Severe Hypoglycemia In Patients Research Articles

Hypoketotic hypoglycemia in citrin deficiency: a case report

BackgroundCitrin deficiency (CD) is a recessive metabolic disease caused by biallelic pathogenic variants in SLC25A13. Although previous studies have reported ketosis in CD, it was observed at the time of euglycemia or mild hypoglycemia. Blood ketone levels concomitant with symptomatic or severe hypoglycemia in CD have not been a topic of focus despite its importance in identifying the etiology of hypoglycemia and assessing the ability of fatty acid utilization. Herein, we describe a patient with CD who had repeated episodes of hypoglycemia with insufficient ketosis.Case presentationA 1-year-old boy with repetitive hypoglycemia was referred to us to investigate its etiology. The fasting load for 13 h led to hypoketotic hypoglycemia, indicating the possibility of partial β-oxidation dysfunction. A genetic test led to the diagnosis of CD. The hypoglycemic episodes disappeared after switching to a medium-chain triglyceride-containing formula.ConclusionsThis case report suggests that symptomatic or severe hypoglycemia in patients with CD could be associated with relatively low levels of ketone bodies, implying that β-oxidation in these patients might possibly be partially disrupted. When encountering a patient with hypoglycemia, clinicians should check blood ketone levels and bear in mind the possibility of CD because excessive intravenous administration of glucose can cause decompensated symptoms in patients with CD as opposed to other disorders presenting with hypoketotic hypoglycemia, such as fatty acid oxidation disorders. Further studies in a large-scale cohort are warranted to confirm our speculation.

Effects of real-time continuous glucose monitoring in type 1 diabetes: a meta-analysis of randomized controlled trials.

Self-monitoring of blood glucose (SMBG) represented a major breakthrough in the treatment of type 1 diabetes. The aim of the present meta-analysis is to assess the effect of continues glucose monitoring (CGM) and flash glucose monitoring (FGM), on glycemic control in type 1 diabetes. The present analysis includes randomized clinical trials comparing CGM or FGM with SMBG, with a duration of at least 12weeks, identified in Medline or clinicaltrials.gov. The principal endpoint was HbA1c at the end of the trial. A secondary endpoint was severe hypoglycemia. Mean and 95% confidence intervals for HbA1c and Mantel-Haenzel odds ratio [MH-OR] for severe hypoglycemia were calculated, using random effect models. A sensitivity analysis was performed using fixed effect models. In addition, the following secondary endpoints were explored, using the same methods: time in range, health-related quality of life, and treatment satisfaction. Separate analyses were performed for trials comparing CGM with SMBG, and those comparing CGM + CSII and SMBG + MDI and CGM-regulated insulin infusion system (CRIS) and CSII + SMBG. CGM was associated with a significantly lower HbA1c at endpoint in comparison with SMBG (- 0.24 [- 0.34, - 0.13]%); CGM was associated with a significantly lower risk of severe hypoglycemia than SMBG. Treatment satisfaction and quality of life were not measured, or not reported, in the majority of studies. FGM showed a significant reduction in the incidence of mild hypoglycemia and an increased treatment satisfaction, but no significant results are shown in HbA1c. CGM + CSII in comparison with SMBG + MDI was associated with a significant reduction in HbA1c. Only two trials with a duration of at least 12weeks compared a CRIS with SMBG + CSII; HbA1c between the two treatment arms was not statistically significant (difference in means: - 0.23 [- 0.91; 0.46]%; p = 0.52). GCM compared to SMBG has showed a reduction in HbA1c and severe hypoglycemia in patient with type 1 diabetes. The comparison between CGM + CSII and SMBG + MDI showed a large reduction in HbA1c; it is conceivable that the effects of CSII + CGM on glycemic control additives. The only comparison available between FGM and SMBG was conducted in patients in good control.

Switching to Degludec is Associated with Reduced Hypoglycaemia, Irrespective of Definition Used or Patient Characteristics: Secondary Analysis of the ReFLeCT Prospective, Observational Study

IntroductionHypoglycaemia is a common side effect of insulin therapy; low or high glycated haemoglobin (HbA1c) levels, history of hypoglycaemia or long diabetes duration are known modifiers of hypoglycaemia risk. In randomised clinical trials, lower rates of hypoglycaemia have been observed with the new-generation insulin analogue, long-acting insulin degludec, compared with other basal insulins.MethodsThe ReFLeCT study was a prospective observational study over 12 months. Patient-reported diary data on hypoglycaemia were collected from patients with type 1 diabetes (T1D) or type 2 diabetes (T2D) who were switching from other basal insulins to insulin degludec (degludec) at their physician’s discretion in routine clinical care. Two secondary analyses were undertaken to investigate the change in number of hypoglycaemic events: a post hoc analysis using the updated American Diabetes Association (ADA) level 1, 2 and 3 hypoglycaemia definitions, and a pre-specified analysis using patient characteristics (baseline HbA1c, diabetes duration, and physician’s rationale for initiating degludec).ResultsSwitching to degludec was associated with significantly fewer hypoglycaemic events for all definitions in T1D, and level 1 and 2 in T2D (too few level 3 events for statistical comparison). Moreover, patient characteristics did not influence the observed reduction in hypoglycaemia in T1D and T2D.ConclusionThese results demonstrate that switching to degludec from other basal insulins was associated with reduced rates of hypoglycaemia, irrespective of the definition used or baseline patient characteristics.Trial RegistrationNCT02392117Electronic Supplementary MaterialThe online version of this article (10.1007/s13300-020-00875-1) contains supplementary material, which is available to authorized users.

Risk of severe hypoglycaemia and its impact in type 2 diabetes in DEVOTE.

AimsTo undertake a post‐hoc analysis, utilizing a hypoglycaemia risk score based on DEVOTE trial data, to investigate if a high risk of severe hypoglycaemia was associated with an increased risk of cardiovascular events, and whether reduced rates of severe hypoglycaemia in patients identified as having the highest risk affected the risk of cardiovascular outcomes.Materials and MethodsThe DEVOTE population was divided into quartiles according to patients' individual hypoglycaemia risk scores. For each quartile, the observed incidence and rate of severe hypoglycaemia, major adverse cardiovascular event (MACE) and all‐cause mortality were determined to investigate whether those with the highest risk of hypoglycaemia were also at the greatest risk of MACE and all‐cause mortality. In addition, treatment differences within each risk quartile [insulin degludec (degludec) vs. insulin glargine 100 units/mL (glargine U100)] in terms of severe hypoglycaemia, MACE and all‐cause mortality were investigated.ResultsPatients with the highest risk scores had the highest rates of severe hypoglycaemia, MACE and all‐cause mortality. Treatment ratios between degludec and glargine U100 in the highest risk quartile were 95% confidence interval (CI) 0.56 (0.39; 0.80) (severe hypoglycaemia), 95% CI 0.76 (0.58; 0.99) (MACE) and 95% CI 0.77 (0.55; 1.07) (all‐cause mortality).ConclusionsThe risk score demonstrated that a high risk of severe hypoglycaemia was associated with a high incidence of MACE and all‐cause mortality and that, in this high‐risk group, those treated with degludec had a lower incidence of MACE. These observations support the hypothesis that hypoglycaemia is a risk factor for cardiovascular events.

2290-PUB: Donor HLA-DR4 Positivity and Islet Transplantation Outcomes

Islet transplantation (ITx) has demonstrated efficacy in improving glycemic control and abolishing severe hypoglycemia in patients affected with type 1 diabetes (T1D). Several factors account for graft loss and recurrence of autoimmunity has been suggested as a contributor to graft failure but remains controversial. We hypothesized that ITx recipients of HLA DR4+ donors could be at increased risk for recurrence of autoimmunity, as DR4+ is a well-known risk factor for T1D. We evaluated 50 ITx recipients transplanted at the Diabetes Research Institute, University of Miami, who have been followed from 2000 to 2019. Out of the 50 subjects, 7 received islet after kidney transplantation and 43 islet transplantation alone. Subjects received an average of 2 islet infusions from 1 to 5 donors. The data was analyzed using Kaplan-Meier Survival Curves, along with log-rank and Wilcoxon tests statistics. No significant association was found between Donor DR4+ and islet transplant outcomes (>0.05). However, our study is limited by the small sample size, use of multiple donors as well as differences in immunosuppression regimens and use of GLP-1 analogs and DPP-4 inhibitors which may have affected outcomes. Our data suggests that donor DR4+ is not associated with transplantation outcomes in our study cohort. Further studies are required to validate these findings. Disclosure C. Chavez: None. V. Fuenmayor: None. D. Baidal: None. A.M. Alvarez: None. N. Padilla: None. C. Ricordi: None. R. Alejandro: None. Funding Diabetes Research Institute Foundation; State of Florida; JDRF; The Leona M. and Harry B. Helmsley Charitable Trust; University of Miami Clinical and Translational Science Institute

269-OR: Effect of Insulin Degludec on Frequency of Severe Hypoglycemia in Patients with Type 1 Diabetes Prone to Nocturnal Severe Hypoglycemia: The HypoDeg Trial

Background and Aims: The long-acting insulin analog degludec reduces the risk of nocturnal hypoglycemia in patients with type 1 diabetes (T1D). The HypoDeg trial compared the effect of insulin degludec to insulin glargine U100 on frequency of nocturnal hypoglycemia in T1D patients with recurrent nocturnal severe hypoglycemia and reported a significant 37% relative risk reduction (RRR) of symptomatic nocturnal hypoglycemia ≤ 3.0 mmol/L with insulin degludec. Here we report the data on severe hypoglycemia (SH). Materials and Methods: In this investigator-initiated, prospective, randomized, open-label, blinded-endpoint crossover trial conducted at 10 centers in Denmark, we recruited 149 T1D patients (>18 years) with ≥2 episodes of nocturnal SH in the preceding two year. Patients were randomly assigned (1:1) to basal-bolus therapy with insulin degludec and insulin aspart or insulin glargine U100 and insulin aspart. A 1-year plus 1-year treatment period was specified, consisting of two 3-month run-in periods, each followed by a 9-month maintenance period. Episodes of SH were reported by telephone and adjudicated blinded to treatment. Results: A total of 136 SH episodes were reported during the maintenance periods: 56 (41%) episodes during treatment with insulin degludec and 80 (59%) episodes during treatment with insulin glargine U100, resulting in a RRR of 35% (95% confidence interval [CI]: 0-60%; p=0.04). This corresponds to an absolute rate reduction of 0.3 episodes (95% CI: 0.0-0.5) per patient-year with insulin degludec. The difference was primarily due to a lower risk of nocturnal episodes (RRR 52%, 95% CI: -10-80%; p=0.08), whereas there was no difference during daytime (RRR 10%, 95% CI: -80-50%; p=0.75). Conclusion: Treatment with insulin degludec in T1D patients with recurrent nocturnal SH resulted in a clinically significant reduced rate of SH compared with insulin glargine U100. Disclosure R.M. Agesen: Employee; Self; Novo Nordisk A/S. A. Alibegovic: Employee; Self; Novo Nordisk A/S. H.U. Andersen: Advisory Panel; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. P. Gustenhoff: Advisory Panel; Self; Abbott Laboratories, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk A/S, Sanofi-Aventis. T.K. Hansen: None. T. Jensen: Stock/Shareholder; Self; Novo Nordisk A/S. C.B. Juhl: None. A.K. Jensen: None. S. Lerche: None. K. Nørgaard: Advisory Panel; Self; Abbott, Medtronic. Research Support; Self; Novo Nordisk A/S. Speaker’s Bureau; Self; Medtronic, Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk Inc. H.D. Parving: None. A.L. Sørensen: None. L. Tarnow: None. B. Thorsteinsson: None. U. Pedersen-Bjergaard: Advisory Panel; Self; Novo Nordisk A/S, Sanofi. Research Support; Self; Novo Nordisk A/S. Funding Novo Nordisk A/S

1102-P: Impact of Treatment with Sotagliflozin on the Incidence of Severe Hypoglycemia in Patients with T1D

Objective: Severe hypoglycemia (SH) is an acute and life-threatening complication of T1D. Factors impacting the risk of SH include A1C, eGFR, insulin dose changes, and use of MDI versus CSII. An adjunctive treatment that simultaneously improves glycemic control and reduces SH across broad groups would be beneficial for patients (pts) with T1D. Methods: Data were pooled from two, 52-week, placebo (PBO)-controlled studies in adults with T1D in the overall population and in prespecified subgroups (Table). SH was defined using Level 3 hypoglycemia criteria and all events were independently adjudicated. Results reflect exposure-adjusted incidence rate per 100 patient-years. Results: Sotagliflozin (SOTA) 400 mg treatment significantly reduced the overall incidence of SH by 41% vs. placebo (relative risk [95% CI] 0.59 [0.35, 0.98]). A dose-responsive reduction was observed in the overall population, and maintained in subgroup analyses (Table), regardless of baseline A1C, eGFR, or percentage reduction in daily insulin dose. Patients using MDI versus CSII alone are generally at higher risk of SH. SOTA 400mg reduced the risk of SH by 69% (relative risk [95% CI] 0.31 [0.13, 0.68]) in MDI-treated pts but did not affect the relatively low rate in those using CSII. Conclusion: These data confirm that SOTA reduced the incidence of SH in pts with T1D, and indicates consistent dose-related risk reduction in almost all subgroups. Disclosure J. Pettus: Consultant; Self; Diasome Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., MannKind Corporation, Novo Nordisk Inc., Sanofi. T. Danne: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic, Novo Nordisk A/S, Sanofi. A.L. Peters: Advisory Panel; Self; Abbott, Bigfoot Biomedical, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, MannKind Corporation, Medscape, Novo Nordisk Inc., Sanofi US. Consultant; Self; Livongo Health. Research Support; Self; Dexcom, Inc., vTv Therapeutics. Other Relationship; Self; Livongo Health, Mellitus Health, Omada Health, Stability Healthcare, Whole Biome Inc. A.K. Carroll: Employee; Self; Lexicon Pharmaceuticals, Inc. Stock/Shareholder; Self; Lexicon Pharmaceuticals, Inc. S. Sawhney: None. W. Jiang: Employee; Self; Lexicon Pharmaceuticals, Inc. Stock/Shareholder; Self; Lexicon Pharmaceuticals, Inc. P.L. Banks: Employee; Self; Lexicon Pharmaceuticals, Inc. J.B. McGill: Advisory Panel; Self; Aegerion Pharmaceuticals, Bayer AG, Lilly Diabetes, Novo Nordisk A/S. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Dexcom, Inc. Research Support; Self; Medtronic, Novo Nordisk Inc., Sanofi. Speaker’s Bureau; Self; Aegerion Pharmaceuticals, Dexcom, Inc., Janssen Pharmaceuticals, Inc.

Nasal glucagon - a new way to treat severe hypoglycemia in patients with diabetes.

Hypoglycaemia is the most frequent acute complication of diabetes in patients treated with insulin. Severe hypoglycaemia can lead to life-threatening disorders. In addition, fear of hypoglycaemia remains a major obstacle to achieving therapeutic goals in diabetics, espe-cially with type 1. As such, both the prevention and treatment of hypoglycemia are so important in diabetes care. Treatment of hypoglycemia is still based on administration of glucose (oral or parenteral depending on the level of consciousness) or of glucagon injected intramuscularly or subcutaneously. In 1983, it was shown for the first time that intranasal glucagon drops increase blood glucose levels in healthy volunteers. In subsequent years, a new powder formulation of glucagon was developed, which is applied intranasally and passively absorbed through the nasal mucosa and it is not necessary to take a deep breath to take it. Intranasal glucagon is as effective as injectable glucagon and devoid of most of the technical problems associated with injectable glucagon. No serious adverse effects of the new preparation have been de-scribed so far. In December 2019 under the name Baqsimi TM (Eli Lilly, USA) has been approved by EMA for the treatment of severe hypoglycemia in patients since 4 years of age. Intranasal glucagon appears to be a breakthrough in the treatment of severe hypoglycemia in diabetic patients treated with insulin in both children and adults.

Antidiabetic Therapy and Rate of Severe Hypoglycaemia in Patients with Type 2 Diabetes and Chronic Kidney Disease of Different Stages - A Follow-up Analysis of Health Insurance Data from Germany.

The presence of chronic kidney disease (CKD) influences the type of antiglycaemic therapy and the risk for hypoglycaemia. In 2006, 2011 and 2016 health insurance data of people with diabetes type 2 were screened for CKD and the presence of severe hypoglycaemia (sHypo). The type of antihyperglycaemic therapy was recorded due to Anatomical Therapeutic Chemical (ATC) codes up to 3 months before suffering sHypo. The prevalence of CKD increased from 5.3% in 2006 to 7.3% in 2011 and 11.2% in 2016. Insulin-based therapies were used in 39.0, 39.1, and 37.9% of patients with, but only in 17.7, 17.4, and 18.8% of patients without CKD. Although the proportion of the CKD stages 1, 2 and 5 decreased, CKD stages 3 and 4 increased. The proportion of sHypo in CKD declined from 2006 (3.5%) to 2011 (3.0%) and 2016 (2.2%) but was still more than 10 times higher as compared to type 2 diabetic patients without CKD (0.3/0.2/0.2%) conferring a significantly higher probability of sHypo (OR 9.30, 95%CI 9.07-9.54) in CKD. The probability of sHypo was significantly lower in 2016 than in 2006 both in patients with (OR 0.58; CI 0.55-0.61) and without CKD (OR 0.70; CI 0.68-0.73). The prevalence of CKD increased from 2006 to 2016. Patients with CKD exhibited a 9-fold increased probability of sHypo, especially in patients treated with insulin plus oral anti-diabetic drugs. However, the rate and risk for sHypo decreased over time, probably as a consequence of new antidiabetic treatment options, better awareness of sHypo, and changed therapy goals.

Evaluating dasiglucagon as a treatment option for hypoglycemia in diabetes

ABSTRACT Introduction Hypoglycemia in diabetes is a common and unresolved complication during diabetes therapy, even life-threatening. Effective and convenient treatment for rescuing severe diabetic hypoglycemia and maintaining euglycemia is in high demand to reduce hypoglycemia-related morbidity and mortality. Dasiglucagon is a novel glucagon analog for diabetic hypoglycemia therapy. Areas covered This review summarizes the reported studies associated with the pharmacokinetics, pharmacodynamics, safety, and tolerability characteristics, as well as clinical application of dasiglucagon for managing diabetic hypoglycemia. Expert opinion Dasiglucagon has demonstrated established solubility and stability in an aqueous formulation. Pharmacokinetics studies have shown dasiglucagon to exhibit higher absorption and a longer plasma elimination half-life than traditional reconstituted glucagon. Pharmacodynamic studies have shown that a full dose of 0.6 mg dasiglucagon could efficiently raise blood glucose level (BGL) by ≥20 mg/dL (9–10 min) from baseline following insulin-induced severe hypoglycemia in patients with type 1 diabetes, as well as rapidly increase BGL with small doses under euglycaemic and hypoglycemic conditions. Dasiglucagon is safe and well tolerated with the main adverse effects being nausea and vomiting. Collectively, dasiglucagon may be a promising candidate for severe diabetic hypoglycemic rescue and a continuous glycemic control in diabetic patients.

Association of insulin regimens with severe hypoglycaemia in patients with type 1 diabetes: A Danish case-control study.

To evaluate the risk of severe hypoglycaemia for patients with Type 1 diabetes (T1D) when exposed to insulin regimens including human insulin only or insulin analogues. A total of 19 896 patients with T1D were extracted from the Danish National Patient Register. Of these, 6379 T1D patients experiencing 1 of more severe hypoglycaemic episodes (total of 17 242 episodes) were matched 1:1 with T1D patients without severe hypoglycaemia. A logistic regression model with last insulin regimen used as exposure was constructed to analyse the effect on severe hypoglycaemia. People on a basal-bolus regimen with insulin analogues had a reduced risk of severe hypoglycaemia of 39% (odds ratio: 0.61, 95% confidence interval: 0.54-0.68) compared to patients on a basal-bolus human insulin only regimen. Furthermore, patients on a premixed regimen containing an insulin analogue had a 58% (odds ratio: 0.42, 95% confidence interval: 0.36-0.49) reduced risk of severe hypoglycaemia compared to patients on premixed human insulin only. This study indicates that use of a basal-bolus insulin regimen with an insulin analogue is safer with respect to severe hypoglycaemia in patients with T1D than the use of a basal-bolus human insulin only regimen.

The use of statins in the elderly is associated with less severe hypoglycemia in patient with diabetes

Three hundred and eighty-nine older patients with diabetes attending an ambulatory diabetes center were included to determine risk factors of severe hypoglycemia (SH). Thirty-three (8.5%) patients had at least one severe hypoglycemia. In multivariate analyze, statin was associated with lower risk and insulin was associated with higher risk of SH.

Hypoglycaemia and cardiac arrhythmias in diabetes.

Hypoglycaemia remains an inevitable risk in insulin-treated type 1 diabetes and type 2 diabetes and has been associated with multiple adverse outcomes. Whether hypoglycaemia is a cause of fatal cardiac arrhythmias in diabetes, or merely a marker of vulnerability, is still unknown. Since a pivotal report in 1991, hypoglycaemia has been suspected to induce cardiac arrhythmias in patients with type 1 diabetes, the so-called ‘dead-in-bed syndrome’. This suspicion has subsequently been supported by the coexistence of an increased mortality and a three-fold increase in severe hypoglycaemia in patients with type 2 diabetes receiving intensive glucose-lowering treatment in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Studies have investigated the association between hypoglycaemia-induced cardiac arrhythmias. In a rat-model, severe hypoglycaemia resulted in a specific pattern of cardiac arrhythmias including QT-prolongation, ventricular tachycardia, second- and third-degree AV block and ultimately cardiorespiratory arrest. In clinical studies of experimentally induced hypoglycaemia, QTc-prolongation, a risk factor of ventricular arrhythmias, is an almost consistent finding. The extent of QT-prolongation seems to be modified by several factors, including antecedent hypoglycaemia, diabetes duration and cardiac autonomic neuropathy. Observational studies indicate diurnal differences in the pattern of electrocardiographic alterations during hypoglycaemia with larger QTc-prolongations during daytime, whereas the risk of bradyarrhythmias may be increased during sleep. Daytime periods of hypoglycaemia are characterized by shorter duration, increased awareness and a larger increase in catecholamines. The counterregulatory response is reduced during nightly episodes of hypoglycaemia, resulting in prolonged periods of hypoglycaemia with multiple nadirs. An initial sympathetic activity at plasma glucose nadir is replaced by increased vagal activity, which results in bradycardia. Here, we provide an overview of the existing literature exploring potential mechanisms for hypoglycaemia-induced cardiac arrhythmias and studies linking hypoglycaemia to cardiac arrhythmias in patients with diabetes.

Glomerular Filtration Rate and Associated Risks of Cardiovascular Events, Mortality, and Severe Hypoglycemia in Patients with Type 2 Diabetes: Secondary Analysis (DEVOTE 11)

Glomerular Filtration Rate and Associated Risks of Cardiovascular Events, Mortality, and Severe Hypoglycemia in Patients with Type 2 Diabetes: Secondary Analysis (DEVOTE 11)

Intensification with dipeptidyl peptidase-4 inhibitor, insulin, or thiazolidinediones and risks of all-cause mortality, cardiovascular diseases, and severe hypoglycemia in patients on metformin-sulfonylurea dual therapy: A retrospective cohort study.

BackgroundAlthough patients with type 2 diabetes mellitus (T2DM) may fail to achieve adequate hemoglobin A1c (HbA1c) control despite metformin-sulfonylurea (Met-SU) dual therapy, a third-line glucose-lowering medication—including dipeptidyl peptidase-4 inhibitor (DPP4i), insulin, or thiazolidinedione (TZD)—can be added to achieve this. However, treatment effects of intensification with the medications on the risk of severe hypoglycemia (SH), cardiovascular disease (CVD), and all-cause mortality are uncertain. Study aim was to compare the risks of all-cause mortality, CVD, and SH among patients with T2DM on Met-SU dual therapy intensified with DPP4i, insulin, or TZD.Methods and findingsWe analyzed a retrospective cohort data of 17,293 patients with T2DM who were free from CVD and on Met-SU dual therapy and who were intensified with DPP4i (n = 8,248), insulin (n = 6,395), or TZD (n = 2,650) from 2006 to 2017. Propensity-score weighting was used to balance out baseline covariates across groups. Hazard ratios (HRs) for all-cause mortality, CVD, and SH were assessed using Cox proportional hazard models. Mean age of all patients was 58.56 ± 11.41 years. All baseline covariates achieved a balance across the 3 groups. Over a mean follow-up period of 34 months with 49,299 person-years, cumulative incidences of all-cause mortality, SH, and CVD were 0.061, 0.119, and 0.074, respectively. Patients intensified with insulin had higher risk of all-cause mortality (HR = 2.648, 95% confidence interval [CI] 2.367–2.963, p < 0.001; 2.352, 95% CI 2.123–2.605, p < 0.001) than those intensified with TZD and DPP4i, respectively. Insulin users had the greatest risk of SH (HR = 1.198, 95% CI 1.071–1.340, p = 0.002; 1.496, 95% CI 1.342–1.668, p < 0.001) compared with TZD and DPP4i users, respectively. Comparing between TZDs and DPP4i, TZDs were associated with a higher risk of SH (HR = 1.249, 95% CI 1.099–1.419, p < 0.001) but not all-cause mortality (HR = 0.888, 95% CI 0.776–1.016, p = 0.084) or CVD (HR = 1.005, 95% CI 0.915–1.104, p = 0.925). Limitations of this study included the lack of data regarding lifestyle, drug adherence, time-varying factors, patients’ motivation, and cost considerations. A limited duration of patients intensifying with TZD might also weaken the strength of study results.ConclusionsOur results indicated that, for patients with T2DM who are on Met-SU dual therapy, the addition of DPP4i was a preferred third-line medication among 3 options, with the lowest risks of mortality and SH and posing no increased risk for CVD events when compared to insulin and TZD. Intensification with insulin had the greatest risk of mortality and SH events.

Glomerular Filtration Rate and Associated Risks of Cardiovascular Events, Mortality, and Severe Hypoglycemia in Patients with Type 2 Diabetes: Secondary Analysis (DEVOTE 11).

IntroductionThe associations of chronic kidney disease (CKD) severity, cardiovascular disease (CVD), and insulin with the risks of major adverse cardiovascular events (MACE), mortality, and severe hypoglycemia in patients with type 2 diabetes (T2D) at high cardiovascular (CV) risk are not known. This secondary, pooled analysis of data from the DEVOTE trial examined whether baseline glomerular filtration rate (GFR) categories were associated with a higher risk of these outcomes.MethodsDEVOTE was a treat-to-target, double-blind trial involving 7637 patients with T2D at high CV risk who were randomized to once-daily treatment with either insulin degludec (degludec) or insulin glargine 100 units/mL (glargine U100). Patients with estimated GFR data at baseline (n = 7522) were analyzed following stratification into four GFR categories.ResultsThe risks of MACE, CV death, and all-cause mortality increased with worsening baseline GFR category (P < 0.05), with a trend towards higher rates of severe hypoglycemia. Patients with prior CVD, CKD (estimated GFR < 60 mL/min/m2), or both were at higher risk of MACE, CV death, and all-cause mortality. Only CKD was associated with a higher rate of severe hypoglycemia, and the risk of MACE was higher in patients with CVD than in those with CKD (P = 0.0003). There were no significant interactions between randomized treatment and GFR category.ConclusionThe risks of MACE, CV death, and all-cause mortality were higher with lower baseline GFR and with prior CVD, CKD, or both. The relative effects of degludec versus glargine U100 on outcomes were consistent across baseline GFR categories, suggesting that the lower rate of severe hypoglycemia associated with degludec use versus glargine U100 use was independent of baseline GFR category.FundingNovo Nordisk.Electronic supplementary materialThe online version of this article (10.1007/s13300-019-00715-x) contains supplementary material, which is available to authorized users.

Needle-free glucagon formulation aims to simplify emergency treatment of severe hypoglycemia

In July, FDA approved glucagon nasal powder (Baqsimi—Eli Lilly), the first glucagon therapy that can be administered without an injection for emergency treatment of severe hypoglycemia in patients with diabetes ages 4 years and older. The agent comes in a single-use dispenser containing one dose of glucagon 3 mg, which is administered into one nostril. Because inhalation is not required, the drug can be successfully administered by another person if the receiver is unconscious. “[U]ntil now, people suffering from a severe hypoglycemic episode had to be treated with a glucagon injection that first had to be mixed in a several-step process,” noted Janet Woodcock, MD, director of FDA’s Center for Drug Evaluation and Research. “This new way to administer glucagon may simplify the process, which can be critical during an episode [of severe hypoglycemia], especially since the patient may have lost consciousness or may be having a seizure.” Injectable glucagon has been approved for use in the United States for several decades. Efficacy and safety of glucagon nasal powder to treat severe hypoglycemia was evaluated in two studies of 83 and 70 adults with diabetes. The studies compared a single 3-mg dose of glucagon nasal powder to a single 1-mg dose of I.M. glucagon injection in causing a blood glucose response to insulin-induced hypoglycemia. Glucagon nasal powder adequately increased blood glucose levels. Similar results were observed in a pediatric study of 48 patients with type 1 diabetes who were older than 4 years. In addition, a Phase I study determined that absorption of glucagon nasal powder was not impaired by nasal congestion resulting from the common cold with or without the use of decongestants. Counsel patients and their family members or caregivers on how to recognize the signs and symptoms of severe hypoglycemia and the risks of prolonged hypoglycemia. Tell them to administer a dose of glucagon nasal power by inserting the device tip into one nostril and pressing the plunger all the way in until the green line is no longer showing. Explain that the medication does not need to be inhaled and will work even if the receiver has a cold or is using cold medication. Family members or caregivers should call emergency assistance immediately after administering the dose. If there has been no response after 15 minutes, an additional 3-mg dose may be administered while waiting for emergency assistance. Be sure to explain that each device contains one dose of glucagon and cannot be reused, so they must use a new dispenser if an additional dose is required. When the receiver responds to treatment, the family member or caregiver should provide oral carbohydrates. Glucagon nasal powder (Baqsimi)Manufacturer: Eli LillyDrug class: AntihypoglycemicIndication: Emergency treatment of severe hypoglycemia in patients with diabetes ages 4 years and olderDosage: 3 mg administered as one actuation of the I.N. device into one nostrilOf note: The agent should not be taken by patients with pheochromocytoma (a rare tumor of adrenal gland tissue) or by patients who have insulinoma (a tumor of the pancreas). Manufacturer: Eli Lilly Drug class: Antihypoglycemic Indication: Emergency treatment of severe hypoglycemia in patients with diabetes ages 4 years and older Dosage: 3 mg administered as one actuation of the I.N. device into one nostril Of note: The agent should not be taken by patients with pheochromocytoma (a rare tumor of adrenal gland tissue) or by patients who have insulinoma (a tumor of the pancreas). Explain that the most common adverse reactions associated with glucagon nasal powder are nausea, vomiting, headache, upper respiratory tract irritation, watery eyes, redness of eyes, and itchiness. Adverse effects are similar to those of injectable glucagon, with the addition of nasal and eye-related symptoms (e.g., watery eyes and nasal congestion) because of the way the drug is administered. Inform patients and their family members or caregivers that allergic reactions can occur and to seek immediate medical attention if they experience any symptoms of serious hypersensitivity reactions. The agent also carries a warning that it should be used with caution by those who have been fasting for long periods, have adrenal insufficiency, or have chronic hypoglycemia, because these conditions result in low levels of releasable glucose in the liver. Patients who are pregnant or plan to become pregnant or are breastfeeding or plan to breastfeed should discuss use with their doctor. Inform patients that it is not known if the agent passes into breast milk.

Multidisciplinary strategies to treat severe hypoglycemia in hospitalized patients with diabetes mellitus reduce inpatient mortality rate: Experience from an academic community hospital

ObjectiveSevere hypoglycemia (blood glucose < 50 mg/dl) in hospitalized patients with diabetes mellitus is associated with poor outcomes such as increased mortality and readmission rates. We study the effects of system based interventions in managing severe hypoglycemia and its impact on outcomes.Research design and methodsWe performed retrospective review of pre- and post- intervention study to quantify severe hypoglycemia in patients admitted in the general internal medicine wards with primary or secondary diagnosis of diabetes mellitus based on ICD-9 and ICD-10 codes. We implemented multidisciplinary interventions including standardization of treatment, education of in-patient medical teams and physician notification and feedback immediately after severe hypoglycemia. The endpoints were the comparative analysis of incidence of severe hypoglycemia, in-patient mortality rate, 30-day mortality rate, 30-day readmission rate, recovery time from hypoglycemia, time to next glucose measurements, use of standardized treatment and physician notification rate pre-and post-intervention.ResultsThe incidence of severe hypoglycemia per patient with diabetes was reduced from 9.6% (233/2416) to 5.6% (202/3607) (p<0.001) post-intervention. The in-patient mortality rate in patients with severe hypoglycemia reduced from 4.1% to 0% (p = 0.019), 30-day mortality rate reduced from 9.8% to 3.8% (p = 0.058) post-intervention. 30-day readmission rate was comparable between pre-intervention (31.7%) and post-intervention (29%) (p = 0.60). In comparison, the mortality and readmission rates of all diabetic patients did not reduce during the same observation periods. Recovery time reduced from 116 (83–161) to 75 (57–102) min (p<0.01), time to next glucose measurement reduced from 39.5 (34–48) to 32 (28–35) min (p<0.01), use of standardized treatment improved from 22.7% (53/233) to 72.2% (146/202) (p<0.001) and physician notification rate increased from 29.2 (68/233) to 84.7% (171/202) post-intervention.ConclusionsOur study shows that multidisciplinary strategies improves the process of early detection and management of severe hypoglycemia and reduce incidence and in-patient mortality rate.

Impaired Awareness of Hypoglycemia Continues to be a Risk Factor for Severe Hypoglycemia Despite the Use of Continuous Glucose Monitoring System in Type 1 Diabetes

Objective: Impaired awareness of hypoglycemia (IAH) is a risk factor for severe hypoglycemia in patients with type 1 diabetes (T1D) not using a continuous glucose monitoring (CGM) system. The current study investigated the prevalence of IAH and its relationship with severe hypoglycemia in T1D patients using CGM systems. Methods: This cross-sectional observational study enrolled 135 patients with T1D and ongoing real-time CGM use. A survey was conducted to assess hypoglycemia awareness with the Gold, Clarke, and Pedersen-Bjergaard questionnaires and the 6-month history of severe hypoglycemia. Other diabetes histories and the CGM glucose data were collected. Results: The Gold, Clarke, and Pedersen-Bjergaard questionnaires demonstrated the overall prevalence of IAH/abnormal awareness to be 33.3%, 43.7%, and 77.0%, respectively. Participant age and duration of T1D were consistently related to IAH or hypoglycemia unawareness with all three questionnaires (P<.05). Amongst the patients using CGM for >6 months, 24.5% were found to have at least one episode of severe hypoglycemia in the preceding 6 months. IAH identified by the Gold and Clarke questionnaires and hypoglycemia unawareness identified by the Pedersen-Bjergaard questionnaire were related to 6-, 4.63-, and 5.83-fold increased risk of severe hypoglycemia (P = .001, .004, and .013), respectively. IAH identified by the Gold/Clarke questionnaires was associated with a longer duration of CGM glucose <54 mg/dL and higher glucose coefficients of variation (P<.05). Conclusion: IAH is highly prevalent and related to a higher risk for severe hypoglycemia in T1D patients using CGM. Abbreviations: CGM = continuous glucose monitoring; CI = confidence interval; HAAF = hypoglycemia-associated autonomic failure; HbA1c = hemoglobin A1C; IAH = impaired awareness of hypoglycemia; T1D = type 1 diabetes.

OR22-3 Closed-Loop Glucagon Pump: A Novel and Effective Strategy for Post-Bariatric Hypoglycemia

Current therapies for post-bariatric hypoglycemia (PBH) are incompletely effective. We previously reported feasibility of an open-loop glucagon system for this challenging syndrome. In this study, patients with PBH were enrolled in a double-masked, placebo-controlled, crossover trial to determine the efficacy of a closed-loop mini-dose glucagon delivery system to reduce severe hypoglycemia after a mixed meal. A novel hypoglycemia detection & mitigation algorithm was embedded in the Artificial Pancreas System connected to a continuous glucose monitor (CGM, Dexcom) driving a patch infusion pump (Insulet) filled with study drug (Xeris liquid glucagon or vehicle). After screening and enrollment, CGM were placed; participants returned after an overnight fast for the 1st of 2 study visits. A liquid mixed meal (Ensure Compact: 64 g CHO, 18 g protein, 236 mL) was consumed, and sensor/plasma glucose were measured serially. The system autonomously delivered up to 2 doses of study drug (300/150 mcg of glucagon or equal volume vehicle) if triggered by the hypoglycemia mitigation algorithm. If plasma glucose fell to <55 mg/dL or neuroglycopenia occurred, rescue IV dextrose was given per protocol. During a 2nd study visit, the protocol was repeated, with pump filled with the other study drug. Twelve participants (11F/1M, age 52+2, postoperative duration 8+1 years, mean+SEM) completed all study visits. In an additional 3 participants, the mixed meal did not trigger either alarm or hypoglycemia, so study drug was not administered, and a second visit was not conducted. For the 12 participants receiving glucagon vs. vehicle during 2 study visits, predictive hypoglycemia alerts prompted automated drug delivery at mean 94+6 vs. 89+5 (p=0.41) minutes post meal, when sensor glucose was 114+7 vs. 121+5 mg/dL (p=0.39). Four participants did not require rescue during either visit; 1 participant required rescue during both visits. Seven participants required rescue glucose after vehicle but not after glucagon (p=0.0082). Similarly, 5 participants had severe hypoglycemia (plasma glucose <55 mg/dL) after vehicle but not after glucagon (p=0.03). Nadir plasma glucose was higher in study visits with glucagon vs. vehicle delivery (67.4±2.7 vs. 58.5±1.9 mg/dL, p=0.004). Glucagon levels were not elevated at time of alert (14.6±1.4 pg/mL) but rose after glucagon delivery (1231±187 vs. vehicle 16 ±1.4 pg/mL at 30 minutes, p = 0.001). No rebound hyperglycemia occurred. Emesis occurred before study drug delivery in 2 visits. Transient pain at infusion site was reported during both glucagon (n=11 of 12) and vehicle (n=10 of 12) study visits. No other adverse advents were observed. Our data demonstrate that a CGM-guided glucagon closed-loop system can detect imminent hypoglycemia and deliver mini-dose glucagon, yielding improvements in post-meal glucose and reducing severe hypoglycemia in patients with PBH.