Mild Hypoglycemia Research Articles

The GesTIO protocol experience: safety of a standardized order set for subcutaneous insulin regimen in elderly hospitalized patients.

In non-critical hospitalized patients with diabetes mellitus, guidelines suggest subcutaneous insulin therapy with basal-bolus regimen, even in old and vulnerable inpatients. To evaluate safety, efficacy, and benefit on clinical management of the GesTIO protocol, a set of subcutaneous insulin administration rules, in old and vulnerable non-ICU inpatients. Retrospective, observational study. Patients admitted to Geriatric Clinic of Padua were studied. 88 patients matched the inclusion criteria: type 2 diabetes or hospital-related hyperglycemia, ≥65years, regular measurements of capillary glycemia, and basal-bolus subcutaneous insulin regimen managed by "GesTIO protocol" for five consecutive days. ratio of patients with blood glucose (BG) <3.9mmol/l; number of BG per patient in target range (5-11.1mmol/l); daily mean BG; and calls to physicians for adjusting insulin therapy. Mean age was 82 ± 7years. 9.1% patients experienced mild hypoglycaemia, and no severe hypoglycaemia was reported. The median number of BG per patients in target range increased from 2.0 ± 2 to 3.0 ± 2 (p < 0.001). The daily mean BG decreased from 11.06 ± 3.03 to 9.64 ± 2.58mmol/l (-12.8%, p < 0.005). The mean number of calls to physicians per patient decreased from 0.83 to 0.45 (p < 0.05). Treatment with GesTIO protocol allows a safe and effective treatment even in very old and vulnerable inpatients with a faster management insulin therapy.

Efficacy of basal-bolus insulin regimens in the inpatient management of non-critically ill patients with type 2 diabetes: A systematic review and meta-analysis.

Hyperglycemia during hospitalization is associated with increased rates of complications and longer hospital stays. Various insulin regimens are used in the inpatient diabetes management of non-critically ill patients. In this systematic review and meta-analysis, we aimed to assess the efficacy and safety of basal-bolus insulin therapy (BBI) by summarizing evidence from studies of BBI versus sliding scale insulin therapy (SSI) in the management of hospitalized non-critically ill type 2 diabetes patients. We searched MEDLINE, EMBASE, Scopus, and the Cochrane Library for studies comparing BBI therapy with SSI therapy in hospitalized non-critically ill patients with type 2 diabetes. Primary outcome was mean daily blood glucose (BG) during admission. Secondary outcomes were incidence of hypoglycemia and length of hospital stay. Results of included randomized controlled trials (RCT) were pooled and meta-analysed to provide estimates of the efficacy of BBI therapy. Five RCTs and seven observational studies were included in the review. Meta-analysis of RCTs showed significantly lower mean daily BG with BBI than SSI. Mean difference in daily BG between the two regimens ranged from 14 to 29 mg/dl. BBI therapy was associated with increased risk of mild hypoglycemia (BG ≤ 70 mg/dl, RR 5.75; 95% CI 2.79-11.83), (BG ≤ 60 mg/dl, RR 4.21; 95% CI 1.61-11.02) compared with SSI therapy. There was no difference in risk of severe hypoglycemia (BG ≤ 40 mg/dl) and no difference in mean length of stay. In conclusion, basal-bolus insulin in the inpatient diabetes management results in significantly lower mean daily BG than sliding scale insulin but is associated with increased risk of mild hypoglycemia.

Cross-Validation of a Glucose-Insulin-Glucagon Pharmacodynamics Model for Simulation Using Data From Patients With Type 1 Diabetes.

Currently, no consensus exists on a model describing endogenous glucose production (EGP) as a function of glucagon concentrations. Reliable simulations to determine the glucagon dose preventing or treating hypoglycemia or to tune a dual-hormone artificial pancreas control algorithm need a validated glucoregulatory model including the effect of glucagon. Eight type 1 diabetes (T1D) patients each received a subcutaneous (SC) bolus of insulin on four study days to induce mild hypoglycemia followed by a SC bolus of saline or 100, 200, or 300 µg of glucagon. Blood samples were analyzed for concentrations of glucagon, insulin, and glucose. We fitted pharmacokinetic (PK) models to insulin and glucagon data using maximum likelihood and maximum a posteriori estimation methods. Similarly, we fitted a pharmacodynamic (PD) model to glucose data. The PD model included multiplicative effects of insulin and glucagon on EGP. Bias and precision of PD model test fits were assessed by mean predictive error (MPE) and mean absolute predictive error (MAPE). Assuming constant variables in a subject across nonoutlier visits and using thresholds of ±15% MPE and 20% MAPE, we accepted at least one and at most three PD model test fits in each of the seven subjects. Thus, we successfully validated the PD model by leave-one-out cross-validation in seven out of eight T1D patients. The PD model accurately simulates glucose excursions based on plasma insulin and glucagon concentrations. The reported PK/PD model including equations and fitted parameters allows for in silico experiments that may help improve diabetes treatment involving glucagon for prevention of hypoglycemia.

Association between mild and severe hypoglycemia in people with type 2 diabetes initiating insulin

AimsPrimary objective: Identify risk factors associated with severe hypoglycemia (SH) and investigate the association between mild hypoglycemia and SH in people with type 2 diabetes starting insulin. Secondary objectives: Investigate the association of demographics and clinical factors with SH incidence. MethodsIntegrated trial database data were obtained for 3 randomized controlled trials that included insulin-naïve people with type 2 diabetes initiating basal (insulin glargine) versus biphasic (insulin lispro mixture) insulin. Standard definitions were used for SH; mild hypoglycemia was defined as all non-SH. Cox regression identified risk factors associated with SH and the correlation between SH and mild hypoglycemia. ResultsData were pooled (N=2931). During 24–48weeks' treatment, 2127 (72.6%) participants experienced ≥1 mild hypoglycemic event but no SH (mean mild hypoglycemia rate=2.33/month). 56 participants (1.9%) experienced ≥1 SH event plus mild hypoglycemia (mean mild hypoglycemia rate=3.95/month); 748 participants (25.5%) had no hypoglycemia. Among factors tested, only mild hypoglycemia rate/month was associated with SH. SH risk was higher (HR=4.24; 95%CI=2.57–6.99;p<0.0001) for participants experiencing multiple mild hypoglycemic events/month compared with those experiencing ≤1 mild hypoglycemic event/month. ConclusionsMild hypoglycemia may predict the first SH event, which is important because SH is a strong and consistent risk factor for morbidity/mortality.

Insulin degludec is associated with less frequent and milder hypoglycemia in insulin-deficient patients with type 1 diabetes compared with insulin glargine or detemir.

The aim of this study was to determine the efficacy of insulin degludec (IDeg) relative to insulin glargine (IGlar) or insulin detemir (IDet) in glycemic control, as evaluated by continuous glucose monitoring (CGM) in insulin-deficient patients with type 1 diabetes. We studied 28 outpatients treated with IGlar or IDet (IGlar/IDet). Basal insulin was switched to IDeg when glycemic control was considered unstable, as judged by the dawn phenomenon or nocturnal hypoglycemia. Whole-day CGM data were also divided into daytime and nighttime data. The dawn phenomenon or nocturnal hypoglycemia under IGlar/IDet treatment was observed in all patients. Among 26 patients who completed the study, there were no significant differences in parameters representing glycemic variability, hyperglycemia, mean glycemic control, and HbA1c or insulin therapy-related quality of life at the night score. Measures of hypoglycemia [whole-day %Low and area under the curve (AUC) below 70] were significantly lower under IDeg treatment than under IGlar/IDet treatment (%Low, 9.6±11.5 vs. 14.7±14.9%, p=0.045; AUC below 70, 85.5±126.0 vs. 145.0±178.6mg/dlh, p=0.030). Dividing patients into two groups according to percentage or degree of hypoglycemia under IGlar/IDet treatment, the whole-day, daytime and nighttime %Low in the high-percentage groups and AUC below 70 in the high-degree groups were significantly ameliorated, respectively (p<0.05). Patients with unstable glycemic control under IGlar/IDet treatment did not improve glycemic control upon switching to IDeg, but the frequency and the degree of hypoglycemia was reduced in insulin-deficient outpatients with type 1 diabetes, especially in those suffering from severe hypoglycemia.

Efficacy and Safety of Vildagliptin as an Add-On Therapy in Inadequately Controlled Type 2 Diabetes Patients Treated With Basal Insulin.

BackgroundThe aim of this study was to investigate the efficacy and safety of vildagliptin as an add-on therapy for patients with type 2 diabetes mellitus inadequately controlled with basal insulin.MethodsTwenty-four patients treated with basal insulin and oral anti-diabetes drugs were randomly allocated into two groups: the control group (did not receive any add-on drugs) and vildagliptin group (received vildagliptin 100 mg/day for 6 months). The primary outcome was changes in hemoglobin A1c (HbA1c) from baseline to end of study.ResultsTreatment with vildagliptin significantly reduced HbA1c from 8.1±0.7% at baseline to 7.1±0.7% (P < 0.01), while there was no significant change of HbA1c in the control group. Vildagliptin group showed significant reduction of HbA1c compared with control group (-1.0±0.3% vs. 0.2±0.8%, P < 0.01). In addition, vildagliptin group showed a significant increase in 1,5-anhydroglucitol compared with the control group (4.5 ± 3.4 vs. 0.5 ± 4.1 μg/mL, P < 0.05). Mild hypoglycemia was reported in one patient of the vildagliptin group and two patients of the control group.ConclusionVildagliptin improved glycemic control without increasing hypoglycemia in Japanese type 2 diabetes inadequately controlled with basal insulin treatment and other oral anti-diabetes drugs. This study was registered with UMIN (University Hospital Medical Information Network ID#000010849).

Glycemic control in acute illness.

Hyperglycemia is commonly observed in critical illness. A landmark large randomized controlled trial (RCT) reported that the incidence of hyperglycemia (blood glucose concentration > 108 mg/dl) was as high as 97.2% in critically ill patients. During the past two decades, a number of RCTs and several meta-analyses and network meta-analyses have been conducted to determine the optimal target for acute glycemic control. The results of those studies suggest that serum glucose concentration would be better to be maintained between 144 and 180 mg/dl. Although there have been studies showing an association of hypoglycemia with worsened clinical outcomes, a causal link has yet to be confirmed. Nonetheless, some researchers are of the view that the data suggest even mild hypoglycemia should be avoided in critically ill patients. Since acutely ill patients who receive insulin infusion are at a higher risk of hypoglycemia, a reliable devices for measuring blood glucose concentrations, such as an arterial blood gas analyzer, should be used frequently. Acute glycemic control in patients with premorbid hyperglycemia is a novel issue. Available literature suggests that blood glucose concentrations considered to be desirable and/or safe in non-diabetic critically ill patients might not be desirable in patients with diabetes. Moreover, the optimal target for acute blood glucose control may be higher in critically ill patients with premorbid hyperglycemia. Further study is required to assess optimal blood glucose control in acutely ill patients with premorbid hyperglycemia.

Hypoglycemic relapse in term infants treated with glucose infusion

Background: Hypoglycemia, being a common, potentially serious problem in neonatology, is screened in at-risk newborzns. However, there is little evidence regarding the screening of hypoglycemic relapse after treatment by glucose infusion. Objectives: We aimed to determine whether measuring blood glucose levels 3, 6, and 9 h after weaning from glucose infusion is appropriate to detect hypoglycemic relapse. Methods: This is a single-center retrospective study (2005–2014) measuring the proportion of infants who experienced hypoglycemic relapse (glucose level <2.5 mmol/L) after withdrawal of glucose infusion as well as the “time to relapse” in a population of 129 consecutive patients treated with glucose infusion for severe or prolonged neonatal hypoglycemia. Results: No newborn (0%, 95% confidence interval [CI]: 0%–2.9%) had hypoglycemic relapse within the first 3 h after weaning from glucose infusion. Five infants (3.9%, 95% CI: 1.7%–8.8%) and three infants (2.3%, 95% CI: 0.8%–6.6%) had hypoglycemic relapse, respectively, 6 and 9 h after weaning. All relapses were of mild severity (blood glucose level: 2.0–2.5 mmol/L). Lower birth weight (BW) (P = 0.008) and small for gestational age (SGA) (P = 0.003) were associated with the increased risk of hypoglycemic relapse. Conclusions: In a population of term newborns presenting with hypoglycemia requiring glucose infusion, only a small proportion presented with mild hypoglycemia relapse after weaning from infusion, lower BW and SGA were the main risk factors. Future research should assess whether it is sufficient to control only at-risk infants for relapse after a progressive weaning from infusion.

Effect of Initiation of Basal Insulin Glargine on Glycemic Control in Patients with Diabetes: Real Life Experience from Hong Kong

Introduction: To assess the changes in glycemic control after initiating or switching to a basal insulin analogue in patients with diabetes mellitus. Methods: A retrospective, observational analysis was conducted using electronic data from a Hong Kong regional hospital. Data from adult patients with type 1 and 2 diabetes mellitus (T1DM and T2DM, respectively) who had been prescribed with basal insulin glargine in 2008-2010, with recorded HbA1c levels at the time of initiation, at 6 and 12 months thereafter, were analysed. Results: Data from 106 eligible patients were analysed. Substantial reduction in HbA1c and fasting sugar levels were reported in both T1DM (Δ HbA1c = 1.5%, Δ FBG = 1.3 mmol/L p < 0.05) and T2DM (Δ HbA1c = 1.2%, Δ FBG = 2.9 mmol/L p < 0.05) patients after 12 months of therapy. A total of 42% of T1DM and 26% of T2DM patients achieved HbA1c levels < 7.0%. After adjustment, T2DM patients who were insulin naive achieved a statistically greater HbA1c reduction (Δ = 1.7%) than those who previous treated with premixed or basal bolus insulin (Δ = 0.3%) (p < 0.05). Percentage of patients experiencing hypoglycaemia reduced from 69% to 62% in T1DM but increased from 26% to 36% in T2DM patients. All hypoglycaemic episodes recorded were either asymptomatic or mild and self-limiting. Only 4% of the patients discontinued treatment at the end of 12 months. Conclusions: In real life clinical practice, a single daily basal insulin analogue therapy provided effective glycemic control with an acceptable risk of mild hypoglycaemia.

THE USE OF ULTRA-LONG-ACTING INSULIN ANALOGUE DEGLUDEC IN TYPE 1 DIABETES MELLITUS IN CLINICAL PRACTICE: THE INFLUENCE ON QUALITY OF LIFE AND SATISFACTION WITH TREATMENT

Background: Maintenance of stable glycemic control is an important prerequisite of effective treatment of patients with type 1 diabetes mellitus (DM). The ultra-long-acting basal insulin degludec allows for reduction of glycemic variability and for a substantial reduction in the rates of hypoglycemia with equivalent glycemic control. Evaluation of the impact of this novel insulin on diabetes-dependent quality of life and patient satisfactions with the treatment is necessary for comprehensive assessment of treatment efficacy.Aim: To study changes of glycated hemoglobin (HbA1c), rates of hypoglycemia, diabetes-dependent quality of life and treatment satisfaction in patients with type 1 DM, who have been switched to insulin degludec.Materials and methods: This open 12-week observational comparative study included 25 patients with type 1 DM (median age, 36 [20; 63] years), who were switched to insulin degludec in combination with a ultra-short insulin analogue. The control group included 21 patients with type 1 DM (median age, 40 [23; 63] years), who continued their treatment with a long-acting insulin analogue glargine. At baseline and at week 12 after switching to insulin degludec, we assessed HbA1c level, mean insulin dose, depression score, diabetes-dependent quality of life and patient satisfaction with the treatment with the use of the Russian versions of the diabetes-specific questionnaires “Audit of Diabetes-Dependent Quality of life” (RuADDQoL), and “Diabetes Treatment Satisfaction Questionnaire” (DTSQ), respectively.Results: At 3 months, there was a significant reduction of the HbA1c levels in the main and the control groups to 7.57% (Ме 7.5 [7.1; 8.4]; р=0.03) and 8.18% (Ме 7.8% [7.4; 8.7]; р=0.04), respectively. The mean reduction of this parameter under treatment with degludec was slightly higher than under treatment with glargine (0.73 vs 0.57%, respectively), at 3 months the difference being statistically significant (p=0.034). To achieve an equivalent glycemic control, the mean daily dose of insulin degludec was reduced by 26%. Switching to insulin degludec was associated with a significant reduction in non-severe hypoglycemia rates by 45% (р&lt;0.001). In the main group, there was an improvement of the mean total weighted score of Ru-ADDQoL from -2.2 (Ме -1.28 [-2; -0.86]) at baseline to -1.5 (Ме -1.28 [-2; -0.86]) at 12 week, with positive changes in the most domains, demonstrating the improvement of quality of life In the reference group, the mean total weighted Ru-ADDQoL score at 3 months increased 0.4 (Me 0.1 [-0.56; -1] to -1.51 (Me -1.23 [-2; -1]). In the glargine group there were no significant changes on any of the Ru-ADDQoL domains. There was a significant improvement in the patients satisfaction with treatment in the degludec group, with an increase of the average DTSQ score by 5 in 3 months of therapy.Conclusion: Based on the results of this short-term observational study, the following conclusion can be drawn: treatment with insulin degludec in type 1 DM is as effective as treatment with insulin glargine; however, it allows for reduction of the mild hypoglycemia rates by 45%. Therefore, this insulin can be recommended, first of all, to those type 1 DM patients who demonstrate substantial glycemic fluctuations, frequent hypoglycemia, hypoglycemic unawareness or who do not achieve the glycemic goals of treatment. Finally, this would lead to better health-related quality of life and more treatment satisfaction.

Self-reported frequency, severity of, and awareness of hypoglycemia in type 2 diabetes patients in Turkey.

ObjectivesHypoglycemia is a common side effect of insulin therapy in type 1 and type 2 diabetes. Limited data exist on the frequency of hypoglycemic events in type 2 diabetic patients in Turkey. Our study investigated self-reported hypoglycemic events and awareness of hypoglycemia in Turkish patients with type 2 diabetes.MethodsPeople with type 2 diabetes older than 18 years of age were recruited from the two university hospital diabetes clinics. The frequency and severity of hypoglycemia and awareness of hypoglycemia during the preceding year were determinated using questionnaires by the face-to-face interview method.ResultsIn this study of 187 patients with type 2 diabetes, 83.4% had impaired awareness of their hypoglycemia, and 62% reported that they had missed some of the symptoms of hypoglycemia. Of the patients reporting hypoglycemic symptoms and severity level, 84.1% experienced mild hypoglycemia, 60% moderate, and 15.5% severe hypoglycemia in the past year. No significant association was made between hypoglycemia awareness and age, body-mass index (BMI), years of diabetes, dose of insulin, duration of insulin use, number of meals, or amount of snacking. A significant correlation was found between A1c levels and hypoglycemia awareness and severity of hypoglycemia. A significant correlation was found between dose of insulin, amount of snacking, and severity of hypoglycemia. No significant association was made between severity of hypoglycemia and age, BMI, years of diabetes, duration of insulin use, or the number of meals. However, the group with severe hypoglycemia had diabetes longer, and the average daily dose of insulin use was higher than in other groups.ConclusionsAccording to the study results, the percentage of patients with impaired awareness of hypoglycemia is high, and 62% of patients reported that they had missed some of the symptoms of hypoglycemia in type 2 diabetes. In addition, the percentage of severe hypoglycemic events is not low. Impaired awareness of hypoglycemia is a major risk factor for severe hypoglycemic events. Patients should be educated about the danger of hypoglycemia. Education should be improved, and a determined attempt should be made to eradicate the problem.

Association of self-reported recurrent mild hypoglycemia with incident cardiovascular disease and all-cause mortality in patients with type 2 diabetes: Prospective analysis of the Joint Asia Diabetes Evaluation Registry.

Severe hypoglycemia is an established risk marker for cardiovascular complications of diabetes, but whether mild hypoglycemia confers similar risks is unclear. We examined the association of self-reported recurrent mild hypoglycemic events with cardiovascular disease (CVD) and all-cause mortality in a prospective cohort of Chinese adults with type 2 diabetes.From June 2007 to May 2015, 19,019 patients in Hong Kong underwent comprehensive assessment of metabolic and complication status using the Joint Asia Diabetes Evaluation program. Recurrent mild hypoglycemic event was determined by self-report of mild-to-moderate hypoglycemic symptoms at least once monthly in previous 3 months. Incident cardiovascular events were identified using hospital discharge diagnosis codes and death using Hong Kong Death Registry.Patients reporting recurrent mild hypoglycemia (n = 1501, 8.1%) were younger, had longer disease duration, worse glycemic control, and higher frequencies of vascular complications at baseline. Over 3.9 years of follow-up, respective incidences of CVD and all-cause death were 18.1 and 10.3 per 1000 person-years and 15.4 and 9.9 per 1000 person-years in patients with and without recurrent mild hypoglycemia. Using multivariate Cox regression analysis, recurrent mild hypoglycemia was not associated with CVD or all-cause mortality. In subgroup analysis, mild hypoglycemia was related to CVD in patients with chronic kidney disease (hazard ratio 1.36, 95% confidence interval 1.01–1.84, P = 0.0435) and those on insulin (hazard ratio 1.37, 95% confidence interval 1.01–1.86, P = 0.0402) adjusted for confounders.Mild hypoglycemia by self-report was frequent in patients with type 2 diabetes and was associated with increased risk of CVD in susceptible groups.

Low-Carbohydrate Diet Impairs the Effect of Glucagon in the Treatment of Insulin-Induced Mild Hypoglycemia: A Randomized Crossover Study.

This study compared the ability of glucagon to restore plasma glucose (PG) after mild hypoglycemia in patients with type 1 diabetes on an isocaloric high-carbohydrate diet (HCD) versus a low-carbohydrate diet (LCD). Ten patients with insulin pump-treated type 1 diabetes randomly completed 1 week of the HCD (≥250 g/day) and 1 week of the LCD (≤50 g/day). After each week, mild hypoglycemia was induced by a subcutaneous insulin bolus in the fasting state. When PG reached 3.9 mmol/L, 100 µg glucagon was given subcutaneously, followed by 500 µg glucagon 2 h later. Compared with the HCD, the LCD resulted in lower incremental rises in PG after the first (mean ± SEM: 1.3 ± 0.3 vs. 2.7 ± 0.4 mmol/L, P = 0.002) and second glucagon bolus (4.1 ± 0.2 vs. 5.6 ± 0.5 mmol/L, P = 0.002). No differences were observed between the diets regarding concentrations of insulin, glucagon, and triglycerides. The LCD reduces the treatment effect of glucagon on mild hypoglycemia. Carbohydrate intake should be considered when low-dose glucagon is used to correct hypoglycemia.

Effects of equivalent sympathetic activation during hypoglycemia on endothelial function and pro-atherothrombotic balance in healthy individuals and obese standard treated type 2 diabetes

ObjectiveRecent studies in type 2 diabetes have reported an association between hypoglycemia and severe cardiovascular adverse events, which are relatively increased in standard versus intensively treated individuals. The aim of this study was to determine the effects of equivalent sympathetic nervous system (SNS) activity during moderate hypoglycemia on in-vivo endothelial function, pro-inflammatory, pro-atherothrombotic, and pro-coagulant responses in healthy and standard treated type 2 diabetes individuals. Research design and methodsEleven type 2 diabetes and 16 healthy individuals participated in single 2day studies. Day 1 involved a 2h hyperinsulinemic/euglycemic clamp and day 2, a 2h hyperinsulinemic/hypoglycemic clamp of 3.2±1mmol/L in type 2 diabetes and (2.9±0.1mmol/L) in healthy individuals. ResultsICAM-1, VCAM-1, P-selectin, PAI-1, VEGF and endothelin-1 (ET-1) fell during hyperinsulinemic euglycemia but increased during hypoglycemia in type 2 diabetes and healthy individuals. Epinephrine and norepinephrine levels were equivalent during hypoglycemia in type 2 DM and healthy individuals. However, despite similar SNS drive but milder and hypoglycemia there were greater ICAM-1, VCAM-1, PAI-1, VEGF and ET-1 responses in the type 2 diabetes group. Endogenous and exogenous nitric oxide mediated arterial vasodilation were also impaired only during hypoglycemia in type 2 diabetes. ConclusionWe conclude that, milder hypoglycemia but equivalent SNS activation results in more diffuse endothelial dysfunction and a greater pro-inflammatory, pro-atherothrombotic and pro-coagulant state in standard treated type 2 diabetes as compared to healthy individuals.

Dose-Dependent Effect of Piragliatin, a Glucokinase Activator, on the QT Interval Following Short-Term Multiple Doses in Patients With Type 2 Diabetes Mellitus.

To determine the effect of piragliatin on the QTcS (QT-corrected study-specific) interval, a double-blind, double-dummy, placebo-controlled, active-comparator, 4-period, 4-treatment, 4-sequence randomized crossover trial was performed in 42 patients with type 2 diabetes mellitus who received 100 and 200mg piragliatin twice daily, placebo, and 400mg moxifloxacin (on day 1 and day 5 only) for 5days. In the categorical analyses, piragliatin did not have a clinically significant effect on the QTcS interval at either dose, and the majority of patients were categorized with low risk for maximum change from baseline (≤30 milliseconds) and a maximum postbaseline QTcS interval as normal (≤450 milliseconds). However, in the analysis of variance model, both piragliatin doses crossed the 10-millisecond threshold (100mg twice daily on day 5, hour 1; 200mg twice daily on days 1 and 5, hours 1 and 2) with P values indicating statistical significance. Headache and mild hypoglycemia were the most frequent adverse events associated with piragliatin treatment. There appeared that the effect of piragliatin treatment on the QTc interval was dose/exposure dependent following short-term multiple doses. Longer-term monitoring of electrocardiograms with pharmacokinetic exposure should continue, especially at conditions for potentially higher pharmacokinetic exposure.

Efficacy and safety of alogliptin in patients with type 2 diabetes mellitus: A multicentre randomized double‐blind placebo‐controlled Phase 3 study in mainland China, Taiwan, and Hong Kong

This study determined the efficacy and safety of once-daily oral alogliptin in patients from mainland China, Taiwan, and Hong Kong with type 2 diabetes mellitus. In this Phase 3 multicenter double-blind placebo-controlled 16-week trial, 506 patients were randomized to receive once-daily alogliptin 25 mg or placebo: 185 in the monotherapy group, 197 in the add-on to metformin group, and 124 in the add-on to pioglitazone group. The primary efficacy variable was the change from baseline (CFB) in HbA1c at Week 16; other efficacy measures included CFB to Week 16 in fasting plasma glucose (FPG), incidence of marked hyperglycemia (FPG ≥11.1 mmol/L), and the incidence of clinical HbA1c ≤6.5% (48 mmol/mol) and ≤7.0% (53 mmol/mol) at Week 16. Safety was assessed throughout the trial. Alogliptin monotherapy provided a significantly greater decrease in HbA1c from baseline to Week 16 compared with placebo (-0.58 %; 95% confidence interval [CI] -0.78%, -0.37 %; P <0.001). As an add-on to metformin or pioglitazone, alogliptin also significantly decreased HbA1c compared with placebo (-0.69% [95% CI -0.87%, -0.51 %; P <0.001] and -0.52% [95% CI -0.75%, -0.28 %; P <0.001], respectively). In any treatment group versus placebo, alogliptin led to greater decreases in FPG (P ≤ 0.004) and a higher percentage of patients who achieved an HbA1c target of ≤6.5% and ≤7.0% (P ≤ 0.003). No weight gain was observed in any treatment group. A similar percentage of patients experienced drug-related, treatment-emergent adverse events in the alogliptin and placebo arms. Four and two patients in the alogliptin and placebo arms, respectively, experienced mild or moderate hypoglycemia. Alogliptin 25 mg once daily reduced HbA1c and FPG and enhanced clinical response compared with placebo when used as monotherapy or as an add-on to metformin or pioglitazone. Therapy with alogliptin was well tolerated.

History of mild hypoglycaemia does not affect the prevalence of diabetes-related distress in people with diabetes.

The occurrence of hypoglycaemia is assumed to be associated with increased diabetes-related distress. We investigated the association of mild hypoglycaemia (MH) with diabetes-related distress in a large outpatient cohort with diabetes type 1 (DM1) and type 2 (DM2). In a cross-sectional study, we recorded MH and simultaneously assessed diabetes-related distress with the PAID questionnaire in 783 people with diabetes [female 43.8%, age 63.7years, duration of diabetes 17.3years, HbA1c 7.0% (53mmol/mol)] in an university outpatient department for metabolic diseases over a period of three months. Participants with and without MH were compared. People with DM1 (n=191) had 1.09 MH per week. Diabetes-related distress was not different comparing people with DM1 with (n=125) and without (n=66) MH (PAID score 18.4±16.2 vs. 16.6±15.0, p=0.449). The frequency of MH per week in people with DM2 on oral antidiabetic therapy (n=182) and with insulin therapy (n=410) is low (0.03 vs. 0.1 episodes). People with DM2 on insulin therapy with (n=72) and without (n=338) MH have a comparable PAID score (17.9±13.3 vs. 16.8±14.9, p=0.552). 14.4% of those with DM1 as well as 12.5% of those with DM2 on insulin feel hypoglycaemic events to be a "somewhat serious problem" or "serious problem". In an outpatient setting, MH is not associated with increased diabetes-related distress or burden in people with DM1 or DM2.

Factors associated with hypoglycemia episodes in hospitalized type 2 diabetes mellitus patients in a tertiary health facility in Malaysia

Purpose: To determine the factors associated with severity of hypoglycemia in hospitalized type 2 diabetes mellitus patients in a tertiary health facility in Malaysia.Methods: This retrospective study involved 207 hospitalised T2DM patients with hypoglycaemia episodes from January 2008 to December 2012 and was conducted in University Malaya Medical Centre, Petaling Jaya, Malaysia. Patients were classified into 2 groups, viz, those who had hypoglycaemia on admission and those who had hypoglycaemia during hospital stay. Patients with hypoglycemia on admission were those admitted due to hypoglycemia while patients with hypoglycemia during hospital stay were those admitted due to other causes but subsequently developed hypoglycemia during hospitalization.Results: The results for the 207 patients investigated show that most of the patients (72.2 %) were asymptomatic during hypoglycemic episodes. The majority of the episodes (57.4 %) experienced by the patients were mild hypoglycemia (&lt; 3.9 mmol/L). Old age (p = 0.011) and presence of stroke (p = 0.033) were found to be significantly associated with severe hypoglycemia (&lt; 2.2 mmol/L) while concurrent use of opioid (p = 0.008) was associated with mild hypoglycemia.Conclusion: The identification of the underlying factors associated with severity of hypoglycemia may help in preventing and resolving hypoglycemia in T2DM patients.Keywords: Hypoglycemia episodes, Type 2 diabetes, Associated factors, Elderly, Stroke, Opiods

Continuous Glucose Monitoring: Impact on Hypoglycemia.

The necessity of strict glycemic control is unquestionable. However, hypoglycemia remains a major limiting factor in achieving satisfactory glucose control, and evidence is mounting to show that hypoglycemia is not benign. Over the past decade, evidence has consistently shown that real-time continuous glucose monitoring improves glycemic control in terms of lowering glycated hemoglobin levels. However, real-time continuous glucose monitoring has not met the expectations of the diabetes community with regard to hypoglycemia prevention. The earlier trials did not demonstrate any effect on either mild or severe hypoglycemia and the effect of real-time continuous glucose monitoring on nocturnal hypoglycemia was often not reported. However, trials specifically designed to reduce hypoglycemia in patients with a high hypoglycemia risk have demonstrated a reduction in hypoglycemia, suggesting that real-time continuous glucose monitoring can prevent hypoglycemia when it is specifically used for that purpose. Moreover, the newest generation of diabetes technology currently available commercially, namely sensor-augmented pump therapy with a (predictive) low glucose suspend feature, has provided more convincing evidence for hypoglycemia prevention. This article provides an overview of the hypoglycemia outcomes of randomized controlled trials that investigate the effect of real-time continuous glucose monitoring alone or sensor-augmented pump therapy with a (predictive) low glucose suspend feature. Furthermore, several possible explanations are provided why trials have not shown a reduction in severe hypoglycemia. In addition, existing evidence is presented of real-time continuous glucose monitoring in patients with impaired awareness of hypoglycemia who have the highest risk of severe hypoglycemia.

Causes of Hypoglycemia in Hospitalized Diabetic Patients Referred to Endocrine Department of a Tertiary Level Hospital of India

Introduction: Diabetes mellitus (DM) results from relative deficiency or reduced effectiveness of endogenous insulin leading to both micro-vascular and macro-vascular complications. Treatment goal is intensive therapy as early as possible in patients with both type-1 and type-2 diabetes to bring the HbA1c to less than 7%. Occurrence of hypoglycemia in a diabetic patient is a common side effect of treatment. This study was aimed to find the causes of Hypoglycemia in diabetes patients. Methods: It was hospital based cross-sectional observational study on admitted diabetes patients with other co-morbid conditions who were on either oral hypoglycemic agents (OHA) or Insulin. Cause of hypoglycemia was elicited by history taking and analysis. Results: Out of 36 diabetics included in this study, seven had severe hypoglycemia, 22 had moderate to mild hypoglycemia. Most of them had various comorbidities. The causes of hypoglycemic episodes were varied. Conclusion: Hypoglycemia can occur despite cautious treatment protocol especially in diabetics with organ dysfunction, which can be prevented by alert and well-coordinated medical team.