Showing papers on "Hypoglycemia published in 2017"

Efficacy and Safety of Degludec versus Glargine in Type 2 Diabetes.

Abstract: BackgroundDegludec is an ultralong-acting, once-daily basal insulin that is approved for use in adults, adolescents, and children with diabetes. Previous open-label studies have shown lower day-to-day variability in the glucose-lowering effect and lower rates of hypoglycemia among patients who received degludec than among those who received basal insulin glargine. However, data are lacking on the cardiovascular safety of degludec. MethodsWe randomly assigned 7637 patients with type 2 diabetes to receive either insulin degludec (3818 patients) or insulin glargine U100 (3819 patients) once daily between dinner and bedtime in a double-blind, treat-to-target, event-driven cardiovascular outcomes trial. The primary composite outcome in the time-to-event analysis was the first occurrence of an adjudicated major cardiovascular event (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) with a prespecified noninferiority margin of 1.3. Adjudicated severe hypoglycemia, as defined b...

Flash Glucose-Sensing Technology as a Replacement for Blood Glucose Monitoring for the Management of Insulin-Treated Type 2 Diabetes: a Multicenter, Open-Label Randomized Controlled Trial.

Abstract: Glycemic control in participants with insulin-treated diabetes remains challenging. We assessed safety and efficacy of new flash glucose-sensing technology to replace self-monitoring of blood glucose (SMBG). This open-label randomized controlled study (ClinicalTrials.gov, NCT02082184) enrolled adults with type 2 diabetes on intensive insulin therapy from 26 European diabetes centers. Following 2 weeks of blinded sensor wear, 2:1 (intervention/control) randomization (centrally, using biased-coin minimization dependant on study center and insulin administration) was to control (SMBG) or intervention (glucose-sensing technology). Participants and investigators were not masked to group allocation. Primary outcome was difference in HbA1c at 6 months in the full analysis set. Prespecified secondary outcomes included time in hypoglycemia, effect of age, and patient satisfaction. Participants (n = 224) were randomized (149 intervention, 75 controls). At 6 months, there was no difference in the change in HbA1c between intervention and controls: −3.1 ± 0.75 mmol/mol, [−0.29 ± 0.07% (mean ± SE)] and −3.4 ± 1.04 mmol/mol (−0.31 ± 0.09%) respectively; p = 0.8222. A difference was detected in participants aged <65 years [−5.7 ± 0.96 mmol/mol (−0.53 ± 0.09%) and −2.2 ± 1.31 mmol/mol (−0.20 ± 0.12%), respectively; p = 0.0301]. Time in hypoglycemia <3.9 mmol/L (70 mg/dL) reduced by 0.47 ± 0.13 h/day [mean ± SE (p = 0.0006)], and <3.1 mmol/L (55 mg/dL) reduced by 0.22 ± 0.07 h/day (p = 0.0014) for intervention participants compared with controls; reductions of 43% and 53%, respectively. SMBG frequency, similar at baseline, decreased in intervention participants from 3.8 ± 1.4 tests/day (mean ± SD) to 0.3 ± 0.7, remaining unchanged in controls. Treatment satisfaction was higher in intervention compared with controls (DTSQ 13.1 ± 0.50 (mean ± SE) and 9.0 ± 0.72, respectively; p < 0.0001). No serious adverse events or severe hypoglycemic events were reported related to sensor data use. Forty-two serious events [16 (10.7%) intervention participants, 12 (16.0%) controls] were not device-related. Six intervention participants reported nine adverse events for sensor-wear reactions (two severe, six moderate, one mild). Flash glucose-sensing technology use in type 2 diabetes with intensive insulin therapy results in no difference in HbA1c change and reduced hypoglycemia, thus offering a safe, effective replacement for SMBG. ClinicalTrials.gov identifier: NCT02082184. Abbott Diabetes Care.

Association of Insulin Pump Therapy vs Insulin Injection Therapy With Severe Hypoglycemia, Ketoacidosis, and Glycemic Control Among Children, Adolescents, and Young Adults With Type 1 Diabetes.

Abstract: Importance Insulin pump therapy may improve metabolic control in young patients with type 1 diabetes, but the association with short-term diabetes complications is unclear. Objective To determine whether rates of severe hypoglycemia and diabetic ketoacidosis are lower with insulin pump therapy compared with insulin injection therapy in children, adolescents, and young adults with type 1 diabetes. Design, Setting, and Participants Population-based cohort study conducted between January 2011 and December 2015 in 446 diabetes centers participating in the Diabetes Prospective Follow-up Initiative in Germany, Austria, and Luxembourg. Patients with type 1 diabetes younger than 20 years and diabetes duration of more than 1 year were identified. Propensity score matching and inverse probability of treatment weighting analyses with age, sex, diabetes duration, migration background (defined as place of birth outside of Germany or Austria), body mass index, and glycated hemoglobin as covariates were used to account for relevant confounders. Exposures Type 1 diabetes treated with insulin pump therapy or with multiple (≥4) daily insulin injections. Main Outcomes and Measures Primary outcomes were rates of severe hypoglycemia and diabetic ketoacidosis during the most recent treatment year. Secondary outcomes included glycated hemoglobin levels, insulin dose, and body mass index. Results Of 30 579 patients (mean age, 14.1 years [SD, 4.0]; 53% male), 14 119 used pump therapy (median duration, 3.7 years) and 16 460 used insulin injections (median duration, 3.6 years). Patients using pump therapy (n = 9814) were matched with 9814 patients using injection therapy. Pump therapy, compared with injection therapy, was associated with lower rates of severe hypoglycemia (9.55 vs 13.97 per 100 patient-years; difference, −4.42 [95% CI, −6.15 to −2.69];P Conclusions and Relevance Among young patients with type 1 diabetes, insulin pump therapy, compared with insulin injection therapy, was associated with lower risks of severe hypoglycemia and diabetic ketoacidosis and with better glycemic control during the most recent year of therapy. These findings provide evidence for improved clinical outcomes associated with insulin pump therapy compared with injection therapy in children, adolescents, and young adults with type 1 diabetes.

Effects of Sotagliflozin Added to Insulin in Patients with Type 1 Diabetes

Abstract: BackgroundIn most patients with type 1 diabetes, adequate glycemic control is not achieved with insulin therapy alone. We evaluated the safety and efficacy of sotagliflozin, an oral inhibitor of sodium–glucose cotransporters 1 and 2, in combination with insulin treatment in patients with type 1 diabetes. MethodsIn this phase 3, double-blind trial, which was conducted at 133 centers worldwide, we randomly assigned 1402 patients with type 1 diabetes who were receiving treatment with any insulin therapy (pump or injections) to receive sotagliflozin (400 mg per day) or placebo for 24 weeks. The primary end point was a glycated hemoglobin level lower than 7.0% at week 24, with no episodes of severe hypoglycemia or diabetic ketoacidosis after randomization. Secondary end points included the change from baseline in glycated hemoglobin level, weight, systolic blood pressure, and mean daily bolus dose of insulin. ResultsA significantly larger proportion of patients in the sotagliflozin group than in the placebo gr...

Toward Defining the Threshold Between Low and High Glucose Variability in Diabetes

Abstract: OBJECTIVE To define the threshold for excess glucose variability (GV), one of the main features of dysglycemia in diabetes. RESEARCH DESIGN AND METHODS A total of 376 persons with diabetes investigated at the University Hospital of Montpellier (Montpellier, France) underwent continuous glucose monitoring. Participants with type 2 diabetes were divided into several groups—groups 1, 2a, 2b, and 3 ( n = 82, 28, 65, and 79, respectively)—according to treatment: 1 ) diet and/or insulin sensitizers alone; 2 ) oral therapy including an insulinotropic agent, dipeptidyl peptidase 4 inhibitors (group 2a) or sulfonylureas (group 2b); or 3 ) insulin. Group 4 included 122 persons with type 1 diabetes. Percentage coefficient of variation for glucose (%CV = [(SD of glucose)/(mean glucose)] × 100) and frequencies of hypoglycemia (interstitial glucose RESULTS Percentages of CV (median [interquartile range]; %) increased significantly ( P P P 36% were compared with those with %CV ≤36%. CONCLUSIONS A %CV of 36% appears to be a suitable threshold to distinguish between stable and unstable glycemia in diabetes because beyond this limit, the frequency of hypoglycemia is significantly increased, especially in insulin-treated subjects.

Association of Neonatal Glycemia with Neurodevelopmental Outcomes at 4.5 Years

Abstract: Importance Hypoglycemia is common during neonatal transition and may cause permanent neurological impairment, but optimal intervention thresholds are unknown. Objective To test the hypothesis that neurodevelopment at 4.5 years is related to the severity and frequency of neonatal hypoglycemia. Design, Setting, and Participants The Children With Hypoglycemia and Their Later Development (CHYLD) Study is a prospective cohort investigation of moderate to late preterm and term infants born at risk of hypoglycemia. Clinicians were masked to neonatal interstitial glucose concentrations; outcome assessors were masked to neonatal glycemic status. The setting was a regional perinatal center in Hamilton, New Zealand. The study was conducted from December 2006 to November 2010. The dates of the follow-up were September 2011 to June 2015. Participants were 614 neonates born from 32 weeks’ gestation with at least 1 risk factor for hypoglycemia, including diabetic mother, preterm, small, large, or acute illness. Blood and masked interstitial glucose concentrations were measured for up to 7 days after birth. Infants with hypoglycemia (whole-blood glucose concentration Exposures Neonatal hypoglycemic episode, defined as at least 1 consecutive blood glucose concentration less than 47 mg/dL, a severe episode ( Main Outcomes and Measures Cognitive function, executive function, visual function, and motor function were assessed at 4.5 years. The primary outcome was neurosensory impairment, defined as poor performance in one or more domains. Results In total, 477 of 604 eligible children (79.0%) were assessed. Their mean (SD) age at the time of assessment was 4.5 (0.1) years, and 228 (47.8%) were female. Those exposed to neonatal hypoglycemia (280 [58.7%]) did not have increased risk of neurosensory impairment (risk difference [RD], 0.01; 95% CI, −0.07 to 0.10 and risk ratio [RR], 0.96; 95% CI, 0.77 to 1.21). However, hypoglycemia was associated with increased risk of low executive function (RD, 0.05; 95% CI, 0.01 to 0.10 and RR, 2.32; 95% CI, 1.17 to 4.59) and visual motor function (RD, 0.03; 95% CI, 0.01 to 0.06 and RR, 3.67; 95% CI, 1.15 to 11.69), with highest risk in children exposed to severe, recurrent, or clinically undetected (interstitial episodes only) hypoglycemia. Conclusions and Relevance Neonatal hypoglycemia was not associated with increased risk of combined neurosensory impairment at 4.5 years but was associated with a dose-dependent increased risk of poor executive function and visual motor function, even if not detected clinically, and may thus influence later learning. Randomized trials are needed to determine optimal screening and intervention thresholds based on assessment of neurodevelopment at least to school age.

Perioperative Hyperglycemia Management: An Update.

Abstract: A substantial body of literature demonstrates a clear association between perioperative hyperglycemia and adverse clinical outcomes.1-3 The risk for post-operative complications and increased mortality relates to both long-term glycemic control and to the severity of hyperglycemia on admission and during the hospital stay.2 The underlying mechanism(s) relating hyperglycemia to poor outcomes is not completely understood. Past and current studies point to physiologic changes that occur in the hyperglycemic state that may contribute to poor outcomes. Elevated blood glucose levels impair neutrophil function, cause an overproduction of reactive oxygen species, free fatty acids and inflammatory mediators. These pathophysiologic changes contribute to direct cellular damage, vascular and immune dysfunction.4 Substantial evidence indicates that correction of hyperglycemia with insulin administration reduces hospital complications and decreases mortality in cardiac5 and general surgery patients.6 However, optimal glucose management during the perioperative period is widely debated. Recent randomized controlled trials targeting conventional targets for glycemic control do not demonstrate the significant risk of hypoglycemia7,8 as seen in prior studies using insulin to maintain tight blood glucose control.9 The pendulum of inpatient care has since moved toward more moderate and individualized glycemic targets. This manuscript reports on the prevalence, diagnosis and pathophysiology of perioperative hyperglycemia and provides a practical outline for the management of surgical patients with diabetes and hyperglycemia. Metabolic Consequences of Surgical Stress and Anesthesia During the fasting state, normal subjects maintain plasma glucose levels between 60-100 mg/dl (3.3-5.5 mmol/l). The stress of surgery and anesthesia alters the finely regulated balance between hepatic glucose production and glucose utilization in peripheral tissues. An increase in the secretion of counterregulatory hormones (catecholamines, cortisol, glucagon, and growth hormone) occurs, causing excessive release of inflammatory cytokines including tumor necrosis factor-α, interleukin-6 and interleukin-1β (Figure 1).10 Cortisol increases hepatic glucose production, stimulates protein catabolism and promotes gluconeogenesis, resulting in elevated blood glucose levels.11 Surging catecholamines increase glucagon secretion and inhibit insulin release by pancreatic β-cells.4 Additionally, the increase in stress hormones leads to enhanced lipolysis and high free fatty acid (FFA) concentrations. Increased FFAs have been shown to inhibit insulin-stimulated glucose uptake12 and limit the intracellular signaling cascade in skeletal muscle responsible for glucose transport activity.13 Evidence also suggests that TNF-α interferes with the synthesis and/or translocation of the glucose transporter GLUT-4 reducing glucose uptake in peripheral tissues.14 These processes result in an altered state of insulin action, leading to a relative state of insulin resistance which is most pronounced on the first postoperative day and may persist for 9-21 days following surgery.15 Open in a separate window Figure 1 The Surgical Stress Response

Effect of Insulin Degludec vs Insulin Glargine U100 on Hypoglycemia in Patients With Type 2 Diabetes: The SWITCH 2 Randomized Clinical Trial.

Abstract: Importance Hypoglycemia, a serious risk for insulin-treated patients with type 2 diabetes, negatively affects glycemic control. Objective To test whether treatment with basal insulin degludec is associated with a lower rate of hypoglycemia compared with insulin glargine U100 in patients with type 2 diabetes. Design, Setting, and Participants Randomized, double-blind, treat-to-target crossover trial including two 32-week treatment periods, each with a 16-week titration period and a 16-week maintenance period. The trial was conducted at 152 US centers between January 2014 and December 2015 in 721 adults with type 2 diabetes and at least 1 hypoglycemia risk factor who were previously treated with basal insulin with or without oral antidiabetic drugs. Interventions Patients were randomized 1:1 to receive once-daily insulin degludec followed by insulin glargine U100 (n = 361) or to receive insulin glargine U100 followed by insulin degludec (n = 360) and randomized 1:1 to morning or evening dosing within each treatment sequence. Main Outcomes and Measures The primary end point was the rate of overall symptomatic hypoglycemic episodes (severe or blood glucose confirmed [ Results Of the 721 patients randomized (mean [SD] age, 61.4 [10.5] years; 53.1% male), 580 (80.4%) completed the trial. During the maintenance period, the rates of overall symptomatic hypoglycemia for insulin degludec vs insulin glargine U100 were 185.6 vs 265.4 episodes per 100 patient-years of exposure (PYE) (rate ratio = 0.70 [95% CI, 0.61-0.80]; P P P = .35; risk difference, −0.8% [95% CI, −2.2% to 0.5%]). Statistically significant reductions in overall and nocturnal symptomatic hypoglycemia for insulin degludec vs insulin glargine U100 were also seen for the full treatment period. Conclusions and Relevance Among patients with type 2 diabetes treated with insulin and with at least 1 hypoglycemia risk factor, 32 weeks’ treatment with insulin degludec vs insulin glargine U100 resulted in a reduced rate of overall symptomatic hypoglycemia. Trial Registration clinicaltrials.gov Identifier:NCT02030600

Effect of Insulin Degludec vs Insulin Glargine U100 on Hypoglycemia in Patients With Type 1 Diabetes: The SWITCH 1 Randomized Clinical Trial.

Abstract: Importance Hypoglycemia, common in patients with type 1 diabetes, is a major barrier to achieving good glycemic control. Severe hypoglycemia can lead to coma or death. Objective To determine whether insulin degludec is noninferior or superior to insulin glargine U100 in reducing the rate of symptomatic hypoglycemic episodes. Design, Setting, and Participants Double-blind, randomized, crossover noninferiority trial involving 501 adults with at least 1 hypoglycemia risk factor treated at 84 US and 6 Polish centers (January 2014-January 12, 2016) for two 32-week treatment periods, each with a 16-week titration and a 16-week maintenance period. Interventions Patients were randomized 1:1 to receive once-daily insulin degludec followed by insulin glargine U100 (n = 249) or to receive insulin glargine U100 followed by insulin degludec (n = 252) and randomized 1:1 to morning or evening dosing within each treatment sequence. Main Outcomes and Measures The primary end point was the rate of overall severe or blood glucose-confirmed ( Results Of the 501 patients randomized (mean age, 45.9 years; 53.7% men), 395 (78.8%) completed the trial. During the maintenance period, the rates of overall symptomatic hypoglycemia were 2200.9 episodes per 100 person-years’ exposure (PYE) in the insulin degludec group vs 2462.7 episodes per 100 PYE in the insulin glargine U100 group for a rate ratio (RR) of 0.89 (95% CI, 0.85-0.94; P P P P P = .002; risk difference, −6.8%; 95% CI, −10.8% to −2.7%). Conclusions and Relevance Among patients with type 1 diabetes and at least 1 risk factor for hypoglycemia, 32 weeks’ treatment with insulin degludec vs insulin glargine U100 resulted in a reduced rate of overall symptomatic hypoglycemic episodes. Trial Registration clinicaltrials.gov Identifier:NCT02034513

Use of Flash Glucose-Sensing Technology for 12 months as a Replacement for Blood Glucose Monitoring in Insulin-treated Type 2 Diabetes.

Abstract: Published evaluations of sensor glucose monitoring use in insulin treated type 2 diabetes are limited. The aim of this study was to assess the impact of flash glucose-sensing technology as a replacement for self-monitoring of blood glucose (SMBG) over a 12-month period in participants with type 2 diabetes who were on intensive insulin therapy. An open-label, randomized, controlled study in adults with type 2 diabetes on intensive insulin therapy from 26 European diabetes centers aimed at assessing flash glucose sensing technology was conducted. Participants (N = 224) were randomized (1:2 respectively) to a control group (n = 75) that used SMBG (FreeStyle Lite™) or to an intervention group (n = 149) which used sensor glucose data (FreeStyle Libre™ Flash Glucose Monitoring System) for self-management over 6 months. All intervention group participants who completed the 6-month treatment phase continued into an additional 6-month open-access phase. A total of 139 intervention participants completed the 6-month treatment phase and continued into the open-access phase. At 12 months (end of open-access period), time in hypoglycemia [sensor glucose <3.9 mmol/L (70 mg/dL)] was reduced by 50% compared to baseline [−0.70 ± 1.85/24 h (mean ± standard deviation); p = 0.0002]. Nocturnal hypoglycemia [2300 to 0600 hours, <3.9 mmol/L (70 mg/dL)] was reduced by 52%; p = 0.0002. There was no change in time in range [sensor glucose 3.9–10.0 mmol/L (70–180 mg/dL)]. SMBG testing fell from a mean of 3.9 (median 3.9) times/day at baseline to 0.2 (0.0), with an average frequency of sensor scanning of 7.1 (5.7) times/day at 12 months, and mean sensor utilization was 83.6 ± 13.8% (median 88.3%) during the open-access phase. During this 6-month extension period no device-related serious adverse events were reported. Nine participants reported 16 instances of device-related adverse events (e.g. infection, allergy) and 28 participants (20.1%) experienced 134 occurrences of anticipated skin symptoms/sensor-insertion events expected with device use (e.g. erythema, itching and rash). The use of flash glucose-sensing technology for glycemic management in individuals with type 2 diabetes treated by intensive insulin therapy over 12 months was associated with a sustained reduction in hypoglycemia and safely and effectively replaced SMBG. ClinicalTrials.gov identifier, NCT02082184.

Macrovascular Complications in Patients with Diabetes and Prediabetes.

Abstract: Diabetes is a significant health problem worldwide, and its association with cardiovascular disease (CVD) was reported in several studies. Hyperglycemia and insulin resistance seen in diabetes and prediabetes lead to an increase in reactive oxygen species, which triggers intracellular molecular signaling. The resulting prothrombotic state and increase in inflammatory mediators expedite atherosclerotic changes and the development of macrovascular complications. Individuals with diabetes or prediabetes have a higher risk of developing myocardial infarction, stroke, and peripheral artery disease. However, no significant difference in cardiovascular morbidity has been observed with tight glycemic control despite a reduction in some CVD outcomes, and the risk of adverse outcomes such as hypoglycemia was increased. Recently, some GLP-1 receptor agonists and SGLT-2 inhibitors have been shown to reduce cardiovascular events and mortality. In this review we give an overview of the risk and pathogenesis of cardiovascular disease among diabetic and prediabetic patients, as well as the implication of recent changes in diabetes management.

Cerebral ischemic damage in diabetes: an inflammatory perspective.

Abstract: Stroke is one of the leading causes of death worldwide. A strong inflammatory response characterized by activation and release of cytokines, chemokines, adhesion molecules, and proteolytic enzymes contributes to brain damage following stroke. Stroke outcomes are worse among diabetics, resulting in increased mortality and disabilities. Diabetes involves chronic inflammation manifested by reactive oxygen species generation, expression of proinflammatory cytokines, and activation/expression of other inflammatory mediators. It appears that increased proinflammatory processes due to diabetes are further accelerated after cerebral ischemia, leading to increased ischemic damage. Hypoglycemia is an intrinsic side effect owing to glucose-lowering therapy in diabetics, and is known to induce proinflammatory changes as well as exacerbate cerebral damage in experimental stroke. Here, we present a review of available literature on the contribution of neuroinflammation to increased cerebral ischemic damage in diabetics. We also describe the role of hypoglycemia in neuroinflammation and cerebral ischemic damage in diabetics. Understanding the role of neuroinflammatory mechanisms in worsening stroke outcome in diabetics may help limit ischemic brain injury and improve clinical outcomes.

Prevention of Hypoglycemia With Predictive Low Glucose Insulin Suspension in Children With Type 1 Diabetes: A Randomized Controlled Trial.

Abstract: OBJECTIVE To investigate whether predictive low-glucose management (PLGM) of the MiniMed 640G system significantly reduces the rate of hypoglycemia compared with sensor-augmented insulin pump in children with type 1 diabetes. RESEARCH DESIGN AND METHODS This randomized, two-arm, parallel, controlled, two-center open-label study included 100 children and adolescents with type 1 diabetes and glycated hemoglobin A1c ≤10% (≤ 86 mmol/mol) and using continuous subcutaneous insulin infusion. Patients were randomly assigned to either an intervention group with PLGM features enabled (PLGM ON) or a control group (PLGM OFF), in a 1:1 ratio, all using the same type of sensor-augmented insulin pump. The primary end point was the number of hypoglycemic events RESULTS The number of hypoglycemic events 140 mg/dL (7.8 mmol/L) in the PLGM ON group (P = 0.0165). CONCLUSIONS The PLGM insulin suspension was associated with a significantly reduced number of hypoglycemic events. Although this was achieved at the expense of increased time in moderate hyperglycemia, there were no serious adverse effects in young patients with type 1 diabetes.

Glycemic control, mortality, and hypoglycemia in critically ill patients: a systematic review and network meta-analysis of randomized controlled trials

Abstract: It is unclear whether tight glycemic control is warranted in all critically ill adults. We employed network meta-analysis to examine the risk of mortality and hypoglycemia associated with different glycemic control targets in critically ill adults. Electronic databases were searched up to 2016 for randomized controlled trials comparing various insulin regimens in critically ill adults with hyperglycemia. Two reviewers independently extracted information and evaluated quality with the Cochrane risk-of-bias tool. Four glycemic control groups were compared: tight (blood glucose: 4.4 < 6.1 mmol/l), moderate (6.1 < 7.8 mmol/l), mild (7.8 < 10.0 mmol/l), and very mild (10.0 to < 12.2 mmol/l). Network meta-analysis was performed by a frequentist approach with multivariate random effects meta-analysis. Thirty-six randomized trials (17,996 patients) were identified. Compared with very mild control, tight control did not reduce the risk of short-term mortality [relative risk (RR) 0.94 (95 % CI 0.83–1.07, p = 0.36)], and neither did mild control [RR 0.88 (0.73–1.06), p = 0.18] or moderate control [RR 1.1 (0.66–1.84), p = 0.72]. However, severe hypoglycemia (<2.2 mmol/l) was more frequent with tight control than very mild control [RR 5.49 (3.22–9.38), p < 0.001] or mild control [RR 4.47 (2.5–8.03), p < 0.001]. Stratified analyses (cause of death, ICU type, time period, or diabetes) did not find significant between-group differences. Ranking analysis revealed the following hierarchy for avoiding death (highest to lowest rank): mild control, tight control, and very mild control. Network meta-analysis showed no mortality benefit of tight glycemic control in critically ill patients, but fivefold more hypoglycemia versus mild or very mild control.

Type 2 Diabetes and Osteoporosis: A Guide to Optimal Management.

Abstract: Context Both type 2 diabetes (T2D) and osteoporosis are affected by aging and quite often coexist. Furthermore, the fracture risk in patients with T2D is increased. The aim of this article is to review updated information on osteoporosis and fracture risk in patients with T2D, to discuss the effects of diabetes treatment on bone metabolism, as well as the effect of antiosteoporotic medications on the incidence and control of T2D, and to provide a personalized guide to the optimal management. Evidence acquisition A systematic literature search for human studies was conducted in three electronic databases (PubMed, Cochrane, and EMBASE) until March 2017. Regarding recommendations, we adopted the grading system introduced by the American College of Physicians. Evidence synthesis The results are presented in systematic tables. Healthy diet and physical exercise are very important for the prevention and treatment of both entities. Metformin, sulfonylureas, dipeptidyl peptidase-4 inhibitors, and glucagon-like peptide-1 receptor agonists should be preferred for the treatment of T2D in these patients, whereas strict targets should be avoided for the fear of hypoglycemia, falls, and fractures. Insulin should be used with caution and with careful measures to avoid hypoglycemia. Thiazolidinediones and canagliflozin should be avoided, whereas other sodium-dependent glucose transporter 2 inhibitors are less well-validated options. Insulin therapy is the preferred method for achieving glycemic control in hospitalized patients with T2D and fractures. The treatment and monitoring of osteoporosis should be continued without important amendments because of the presence of T2D. Conclusions Patients with coexisting T2D and osteoporosis should be managed in an optimal way according to scientific evidence.

Risk of Severe Hypoglycemia in Type 1 Diabetes Over 30 Years of Follow-up in the DCCT/EDIC Study.

Abstract: OBJECTIVE During the Diabetes Control and Complications Trial (DCCT), intensive diabetes therapy achieving a mean HbA 1c of ∼7% was associated with a threefold increase in the rate of severe hypoglycemia (defined as requiring assistance) compared with conventional diabetes therapy with a mean HbA 1c of 9% (612 vs 187 per 100 patient-years) After ∼30 years of follow-up, we investigated the rates of severe hypoglycemia in the DCCT/Epidemiology of Diabetes Inverventions and Complications (EDIC) cohort RESEARCH DESIGN AND METHODS Rates of severe hypoglycemia were reported quarterly during DCCT and annually during EDIC (ie, patient recall of episodes in the preceding 3 months) Risk factors influencing the rate of severe hypoglycemia over time were investigated RESULTS One-half of the DCCT/EDIC cohort reported episodes of severe hypoglycemia During EDIC, rates of severe hypoglycemia fell in the former DCCT intensive treatment group but rose in the former conventional treatment group, resulting in similar rates (366 vs 408 episodes per 100 patient-years, respectively) with a relative risk of 112 (95% CI 091–137) A preceding episode of severe hypoglycemia was the most powerful predictor of subsequent episodes Entry into the DCCT study as an adolescent was associated with an increased risk of severe hypoglycemia, whereas insulin pump use was associated with a lower risk Severe hypoglycemia rates increased with lower HbA 1c similarly among participants in both treatment groups CONCLUSIONS Rates of severe hypoglycemia have equilibrated over time between the two DCCT/EDIC treatment groups in association with advancing duration of diabetes and similar HbA 1c levels Severe hypoglycemia persists and remains a challenge for patients with type 1 diabetes across their life span

Reduction in Hypoglycemia With the Predictive Low-Glucose Management System: A Long-Term Randomized Controlled Trial in Adolescents With Type 1 Diabetes

Abstract: OBJECTIVE Short-term studies with automated systems that suspend basal insulin when hypoglycemia is predicted have shown a reduction in hypoglycemia; however, efficacy and safety have not been established in long-term trials. RESEARCH DESIGN AND METHODS We conducted a 6-month, multicenter, randomized controlled trial in children and adolescents with type 1 diabetes using the Medtronic MiniMed 640G pump with Suspend before low (predictive low-glucose management [PLGM]) compared with sensor-augmented pump therapy (SAPT) alone. The primary outcome was percentage time in hypoglycemia with sensor glucose (SG) RESULTS In an intent-to-treat analysis of 154 subjects, 74 subjects were randomized to SAPT and 80 subjects to PLGM. At baseline, the time with SG 20 min) also declined with PLGM (SAPT vs. PLGM: events/patient-year 227 vs. 139, P CONCLUSIONS In children and adolescents with type 1 diabetes, PLGM reduced hypoglycemia without deterioration in glycemic control.

“Let the Algorithm Do the Work”: Reduction of Hypoglycemia Using Sensor-Augmented Pump Therapy with Predictive Insulin Suspension (SmartGuard) in Pediatric Type 1 Diabetes Patients

Abstract: Background: A sensor-augmented insulin pump (SAP) using the MiniMed® 640G system with SmartGuard™ technology allows an automatic stop of insulin delivery based on prediction of low glucose levels. Since pediatric patients are particularly prone to hypoglycemia, this device may offer additional protection beyond conventional sensor-augmented therapy. Methods: This prospective, pediatric multicenter user evaluation assessed 6 weeks of SAP with SmartGuard (threshold setting for hypoglycemia: 70 mg/dL) compared to a preceding period of 2 weeks with SAP only. The primary outcome was the potential reduction in the frequency of hypoglycemic episodes and hypoglycemic intensity (area under the curve [AUC] and time <70 mg/dL). Results: The study included 24 patients with at least 3 months of insulin pump use (average age: 11.6 ± 5.1 years, 15 female, average type 1 diabetes duration: 7.5 ± 4.2 years, mean ± SD) who had on average 3.2 ± 1.0 predictive suspensions/patient/day. The mean sensor glucose minimum...

Management of Inpatient Hyperglycemia and Diabetes in Older Adults

Abstract: Adults aged 65 years and older are the fastest growing segment of the U.S. population, and their number is expected to double to 89 million between 2010 and 2050. The prevalence of diabetes in hospitalized adults aged 65–75 years and over 80 years of age has been estimated to be 20% and 40%, respectively. Similar to general populations, the presence of hyperglycemia and diabetes in elderly patients is associated with increased risk of hospital complications, longer length of stay, and increased mortality compared with subjects with normoglycemia. Clinical guidelines recommend target blood glucose between 140 and 180 mg/dL (7.8 and 10 mmol/L) for most patients in the intensive care unit (ICU). A similar blood glucose target is recommended for patients in non-ICU settings; however, glycemic targets should be individualized in older adults on the basis of a patient’s clinical status, risk of hypoglycemia, and presence of diabetes complications. Insulin is the preferred agent to manage hyperglycemia and diabetes in the hospital. Continuous insulin infusion in the ICU and rational use of basal-bolus or basal plus supplement regimens in non-ICU settings are effective in achieving glycemic goals. Noninsulin regimens with the use of dipeptidyl peptidase 4 inhibitors alone or in combination with basal insulin have been shown to be safe and effective and may represent an alternative to basal-bolus regimens in elderly patients. Smooth transition of care to the outpatient setting is facilitated by providing oral and written instructions regarding timing and dosing of insulin as well as education in basic skills for home management.

Meta-analysis of lower perioperative blood glucose target levels for reduction of surgical-site infection

Abstract: BACKGROUND There is a clear association between hyperglycaemia and surgical-site infection (SSI). Intensive glucose control may involve a risk of hypoglycaemia, which in turn results in potentially severe complications. A systematic review was undertaken of studies comparing intensive versus conventional glucose control protocols in relation to reduction of SSI and other outcomes, including hypoglycaemia, mortality and stroke. METHODS PubMed, Embase, CENTRAL, CINAHL and WHO databases from 1 January 1990 to 1 August 2015 were searched. Inclusion criteria were RCTs comparing intensive with conventional glucose control protocols, and reporting on the incidence of SSI. Meta-analyses were performed with a random-effects model, and meta-regression was subsequently undertaken. Targeted blood glucose levels, achieved blood glucose levels, and important adverse events were summarized. RESULTS Fifteen RCTs were included. The summary estimate showed a significant benefit for an intensive compared with a conventional glucose control protocol in reducing SSI (odds ratio (OR) 0·43, 95 per cent c.i. 0·29 to 0·64; P < 0·001). A significantly higher risk of hypoglycaemic events was found for the intensive group compared with the conventional group (OR 5·55, 2·58 to 11·96), with no increased risk of death (OR 0·74, 0·45 to 1·23) or stroke (OR 1·37, 0·26 to 7·20). These results were consistent both in patients with and those without diabetes, and in studies with moderately strict and very strict glucose control. CONCLUSION Stricter and lower blood glucose target levels of less than 150 mg/dl (8·3 mmol/l), using an intensive protocol in the perioperative period, reduce SSI with an inherent risk of hypoglycaemic events but without a significant increase in serious adverse events.

Critical role for GLP-1 in symptomatic post-bariatric hypoglycaemia

Abstract: Post-bariatric hypoglycaemia (PBH) is a rare, but severe, metabolic disorder arising months to years after bariatric surgery. It is characterised by symptomatic postprandial hypoglycaemia, with inappropriately elevated insulin concentrations. The relative contribution of exaggerated incretin hormone signalling to dysregulated insulin secretion and symptomatic hypoglycaemia is a subject of ongoing inquiry. This study was designed to test the hypothesis that PBH and associated symptoms are primarily mediated by glucagon-like peptide-1 (GLP-1). We conducted a double-blinded crossover study wherein eight participants with confirmed PBH were assigned in random order to intravenous infusion of the GLP-1 receptor (GLP-1r) antagonist. Exendin (9-39) (Ex-9), or placebo during an OGTT on two separate days at the Stanford University Clinical and Translational Research Unit. Metabolic, symptomatic and pharmacokinetic variables were evaluated. Results were compared with a cohort of BMI- and glucose-matched non-surgical controls (NSCs). Infusion of Ex-9 decreased the time to peak glucose and rate of glucose decline during OGTT, and raised the postprandial nadir by over 70%, normalising it relative to NSCs and preventing hypoglycaemia in all PBH participants. Insulin AUC and secretion rate decreased by 57% and 71% respectively, and peak postprandial insulin was normalised relative to NSCs. Autonomic and neuroglycopenic symptoms were significantly reduced during Ex-9 infusion. GLP-1r blockade prevented hypoglycaemia in 100% of individuals, normalised beta cell function and reversed neuroglycopenic symptoms, supporting the conclusion that GLP-1 plays a primary role in mediating hyperinsulinaemic hypoglycaemia in PBH. Competitive antagonism at the GLP-1r merits consideration as a therapeutic strategy. ClinicalTrials.gov NCT02550145

Pharmacokinetic and Pharmacodynamic Characteristics of Dasiglucagon, a Novel Soluble and Stable Glucagon Analog

Abstract: OBJECTIVE Treatment of severe hypoglycemia outside of the hospital setting is limited to glucagon formulations requiring reconstitution before use, which may lead to erroneous or delayed glucagon administration. We compared the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics and safety and tolerability of different doses of dasiglucagon, a novel soluble glucagon analog, with approved pediatric and full doses of GlucaGen in insulin-induced hypoglycemia in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS In this single-center, randomized, double-blind trial, 58 patients with type 1 diabetes received single subcutaneous injections of 0.1, 0.3, 0.6, or 1.0 mg dasiglucagon or 0.5 or 1.0 mg GlucaGen in a state of hypoglycemia (blood glucose target 55 mg/dL) induced by an intravenous insulin infusion. RESULTS Dasiglucagon demonstrated a dose-dependent and rapid increase in plasma concentrations, reaching a maximum at ∼35 min with a half-life of ∼0.5 h. Dasiglucagon rapidly increased plasma glucose (PG) by ≥20 mg/dL (9–14 min) to PG ≥70 mg/dL (within 6–10 min), similar to GlucaGen, but with a longer-lasting and greater effect on PG. All patients on both treatments reached these end points within 30 min (predefined success criteria). Both treatments were well tolerated. Nausea was the most frequent adverse event, occurring at a similar rate (44–56%). CONCLUSIONS Dasiglucagon was well tolerated and showed an early PD response similar to that of GlucaGen at corresponding doses, suggesting comparable clinical effects of the two glucagon formulations. Dasiglucagon has the potential to become an effective and reliable rescue treatment for severe hypoglycemia in a ready-to-use pen.

Continuous subcutaneous insulin infusion versus multiple daily injections in individuals with type 1 diabetes: a systematic review and meta-analysis

Abstract: The relative efficacy of continuous subcutaneous insulin infusion and multiple daily injections in individuals with type 1 diabetes is unclear. We sought to synthesize the existing evidence about the effect of continuous subcutaneous insulin infusion on glycosylated hemoglobin, hypoglycemic events, and time spent in hypoglycemia compared to multiple daily injections. We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and Database of Systematic Reviews, and Scopus from January 2008 through November 2015 for randomized controlled trials that enrolled children or adults with type 1 diabetes. Trials identified in a previous systematic review and published prior to 2008 were also included. We included 25 randomized controlled trials at moderate risk of bias. Meta-analysis showed a significant reduction in glycosylated hemoglobin in patients treated with continuous subcutaneous insulin infusion compared to multiple daily injections (mean difference 0.37; 95 % confidence interval, 0.24–0.51). This effect was demonstrated in both children and adults. There was no significant difference in minor or severe hypoglycemic events. Continuous subcutaneous insulin infusion was associated with lower incidence of nocturnal hypoglycemia. There was no significant difference in the time spent in hypoglycemia. In children and adults with type 1 diabetes and compared to multiple daily injections, continuous subcutaneous insulin infusion is associated with a modest reduction in glycosylated hemoglobin. There was no difference in severe or minor hypoglycemia, but likely a lower incidence of nocturnal hypoglycemia with continuous subcutaneous insulin infusion.

Evaluation of FreeStyle Libre Flash Glucose Monitoring System on Glycemic Control, Health-Related Quality of Life, and Fear of Hypoglycemia in Patients with Type 1 Diabetes.

Abstract: Background/objectives:In the current era of modern technology and the development of smart devices such as the flash glucose monitoring (FGM) systems, patients can easily monitor their glucose levels more frequently without any inconvenience. In this study, we evaluate the effect of FreeStyle Libre FGM system on glycemic control, hypoglycemia, health-related quality of life (QoL), and the fear of hypoglycemia (FOH) among children and young people with type 1 diabetes (T1D).Design and methods:A prospective study was conducted at the Diabetes Treatment Center, Prince Sultan Military Medical City, Riyadh, Saudi Arabia, between January 2017 and May 2017 on 47 (aged 13-19 years) registered patients with T1D who used conventional finger-pricking method for self-testing the glucose. At baseline visit, the FGM sensors were placed on each participant by a trained diabetes educator. The data collected from the sensors were computed to generate the respective ambulatory glucose profiles so as to determine the total ...

Glyburide Versus Metformin and Their Combination for the Treatment of Gestational Diabetes Mellitus: A Randomized Controlled Study

Abstract: OBJECTIVE To compare the efficacy and safety of glyburide versus metformin and their combination for the treatment of gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS In this prospective randomized controlled study, we randomly assigned patients with GDM at 13–33 weeks gestation and whose blood glucose was poorly controlled by diet to receive either glyburide or metformin. If optimal glycemic control was not achieved, the other drug was added. If adverse effects occurred, the drug was replaced. If both failed, insulin was given. The primary outcomes were the rate of treatment failure and glycemic control after the first-line medication according to mean daily glucose charts. RESULTS Glyburide was started in 53 patients and metformin in 51. In the glyburide group, the drug failed in 18 (34%) patients due to adverse effects (hypoglycemia) in 6 (11%) and lack of glycemic control in 12 (23%). In the metformin group, the drug failed in 15 (29%) patients, due to adverse effects (gastrointestinal) in 1 (2%) and lack of glycemic control in 14 (28%). Treatment success after second-line therapy was higher in the metformin group than in the glyburide group (13 of 15 [87%] vs. 9 of 18 [50%], respectively; P = 0.03). In the glyburide group, nine (17%) patients were eventually treated with insulin compared with two (4%) in the metformin group (P = 0.03). The combination of the drugs reduced the need for insulin from 33 (32%) to 11 (11%) patients (P = 0.0002). Mean daily blood glucose and other obstetrical and neonatal outcomes were comparable between groups, including macrosomia, neonatal hypoglycemia, and electrolyte imbalance. CONCLUSIONS Glyburide and metformin are comparable oral treatments for GDM regarding glucose control and adverse effects. Their combination demonstrates a high efficacy rate with a significantly reduced need for insulin, with a possible advantage for metformin over glyburide as first-line therapy.

Pharmacologic Management of Type 2 Diabetes Mellitus: Available Therapies.

Abstract: Choices for the treatment of type 2 diabetes mellitus (T2DM) have multiplied as our understanding of the underlying pathophysiologic defects has evolved. Treatment should target multiple defects in T2DM and follow a patient-centered approach that considers factors beyond glycemic control, including cardiovascular risk reduction. The American Association of Clinical Endocrinologists/American College of Endocrinology and the American Diabetes Association recommend an initial approach consisting of lifestyle changes and monotherapy, preferably with metformin. Therapy choices are guided by glycemic efficacy, safety profiles, particularly effects on weight and hypoglycemia risk, tolerability, patient comorbidities, route of administration, patient preference, and cost. Balancing management of hyperglycemia with the risk of hypoglycemia and consideration of the effects of pharmacotherapy on weight figure prominently in US-based T2DM recommendations, whereas less emphasis has been placed on the ability of specific medications to affect cardiovascular outcomes. This is likely because, until recently, specific glucose-lowering agents have not been shown to affect cardiorenal outcomes. The Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose (EMPA-REG OUTCOME), the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial, and the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes 6 (SUSTAIN-6) recently showed a reduction in overall cardiovascular risk with empagliflozin, liraglutide, and semaglutide treatment, respectively. Moreover, empagliflozin has become the first glucose-lowering agent indicated to reduce the risk of cardiovascular death in adults with T2DM and established cardiovascular disease. Results from cardiovascular outcomes trials have prompted an update to the 2017 American Diabetes Association standards of care, which now recommend consideration of empagliflozin or liraglutide for patients with suboptimally controlled long-standing T2DM and established atherosclerotic cardiovascular disease because these agents have been shown to reduce cardiovascular and all-cause mortality when added to standard care.

Diurnal Differences in Risk of Cardiac Arrhythmias During Spontaneous Hypoglycemia in Young People With Type 1 Diabetes.

Abstract: OBJECTIVE Hypoglycemia may exert proarrhythmogenic effects on the heart via sympathoadrenal stimulation and hypokalemia. Hypoglycemia-induced cardiac dysrhythmias are linked to the “dead-in-bed syndrome,” a rare but devastating condition. We examined the effect of nocturnal and daytime clinical hypoglycemia on electrocardiogram (ECG) in young people with type 1 diabetes. RESEARCH DESIGN AND METHODS Thirty-seven individuals with type 1 diabetes underwent 96 h of simultaneous ambulatory ECG and blinded continuous interstitial glucose monitoring (CGM) while symptomatic hypoglycemia was recorded. Frequency of arrhythmias, heart rate variability, and cardiac repolarization were measured during hypoglycemia and compared with time-matched euglycemia during night and day. RESULTS A total of 2,395 h of simultaneous ECG and CGM recordings were obtained; 159 h were designated hypoglycemia and 1,355 h euglycemia. A median duration of nocturnal hypoglycemia of 60 min (interquartile range 40–135) was longer than daytime hypoglycemia of 44 min (30–70) (P = 0.020). Only 24.1% of nocturnal and 51.0% of daytime episodes were symptomatic. Bradycardia was more frequent during nocturnal hypoglycemia compared with matched euglycemia (incident rate ratio [IRR] 6.44 [95% CI 6.26, 6.63], P CONCLUSIONS Asymptomatic hypoglycemia was common. We identified differences in arrhythmic risk and cardiac repolarization during nocturnal versus daytime hypoglycemia in young adults with type 1 diabetes. Our data provide further evidence that hypoglycemia is proarrhythmogenic.

The efficacy and safety of SGLT2 inhibitors for adjunctive treatment of type 1 diabetes: a systematic review and meta-analysis.

Abstract: To assess the efficacy and safety of the SGLT-2 inhibitors as adjunct therapy to insulin in T1DM, clinical trials indexed in PubMed, Cochrane Library, EMbase from inception through April 5, 2016. A meta-analysis was conducted on trials of SGLT-2 inhibitors in patients with T1DM on insulin therapy using RevMan 5.3 software. Of the 371 articles identified, ten met eligibility criteria. Seven clinical trials including four randomized controlled trials and 581 patients were included. Compared with the control group, SGLT-2 inhibitors group had significantly reduced fasting plasma glucose by 0.69 mmol/L [1.32; 0.07], glycosylated hemoglobin A1C by 0.37% [0.54; 0.20], body weight by 2.54 kg [3.48; 1.60] and total daily insulin dose by 6.22 IU [8.04; 4.40]. The total incidence of adverse events (AEs), hypoglycemia, and genital and urinary infections were also similar to placebo, while an increased incidence of diabetic ketoacidosis (DKA) (n = 16) was seen in SGLT-2 inhibitors group. The present study demonstrates that SGLT-2 inhibitors are effective as adjunct therapy to insulin in T1DM, heralding improved glycemic control, reduced body weight and total daily insulin dose without an increase in total AEs, hypoglycemia, or genital and urinary infections. However, the risk of DKA should be carefully monitored in future clinical trials.