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     

Economic and Clinical Impact of Inpatient Diabetic Hypoglycemia

ObjectiveTo assess the clinical and economic impact of hypoglycemia that develops during hospitalization of patients with diabetes.MethodsIn this retrospective cohort study, data from 70 hospitals were used to identify the first inpatient encounter for adult patients with diabetes. Patients were included if all blood glucose measurements were 70 mg/dL or higher during the first 24 hours and their primary discharge diagnosis was for a condition other than hypoglycemia. Those who developed laboratory evidence of hypoglycemia (blood glucose < 70 mg/dL after 24 hours) were compared with patients whose blood glucose values were all 70 mg/dL or higher. An alternative definition of hypoglycemia (blood glucose < 50 mg/dL after 24 hours) was also evaluated. We adjusted for potential confounders with multivariate models.ResultsHypoglycemia had an adverse effect on all outcomes among more than 100 000 diabetic patients. After adjustment, patients with diabetes who developed hypoglycemia had higher charges (38.9%), longer lengths of stay (3.0 days), higher mortality (odds ratio, 1.07; 95% confidence interval, 1.02-1.11), and higher odds of being discharged to a skilled nursing facility (odds ratio, 1.58; 95% confidence interval, 1.48-1.69) than diabetic patients without hypoglycemia (P < .01 for all). In all cases, using the lower threshold (< 50 mg/dL) to define hypoglycemia resulted in similar findings with a larger magnitude of differences.ConclusionsAlthough a direct causal relationship cannot be inferred, these study findings suggest the importance of carefully maintaining euglycemia during hospitalizations. Whether the observed worse outcomes were due to hypoglycemia itself or whether they were a marker of worse outcomes due to other causes requires further research. (Endocr Pract. 2009;15:302-312)     

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     

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     

Self-Report of Hypoglycemia and Health-Related Quality of Life in Patients with Type 1 and Type 2 Diabetes

ObjectiveTo establish the prevalence of self-reported hypoglycemia among ambulatory patients with diabetes and assess its impact on health-related quality of life (HRQoL).MethodsThis study was a cross-sectional analysis of a postal survey disbursed during the first quarter of 2010 to 875 adults with type 1 or 2 diabetes identified on the basis of an index clinical encounter for diabetes management between August 1, 2005 and June 30, 2006. The survey included questions regarding hypoglycemia, self-rating of health, and questions adapted from Confidence in Diabetes Self-Care, Generalized Anxiety Disorder-7, EuroQol5-D, and the Hypoglycemic Fear Survey. Data were analyzed using a two-sample t test for continuous variables and a chi-square test for categorical variables, with multivariate analysis to adjust for age, gender, diabetes duration, and Charlson comorbidity index.ResultsThe survey was completed by 418 patients (47.8% response rate). Of the respondents, 26 of 92 (28.3%) with type 1 and 55 of 326 (16.9%) with type 2 diabetes reported at least one episode of severe hypoglycemia within the previous 6 months. Fear of hypoglycemia, including engagement in anticipatory avoidance behaviors, was highest in patients with type 2 diabetes reporting severe hypoglycemia and all patients with type 1 diabetes (P<.001). HRQoL was lower in patients with type 2 (but not type 1) diabetes reporting severe hypoglycemia (P<.01).ConclusionClinicians and health systems should incorporate screening for hypoglycemia into the routine health assessment of all patients with diabetes. Fear of hypoglycemia places patients at risk for counterproductive behaviors, impairs HRQoL, and should be considered in individualizing glycemic goals. (Endocr Pract. 2013; 19:792-799)     

Can Continuous Glucose Monitoring Provide Objective Documentation of Hypoglycemia Unawareness?

ObjectiveTo establish criteria defining hypoglycemia as detected by the continuous glucose monitoring system (CGMS) in patients with type 1 diabetes that best predict hypoglycemia unawareness (HUN), established by a validated questionnaire.MethodsAdult patients were selected for inclusion in this study if they had long-standing type 1 diabetes, a fasting level of C peptide of ≤ 0.6 ng/mL, commitment to achieving glycemic control, and a hemoglobin A1c value no higher than 9%. After clinical data and self-monitoring of plasma glucose data were collected, patients underwent a 72-hour glucose monitoring session with use of a Medtronic-MiniMed CGMS. The presence of HUN was determined by a questionnaire. Factors independently associated with HUN were estimated by multivariate independent analysis.ResultsOur study group consisted of 60 patients (33 women and 27 men) who ranged in age from 18 to 84 years (mean, 50.4) and had had diabetes for 5 to 56 years (mean, 23.8). The best predictor of HUN was the maximal duration of hypoglycemia, as determined by the CGMS (P = 0.001). Detection of hypoglycemic episodes with a duration of more than 90 minutes identified patients who had HUN with an 88% specificity and 75% sensitivity. HUN was also significantly associated with use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (P = 0.003) and with a longer duration of diabetes (P = 0.008).ConclusionThe CGMS can be used for objective detection of patients with HUN. (Endocr Pract. 2005; 11:83-90)     

The Emerging Role Of Adjunctive Noninsulin Antihyperglycemic Therapy In The Management Of Type 1 Diabetes

Objective: Review available data on adjunctive therapies for type 1 diabetes (T1D), with a special focus on newer antihyperglycemic agents.Methods: Published data on hypoglycemia, obesity, mortality, and goal attainment in T1D were reviewed to determine unmet therapeutic needs. PubMed databases and abstracts from recent diabetes meetings were searched using the term “type 1 diabetes” and the available and investigational sodium-glucose cotransporter (SGLT) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, dipeptidyl peptidase 4 inhibitors, and metformin.Results: The majority of patients with T1D do not meet glycated hemoglobin (A1C) goals established by major diabetes organizations. Hypoglycemia risks and a rising incidence of obesity and metabolic syndrome featured in the T1D population limit optimal use of intensive insulin therapy. Noninsulin antihyperglycemic agents may enable T1D patients to achieve target A1C levels using lower insulin doses, which may reduce the risk of hypoglycemia. In pilot studies, the SGLT2 inhibitor dapagliflozin and the GLP-1 receptor agonist liraglutide reduced blood glucose, weight, and insulin dose in patients with T1D. Phase 2 studies with the SGLT2 inhibitor empagliflozin and the dual SGLT1 and SGLT2 inhibitor sotagliflozin, which acts in the gut and the kidney, have demonstrated reductions in A1C, weight, and glucose variability without an increased incidence of hypoglycemia.Conclusion: Newer antihyperglycemic agents, particularly GLP-1 agonists, SGLT2 inhibitors, and dual SGLT1 and SGLT2 inhibitors, show promise as adjunctive treatment for T1D that may help patients achieve better glucose control without weight gain or increased hypoglycemia.Abbreviations:A1C = glycated hemoglobinBMI = body mass indexCI = confidence intervalDKA = diabetic ketoacidosisDPP-4 = dipeptidyl peptidase 4GLP-1 = glucagonlike peptide 1PYY = polypeptide tyrosine tyrosineSGLT = sodium-glucose cotransporterSGLT1 = sodium-glucose cotransporter 1SGLT2 = sodium-glucose cotransporter 2T1D = type 1 diabetesT2D = type 2 diabetesTDD = total daily dosage     

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)     

Liraglutide as Additional Treatment to Insulin in Obese Patients with Type 1 Diabetes Mellitus

ObjectiveBecause approximately 40% of patients with type 1 diabetes have the metabolic syndrome, we tested the hypothesis that addition of liraglutide to insulin in obese patients with type 1 diabetes will result in an improvement in plasma glucose concentrations, a reduction in hemoglobin A1c (HbA1c), a fall in systolic blood pressure, and weight loss.MethodsThis is a retrospective analysis of data obtained from 27 obese patients with type 1 diabetes treated with liraglutide in addition to insulin. Patients were also treated for hypertension. Paired t tests were used to compare the changes in HbA1c, insulin doses, body weight, body mass index, 4-week mean blood glucose concentrations (28-day insulin pump mean blood glucose), blood pressure, and lipid parameters prior to and 180 ± 14 days after liraglutide therapy.ResultsMean glucose concentrations fell from 191 ± 6 to 170 ± 6 mg/dL (P = .002). HbA1c fell from 7.89 ± 0.13% to 7.46 ± 0.13% (P = .001), without an increase in frequency of hypoglycemia. Mean body weight fell from 96.20 ± 3.68 kg to 91.56 ± 3.78 kg (P<.0001). Daily total and bolus doses of insulin fell from 73 ± 6 to 60 ± 4 (P = .008) units and from 40 ± 5 to 29 ± 3 units (P = .011), respectively. Mean systolic blood pressure fell from 130 ± 3 to 120 ± 4 mm Hg (P = .020).ConclusionAddition of liraglutide to insulin in obese patients with type 1 diabetes mellitus leads to improvements in glycemic control and HbA1c and to reductions in insulin dose, systolic blood pressure, and body weight. (Endocr Pract. 2013;19:963-967)     

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)     

Glycemic Control After Hospital Discharge in Insulin-Treated Type 2 Diabetes: A Randomized Pilot Study of Daily Remote Glucose Monitoring

ObjectiveLittle is known about glycemic control in type 2 diabetes patients treated with insulin in the high-risk period between hospital discharge and follow-up. We sought to assess the impact of remote glucose monitoring on postdischarge glycemic control and insulin titration.MethodsWe randomly assigned 28 hospitalized type 2 diabetes patients who were discharged home on insulin therapy to routine specialty care (RSC) or RSC with daily remote glucose monitoring (RGM). We compared the primary outcome of mean blood glucose and exploratory outcomes of hypoglycemia/hyperglycemia rates, change in hemoglobin A_1c and glycated albumin, and insulin titration frequency between groups.ResultsMean blood glucose was not significantly different between the treatment arms (144 ± 34 mg/dL in the RSC group and 172 ± 41 mg/dL in the RGM group; not significant), nor were there significant differences in any of the other measures of glycemia during the month after discharge. Hypoglycemia (glucometer reading < 60 mg/dL) was common, occurring in 46% of subjects, with no difference between groups. In as-treated analysis, insulin dose adjustments (29% with an increase and 43% with decrease in insulin dose) occurred more frequently in the patients who used RGM (average of 2.8 vs. 1.2 dose adjustments; P = .03).ConclusionIn this pilot trial in insulin-treated type 2 diabetes, RGM did not affect glycemic control after hospital discharge; however, the high rate of hypoglycemia in the postdischarge transition period and the higher frequency of insulin titration in patients who used RGM suggest a safety role for such monitoring in the transition from hospital to home. (Endocr Pract. 2015;21:115-121)     

Reduced Hypoglycemia and Comparable Efficacy with Insulin Glargine 300 U/ML Versus Insulin Glargine 100 U/ML in Patients with Type 2 Diabetes Achieving Different Levels of Prebreakfast Self-Monitored Plasma Glucose

Objective: To evaluate the efficacy and safety of insulin glargine 300 U/mL (Gla-300) and insulin glargine 100 U/mL (Gla-100) in patients with type 2 diabetes (T2D) who reached prebreakfast self-monitored plasma glucose (SMPG) levels <100 and <130 mg/dL.Methods: This was a post hoc analysis of insulin-naïve (EDITION 3, NCT01676220) and experienced (EDITION 2, NCT01499095) patients with uncontrolled T2D, randomized to 6 months of Gla-300 versus Gla-100 treatment. Endpoints included glycated hemoglobin A1c change, hypoglycemia incidence, and event rates. Separate comparisons were done for patients achieving prebreak-fast fasting glucose of <100 versus ≥100 mg/dL and <130 versus ≥130 mg/dL.Results: Efficacy did not differ significantly between treatments in either study. Overall, basal insulin doses were ~10% higher with Gla-300 versus Gla-100. EDITION 2: overall and documented (≤70 mg/dL) hypoglycemia rates were significantly lower with Gla-300 versus Gla-100 in all SMPG groups except <100 mg/dL; nocturnal hypoglycemia rates were significantly lower with Gla-300 in all SMPG groups. EDITION 3: overall hypoglycemia rates were significantly lower with Gla-300 in patients with SMPG ≥100 mg/dL and those with SMPG <130 mg/dL; documented hypoglycemia rates were significantly lower in all SMPG groups except ≥130 mg/dL. Nocturnal and nocturnal documented hypoglycemia rates did not differ by treatment group. Hypoglycemia incidence did not differ by treatment in any SMPG group.Conclusion: In patients with T2D initiating basal insulin or previously treated for ≥6 months with basal insulin, Gla-300 provides similar efficacy to Gla-100 and reduces risk of hypoglycemia for many patients, despite a ~10% higher insulin dose.Abbreviations: A1C = glycated hemoglobin A1c; ADA = American Diabetes Association; Gla-100 = insulin glargine 100 U/mL; Gla-300 = insulin glargine 100 U/mL; OAD = oral antidiabetes drug; SMPG = self-monitored plasma glucose; T2D = type 2 diabetes     

Hypoglycemia Rates After Restriction of High-Dose Glargine in Hospitalized Patients

Objective: Hypoglycemia remains one of the main challenges of insulin therapy. To reduce insulin-related hypoglycemia at our institution, we restricted inpatient ordering of high glargine doses (≥0.5 U/kg/day) to endocrine staff in May 2013. This retrospective cohort study assesses its effect on hypoglycemia and glycemic control within 48 hours of admission (ADM).Methods: We identified 692 adult patients hospitalized at Boston Medical Center who received glargine upon ADM from November 1, 2012 through April 30, 2013 as the pre-intervention group, and 651 adult patients admitted between November 1, 2013 and April 30, 2014 as the postintervention group. Demographics, medical history, home insulin regimen, concurrent oral diabetes medications or glucocorticoid administration, ADM serum creatinine, all blood glucose levels (BG) ≤48 hours of ADM, and hemoglobin A1c values ≤3 months were assessed. Hypoglycemia was defined as BG ≤70 mg/dL, and hyperglycemia as BG ≥200 mg/dL. Multivariable regression models assessed potential associations between covariates and incidence of hypoglycemia and average BG ≤48 hours of ADM.Results: Demographics were similar between groups. Significantly less patients received high-dose glargine in the post-intervention group (5.2% vs. 0.3%, P<.001). Incidences of hypoglycemia were significantly lower in the postintervention group (20.9% vs. 17.8%, P<.001 per ADM; 3.4% vs. 2.3%, P = .001 per BG measurements [BGM]). Mean BG levels ≤48 hours of ADM and incidence of hyperglycemia were not significantly different. The adjusted incident rate ratio of hypoglycemia was 0.63 per ADM and 0.74 per BGM in the postintervention group compared to the pre-intervention group (P = .001 and P = .063, respectively).Conclusion: We found that implementation of a restriction on high doses of glargine resulted in lower rates of hypoglycemia without worsening glycemic control.Abbreviations:ADM = admissionBG = blood glucoseBGM = blood glucose measurementsBMC = Boston Medical CenterBMI = body mass indexEMR = electronic medical recordHgbA1c = hemoglobin A1cIRR = incidence rate ratioNPH = neutral protamine HagedornTDD = total daily doseT2D = type 2 diabetes     

How Patients With Type 1 Diabetes Translate Continuous Glucose Monitoring Data into Diabetes Management Decisions

Objective: To understand how patients use continuous glucose monitoring (CGM) data in their diabetes management.Methods: We surveyed patients who regularly used CGM (>6 days per week), using 70 questions, many scenario-based. The survey had 6 sections: patient characteristics, general CGM use, hypoglycemia prevention and management, hyperglycemia prevention and management, insulin dosing adjustments (both for incidental hyperglycemia not at meals and at mealtimes), and real-time use versus retrospective analysis.Results: The survey was completed by 222 patients with type 1 diabetes. In response to a glucose of 220 mg/dL, the average correction dose adjustment based on rate of change arrows varied dramatically. Specifically, when the CGM device showed 2 arrows up (glucose increasing >3 mg/dL/minute), respondents stated they would increase their correction bolus, on average, by 140% (range, 0 to 600%). Conversely, 2 arrows down (glucose decreasing >3 mg/dL/minute) caused respondents to reduce their dose by 42%, with 24% omitting their dose entirely. Furthermore, 59% of respondents stated they would delay a meal in response to rapidly rising glucose, whereas 60% would wait until after a meal to bolus in response to falling glucose levels. With a glucose value of 120 mg/dL and a falling glucose trend, 70% of respondents would prophylactically consume carbohydrates to avoid hypoglycemia.Conclusion: CGM users utilize CGM data to alter multiple aspects of their diabetes care, including insulin dose timing, dose adjustments, and in hypoglycemia prevention. The insulin adjustments are much larger than common recommendations. Additional studies are needed to determine appropriate insulin adjustments based on glucose trend data.Abbreviations: A_1c = hemoglobin A_1c CGM = continuous glucose monitoring ROC = rate of change SMBG = self-monitored blood glucose     

Octreotide Therapy for Recurrent Refractory Hypoglycemia Due to Sulfonylurea In Diabetes-Related Kidney Failure

ObjectiveTo describe a patient with kidney insufficiency from diabetes treated with glyburide, who presented with prolonged and recurrent hypoglycemia unresponsive to large intravenous doses of glucose, which was treated successfully with intravenously administered octreotide, and to review the therapeutic options for hypoglycemia.MethodsWe present a case report of a 66-year-old man with diabetes causing chronic kidney disease, who was treated with orally administered glyburide, 7.5 mg twice a day. He initially presented to another hospital because of hypoglycemia and was treated with intravenously administered glucose and discharged. The next day, his family brought him to our emergency department because of recurring low blood glucose levels and symptoms of sweating, fever, and nightmares. Laboratory tests revealed a blood glucose level of 33 mg/dL and a creatinine concentration of 6.2 mg/dL.ResultsThe patient was treated with a 5% dextrose and, subsequently, a 10% dextrose infusion without any sustained improvement. The blood glucose level remained low despite the additional administration of 3 ampules of 50% dextrose in water. The patient was given a bolus of octreotide (50 μg subcutaneously) 14 hours after his second presentation. He received another 50-μg dose of octreotide 6 hours later. After this bolus, the hypoglycemia resolved, and he no longer required intravenous administration of glucose to maintain euglycemia.ConclusionPatients with diabetes and kidney disease frequently have persistent and difficult-to-treat hypoglycemia, unresponsive to conventional therapy. Octreotide is an effective and safe treatment for patients with refractory hypoglycemia attributable to sulfonylureas. (Endocr Pract. 2007;13:417-423)     

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)     

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)     

Long-Acting Subcutaneously Administered Insulin for Glycemic Control Immediately After Cardiac Surgery

ObjectiveTo test the hypothesis that subcutaneous administration of basal insulin begun immediately after cardiac surgery can decrease the need for insulin infusion in patients without diabetes and save nursing time.MethodsAfter cardiac surgery, 36 adult patients without diabetes were randomly assigned to receive either standard treatment (control group) or insulin glargine once daily in addition to standard treatment (basal insulin group). Standard treatment included blood glucose measurements every 1 to 4 hours and intermittent insulin infusion to maintain blood glucose levels between 100 and 150 mg/dL. The study period lasted up to 72 hours.ResultsThere were no differences in demographics or baseline laboratory characteristics of the 2 study groups. Mean daily blood glucose levels were lower in the basal insulin group in comparison with the control group, but the difference was not statistically significant (129.3 ± 9.4 mg/ dL versus 132.6 ± 7.3 mg/dL; P = .25). The mean duration of insulin infusion was significantly shorter in the basal insulin group than in the control group (16.3 ± 10.7 hours versus 26.6 ± 17.3 hours; P = .04). Nurses tested blood glucose a mean of 8.3 ± 3.5 times per patient per day in the basal insulin group and 12.0 ± 4.7 times per patient per day in the control group (P = .01). There was no occurrence of hypoglycemia (blood glucose level < 60 mg/dL) in either group.ConclusionOnce-daily insulin glargine is safe and may decrease the duration of insulin infusion and reduce nursing time in patients without diabetes who have hyperglycemia after cardiac surgery. (Endocr Pract. 2011;17: 558-562)     

Potential Place of SGLT2 Inhibitors in Treatment Paradigms for type 2 Diabetes Mellitus

Objective: Following the first Food and Drug Administration (FDA) approval in 2013, sodium glucose cotransporter 2 (SGLT2) inhibitors have generated much interest among physicians treating patients with type 2 diabetes mellitus (T2DM). Here, the role in treatment with this drug class is considered in the context of T2DM treatment paradigms.Methods: The clinical trials for the SGLT2 inhibitors are examined with a focus on canagliflozin, dapagliflozin, and empagliflozin.Results: Evidence from clinical trials in patients with T2DM supports the use of SGLT2 inhibitors either as monotherapy or in addition to other glucose-lowering treatments as adjuncts to diet and exercise, and we have gained significant clinical experience in a relatively short time.Conclusion: The drugs appear to be useful in a variety of T2DM populations, contingent primarily on renal function. Most obviously, SGLT2 inhibitors appear to be well suited for patients with potential for hypoglycemia or weight gain. In clinical trials, patients treated with SGLT2 inhibitors have experienced moderate weight loss and a low risk of hypoglycemic events except when used in combination with an insulin secretagogue. In addition, SGLT2 inhibitors have been shown to reduce blood pressure, so they may be beneficial in patients with T2DM complicated by hypertension. SGLT2 inhibitors were incorporated into the 2015 American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) position statement on the management of hyperglycemia and received an even more prominent position in the American Association of Clinical Endocrinologists (AACE)/American College of Endocrinology (ACE) comprehensive diabetes management guidelines and algorithm.Abbreviations: AE = adverse event A1C = glycated hemoglobin CI = confidence interval CKD = chronic kidney disease DKA = diabetic ketoacidosis DPP-4 = dipeptidyl peptidase 4 eGFR = estimated glomerular filtration rate FDA = Food and Drug Administration FPG = fasting plasma glucose GLP-1 = glucagon-like peptide 1 HDL-C = high-density lipoprotein cholesterol HR = hazard ratio LADA = late-onset autoimmune diabetes of adulthood LDL-C = low-density lipoprotein cholesterol MACE = major adverse cardiovascular events SGLT1 = sodium glucose cotransporter 1 SGLT2 = sodium glucose cotransporter 2 T1DM = type 1 diabetes mellitus T2DM = type 2 diabetes mellitus UACR = urine albumin to creatinine ratio