Hypoglycemic Episodes In Patients Research Articles

Experimental pharmacological approaches to reverse impaired awareness of hypoglycemia-a review.

The colossal global burden of diabetes management is compounded by the serious complication of hypoglycemia. Protective physiologic hormonal and neurogenic counterregulatory responses to hypoglycemia are essential to preserve glucose homeostasis and avert serious morbidity. With recurrent exposure to hypoglycemic episodes over time, these counterregulatory responses to hypoglycemia can diminish, resulting in an impaired awareness of hypoglycemia (IAH). IAH is characterized by sudden neuroglycopenia rather than preceding cautionary autonomic symptoms. IAH increases the risk of subsequent sudden and severe hypoglycemic episodes in patients with diabetes. The postulated causative mechanisms behind IAH are complex and varied. It is therefore challenging to identify a single effective therapeutic strategy. In this review, we closely examine the efficacy and feasibility of a myriad of pharmaceutical interventions in preventing and treating IAH as described in clinical and preclinical studies. Pharmaceutical agents outlined include N-acetyl cysteine, GABA A receptor blockers, opioid receptor antagonists, AMP activated protein kinase agonists, potassium channel openers, dehydroepiandrosterone, metoclopramide, antiadrenergic agents, antidiabetic agents and glucagon.

Sensor-Augmented Insulin Pump with Predictive Low-Glucose Suspend (PLGS): Determining Optimal Settings of Pump and Sensor in a Multicenter Cohort of Patients with Type 1 Diabetes.

IntroductionThe use of predictive low-glucose suspend (PLGS) sensor-augmented pumps has been shown to lead to a significant reduction in hypoglycemic episodes in patients with type 1 diabetes (T1D), but their effects on hyperglycemia exposure are heterogeneous. The aim of this study was to determine the settings of the Medtronic 640G system to obtain the optimal balance between occurrence of both hypoglycemia and hyperglycemia.MethodsThe hypo- and hyperglycemia area under the curve (AUC), as well as system settings [hypoglycemic threshold, mean insulin total daily dose (TDD), mean basal insulin percentage, and mean daily duration of PLGS] were collected between 2 and 12 times during 1 year in patients from four university hospital centers. Univariate/multivariate analyses and receiver operating characteristics (ROC) curves were performed to determine factors associated with hyper- and hypoglycemia AUC.ResultsA total of 864 observations were analyzed from 110 patients with T1D. Two preselected settings predictive of low hyperglycemia AUC were a basal insulin percentage < 52.0% [sensitivity (Se) = 0.66 and specificity (Sp) = 0.53] and a PLGS duration > 157.5 min/day (Se = 0.47 and Sp = 0.73). The preselected setting predictive of a low hypoglycemia AUC was a PLGS duration ≤ 174.4 min (Se = 0.83 and Sp = 0.51). Between-visit variation of PLGS and TDD was positively correlated (r = 0.61; p < 0.0001).ConclusionThe most important Medtronic 640G setting was the mean daily PLGS duration, where a value between 157.5 and 174.4 min/day was associated with the best reduction in both hypo- and hyperglycemia AUC. In this study, we showed that PLGS duration could be indirectly modified through total daily insulin dose adaptation.Trial Registration: This study is registered in clinicaltrials.gov (NCT 03047486).

Use of Continuous Glucose Monitoring in Patient with Coronary Artery Disease and Type 2 Diabetes Mellitus: Case Report

We present a clinical case of continuous monitoring in a patient with coronary artery disease and concomitant type 2 diabetes mellitus. A 75-year-old patient with a history of coronary artery bypass graft surgery more than 10 years ago was admitted to the Ukrainian Children’s Cardiac Center, Clinic for Adults with complaints of angina pectoris. The patient had progressive atherosclerotic lesions of the coronary arteries despite of controlled risk factors (normal weight, regular monitoring of blood pressure, lipid profile, blood glucose and glycated hemoglobin [HbA1c], active lifestyle). The heart team decided to perform percutaneous coronary intervention which resulted in thrombolysis in myocardial infarction (TIMI) 3 flow.&#x0D; During continuous glycemic monitoring in the patient we detected nocturnal asymptomatic episodes of hypoglycemia. Together with endocrinologist we performed adjustment of drug treatment: the hypoglycemic drug sulfonylurea was changed to a sodium-glucose cotransporter 2 inhibitor. Three months later we repeated monitoring of glycemia and no episodes of hypoglycemia were detected, HbA1c was 6.4%.&#x0D; Conclusions. This case report shows that continuous glucose monitoring is an optimal method for diagnosing silent episodes of hypoglycemia and should be considered along with the control of the HbA1c level as an important auxiliary method for controlling type 2 diabetes mellitus in patients with cardiovascular diseases. Because glucose-lowering drugs such as sulfonylureas are risk factors for hypoglycemic episodes in patients with coronary artery disease, they should be changed to more effective and safer medications if possible.

Updates in diabetic neuropathy: A call for new diagnostic and treatment approaches.

Diabetic polyneuropathy (DPN) is a serious complication of both type 1 and type 2 diabetes. The major clinical manifestations of DPN are neuropathic pain, diabetic foot (which is associated with ulcers, gangrene, and amputation), and autonomic neuropathy. Diabetic sensorimotor peripheral neuropathy (DSPN) is the most common form of DPN and affects approximately 50% of people with type 1 or 2 diabetes during their lifetime (1) . Despite its major clinical impact, DPN remains underdiagnosed and undertreated. To reduce the burdens of DPN, there is an urgent need to develop both novel diagnostic procedures that enable to improve the early detection of the disease and new treatments that address multiple mechanistic pathways (Figure) (2) .

Should We Monitor Glucose and Biomarkers in Diabetics over Heart Surgery?

Hyperglycemia is associated with adverse outcomes after coronary artery bypass grafting (CABG). While there is a consensus that blood glucose control may benefit patients undergoing CABG, the role of biomarkers, optimal method, and duration of such monitoring are still unclear. The aim of this study is to define the efficacy of a continuous glucose monitoring system (CGMS) and link it to pro-inflammatory biomarkers while on insulin pump therapy in diabetic patients undergoing CABG. We prospectively assessed CGMS for 72 h in 105 patients including 52 diabetics undergoing isolated CABG. In diabetics, CGMS was connected to an insulin pump for precise glucose control. On top of conventional biomarkers (HbA1C, lipid profile), high sensitive C-reactive protein (hs-CRP), Regulated upon Activation Normal T cell Expressed and presumably Secreted (RANTES), and leptin levels were collected before surgery, 1 h, 12 h, 7 days, and at 1 year after CABG. Overall, CGMS revealed high glucose independently from underlying diabetes during first 48 h following CABG but was higher (p < 0.05) in diabetics. The insulin pump improved glycemic control over early follow-up (72 h) post-CABG. There were no hypoglycemic episodes in patients on insulin pump therapy and those receiving bolus insulin therapy. We revealed a lower rate of postpericardiotomy syndrome (PCTS) in patients on insulin pump therapy compared to patients prescribed bolus insulin therapy in the early postoperative period (p = 0.03). Hs-CRP and RANTES levels were lower in patients with T2DM on insulin pump therapy compared to patients prescribed bolus insulin therapy in the early postoperative period (p < 0.05). It is most likely due to the fact that insulin pump therapy decreases systemic inflammatory response. Further controlled trials should assess whether CGMS improves outcomes after cardiac surgery.

Perioperative glycemic control in patients with coronary artery disease and diabetes mellitus type 2 undergoing coronary artery bypass grafting: results of pilot study

BACKGROUND: According to different studies, diabetes mellitus type 2 (DM2) is associated with higher mortality after undergoing coronary artery bypass grafting (CABG). Perioperative hyperglycaemia, even in non-DM2 patients, is associated with adverse outcomes after CABG. Thus, successful perioperative blood glucose control (BGC) is mandatory to reduce the risk of death and postoperative complications. Nowadays, the most effective method for BGC in the operating room is still unknown.&#x0D; AIMS: To assess the continuous glucose monitoring (CGM) efficacy in association with insulin pump therapy in patients with coronary artery disease (CAD) and DM2 undergoing CABG in intra- and early postoperative periods.&#x0D; METHODS: The study involved 97 patients undergoing isolated CABG. Patients were divided into two groups: 48 patients with DM2 and 49 patients without DM2. In both groups of patients, we used CGM in intra- and early postoperative periods (72 hours). In some patients with DM2, CGM was associated with insulin pump therapy (MiniMed Paradigm Veo 554/754) to successfully control postoperative glucose level. Besides commonly used tests (such as HbA1C and lipid profile), we analysed high sensitive C-reactive protein (hs-CRP) levels before surgery, and then at 1 hour, 12 hours and 7 days after CABG in order to estimate their prognostic value.&#x0D; RESULTS: During the 48 hours after CABG, there was a trend towards having higher glucose levels in both groups of patients with and without DM2 according to CGM. In patients with DM2, the glucose level was significantly increased (р0,05). Insulin pump therapy resulted in glycemic control improvement in early follow-up (72 hours). Moreover, there were no hypoglycaemic episodes in patients on insulin pump therapy and also in patients prescribed bolus insulin therapy. We revealed the trend towards lower rate of postpericardiotomy syndrome (PCTS) in patients on insulin pump therapy compared to patients prescribed bolus insulin therapy in the early postoperative period (p=0,1). Hs-CRP level was lower in patients with DM2 who were on insulin pump therapy compared to patients prescribed bolus insulin therapy in the early postoperative period (р0,05). This most likely confirms that insulin pump therapy decreases systemic inflammatory response.&#x0D; CONCLUSIONS: Thus, we demonstrated the CGM feasibility, safety and efficacy in association with insulin pump therapy in patients with DM2 undergoing CABG.

The effect of insulin degludec on risk of symptomatic nocturnal hypoglycaemia in adults with type 1 diabetes and high risk of nocturnal severe hypoglycaemia (the HypoDeg trial): study rationale and design

BackgroundHypoglycaemia, especially nocturnal, remains the main limiting factor of achieving good glycaemic control in type 1 diabetes.The effect of first generation long-acting insulin analogues in reducing nocturnal hypoglycaemia is well documented in patient with type 1 diabetes. The effect of the newer long-acting insulin degludec on risk of nocturnal hypoglycaemia remains undocumented in patients with type 1 diabetes and recurrent severe nocturnal hypoglycaemia.The HypoDeg trial is designed to investigate whether insulin degludec in comparison with insulin glargine U100 is superior in limiting the occurrence of nocturnal hypoglycaemia in patients with recurrent nocturnal severe hypoglycaemia. This paper reports the study design of the HypoDeg trial.Methods/designA Danish investigator-initiated, prospective, randomised, open, blinded endpoint (PROBE), multicentre, two-year cross-over study investigating the effect of insulin degludec versus insulin glargine U100 on frequency of nocturnal hypoglycaemia in patients with type 1 diabetes and one or more episodes of nocturnal severe hypoglycaemia during the preceding two years as the major inclusion criteria. Patients are randomised (1:1) to basal therapy with insulin degludec or insulin glargine. Insulin aspart is used as bolus therapy in both treatment arms.DiscussionIn contrast to most other insulin studies the HypoDeg trial includes only patients at high risk of hypoglycaemia. The HypoDeg trial will compare treatment with insulin degludec to insulin glargine U100 in terms of risk of nocturnal hypoglycaemic episodes in patients with type 1 diabetes with the greatest potential to benefit from near-physiological insulin replacement therapy. www.clinicaltrials.gov: NCT02192450.

1830-P: Empagliflozin as Well as Anakinra Reduces Symptomatic Postprandial Hypoglycemia after Gastric Bypass

Background: Postprandial hypoglycemia (PPH) is a debilitating complication after bariatric surgery, due to an exaggerated hyperinsulinemic response after carbohydrate ingestion. Recent studies have shown that IL-1β contributes to the postprandial stimulation of insulin. Similarly, lowering hyperglycemic peak by SGLT2-inhibition may reduce insulin secretion. We investigated whether the IL-1 receptor antagonist anakinra or empagliflozin influence PPH in patients after gastric bypass. Methods: We included 12 subjects with PPH after gastric bypass in a placebo controlled, double-blind, randomized, cross-over proof-of-concept study. Subjects received on each of the 3 study days either empagliflozin, anakinra or the respective placebos followed by a mixed-meal-test (MMT) with assessment of hypoglycaemia. Results: Treatment with empagliflozin reduced glycaemia at 30 (11.2 vs. 10.1 mmol/l), 60 (9.1 vs. 6.9 mmol/l) and 90 (4.5 vs. 3.5 mmol/l) minutes of the MMT compared to placebo and was followed by a significant reduction of hypoglycemic events (n = 2, 16.6%) compared to placebo (n = 8, 61.5%). Treatment with anakinra showed a similar glucose curve as placebo, but was also followed by a significantly reduced rate of hypoglycemic events (n = 2, 16.6%). Both treatment interventions showed lowered insulin and c-peptide levels compared to placebo (p&amp;lt;0.001). Conclusion: Empagliflozin as well as Anakinra significantly reduced hypoglycemic episodes in patients after gastric bypass by decreased insulin secretion. Therefore, empagliflozin and IL-1 antagonism, could be promising novel therapeutic options for patients with refractory PPH after gastric bypass. Disclosure M. Hepprich: None. B. Schelker: None. S.J. Wiedemann: None. B. Trinh: None. M. Böni-Schnetzler: None. M.Y. Donath: Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Merck &amp; Co., Inc., Novartis AG, Novo Nordisk A/S, Sanofi. Funding University of Basel

Incidence rate and patient characteristics of severe hypoglycemia in treated type 2 diabetes mellitus patients in Japan: Retrospective Diagnosis Procedure Combination database analysis.

Aims/IntroductionTo evaluate the incidence rate of and identify factors associated with severe hypoglycemic episodes in patients with treated type 2 diabetes mellitus.Materials and MethodsUsing Diagnosis Procedure Combination hospital‐based medical database, we carried out a retrospective cohort study to assess the incidence rate of severe hypoglycemia in treated type 2 diabetes mellitus patients. We evaluated the associations between severe hypoglycemia and age, sex, complications, and current use of insulin or sulfonylurea (SU) in a nested case–control study.ResultsOf 166,806 eligible patients, 1,242 had episodes of severe hypoglycemia during the observational period. The incidence rate of the first hypoglycemic events was 3.70/1,000 patient years. Based on the nested case–control analysis, age was associated with hypoglycemic events with adjusted odds ratios (ORs) of 1.64 or 65–74‐year‐old patients and 3.79 for ≥75‐year‐old patients in comparison with 20–64‐year‐old patients. Comorbidities, such as cognitive impairment, cancer, macrovascular disease and diabetic complications (retinopathy, nephropathy and neuropathy), were associated with severe hypoglycemia, with adjusted ORs ranging from 1.25 to 3.80. Severe hypoglycemic events also increased in patients with current use of both SU and insulin, either SU or insulin, with adjusted ORs of 18.36, 6.31 or 14.07, respectively, compared with patients with other antihyperglycemic agents. In patients with an SU glimepiride, adjusted ORs increased dose‐dependently from 3.65 (≤1 mg) to 13.34 (>2 mg).ConclusionsThe incidence rate of severe hypoglycemia in this cohort was 3.70/1,000 patient years. Age, cognitive impairment, cancer, diabetic complications, current use of insulin + SU and SU dosage were identified as risk factors for severe hypoglycemia.

A novel nasal powder formulation of glucagon: toxicology studies in animal models.

BackgroundGlucagon nasal powder (GNP), a novel intranasal formulation of glucagon being developed to treat insulin-induced severe hypoglycemia, contains synthetic glucagon (10 % w/w), beta-cyclodextrin, and dodecylphosphocholine. The safety of this formulation was evaluated in four studies in animal models.MethodsThe first study evaluated 28-day sub-chronic toxicology in rats treated intranasally with 1 and 2 mg of GNP/day (0.1 and 0.2 mg glucagon/rat/day). The second study evaluated 28-day sub-chronic toxicology in dogs administered 20 and 40 mg of formulation/dog/day (2 and 4 mg glucagon/dog/day) intranasally. A pulmonary insufflation study assessed acute toxicology following intra-tracheal administration of 0.5 mg of GNP (0.05 mg glucagon) to rats. Local tolerance to 30 mg of GNP (equivalent to 3 mg glucagon, the final dose for humans) was tested through direct administration into the eyes of rabbits.ResultsThere were no test article-related adverse effects on body weight and/or food consumption, ophthalmology, electrocardiography, hematology, coagulation parameters, clinical chemistry, urinalysis, or organ weights, and no macroscopic findings at necropsy in any study. In rats, direct intra-tracheal insufflation at a dose of 0.5 mg of GNP/rat (0.05 mg glucagon/rat) did not result in adverse clinical, macroscopic, or microscopic effects. In dogs, the only adverse findings following sub-chronic use were transient (<30 s) salivation and sneezing immediately post-treatment and mild to moderate reversible histological changes to the nasal mucosa. Daily dosing over 28 days in rats resulted in mild to moderate, unilateral or bilateral erosion/ulceration of the olfactory epithelium, frequently with minimal to mild, acute to sub-acute inflammation of the lamina propria at the dorsal turbinates of the nasal cavity in 2/10 males and 3/10 females in the high-dose group (0.2 mg glucagon/day). These lesions resolved completely over 14 days. Histological examination of tissues from both sub-chronic studies in dogs and rats revealed no microscopic findings. In rabbits, clinical observations noted in the GNP-treated eye and/or surrounding areas included ≥1 of the following: clear discharge, red conjunctiva, partial closure, and swelling of the peri-orbital area, which correlated with erythema and edema noted during ocular observations and grading.DiscussionThe studies reported here revealed no safety concerns associated with GNP in animal models. Studies published earlier have highlighted the local safety profile of intranasally administered cyclodextrins (a component of GNP). The choline group, the phosphate group, and the saturated 12-carbon aliphatic chain that are present in the dodecylphosphocholine excipient used in GNP are all present in the phospholipids and lecithins seen ubiquitously in mammalian cell membranes and are unlikely to pose safety concerns; this notion is supported by several studies conducted by the authors that revealed no safety concerns. Taken together, these results suggest that intranasal delivery of GNP holds promise as a future rescue medication for use by caregivers to treat insulin-induced hypoglycemic episodes in patients with type 1 or type 2 diabetes.ConclusionThis novel drug product is well tolerated in animal models.Electronic supplementary materialThe online version of this article (doi:10.1186/s40360-015-0026-9) contains supplementary material, which is available to authorized users.

Hypoglycaemic episodes in patients with type 2 diabetes – risk factors and associations with patient-reported outcomes: The PANORAMA Study

AimTo explore the frequency of hypoglycaemic episodes, their risk factors, and associations with patient-reported outcomes in patients with type 2 diabetes enrolled in the PANORAMA cross-sectional study. MethodsFive thousand seven hundred and eighty-three patients aged ≥ 40 years with type 2 diabetes duration ≥ 1 year were recruited in nine European countries. Patients reported severe and non-severe hypoglycaemic episodes during the past year at a single study visit. Patient-reported outcomes were measured by the Audit of Diabetes-Dependent Quality of Life, Diabetes Treatment Satisfaction Questionnaires, Hypoglycaemia Fear Survey-II, and EQ-5D Visual Analog Scale. ResultsDuring the previous year, 4.4% of the patients experienced ≥1 severe hypoglycaemic episode; among those without severe hypoglycaemia, 15.7% experienced ≥1 non-severe episode. Patients experiencing any hypoglycaemic episode reported a greater negative impact of diabetes on quality of life, greater fear of hypoglycaemia, less treatment satisfaction and worse health status than those with no episodes. In multivariate analyses hypoglycaemia was significantly associated with longer diabetes duration; presence of microvascular and, to a lesser extent, macrovascular complications; treatment with insulin, glinides or sulfonylureas; and use of self-monitoring blood glucose. ConclusionIn patients with type 2 diabetes, severe hypoglycaemic episodes were not uncommon and one in five experienced some form of hypoglycaemia during the previous year. Hypoglycaemia was associated with more negative patient-reported outcomes. The risk of hypoglycaemia increased with diabetes duration, presence of diabetes-related complications, use of self-monitoring blood glucose, insulin secretagogues, and insulin treatment.

Pasireotide (SOM230) prevents sulfonylurea-induced hypoglycemia in rats.

Persistent hypoglycemia is a serious condition that is frequently reported in patients undergoing sulfonylurea treatment, often necessitating hospitalization in the event of overdose. Somatostatin is a regulatory hormone with a broad range of physiological actions that include the inhibition of insulin and glucagon secretion, predominantly via activation of the somatostatin receptor subtypes sstr5 and sstr2, respectively. Previous studies have demonstrated that octreotide, a potent somatostatin analogue with high affinity for sstr2 and moderate affinity for sstr5, significantly increases serum glucose levels and prevents recurrence of hypoglycemic episodes in patients with sulfonylurea-induced hypoglycemia. Pasireotide (SOM230) is a multireceptor-targeted somatostatin analogue with a 39-, 30- and 5-fold higher binding affinity for sstr5, sstr1 and sstr3, respectively, and a slightly lower (0.4-fold) affinity for sstr2 compared with octreotide. This study evaluated the effects of pasireotide and octreotide in rats with glyburide-induced hypoglycemia. In fasted rats, pasireotide (10 and 30 µg/kg) prevented glyburide-induced hypoglycemia in a dose-dependent manner for up to 6 h. Qualitatively similar results were observed in non-fasted rats. However, the antihypoglycemic effect of pasireotide was stronger in non-fasted rats, resulting in transient hyperglycemia. In contrast to pasireotide, octreotide 10 µg/kg did not prevent glyburide-induced hypoglycemia in fasted and non-fasted rats, while octreotide 30 µg/kg resulted in small but significant increases in blood glucose at 3 h post-dose only. These findings suggest that pasireotide could have a more potent effect than octreotide in the management of patients with severe hypoglycemia caused by hyperinsulinemia.

Severe Hypoglycemia and Cardiovascular Disease in Type 2 Diabetes.

Severe Hypoglycemia and Cardiovascular Disease in Type 2 Diabetes.

Insulin degludec improves long-term glycaemic control similarly to insulin glargine but with fewer hypoglycaemic episodes in patients with advanced type 2 diabetes on basal-bolus insulin therapy.

The aim of the present study was to compare the long-term safety and efficacy of insulin degludec with those of insulin glargine in patients with advanced type 2 diabetes (T2D) over 78 weeks (the 52-week main trial and a 26-week extension). Patients were randomized to once-daily insulin degludec or insulin glargine, with mealtime insulin aspart ± metformin ± pioglitazone, and titrated to pre-breakfast plasma glucose values of 3.9-4.9 mmol/l (70-88 mg/dl). After 78 weeks, the overall rate of hypoglycaemia was 24% lower (p = 0.011) and the rate of nocturnal hypoglycaemia was 31% lower (p = 0.016) with insulin degludec in the extension trial set, while both groups of patients achieved similar glycaemic control. Rates of adverse events and total insulin doses were similar for both groups in the safety analysis set. During 18 months of treatment, insulin degludec + mealtime insulin aspart ± oral antidiabetic drugs in patients with T2D improves glycaemic control similarly, but confers lower risks of overall and nocturnal hypoglycaemia than with insulin glargine treatment.

Association of Depression with Severe Hypoglycemic Episodes in Patients with Type 2 Diabetes: The ABCD Cohort Study

To examine the association of depressive symptoms with risk of severe hypoglycemic episodes in type 2 diabetes (T2DM) patients in Alberta.

Optimal Time for Capillary Blood Glucose Monitoring in Patients with Type 2 Diabetes Treated with Insulin: A Cross-Sectional Observation Study

Our objective was to determine the frequency and time of day when we detect the greatest number of hyperglycaemic and hypoglycaemic episodes in patients with type 2 diabetes mellitus (DM) on insulin. We also studied whether any clinical feature could be associated with more frequent hypoglycaemia or hyperglycaemia. We conducted an observational study of 51 patients with type 2 diabetes mellitus who were on insulin and metabolically stable. We followed the patients for 8 weeks, performing two daily capillary blood glucose measurements before and 2 hours after each of the three main meals in turn. A profile was also prepared from 6 capillary blood glucose measurements performed before and after meals every 4 days. The likelihood of observing hyperglycaemia increased 48% before dinner (taking pre-breakfast capillary blood glucose as a reference). The likelihood of observing hypoglycaemia was 3.4 times greater in pre-lunch capillary blood glucose measurements and was more frequent in patients with lower BMI. In patients with type 2 DM stabilised by insulin, performing pre-dinner capillary blood glucose measurements identifies hyperglycaemia more often than at other times of the day, while pre-lunch measurement identifies hypoglycaemia more often, the latter being more common in patients with lower BMI.

Saxagliptin versus glipizide as add-on therapy to metformin: assessment of hypoglycemia

Objective:To compare characteristics of hypoglycemic episodes in patients with type 2 diabetes receiving saxagliptin or glipizide add-on therapy to metformin.Patients and methods:This was a post hoc analysis of an international, randomized, parallel-group, double-blind, active-controlled, phase 3 trial. The 52-week trial and 52-week extension were conducted from December 2007 to August 2010. Patients aged ≥18 years with glycated hemoglobin (HbA1c) >6.5% to 10.0% receiving stable metformin doses (≥1500 mg/d) were randomized 1:1 to add-on therapy with saxagliptin 5 mg/d or glipizide 5 to 20 mg/d (titrated to optimal effect or highest tolerable dose during the initial 18 weeks). Hypoglycemic episodes were recorded in patient diaries. Confirmed hypoglycemic events were defined as fingerstick glucose ≤50 mg/dL (≤2.8 mmol/L) with associated symptoms.Results:Of 858 patients randomized, 428 received saxagliptin + metformin, and 430 received glipizide + metformin. Saxagliptin was noninferior to glipizide in lowering HbA1c. Hypoglycemia with saxagliptin + metformin and glipizide + metformin was reported by 15 (24 events) and 165 (896 events) patients, respectively, through week 104. The mean (SD) number of hypoglycemic events per patient reporting hypoglycemia was lower with saxagliptin + metformin versus glipizide + metformin through weeks 52 (1.5 [SD 0.88] vs 4.8 [SD 4.9], respectively) and 104 (1.6 [SD 0.99] vs 5.4 [SD 5.8]). Most patients receiving glipizide + metformin with hypoglycemia had multiple events (124/165 patients [75%]). Confirmed hypoglycemia, major events, and severe events occurred only with glipizide + metformin. Time to first hypoglycemic event was shorter with glipizide versus saxagliptin. Limitations of this analysis include its post hoc nature, a high rate of study discontinuation, and exclusion of patients with serious comorbidities and complications.Conclusion:Saxagliptin + metformin was associated with fewer patients reporting hypoglycemia and fewer and less severe hypoglycemic events in those experiencing hypoglycemia compared with glipizide + metformin.ClinicalTrials.gov registration number:ClinicalTrials.gov identifier: NCT00575588.

Evaluation of a 5‐day education programme in Type 1 diabetes: achieving individual targets with a patient‐centred approach

To evaluate if a single inpatient education training programme can achieve individualized therapeutic targets. Patients with Type 1 diabetes participating in a flexible intensive therapy programme were consecutively included in a prospective monocentric study. They all participated in the same education programme which had a patient-centred approach. Before the intervention, patients were divided into three groups according to their main therapeutic target: Group 1, to decrease HbA1c concentration in patients with baseline HbA1c ≥ 58mmol/mol (7.5%); Group 2, to improve quality of life and satisfaction with treatment in patients with baseline HbA1c < 58mmol/mol (7.5%); and Group 3, to decrease the frequency of hypoglycaemic episodes in patients with severe or frequent hypoglycaemic episodes. Therapeutic targets were evaluated at 12months. Quality of life and treatment satisfaction were evaluated with validated questionnaires completed at baseline and 6months. In Group 1 (n = 74), the mean ± sd HbA1c concentration decreased from 75 ± 15mmol/mol (9.0 ±1.4%) to 68±15mmol/mol (8.4 ± 1.4%; P < 0.001), with 53% of patients experiencing a decrease in HbA1c concentration of at least 6mmol/mol (0.5%), without weight gain or more frequent hypoglycaemia. In Group 2 (n = 12), patient satisfaction with treatment improved significantly (P < 0.0001). In Group 3 (n = 35), minor hypoglycaemia significantly decreased from a mean±sd of 6.6 ± 4.7 to 3.2 ± 3.0 hypoglycaemic episodes/week (P < 0.001) and the incidence of severe hypoglycaemia dropped significantly from a mean ± sd of 2.31 ± 3.07 to 0.86 ± 2.46 episodes/patient/year (P < 0.001). Many patients with different needs, who attended the same flexible intensive therapy education programme, which had a patient-centred approach, were able to achieve their individual therapeutic targets.

Association of Depression With Increased Risk of Severe Hypoglycemic Episodes in Patients With Diabetes

Although psychosocial and clinical factors have been found to be associated with hypoglycemic episodes in patients with diabetes, few studies have examined the association of depression with severe hypoglycemic episodes. This study examined the prospective association of depression with risk of hypoglycemic episodes requiring either an emergency department visit or hospitalization. In a longitudinal cohort study, a sample of 4,117 patients with diabetes enrolled between 2000 and 2002 were observed from 2005 to 2007. Meeting major depression criteria on the Patient Health Questionnaire-9 was the exposure of interest, and the outcome of interest was an International Classification of Disease, Ninth Revision code for a hypoglycemic episode requiring an emergency department visit or hospitalization. Proportional hazard models were used to analyze the association of baseline depression and risk of one or more severe hypoglycemic episodes. Poisson regression was used to determine whether depression status was associated with the number of hypoglycemic episodes. After adjusting for sociodemographic, clinical measures of diabetes severity, non-diabetes-related medical comorbidity, prior hypoglycemic episodes, and health risk behaviors, depressed compared with nondepressed patients who had diabetes had a significantly higher risk of a severe hypoglycemic episode (hazard ratio = 1.42, 95% CI, 1.03-1.96) and a greater number of hypoglycemic episodes (odds ratio = 1.34, 95% CI, 1.03-1.74). Depression was significantly associated with time to first severe hypoglycemic episode and number of hypoglycemic episodes. Research assessing whether recognition and effective treatment of depression among persons with diabetes prevents severe hypoglycemic episodes is needed.

Langzeitwirkung von Dapagliflozin bei Typ-2-Diabetikern unter hoch dosierter Insulintherapie

Dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2, may improve glycemic control with a lower dose of insulin and attenuate the associated weight gain in patients with inadequate control despite high doses of insulin. To evaluate the efficacy and safety of adding dapagliflozin therapy in patients whose type 2 diabetes mellitus is inadequately controlled with insulin with or without oral antidiabetic drugs. A 24-week, randomized, placebo-controlled, multicenter trial followed by a 24-week extension period. An additional 56-week extension period is ongoing. (ClinicalTrials.gov registration number: NCT00673231). 126 centers in Europe and North America from 30 April 2008 to 19 November 2009. 808 patients with inadequately controlled type 2 diabetes mellitus receiving at least 30 U of insulin daily, with or without up to 2 oral antidiabetic drugs. Patients were randomly assigned in a 1:1:1:1 ratio and allocated with a computer-generated scheme to receive placebo or 2.5, 5, or 10 mg of dapagliflozin, once daily, for 48 weeks. The primary outcome was change in hemoglobin A1c from baseline to 24 weeks. Secondary outcomes included changes in body weight, insulin dose, and fasting plasma glucose level at 24 weeks and during the 24-week extension period. Adverse events were evaluated throughout both 24-week periods. 800 patients were analyzed. After 24 weeks, mean hemoglobin A1c decreased by 0.79 % to 0.96 % with dapagliflozin compared with 0.39 % with placebo (mean difference, -0.40 % [95 % CI, -0.54 % to -0.25 %] in the 2.5-mg group, -0.49 % [CI, -0.65 % to -0.34 %] in the 5-mg group, and -0.57 % [CI, -0.72 % to -0.42 %] in the 10-mg group). Daily insulin dose decreased by 0.63 to 1.95 U with dapagliflozin and increased by 5.65 U with placebo (mean difference, -7.60 U [CI, -10.32 to -4.87 U] in the 2.5-mg group, -6.28 U [CI, -8.99 to -3.58 U] in the 5-mg group, and -6.82 U [CI, -9.56 to -4.09 U] in the 10-mg group). Body weight decreased by 0.92 to 1.61 kg with dapagliflozin and increased by 0.43 kg with placebo (mean differences, -1.35 kg [CI, -1.90 to -0.80 kg] in the 2.5-mg group, -1.42 kg [CI, -1.97 to -0.88 kg] in the 5-mg group, and -2.04 kg [CI, -2.59 to -1.48 kg] in the 10-mg group). These effects were maintained at 48 weeks. Compared with the placebo group, patients in the pooled dapagliflozin groups had a higher rate of hypoglycemic episodes (56.6 % vs. 51.8 %), events suggesting genital infection (9.0 % vs. 2.5 %), and events suggesting urinary tract infection (9.7 % vs. 5.1 %). Insulin doses were not titrated to target, and the study was not designed to evaluate long-term safety. Dapagliflozin improves glycemic control, stabilizes insulin dosing, and reduces weight without increasing major hypoglycemic episodes in patients with inadequately controlled type 2 diabetes mellitus.