypoglycemia and thereby reduce patient quality of life. Our objective was to assess the impact of the severity and frequency of self-reported hypoglycemia on health-related quality of life (HRQoL) among patients with type 2 diabetes treated with oral antihyperglycemic agents.

Findings

A follow-up survey was conducted in participants with self-reported type 2 diabetes treated with oral antihyperglycemic agents from the US National Health and Wellness Survey 2007. Data were collected on the severity and frequency of hypoglycemic episodes in the 6 months prior to the survey, with severity defined as mild (no interruption of activities), moderate (some interruption of activities), severe (needed assistance of others), or very severe (needed medical attention). HRQoL was assessed using the EuroQol-5D Questionnaire (EQ-5D) US weighted summary score (utility) and Worry subscale of the Hypoglycemia Fear Survey (HFS). Of the participants who completed the survey (N = 1,984), mean age was 58 years, 57% were male, 72% reported an HbA_1c <7.0%, and 50% reported treatment with a sulfonylurea-containing regimen. Hypoglycemic episodes were reported by 63% of patients (46% mild, 37% moderate, 13% severe and 4% very severe). For patients reporting hypoglycemia, mean utility score was significantly lower (0.78 versus 0.86, p < 0.0001) and mean HFS score was significantly higher (17.5 versus 6.2, p < 0.0001) compared to patients not reporting hypoglycemia. Differences in mean scores between those with and without hypoglycemia increased with the level of severity (mild, moderate, severe, very severe) for utility (0.03, 0.09, 0.18, 0.23) and HFS (6.1, 13.9, 20.1, 25.6), respectively. After adjusting for age, gender, weight gain, HbA_1c, microvascular complications, and selected cardiovascular conditions, the utility decrement was 0.045 (by level of severity: 0.009, 0.055, 0.131, 0.208), and the HFS increase was 9.6 (by severity: 5.3, 12.4, 17.6, 23.2). HRQoL further decreased with greater frequency of hypoglycemic episodes.

Conclusions

Self-reported hypoglycemia is independently associated with lower HRQoL, and the magnitude of this reduction increases with both severity and frequency of episodes in patients with type 2 diabetes treated with oral antihyperglycemic agents.

     

Impaired Awareness of Hypoglycemia Continues to be a Risk Factor for Severe Hypoglycemia Despite the Use of Continuous Glucose Monitoring System in Type 1 Diabetes

Objective: Impaired awareness of hypoglycemia (IAH) is a risk factor for severe hypoglycemia in patients with type 1 diabetes (T1D) not using a continuous glucose monitoring (CGM) system. The current study investigated the prevalence of IAH and its relationship with severe hypoglycemia in T1D patients using CGM systems.Methods: This cross-sectional observational study enrolled 135 patients with T1D and ongoing real-time CGM use. A survey was conducted to assess hypoglycemia awareness with the Gold, Clarke, and Pedersen-Bjergaard questionnaires and the 6-month history of severe hypoglycemia. Other diabetes histories and the CGM glucose data were collected.Results: The Gold, Clarke, and Pedersen-Bjergaard questionnaires demonstrated the overall prevalence of IAH/abnormal awareness to be 33.3%, 43.7%, and 77.0%, respectively. Participant age and duration of T1D were consistently related to IAH or hypoglycemia unawareness with all three questionnaires (P<.05). Amongst the patients using CGM for >6 months, 24.5% were found to have at least one episode of severe hypoglycemia in the preceding 6 months. IAH identified by the Gold and Clarke questionnaires and hypoglycemia unawareness identified by the Pedersen-Bjergaard questionnaire were related to 6-, 4.63-, and 5.83-fold increased risk of severe hypoglycemia (P = .001, .004, and .013), respectively. IAH identified by the Gold/Clarke questionnaires was associated with a longer duration of CGM glucose <54 mg/dL and higher glucose coefficients of variation (P<.05).Conclusion: IAH is highly prevalent and related to a higher risk for severe hypoglycemia in T1D patients using CGM.Abbreviations: CGM = continuous glucose monitoring; CI = confidence interval; HAAF = hypoglycemia-associated autonomic failure; HbA1c = hemoglobin A1C; IAH = impaired awareness of hypoglycemia; T1D = type 1 diabetes     

Continuous Subcutaneous Infusion of Insulin Lispro in Children and Adolescents with Type 1 Diabetes Mellitus

ObjectiveTo provide a comprehensive review of insulin lispro administered by continuous subcutaneous insulin infusion (CSII) in children and adolescents.MethodsWe performed PubMed literature searches to identify clinical studies of insulin lispro administered via CSII within pediatric and adolescent populations.ResultsTwenty-six studies involving 2521 pediatric patients with type 1 diabetes mellitus met inclusion criteria. Of these, 10 were randomized controlled trials (RCTs), 6 of which compared insulin lispro CSII with multiple daily injection (MDI) therapy. We identified 7 additional prospective, nonrandomized studies and 9 retrospective studies. Within the RCTs, endpoint hemoglobin A_1c levels ranged from 6.3% to 8.5% for insulin lispro CSII therapy and from 6.2% to 8.7% for those trials with MDI comparator arms. In those trials that compared insulin lispro CSII with MDI, the endpoint hemoglobin A_1c achieved with insulin lispro was similar or improved compared with observations in the MDI treatment arm. In the RCTs, severe hypoglycemia rates of 0.1 to 0.3 episodes/patient per year were reported for insulin lispro CSII therapy; those trials with MDI comparator arms reported relatively similar severe hypoglycemia rates (0.1 to 0.5 episodes/patient per year). Events of diabetic ketoacidosis (DKA) were rare. Where reported, insulin lispro CSII and MDI therapy demonstrated a similar occurrence of DKA and incidence of severe hypoglycemia. Prospective and retrospective studies demonstrated results similar to the RCT findings.ConclusionsIn 26 studies of more than 2500 pediatric and adolescent patients with type 1 diabetes, with more than 1000 patients specifically receiving insulin lispro CSII, insulin lispro CSII therapy consistently demonstrated similar or improved efficacy and safety vs studied comparators. (Endocr Pract. 2012;18:418-424)     

Glycemic Variation and Hypoglycemia in Patients with well-Controlled Type 1 Diabetes on a Multiple Daily Insulin Injection Program with use of Glargine and Ultralente as Basal Insulin

ObjectiveTo evaluate glycemic variation and hypo-glycemia in patients with well-controlled type 1 diabetes receiving multiple daily insulin injections during glargine and Ultralente use as basal insulin in a clinical trial.MethodsTwenty-two patients (12 men and 10 women, median age, 43 years), with a hemoglobin A1c level < 7.8%, were randomized in a crossover design to receive either insulin glargine or Ultralente insulin as basal insulin for 4 months each, with insulin aspart as prandial insulin. Continuous glucose monitoring and the Fear of Hypoglycemia questionnaire were used at baseline and at the end of each treatment period.ResultsWhereas the mean amplitude of glycemic excursions showed a correlation with the area under the curve of blood glucose < 3.89 mmol/L per day, the number of periods during the day with hypoglycemia was significantly correlated with the M value. Measures of glycemic variation did not differ significantly between glargine and Ultralente treatment. With use of glargine therapy, the SD of blood glucose levels showed a tendency to be lower and the SD of nocturnal blood glucose concentrations was significantly lower. Glucose concentrations were significantly lower during the 1 hour before and the 3 hours after lunch with use of Ultralente. The “Worry” scale on the Fear of Hypoglycemia questionnaire was less during Ultralente therapy and correlated with the number of times blood glucose concentrations were < 3.89 mmol/L daily.ConclusionMeasures of glycemic variability and hypoglycemia need to be studied more in clinical trials of glycemic control in patients with type 1 diabetes. Glycemic variability is less, particularly at night, with glargine as basal insulin. (Endocr Pract. 2007;13:244-250)     

De-Intensification of Diabetes Treatment in Elderly Patients with Type 2 Diabetes Mellitus

Objective: De-intensification of diabetes treatment is recommended in elderly patients with tight glycemic control at high risk of hypoglycemia. However, rates of de-intensification in endocrine practice are unknown. We conducted a retrospective study to evaluate the rate of de-intensification of antidiabetic treatment in elderly patients with type 2 diabetes mellitus (T2DM) and tight glycemic control.Methods: All patients with ≥2 clinic visits over a 1-year period at a major academic diabetes center were included. De-intensification of diabetes treatment was defined as a decrease or discontinuation of any antidiabetic drug without adding another drug, or a reduction in the total daily dose of insulin or a sulfonylurea drug with or without adding a drug without risk of hypoglycemia.Results: Out of 3,186 unique patients, 492 were ≥65 years old with T2DM and hemoglobin A1c (HbA1c) <7.5% (<58 mmol/mol). We found 308 patients treated with a sulfonylurea drug or insulin, 102 of whom had hypoglycemia as per physician note. Among these 102 patients, 38 (37%) were advised to de-intensify therapy. In a subgroup analysis of patients ≥75 years old with HbA1c <7% (<53 mmol/mol), we found that out of 23 patients treated with a sulfonylurea drug or insulin and reporting hypoglycemia, 11 (43%) were advised de-intensification of therapy. There were no significant predictors of de-intensification of treatment.Conclusion: Our study suggests that de-intensification of antidiabetic medications is uncommon in elderly patients with T2DM. Strategies may need to be developed to prevent the potential harm of overtreatment in this population.Abbreviations: ADA = American Diabetes Association; CGM = continuous glucose monitoring; HbA1c = hemoglobin A1c; T2DM = type 2 diabetes mellitus; UKPDS = United Kingdom Prospective Diabetes Study     

Residual dysphasia after severe hypoglycemia in a patient with immune-mediated primary Adrenal insufficiency and type 1 diabetes mellitus: Case report and systematic review of the literature

ObjectiveTo describe a 24-year-old patient with immune-mediated primary adrenal insufficiency and type 1 diabetes mellitus (T1DM) receiving intensive diabetes management who was comatose at presentation attributable to severe hypoglycemia and had residual dysphasia after recovery and to summarize the related literature.MethodsWe present a case report and the findings on systematic review of the pertinent literature to identify the cumulative incidence of severe hypoglycemia with use of intensive insulin therapy in patients with primary adrenal insufficiency and T1DM and to determine the incidence of dysphasia after severe hypoglycemia.ResultsAfter 5 days of mechanical ventilation, our patient was revived. He had severe dysphasia after recovery of consciousness. Magnetic resonance imaging of the brain revealed encephalomalacia in the left temporal, frontal, and parietal lobes. After 6 years of follow-up, he continues to have residual deficits of expressive dysphasia and difficult-to-control seizures but no other neurologic disorders. Systematic review of the literature revealed that studies from the 1950s reported mortality due to hypoglycemia in such a cohort, but no recent studies have described the cumulative incidence of severe hypoglycemia in a cohort of patients with primary adrenal insufficiency and T1DM. To the best of our knowledge, we report the first findings on magnetic resonance imaging of the head in such a patient.ConclusionFortunately, residual dysphasia is an infrequent outcome after severe hypoglycemia. (Endocr Pract. 2007;13:384-388)     

Clinical Efficacy and Patient Satisfaction with U-500 Insulin Pump Therapy in Patients with Type 2 Diabetes

ObjectiveTo determine the safety and efficacy of U-500 regular insulin in pump therapy and to assess satisfaction with U-500 insulin pump therapy in patients with type 2 diabetes and severe insulin resistance.MethodsWe performed a retrospective review of medical records of 6 patients with type 2 diabetes and insulin resistance who had been using U-500 insulin pump therapy for at least 6 months. In addition, we conducted a telephone follow-up patient satisfaction survey.ResultsThe mean age of the patients was 57 ± 6 years. Of the 6 patients (3 men and 3 women), 4 were white, 1 was black, and 1 was Asian. The mean hemoglobin A1c value before continuous subcutaneous insulin infusion therapy with U-500 regular insulin was 9.1% ± 1.8%, and the mean U-100 insulin dose required was 391 ± 91 U/day. In comparison, the mean U-500 insulin dose required at 6 months was 59.2 ± 13.6 U/day, which is equivalent to 296 ± 68 U/day of U-100 insulin (P = 0.04), and the mean hemoglobin A1c value at 6 months after treatment with the insulin pump using U-500 regular insulin was 6.9% ± 0.9% (P = 0.03). In addition, our study patients lost a mean of 6.1 lb during the 6-month period, and no patient had clinically significant episodes of hypoglycemia. The majority of the patients reported a higher satisfaction with the U-500 insulin pump therapy in comparison with conventional insulin treatment.ConclusionU-500 insulin pump therapy is a novel alternative for patients with type 2 diabetes and severe insulin resistance who have not met glycemic control goals with use of standard intensive insulin regimens. (Endocr Pract. 2007;13:721-725)     

Factors Associated With Insulin Pump Discontinuation in Adults With Diabetes: A Time-to-Invent Analysis and Prediction Model

ObjectiveInsulin pump discontinuation has mostly been studied in children and adolescents living with diabetes. We aimed to assess the rate of insulin pump continuation in a population of adult patients with diabetes, at 18 months after initiation; determine the factors associated with pump discontinuation; and develop a simple prediction model.MethodsThis single-center, retrospective study included all adult patients with type 1 diabetes or type 2 diabetes who started insulin pump treatment between January 2015 and June 2018. The exclusion criteria were pregnancy, short-term pregnancy plans, and insulin pump discontinuation within the previous 6 months. The probability of insulin pump continuation after 18 months was estimated using the Kaplan-Meier method. Factors associated with insulin pump discontinuation were studied using a Cox regression model, and an exponential model was built for prediction purposes.ResultsThe study included 315 patients. The mean age was 41 years, the mean duration of diabetes was 16 years, 50% were men, 74% had type 1 diabetes, and the mean hemoglobin A1c level was 9.1% (76 mmol/mol). After 18 months, the rate of insulin pump continuation was 0.80 (95% Confidence Interval (CI), 0.76-0.85). By multivariate analysis, the occurrence of severe hypoglycemia in the previous year was associated with insulin pump discontinuation (hazard ratio, 2.42; 95% CI, 1.30-4.51), while other factors did not reach statistical significance.ConclusionInsulin pump discontinuation occurred in 20% of patients at 18 months after initiation and was mainly associated with a recent history of severe hypoglycemia. The type of diabetes and glycemic control at baseline were not associated with treatment discontinuation.     

The Effect of Long-Term Use of U-500 Insulin Via Continuous Subcutaneous Infusion on Durability of Glycemic Control and Weight in Obese,Insulin-Resistant Patients with Type 2 Diabetes

ObjectiveTo evaluate the long-term efficacy and safety of U-500 insulin administered via continuous subcutaneous insulin infusion (CSII) in patients with insulin-resistant type 2 diabetes and high insulin requirements.MethodsWe retrospectively reviewed the effects of U-500 insulin administered via CSII on durability of gly-cemic control (HbAlc), body weight, total daily insulin dose, and incidence of hypoglycemia in 59 patients with insulin-resistant type 2 diabetes (duration of treatment 1 to 9.5 years; mean treatment duration 49 months). All variables were analyzed by 1-way analysis of variance (ANOVA) from pre-U-500 baseline to time points from 3 to 114 months.ResultsAfter 3 months of U-500 insulin use, hemoglobin A1c dropped significantly from a mean baseline of 8.3% to a mean value of 7.3% (P = .003), and this improvement was sustained for over 66 months of use. There was no significant overall change in body weight or total daily insulin dose over time with the use of U-500 insulin. For those subjects who did gain weight, there was a parallel increase in insulin dose that correlated with weight gain.The overall incidence of severe hypoglycemia was low over the study period, with a mean occurrence of 0.1 episodes per patient per year.ConclusionsU-500 insulin is safe and effective for extended use (up to 9.5 years) in patients with insulin-resistant type 2 diabetes who require high insulin doses, and provides sustained glycemic control without causing excessive weight gain. (Endocr Pract. 2013;19:196-201)     

Risk Factors for Hypoglycemia in Inpatients with Total Parenteral Nutrition and Type 2 Diabetes: A Post HOC Analysis of the Insupar Study

Objective: Treatment of hyperglycemia with insulin is associated with increased risk of hypoglycemia in type 2 diabetes mellitus (T2DM) patients receiving total parenteral nutrition (TPN). The aim of this study was to determine the predictors of hypoglycemia in hospitalized T2DM patients receiving TPN.Methods: Post hoc analysis of the INSUPAR study, which is a prospective, open-label, multicenter clinical trial of adult inpatients with T2DM in a noncritical setting with indication for TPN.Results: The study included 161 patients; 31 patients (19.3%) had hypoglycemic events, but none of them was severe. In univariate analysis, hypoglycemia was significantly associated with the presence of diabetes with end-organ damage, duration of diabetes, use of insulin prior to admission, glycemic variability (GV), belonging to the glargine insulin group in the INSUPAR trial, mean daily grams of lipids in TPN, mean insulin per 10 grams of carbohydrates, duration of TPN, and increase in urea during TPN. Multiple logistic regression analysis showed that the presence of diabetes with end-organ damage, GV, use of glargine insulin, and TPN duration were risk factors for hypoglycemia.Conclusion: The presence of T2DM with end-organ damage complications, longer TPN duration, belonging to the glargine insulin group, and greater GV are factors associated with the risk of hypoglycemia in diabetic noncritically ill inpatients with parenteral nutrition.Abbreviations: ADA = American Diabetes Association; BMI = body mass index; CV% = coefficient of variation; DM = diabetes mellitus; GI = glargine insulin; GV = glycemic variability; ICU = intensive care unit; RI = regular insulin; T2DM = type 2 diabetes mellitus; TPN = total parenteral nutrition     

Insulin Therapy and Hypoglycemia in Type 2 Diabetes Mellitus

Background: Iatrogenic hypoglycemia, the limiting factor in the glycemic management of diabetes mellitus (DM), is the result of therapeutic insulin excess and compromised physiological and behavioral defenses against falling plasma glucose concentrations.Objective: The goal of this article was to review the available evidence on insulin therapy and hypoglycemia, with a focus on type 2 DM.Methods: This review was based on the author's clinical experience, his >3 decades of translational research in the area of hypoglycemia, and his knowledge of the relevant preclinical and clinical literature.Results: Glycemic defenses become compromised rapidly in type 1 DM but slowly in type 2 DM. As a result, the frequency of hypoglycemia increases progressively as patients approach the insulin-deficient end of the spectrum of type 2 DM. Indeed, it appears that most episodes of hypoglycemia, including those of severe hypoglycemia, occur in individuals with type 2 DM. The conventional risk factors for hypoglycemia are based on relative or absolute insulin excess. It is clear that the pathogenesis of hypoglycemia-associated autonomic failure, and thus an increased risk for iatrogenic hypoglycemia, stems fundamentally from insulin deficiency. Relevant additional risk factors include the degree of insulin deficiency, a history of severe hypoglycemia, hypoglycemia unawareness, or both, as well as recent antecedent hypoglycemia, prior exercise and sleep, and aggressive glycemic therapy per se in advanced type 2 DM, just as in type 1 DM. The prevention of hypoglycemia involves the practice of hypoglycemia risk reductionȔdiscussion of the issue, application of the principles of aggressive therapy, and consideration of both the conventional risk factors and those relevant to compromised glycemic defensesȔin advanced type 2 DM, just as in type 1 DM. With this approach, it is possible to improve glycemic control and reduce the frequency of hypoglycemia in many people with DM.Conclusions: Pending the prevention and cure of DM, people with this disease need safe and effective therapies. Ultimately, that will require glucose-regulated insulin replacement or secretion. In the meantime, insight into the mechanisms of hypoglycemia-associated autonomic failure may lead to interventions that will further improve the lives of people affected by DM by reducing the frequency of hypoglycemia without compromising glycemic control.(Insulin. 2007;2:127-133)     

Diabetes Duration and the Efficacy and Safety of Insulin Glargine Versus Comparator Treatment in Patients with Type 2 Diabetes Mellitus

ObjectiveTo evaluate the effect of diabetes duration on efficacy and safety in patients with type 2 diabetes mellitus (T2DM) using insulin glargine versus comparator (oral antidiabetic drugs [OADs], dietary changes, or other insulins).MethodsData were pooled from randomized controlled clinical trials conducted in adults with T2DM with at least 24-week treatment with insulin glargine or a comparator, where predefined insulin titration algorithms were utilized to achieve fasting plasma glucose (FPG) concentrations of ≤ 100 mg/dL. Glycated hemoglobin A1C (A1C), FPG, and insulin dose and safety (hypoglycemia) outcomes were analyzed.ResultsNine studies were included in the analysis of 2,930 patients. Patients with shorter duration of diabetes were more likely to have greater reductions in A1C compared with those who had longer-duration disease (P < .0001). Disease duration did not affect change in FPG concentrations (P = .9017), but lower weight-adjusted insulin dose was correlated with longer-duration disease (P < .0001). Patients with longer-duration diabetes had increased risks of symptomatic hypoglycemia, confirmed hypoglycemia (self-monitored blood glucose < 50 mg/dL and < 70 mg/dL), and nocturnal hypoglycemia (all P < .001). No significant relationship was found between severe hypoglycemia and duration of diabetes. However, treatment with insulin glargine lowered A1C values more effectively than comparator treatments with fewer hypoglycemic episodes.ConclusionPatients with shorter-duration T2DM better achieved target A1C levels and had less hypoglycemia than those with longer disease duration. Insulin glargine was associated with reduced A1C and fewer hypoglycemic events than comparators, regardless of disease duration. (Endocr Pract. 2014;20:120-128)     

Effects of Pramlintide in Patients with Type 2 Diabetes Mellitus: An Analysis Using Daily Insulin Dose Tertiles

ObjectiveThe purpose of the analysis was to investigate if the efficacy and tolerability of 6 months of pramlintide therapy in patients with type 2 diabetes mellitus (T2DM) differed with increasing levels of concomitant insulin doses, using data from 3 previously described clinical trials.MethodsIn this post hoc analysis, data from 2 pooled, placebo-controlled pivotal trials and 1 clinical practice trial were evaluated by baseline insulin use tertile in patients with T2DM.ResultsIn the pivotal trials, both glycated hemoglobin (A1C) and body weight decreased similarly across tertiles with pramlintide. A1C decreased slightly and body weight remained relatively unchanged across tertiles with placebo. Similarly, in the clinical practice trial, pramlintide was associated with decreases in A1C, body weight, and total daily insulin use across the tertiles. Overall, the most common adverse events were gastrointestinal in nature, and the rate of severe hypoglycemia was low.ConclusionThese results suggest that pramlintide therapy was associated with improved A1C and decreased body weight, with a low rate of severe hypoglycemia, among patients with T2DM, regardless of baseline insulin use. (Endocr Pract. 2014;20:1070-1075)     

Hypoglycemia: Still The Limiting Factor in the Glycemic Management of Diabetes

ObjectiveTo review the prevalence of, risk factors for, and prevention of hypoglycemia from the perspective of the pathophysiologic aspects of glucose counterregulation in diabetes.MethodsThis review is based on personal experience and research and the relevant literature.ResultsAlthough it can result from insulin excess alone, iatrogenic hypoglycemia is generally the result of the interplay of therapeutic insulin excess and compromised defenses against declining plasma glucose concentrations. Failure of β-cells of the pancreas—early in patients with type 1 diabetes mellitus but later in those with type 2 diabetes mellitus (T2DM)—causes loss of the first 2 physiologic defenses: a decrease in insulin and an increase in glucagon. Such patients are critically dependent on epinephrine, the third physiologic defense, and neurogenic symptoms that prompt the behavioral defense (carbohydrate ingestion). An attenuated sympathoadrenal response to declining glucose levels—caused by recent antecedent hypoglycemia, prior exercise, or sleep—causes hypoglycemia-associated autonomic failure (HAAF) and thus a vicious cycle of recurrent hypoglycemia. Accordingly, hypoglycemia is infrequent early in T2DM but becomes increasingly more frequent in advanced (absolutely endogenous insulin-deficient) T2DM, and risk factors for HAAF include absolute endogenous insulin deficiency; a history of severe hypoglycemia, hypoglycemia unawareness, or both; and aggressive glycemic therapy per se.ConclusionBy practicing hypoglycemia risk reduction— addressing the issue, applying the principles of aggressive glycemic therapy, and considering both the conventional risk factors and those indicative of HAAF— it is possible both to improve glycemic control and to minimize the risk of hypoglycemia in many patients. (Endocr Pract. 2008;14:750-756)     

Continuous Subcutaneous Pramlintide Infusion Therapy In Patients With Type 1 Diabetes: Observations From A Pilot Study

ObjectiveTo investigate the efficacy and safety of continuous (basal-bolus) subcutaneous pramlintide infusion (CSPI) in patients with type 1 diabetes mellitus.MethodsA 16-week, open-label, single-arm pilot study enrolled 11 patients (mean ± SD values: age, 39.9 ± 4.0 years; hemoglobin A1c, 8.20% ± 0.60%; weight, 92.3 ± 18.4 kg; body mass index, 29.7 ± 5.1 kg/m²) with longterm type 1 diabetes mellitus (20.7 ± 1.3 years; duration of pump therapy, 9.5 ± 6.0 years). Pramlintide basal infusion was begun with continuous subcutaneous infusion at 9 μg/h. After 3 days, premeal bolus doses of pramlintide were initiated at 15 μg and titrated to 60 μg per meal. Basal and bolus insulin doses were reduced 10% on initiation of CSPI and adjusted thereafter as needed to prevent hypoglycemia.ResultsAfter 16 weeks of pramlintide therapy, mean ± SD hemoglobin A1c decreased to 7.85% ± 0.74% (-0.35%). The fasting glucose level declined from 198.2 ± 66.9 mg/dL to 135.8 ± 63.9 mg/dL. The mean weight decreased to 91.8 ± 20.1 kg (-0.5 kg) at week 12. The daily bolus insulin requirement decreased 20%; daily basal insulin was unchanged (27.7 ± 11.7 U). All patients experienced mild postprandial hypoglycemia, but no severe hypoglycemia was reported. Three of the 11 study participants experienced mild initial nausea, but all patients successfully titrated bolus doses to 60 μg within 3 weeks.ConclusionIn this pilot study of 11 patients with type 1 diabetes using insulin pumps, CSPI seemed safe and well tolerated, did not alter pramlintide pharmacokinetic variables, and reduced fasting glucose levels. Larger studies of this method for pramlintide administration seem warranted. (Endocr Pract. 2009;15:689-695)     

Hypoglycemia in childhood type 1 diabetes mellitus: Understanding and managing the dark side of intensive insulin therapy

Background: Despite the availability of advanced insulin delivery systems, blood glucose-monitoring equipment, and insulin analogue formulations, hypoglycemia remains a significant concern in the treatment of children and adolescents with type 1 diabetes mellitus (DM). Furthermore, patients who manage their blood glucose levels most effectively may also be the ones at greatest risk for hypoglycemia.Objective: The aim of this article was to review current issues surrounding the pathophysiology and frequency of hypoglycemia in children and adolescents with type 1 DM.Methods: Relevant articles for this review were identified through a search of MEDLINE (1992–2007; English-language articles only). The search terms used were children, adolescents, hypoglycemia, diabetes, insulin, and continuous subcutaneous insulin infusion.Results: The threat of severe hypoglycemia remains a major obstacle to the effective treatment of type 1 DM. Basalbolus therapy, using continuous subcutaneous insulin infusion or multiple daily injections, is the most effective and flexible method available for maintaining good glycemic control in children as well as in adults. Insulin analogues can be used effectively in these regimens and may be helpful toward addressing risks for hypoglycemia. Patient education should also be given a high priority in addressing the risk of hypoglycemia in children and adolescents with type 1 DM. The development of continuous glucose-monitoring systems offers the potential for an even brighter future for this group of patients.Conclusions: Recent advances in DM technology reduce but do not eliminate the risk of hypoglycemia in youth with type 1 DM. These observations underscore the need for a closed-loop insulin delivery system in which the rate of insulin infusion is regulated by real-time changes in glucose concentrations. (Insulin. 2007;2:157–165)Key words: type 1 diabetes mellitus; hypoglycemia; children; adolescents; insulin analogue; continuous subcutaneous insulin infusion; multiple daily injections; basal-bolus therapy.Accepted for publication 09052007     

Postmortem Diagnosis of Diabetic Ketoacidosis Presenting as the "Dead-in-Bed Syndrome"

Objective:To report a case of a young male with type 1 diabetes mellitus found dead in his bed, initially assumed to have died from hypoglycemia (i.e., the “dead in bed” syndrome). However, his autopsy findings revealed that diabetic ketoacidosis (DKA) was the cause of death.MethodsWe present the laboratory and autopsy findings of the patient, highlighting the importance of laboratory analyses of the vitreous humor and microscopy of kidney tissue when investigating the cause of sudden death in patients with type 1 diabetes.ResultsA 25-year-old healthy male with type 1 diabetes on continuous subcutaneous insulin infusion therapy was found dead in his undisturbed bed. An autopsy included vitreous humor analyses. His results were as follows: glucose of 755 mg/dL (reference range 70-105 mg/dL), anion gap > 36 mEq (reference range 4-12 mEq/L), elevated acetone at 66 mg/dL (reference range negative), which were consistent with DKA. Renal microscopy demonstrated subnuclear vacuoles in the proximal tubules, 1 of 2 lesions were described as an Armanni-Ebstein lesion, which is a postmortem finding in patients who die from diabetic coma.ConclusionThe most likely cause of death at home in young patients with type 1 diabetes is severe hypoglycemia. However, an autopsy of the present case confirmed DKA based on vitreous humor biochemistry and microscopic examination of the kidneys, which demonstrated the Armanni-Ebstein phenomenon. Analysis of the vitreous fluid and microscopic examination of the kidneys for the presence of Armanni-Ebstein lesion can be used to help determine the cause of death in patients with type 1 diabetes mellitus. (Endocr Pract. 2014;20:e123-e125)     

Patients Achieving Good Glycemic Control (HBA1c <7%) Experience A Lower Rate of Hypoglycemia With Insulin Degludec Than with Insulin Glargine: A Meta-Analysis of Phase 3A Trials

Objective: Meta-analysis to compare hypoglycemia rates of basal insulin degludec (IDeg) with insulin glargine (IGlar) in patients with diabetes achieving good glycemic control (hemoglobin A_1c [HbA_1c] <7% at end of trial).Methods: In a preplanned meta-analysis, patient data from 7 randomized, treat-to-target, 26- or 52-week trials in patients with type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) who administered IDeg (n = 2,899) or IGlar (n = 1,431) once daily were analyzed. Using a negative binomial regression model, this meta-analysis compared hypoglycemia rates in patients achieving HbA_1c <7% at end of trial with IDeg (n = 1,347) and IGlar (n = 697).Results: In all trials, IDeg was noninferior to IGlar in HbA_1c reduction from baseline. At end of trial, 2,044 patients (T2DM, n = 1,661; T1DM, n = 383) achieved HbA_1c <7%. The overall confirmed hypoglycemia rate, defined as plasma glucose <56 mg/dL or severe hypoglycemia if requiring assistance, was significantly lower with IDeg versus IGlar (estimated rate ratio [ERR] IDeg:IGlar, 0.86; 95% confidence interval [CI], 0.76 to 0.98). The nocturnal confirmed hypoglycemia rate, defined as occurring between midnight and 6:00 am, was significantly lower with IDeg (ERR, 0.63; 95% CI, 0.52 to 0.77). In the maintenance period (16 weeks onward when average insulin dose and glycemic levels stabilized), the overall confirmed hypoglycemia rate was significantly lower (ERR, 0.79; 95% CI, 0.68 to 0.92) and the nocturnal confirmed hypoglycemia rate was significantly lower (ERR, 0.57; 95% CI, 0.45 to 0.72) with IDeg versus IGlar.Conclusion: Patients with T1DM and T2DM achieved HbA_1c <7% with significantly lower rates of overall and nocturnal confirmed hypoglycemia with IDeg versus IGlar. The lower hypoglycemia rate with IDeg was more pronounced in the maintenance period.Abbreviations: ERR = estimated rate ratio; HbA_1c = hemoglobin A_1c; IDeg = insulin degludec; IGlar = insulin glargine; NPH = Neutral Protamine Hagedorn; PG = plasma glucose; T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus     

Improved Glycemic Control with Insulin Glargine Versus Pioglitazone as Add-On Therapy to Sulfonylurea or Metformin in Patients with Uncontrolled Type 2 Diabetes Mellitus

ObjectiveTo compare glycemic control with add-on insulin glargine versus pioglitazone treatment in patients with type 2 diabetes.MethodsThis 48-week, multicenter, parallel-group, open-label study randomized 389 adults with poorly controlled type 2 diabetes (glycated hemoglobin A1c [A1C], 8.0% to 12.0%), despite ≥ 3 months of sulfonylurea or metformin monotherapy, to receive add-on therapy with insulin glargine or pioglitazone. Outcomes included A1C change from baseline to end point (primary), percentage of patients achieving A1C levels ≤ 7.0%, and changes from baseline in fasting plasma glucose, body mass index, weight, and serum lipids. The safety analysis included incidence of adverse events and rates of hypoglycemia.ResultsAt end point, insulin glargine yielded a significantly greater reduction in A1C in comparison with pioglitazone (-2.48% versus -1.86%, respectively; 95% confidence interval, -0.93 to -0.31; P = .0001, 48-week modified intent-to-treat population). Insulin glargine also yielded significantly greater reductions in fasting plasma glucose at all time points (end point difference, -34.9 mg/ dL; 95% confidence interval, -47.6 to -22.2; P < .0001). In comparison with pioglitazone, insulin glargine resulted in a lower overall incidence of possibly related treatmentemergent adverse events (12.0% versus 20.7%) and fewer study discontinuations (2.2% versus 9.1%), but a higher rate (per patient-year) of confirmed clinically relevant hypoglycemic episodes (blood glucose < 70 mg/dL and all severe hypoglycemia) (4.97 versus 1.04; P <.0001) and severe hypoglycemia (0.07 versus 0.01; P = .0309). Weight and body mass index changes were similar between the 2 treatment groups.ConclusionThe addition of insulin glargine early in the diabetes treatment paradigm in patients for whom sulfonylurea or metformin monotherapy had failed resulted in significantly greater improvements in glycemic control in comparison with the addition of pioglitazone. Although severe hypoglycemia was more frequent in patients with insulin glargine therapy, hypoglycemic events occurred in < 5% of patients in the insulin glargine treatment group. (Endocr Pract. 2010;16:588-599)