Occurrence Of Hypoglycemic Events Research Articles

Patient preferences for the treatment of type 2 diabetes in Australia:a discrete choice experiment.

Australia has a high proportion of migrants, with an increasing migration rate from India. Type 2 diabetes is a chronic condition common amongst the Indian population. The decision to initiate and continue medication therapy (conventional or ayurvedic medicine) is complex and is influenced by a wide range of factors. To determine preferences for conventional vs. ayurvedic medicines in Indian migrants with diabetes, and to identify the factors that may influence their preferences. A discrete choice experiment was conducted with participants in Australia who were migrants from India with type 2 diabetes (n=141). Each respondent evaluated eight choice tasks consisting of eight attributes describing medicines and outcomes of medication taking; and were asked to choose 'conventional', or 'ayurvedic' medicine. A mixed multinomial logit model was used to estimate preferences. Overall, respondents' preference to initiate a medicine was negative for both conventional (β=-2.33164, p<0.001) and ayurvedic medicines (β=-3.12181, p<0.001); however, significant heterogenicity was noted in participants' preferences (SD: 2.33122, p<0.001). Six significant attributes were identified to influence preferences. In decreasing rank order: occurrence of hypoglycaemic events (relative importance, RI=24.33%), weight change (RI=20.00%), effectiveness of medicine (RI=17.91%), instructions to take with food (RI=17.05%), side effects (RI=13.20%) and formulation (RI=7.49%). Respondents preferred to initiate a medicine despite potential side effects. There was a greater preference for conventional medicine, though neither were preferred. Medicine attributes and medication-taking outcomes influenced people's preferences for an antidiabetic medicine. It is important to identify individual preferences during healthcare consultations to ensure optimal medication-taking.

Altered muscle mitochondrial, inflammatory and trophic markers, and reduced exercise training adaptations in type 1 diabetes.

Growing evidence of impaired skeletal muscle health in people with type 1 diabetes points toward the presence of a mild myopathy in this population. However, this myopathic condition is not yet well characterised and often overlooked, even though it might affect the whole‐body glucose homeostasis and the development of comorbidities. This study aimed to compare skeletal muscle adaptations and changes in glycaemic control after 12 weeks of combined resistance and aerobic (COMB) training between people with type 1 diabetes and healthy controls, and to determine whether the impaired muscle health in type 1 diabetes can affect the exercise‐induced adaptations. The COMB training intervention increased aerobic capacity and muscle strength in both healthy and type 1 diabetes sedentary participants, although these improvements were higher in the control group. Better glucose control, reduced glycaemic fluctuations and fewer hypoglycaemic events were recorded at post‐ compared to pre‐intervention in type 1 diabetes. Analysis of muscle biopsies showed an alteration of muscle markers of mitochondrial functions, inflammation, ageing and growth/atrophy compared to the control group. These muscular molecular differences were only partially modified by the COMB training and might explain the reduced exercise adaptation observed in type 1 diabetes. In brief, type 1 diabetes impairs many aspects of skeletal muscle health and might affect the exercise‐induced adaptations. Defining the magnitude of diabetic myopathy and the effect of exercise, including longer duration of the intervention, will drive the development of strategies to maximise muscle health in the type 1 diabetes population.Key points Type 1 diabetes negatively affects skeletal muscle health; however, the effect of structured exercise training on markers of mitochondrial function, inflammation and regeneration is not known.Even though participants with type 1 diabetes and healthy control were comparable for cardiorespiratory fitness (V˙O2max) and muscle strength at baseline, molecular markers related to muscle health were decreased in type 1 diabetes.After training, both groups increased V˙O2max and muscle strength; however, a larger improvement was achieved by the control group.The training intervention decreased glucose fluctuations and occurrence of hypoglycaemic events in type 1 diabetes, while signs of mild myopathy found in the muscle of participants with type 1 diabetes only partially improved after trainingImproving muscle health by specific exercise protocols is of considerable clinical interest in therapeutic strategies for improving type 1 diabetes management and preventing or delaying long‐term complications.

Basal Insulin Fc (BIF), A Novel Insulin Suited For Once Weekly Dosing For The Treatment of Patients With Diabetes Mellitus

Abstract An optimally designed once-weekly basal insulin with reduced day-to-day pharmacokinetic (PK)/pharmacodynamic (PD) fluctuations compared to daily basal insulins should have a low peak-to-trough ratio at steady state. An insulin with this flat profile could improve glycemic efficacy while reducing hypoglycemia. Basal insulin Fc (BIF; LY3209590) is an insulin IgG Fc-fusion protein developed for once weekly dosing. The results of the first in-human studies of BIF assessing the safety, tolerability, PK, and PD following single and once-weekly doses of BIF are presented below. The single ascending dose (SAD) study assessed 6 dose levels of BIF, administered to healthy subjects or patients with type 2 diabetes mellitus (T2DM). In the multiple ascending dose (MAD) study, patients with T2DM previously treated with basal insulin received a one-time loading dose at Week 1 followed by a once-weekly maintenance dose for 5 additional weeks. Four fixed-dose maintenance dose levels were evaluated. The loading dose was implemented to rapidly achieve steady-state BIF concentration at each dose level. Patients with T2DM in the control group received insulin glargine at the same dose as their previous daily insulin dose. Key objectives were safety and tolerability, PK endpoints with a focus on half-life and peak-to-trough ratio at steady state, and finally PD measures. The SAD study included 57 patients with T2DM and 16 healthy subjects. The mean age of patients with T2DM was 58.4 years and the mean BMI was 29.5±3.2 kg/m2. The mean age of healthy subjects was 35.8±9.3 years and the mean BMI was 26.1±3.1 kg/m2. In the SAD study, BIF demonstrated linear PK with dose-proportional concentration profiles in healthy subjects and patients with T2DM. The maximum BIF concentration was reached on Day 4. BIF had a mean half-life of approximately 17 days in patients with T2DM. Following a single dose of BIF, a decrease in FBG was observed on Day 1 and was sustained until at least 5 days post-dose. In the MAD study in 33 subjects with T2DM aged between 40 and 69 years, BIF demonstrated a nearly peak-less PK profile over a one-week dosing interval with a peak-to-trough ratio of ~1.1 at steady state. This flat profile is in contrast to insulin glargine. Following once-daily dosing, insulin glargine has a daily peak-to-trough ratio of ~2. Over the 6-week duration, the 7-point glucose profiles remained constant over time and were similar to insulin glargine profiles. BIF was well tolerated and had a safety profile similar to insulin glargine-treated subjects. In particular, hypoglycemia rates were also similar to insulin glargine and there was no occurrence of hypoglycemic events with cognitive dysfunction. These data support continued development of BIF as a once-weekly insulin treatment of diabetes mellitus.

The Glycemic Effect of Liraglutide Evaluated by Continuous Glucose Monitoring in Persons with Type 2 Diabetes Receiving Dialysis

Aims: The aim of this study was to evaluate the effect of liraglutide treatment on glucose variability and the risk of hypoglycemia by continuous glucose monitoring (CGM) in persons with type 2 diabetes (T2D) and dialysis-dependent end-stage renal disease (ESRD). Materials and Methods: We assessed CGM data from a previous trial where 24 persons with T2D and dialysis-dependent ESRD were allocated (1:1) to 12 weeks of double-blinded treatment with liraglutide (titrated to maximum tolerable dose up to 1.8 mg) or placebo as an add-on to preexisting antidiabetic treatment. CGM (Ipro2^®; Medtronic) was performed for up to 7 days at baseline and at weeks 2, 6, and 10. A linear mixed model was used to compare the 2 study arms. Results: A CGM was worn at baseline by 12 persons in the liraglutide group and 10 in the placebo group (7 and 9 completed week 10, respectively). Glycated hemoglobin A_1c (p = 0.81) and glucose variability was similar between the groups (standard deviation, p = 0.33; coefficient of variation, p = 0.16). Comparing baseline and week 10, the number of hypoglycemic events (glucose values between <3.9 and 3.0 mmol/L) increased in the liraglutide group compared with the placebo group (p = 0.02). The occurrence of hypoglycemic events below 3.0 mmol/L was similar between the groups (p = 0.36). Conclusions: In the present cohort of persons with T2D and dialysis-dependent ESRD, liraglutide treatment increased the risk of hypoglycemic events as compared to placebo (no difference was found for hypoglycemic events below 3.0 mmol/L). The majority of participants were co-treated with insulin.

Cerebral perfusion in pediatric type 1 diabetes: relation to vascular complications, psychological and neurophysiological functions

Regional cerebral hypoperfusion has been reported in patients with type 1 diabetes mellitus. Diabetic children also manifest a higher rate of mild cognitive dysfunction and electro-encephalographic abnormalities and these are best predicted by the occurrence of hypoglycemic events relatively early in life. More recent studies point toward the deleterious effect of chronic hyperglycemia on cognitive functioning and brain structure as measured with MRI. To study the relation between Regional cerebral perfusion in children and adolescents with type 1 diabetes measured by Single photon emission tomography (SPECT) and the vascular complications, psychological and neurophysiologic functions. One hundred children and adolescents with type 1 DM (64 females; mean age 15.3 ± 3.1 years) and 40 age- and sex-matched healthy control subjects were prospectively enrolled. Exclusion criteria comprised recent episodes of severe hypoglycemia or diabetic ketoacidosis (DKA) within the last 6 weeks. Regional cerebral blood flow was measured using SPECT. Patients underwent electro-encephalogram (EEG) and long latency evoked potential assessment, as well as Psychiatric assessment. Our study showed significant mean frontal and mean basal ganglia hypo perfusion in children having diabetes of more than 10 years duration compared to controls (P < 0.05). Mean frontal and basal ganglia perfusion were significantly related to different grades of hypoglycemia and longer diabetes duration but were not affected by history of diabetic ketoacidosis. Regional cerebral blood flow was not correlated to P300 latency or amplitude, EEG or psychiatric morbidity. Cerebral perfusion is affected by the duration of diabetes, and attacks of hypoglycemia, though not correlated to EEG findings or psychiatric morbidities. Frontal and basal ganglia are most areas affected.

Hypoglycemic events analysis via recurrent time-to-event (HEART) models

Diabetes affects an estimated 25.8 million people in the United States and is one of the leading causes of death. A major safety concern in treating diabetes is the occurrence of hypoglycemic events. Despite this concern, the current methods of analyzing hypoglycemic events, including the Wilcoxon rank sum test and negative binomial regression, are not satisfactory. The aim of this article is to propose a new model to analyze hypoglycemic events with the goal of making this model a standard method in industry. Our method is based on a gamma frailty recurrent event model. To make this method broadly accessible to practitioners, this article provides many details of how this method works and discusses practical issues with supporting theoretical proofs. In particular, we make efforts to translate conditions and theorems from abstract counting process and martingale theories to intuitive and clinical meaningful explanations. For example, we provide a simple proof and illustration of the coarsening at random condition so that the practitioner can easily verify this condition. Connections and differences with traditional methods are discussed, and we demonstrate that under certain scenarios the widely used Wilcoxon rank sum test and negative binomial regression cannot control type 1 error rates while our proposed method is robust in all these situations. The usefulness of our method is demonstrated through a diabetes dataset which provides new clinical insights on the hypoglycemic data.

Kinetic Modeling of Human Hepatic Glucose Metabolism in Type 2 Diabetes Mellitus Predicts Higher Risk of Hypoglycemic Events in Rigorous Insulin Therapy

A major problem in the insulin therapy of patients with diabetes type 2 (T2DM) is the increased occurrence of hypoglycemic events which, if left untreated, may cause confusion or fainting and in severe cases seizures, coma, and even death. To elucidate the potential contribution of the liver to hypoglycemia in T2DM we applied a detailed kinetic model of human hepatic glucose metabolism to simulate changes in glycolysis, gluconeogenesis, and glycogen metabolism induced by deviations of the hormones insulin, glucagon, and epinephrine from their normal plasma profiles. Our simulations reveal in line with experimental and clinical data from a multitude of studies in T2DM, (i) significant changes in the relative contribution of glycolysis, gluconeogenesis, and glycogen metabolism to hepatic glucose production and hepatic glucose utilization; (ii) decreased postprandial glycogen storage as well as increased glycogen depletion in overnight fasting and short term fasting; and (iii) a shift of the set point defining the switch between hepatic glucose production and hepatic glucose utilization to elevated plasma glucose levels, respectively, in T2DM relative to normal, healthy subjects. Intriguingly, our model simulations predict a restricted gluconeogenic response of the liver under impaired hormonal signals observed in T2DM, resulting in an increased risk of hypoglycemia. The inability of hepatic glucose metabolism to effectively counterbalance a decline of the blood glucose level becomes even more pronounced in case of tightly controlled insulin treatment. Given this Janus face mode of action of insulin, our model simulations underline the great potential that normalization of the plasma glucagon profile may have for the treatment of T2DM.

Impairment and recovery of elementary cognitive function induced by hypoglycemia in type-1 diabetic patients and healthy controls.

Although neuroendocrine changes after induction of hypoglycemia, in patients with diabetes and healthy persons, are thoroughly investigated, cognitive adaptation processes are still insufficiently understood. Changes in cognitive functions are mainly investigated by psychometric tests, which represent a summation of different cognitive processes. We aimed at dissecting cognitive adaptation into single components, i.e. stimulus selection, response choice, and reaction speed during a hyperinsulinemic hypoglycemic clamp in patients with type-1 diabetes and matched healthy controls. Using novel neurophysiological analyses, the event-related potentials of early stimulus selection (selection negativity) and response selection (lateralized readiness potential) were studied, in addition to reaction time (RT). A total of 12 diabetic patients and 12 normal volunteers were studied while receiving a hyperinsulinemic hypoglycemic clamp. RTs and the event-related potentials related to stimulus selection and response selection were significantly delayed during hypoglycemia in both groups, whereas early evoked potentials (P100) were unaltered. This suggests that hypoglycemia delays stimulus selection, with the consequence that also central and motor processing are delayed. In addition, patients with diabetes showed an earlier negative shift over the frontal cortex, which, when compared with the controls, reveals better adaptation to hypoglycemia in frontal cortical brain regions. After restoration of euglycemia stimulus selection, response selection and RT returned to baseline level in the type-1 group. In the control group, however, response selection and RTs were still delayed. This suggests that type-1 patients, possibly because of the past occurrence of hypoglycemic events, might be able to better cope with the hypoglycemic state than healthy volunteers who lack such a history. In summary, our data demonstrate, for the first time, that cognitive adaptation processes to an experimental hypoglycemic episode can clearly be dissected into their single components.