Comparative Study of the Impact of Metformin Versus Insulin on Adverse Pregnancy Outcomes in Women Diagnosed with Gestational Diabetes Mellitus: A Meta-Analysis.

Objective: This systematic comparative analysis aimed to assess the efficacy of metformin (MET) versus insulin (INS) in the treatment of gestational diabetes mellitus (GDM), providing valuable insights for future GDM management strategies. Methods: We conducted a comprehensive search of clinical studies related to MET and INS interventions in GDM through online literature databases, applying predefined inclusion and exclusion criteria. The quality of the included studies was rigorously evaluated. Data on fasting plasma glucose (FPG), glycosylated hemoglobin (HbA1c), pregnancy weight gain (PWG), premature delivery rate (PDR), and neonatal outcomes among GDM patients were extracted and analyzed using Review Manager 5.3 software. Results: We identified eleven high-quality studies comprising 8679 participants following careful screening and assessment. Our meta-analysis revealed a significant reduction in the incidence of excessive PWG and neonatal hypoglycemia in the MET treatment group (research group) compared to the INS treatment group (control group) (P < .05). Conclusions: Our findings support the effectiveness and safety of MET in achieving optimal blood glucose control in GDM. These results suggest the potential for broader clinical adoption of MET in GDM management.

Metformin Plus Insulin for Preexisting Diabetes or Gestational Diabetes in Early Pregnancy: The MOMPOD Randomized Clinical Trial.

Importance: Insulin is recommended for pregnant persons with preexisting type 2 diabetes or diabetes diagnosed early in pregnancy. The addition of metformin to insulin may improve neonatal outcomes. Objective: To estimate the effect of metformin added to insulin for preexisting type 2 or diabetes diagnosed early in pregnancy on a composite adverse neonatal outcome. Design, Setting, and Participants: This randomized clinical trial in 17 US centers enrolled pregnant adults aged 18 to 45 years with preexisting type 2 diabetes or diabetes diagnosed prior to 23 weeks' gestation between April 2019 and November 2021. Each participant was treated with insulin and was assigned to add either metformin or placebo. Follow-up was completed in May 2022. Intervention: Metformin 1000 mg or placebo orally twice per day from enrollment (11 weeks -<23 weeks) through delivery. Main Outcome and Measures: The primary outcome was a composite of neonatal complications including perinatal death, preterm birth, large or small for gestational age, and hyperbilirubinemia requiring phototherapy. Prespecified secondary outcomes included maternal hypoglycemia and neonatal fat mass at birth, and prespecified subgroup analyses by maternal body mass index less than 30 vs 30 or greater and those with preexisting vs diabetes early in pregnancy. Results: Of the 831 participants randomized, 794 took at least 1 dose of the study agent and were included in the primary analysis (397 in the placebo group and 397 in the metformin group). Participants' mean (SD) age was 32.9 (5.6) years; 234 (29%) were Black, and 412 (52%) were Hispanic. The composite adverse neonatal outcome occurred in 280 (71%) of the metformin group and in 292 (74%) of the placebo group (adjusted odds ratio, 0.86 [95% CI 0.63-1.19]). The most commonly occurring events in the primary outcome in both groups were preterm birth, neonatal hypoglycemia, and delivery of a large-for-gestational-age infant. The study was halted at 75% accrual for futility in detecting a significant difference in the primary outcome. Prespecified secondary outcomes and subgroup analyses were similar between groups. Of individual components of the composite adverse neonatal outcome, metformin-exposed neonates had lower odds to be large for gestational age (adjusted odds ratio, 0.63 [95% CI, 0.46-0.86]) when compared with the placebo group. Conclusions and Relevance: Using metformin plus insulin to treat preexisting type 2 or gestational diabetes diagnosed early in pregnancy did not reduce a composite neonatal adverse outcome. The effect of reduction in odds of a large-for-gestational-age infant observed after adding metformin to insulin warrants further investigation. Trial Registration: ClinicalTrials.gov Identifier: NCT02932475.

Insulin concentrations following termination of high-dose insulin euglycemic therapy.

INTRODUCTION: High-dose insulin therapy is used in patients with calcium channel blocker and beta-adrenergic antagonist overdoses. The pharmacokinetics of insulin are scantly reported following high-dose insulin therapy. We present two cases of persistently elevated insulin concentrations following high-dose insulin therapy. CASE REPORTS: A 50-year-old woman and a 45-year-old man experienced hypotension after overdosing on amlodipine and atenolol. They were treated with high-dose insulin therapy for 54 hours at 2 units/kilogram/hour and 48 hours at 10 units/kilogram/hour, respectively. Following termination, serum insulin elimination was studied. Insulin concentrations remained greater than 1,000 µU/mL (fasting reference 2.6-24.9 µU/mL) for longer than 4 hours (case 1) and 11 hours (case 2) and greater than 300 µU/mL for longer than 8 hours and 21 hours, respectively. Insulin concentrations decreased with apparent first-order elimination half-lives of 13.0 hours and 6.0 hours. DISCUSSION: Following high-dose insulin therapy, insulin concentrations remained elevated for longer than expected based on normal pharmacokinetics in therapeutic dosing. Three previous cases reported insulin half-lives of between 2.2 hours and 18.7 hours. The current cases add to the existing data that insulin has a variable but prolonged half-life following high-dose insulin therapy. CONCLUSIONS: These findings suggest that patients are at prolonged risk of hypoglycemia following cessation of high-dose insulin infusions.

Association of Higher-Dose Fluoroquinolone Therapy With Serious Adverse Events in Older Adults With Advanced Chronic Kidney Disease.

Importance: Population-based data are needed to inform the safe prescribing of fluoroquinolone antibiotics to patients with advanced chronic kidney disease (CKD). Objective: To quantify the 14-day risk of a hospital visit with nervous system and/or psychiatric disorders, hypoglycemia, or a collagen-associated event in patients with advanced CKD newly prescribed a fluoroquinolone at a higher vs a lower dose. Design, Setting, and Participants: This population-based cohort study in Ontario, Canada (January 1, 2008, to March 17, 2020) used linked health care data to identify new users of fluoroquinolone antibiotics. Participants included adults 66 years or older with advanced CKD (an estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2 but not receiving dialysis). Data analysis was performed from January 1 to April 30, 2021. Exposures: A new prescription for a higher-dose fluoroquinolone (ciprofloxacin, 501-1000 mg/d; levofloxacin, 501-750 mg/d; or norfloxacin, 401-800 mg/d) vs a lower-dose fluoroquinolone (ciprofloxacin, 500 mg/d; levofloxacin, 250-500 mg/d; or norfloxacin, 400 mg/d). Main Outcomes and Measure: The primary outcome was the 14-day risk of a hospital visit with nervous system and/or psychiatric disorders, hypoglycemia, or a collagen-associated event. Secondary outcomes included a hospital visit with sepsis, retinal detachment or other tendinopathies, all-cause hospitalization, all-cause mortality, and sudden cardiac death. Inverse probability of treatment weighting on the propensity score was used to balance comparison groups on baseline health. Weighted risk ratios and risk differences were obtained using modified Poisson regression and binomial regression, respectively. Results: Of 11 917 patients (median age, 83 years [IQR, 77-89 years]; 7438 women [62.4%]; median eGFR, 25 [IQR, 21-28] mL/min/1.73 m2) included in the analysis, 5482 (46.0%) received a higher-dose and 6435 (54.0%) received a lower-dose fluoroquinolone. After weighting, the primary composite outcome-a hospital visit with nervous system and/or psychiatric disorders, hypoglycemia, or a collagen-associated event-occurred in 68 of 5482 patients (1.2%) treated with a higher-dose fluoroquinolone and in 47 of 5516 (0.9%) treated with a lower-dose fluoroquinolone (weighted risk ratio, 1.45 [95% CI, 1.01-2.08]; weighted risk difference, 0.39% [95% CI, 0.01%-0.76%]). The risk of sepsis, retinal detachment, all-cause hospitalization, all-cause mortality, and sudden cardiac death did not differ significantly between groups. Conclusions and Relevance: These findings suggest that older patients with advanced CKD who were prescribed a fluoroquinolone at a higher-than-recommended dose were significantly more likely to experience the composite outcome of a hospital visit with nervous system and/or psychiatric disorders, hypoglycemia, or a collagen-associated event, although the absolute risk of these events was less than 2%.

Quality of life in people with type 2 diabetes in the 3 years following initiation of second-line therapy: The DISCOVER study.

AIMS: To assess changes in health-related quality of life (HRQoL) in DISCOVER, a 3-year, longitudinal, observational study of patients with type 2 diabetes initiating a second-line glucose-lowering therapy. METHODS: HRQoL was assessed using the physical and mental component summary (PCS and MCS) scores of the 36-item Short-Form Health Survey version 2 (score ranges: 0-100; higher denotes better HRQoL) and the Hypoglycaemia Fear Survey II (HFS-II; score range: 0-132 scale; higher indicates greater fear of hypoglycaemia). Latent class growth modelling (LCGM) was used to identify patients with similar score trajectories. RESULTS: Mean baseline PCS (n = 7428), MCS (n = 7453), and HFS-II (n = 5005) scores were 48.0, 45.4, and 15.4, respectively, and remained stable during follow-up. LCGM revealed subgroups with low or decreasing HRQoL. Patients in these subgroups tended to be older, had more comorbidities, and a lower socioeconomic status than in other subgroups. Use of insulin and sulfonylureas was highest in the subgroup with the highest fear of hypoglycaemia. CONCLUSIONS: Overall, HRQoL remained stable in DISCOVER patients during follow-up. However, LCGM suggests that some patient characteristics and use of sulfonylureas or insulin are associated with low or decreasing HRQoL, potentially warranting the use of alternative therapies.

AMPK-mediated potentiation of GABAergic signalling drives hypoglycaemia-provoked spike-wave seizures.

Metabolism regulates neuronal activity and modulates the occurrence of epileptic seizures. Here, using two rodent models of absence epilepsy, we show that hypoglycaemia increases the occurrence of spike-wave seizures. We then show that selectively disrupting glycolysis in the thalamus, a structure implicated in absence epilepsy, is sufficient to increase spike-wave seizures. We propose that activation of thalamic AMP-activated protein kinase, a sensor of cellular energetic stress and potentiator of metabotropic GABAB-receptor function, is a significant driver of hypoglycaemia-induced spike-wave seizures. We show that AMP-activated protein kinase augments postsynaptic GABAB-receptor-mediated currents in thalamocortical neurons and strengthens epileptiform network activity evoked in thalamic brain slices. Selective thalamic AMP-activated protein kinase activation also increases spike-wave seizures. Finally, systemic administration of metformin, an AMP-activated protein kinase agonist and common diabetes treatment, profoundly increased spike-wave seizures. These results advance the decades-old observation that glucose metabolism regulates thalamocortical circuit excitability by demonstrating that AMP-activated protein kinase and GABAB-receptor cooperativity is sufficient to provoke spike-wave seizures.

Hypoglycemia Due to Acquired Carnitine Deficiency in a Pediatric Patient Receiving Chemotherapy.

We describe a 21-month-old male with relapsed clear cell sarcoma of the kidney receiving enteral nutrition who experienced recurrent, ketotic hypoglycemia. During relapse therapy, he had recurrent hypoglycemia episodes, in the setting of hematochezia and diarrhea. Evaluation revealed low carnitine levels. He received supplementation with oral levocarnitine throughout the remainder of treatment, resulting in normalization of serum carnitine levels and no further hypoglycemia. We believe adverse effects of the chemotherapy on his single kidney and gastrointestinal insult resulted in hypoglycemia and carnitine deficiency. Our case highlights that carnitine deficiency should be considered when acute onset hypoglycemia without obvious cause occurs.

Evaluation of high-dose insulin/euglycemia therapy for suspected ß-blocker or calcium channel blocker overdose following guideline implementation.

PURPOSE: High-dose insulin/euglycemia (HDIE) is targeted therapy for ß-blocker and calcium channel blocker overdose. A guideline using concentrated insulin infusions (20 units/mL), aggressive monitoring, and supportive recommendations was implemented. We sought to evaluate safety before and after HDIE guideline implementation and describe the patient population, insulin doses, supplemental dextrose, vasopressor use, hospital and intensive care unit (ICU) lengths of stay, and mortality. METHODS: Retrospective review was performed of patients receiving HDIE before and after guideline implementation at an academic medical center and community hospital from March 2011 through December 2019. Information on patient and overdose demographics, ingestion data, vital signs, interventions, adverse events, and disposition was collected. Data are presented descriptively with comparisons using Mann-Whitney U analysis and Fisher's exact tests. RESULTS: During the study period, 27 patients were treated with HDIE, 10 before guideline implementation (37%; mean [SD] initial insulin dose, 0.49 [0.35] units/kg/h; mean [SD] maximum insulin dose, 2.25 [3.29] units/kg/h; median [interquartile range] duration, 10 [5.5-18.75] hours) and 17 after guideline implementation (63%; mean [SD] initial insulin dose, 1.01 [0.34] units/kg/h; mean [SD] maximum insulin dose, 2.99 [5.05] unit/kg/h; median [interquartile range] duration, 16 [11.5-37] hours). Hypoglycemia, hypokalemia, and volume overload occurred in 80% vs 29% (P = 0.018), 40% vs 53% (P = 0.69), and 50% vs 65% (P = 0.69) of patients in the preguideline vs postguideline group, respectively. Most patients received an initial insulin bolus (85%; mean [SD], 70.3 [21.8] units, 0.9 [0.26] units/kg) and vasopressor infusion (85%). More postguideline patients received a dextrose infusion with a concentration of 20% or higher (93% vs 50%, P = 0.015). There were no differences in cardiac arrest, in-hospital mortality, or hospital or ICU length of stay between the groups. CONCLUSION: Hypoglycemia was reduced using an HDIE guideline and concentrated insulin.

The Impact of Hypoglycemia and EPA and DHA Supplementation on Brain-Derived Neurotrophic Factor Level in Pregnant Women with Type 1 Diabetes: A Prospective Cohort Study.

BACKGROUND: In addition to its neuroprotective effect, Brain-derived neurotrophic factor (BDNF) also plays a role in glucose and lipid metabolism. This study aims: a) to find changes in the BDNF concentration during pregnancy in type 1 diabetes. b) to prove the effect of DHA and EPA supplementation on changes in BDNF concentrations c) to investigate the impact of hypoglycemia on BDNF concentration. SUBJECTS AND METHODS: The data from this study were from the PRE-HYPO cohort study. Twenty-one of them were on a standard diabetic diet enriched with EPA and DHA (EPA 120 mg/day and DHA 616 mg/day; Exposed group), and nineteen pregnant diabetic women were on the standard diabetic diet without EPA and DHA supplementation (Non-exposed group). In the first trimester of pregnancy, fifteen pregnant women developed hypoglycemia episodes (≤3.9 mmol/L; HYPO+ group), and twenty-five pregnant women did not have hypoglycemia episodes (HYPO- group). RESULTS: BDNF concentration significantly decreased during pregnancy from the first to the third trimester, in Non-exposed from 25.1 (22.0-30.2) to 22.1 (16.3-28.2), P<0.05, in the Exposed group from 22.1 (19.8-25.9) to 18.1 (14.8-18.9), P<0.01. Pregnant patients with hypoglycemia episodes (HYPO+ subgroup) had significantly higher BDNF in the third trimester of pregnancy [22.5 (20.6-28.4)] when compared with patients who did not develop hypoglycemia [16.3 (14.3-18.8), P<0.001]. In the third trimester of pregnancy, BDNF and n-6 PUFAs were associated with hypoglycemia (OR 1.818 95 % CI 1.079-3.003, P=0.025; OR 1.103 95 % CI 1.001-1.217, P=0.048). Total F.A.s were inversely associated with hypoglycemia (OR 0.969 95% CI 0.939-0.998, P=0.048). CONCLUSION: Pregnant women with hypoglycemia (HYPO+ group) had higher concentrations of BDNF in the first and third trimesters of pregnancy compared to those without hypoglycemia. An increase in body weight during pregnancy leads to a decrease in BDNF concentration.

Mentha longifolia Alleviates Exogenous Serotonin-Induced Diabetic Hypoglycemia and Relieves Renal Toxicity via ROS Regulation.

Diabetic kidney disease is one of the most common microvascular complications of diabetes mellitus with consequences of diabetic nephropathy. Here we amined to evaluate the nephroprotective potential of methanolic Mentha longifolia (MML) against serotonin-induced hypoglycemia allied toxicity in the rat model of diabetes. Diabetes was induced in rats via alloxan administration and validated by blood glucose level measurement. After that, the animals were treated with serotonin and methanolic extract of Mentha longifolia. Surprisingly, serotonin treatment significantly reduced the glucose levels to hypoglycemic conditions, accompanied by impaired redox defense system, abnormal kidney histopathology, dyslipidemia, and altered level of liver toxicity markers. Interestingly these changes were rescued by the methanolic extract of M. longifolia. The present study suggests that impaired serotonin levels during diabetic conditions may accelerate hypoglycemic allied free radical-dependent abnormalities; however, medicinal plants like M. longifolia can reduce these deleterious effects by scavenging free radicals and their associated toxicity.

Analysis of the clinical characteristics of insulin autoimmune syndrome induced by alpha-lipoic acid.

WHAT IS KNOWN AND OBJECTIVE: Alpha-lipoic acid (ALA) is widely used as a dietary supplement and antiageing agent. Insulin autoimmune syndrome (IAS) is the most serious adverse reaction reported with the use of ALA. The purpose of this study was to explore the clinical characteristics of ALA-induced IAS and provide a scientific reference for clinical diagnosis, treatment and prevention. METHODS: We collected literature on IAS cases induced by ALA for retrospective analysis in Chinese and English. RESULTS AND DISCUSSION: The median age of 37 patients (28 females and 9 males) was 61 years (range 32-82). The symptoms occurred at night and in the early morning (60.7%), in the late postprandial period (50.0%) or after fasting (35.7%), within hours in some patients and up to 2 months in others after stopping ALA or during medication treatment. Autonomic nervous system symptoms (81.1%) and neurological hypoglycaemia (64.9%) are the main clinical manifestations of hypoglycaemia. The blood glucose concentration at the onset of hypoglycaemia was 2.19 mmol/L (median, range 1.09-3.52), the insulin concentration was ≥100 µIU/ml (94.6%), and the C-peptide concentration was ≤20 ng/ml (83.3%). Testing for IgG insulin autoantibodies (IAAs) was positive in 37 patients. Pancreatic imaging was unremarkable on computed tomography (CT), magnetic resonance imaging (MRI) and abdominal sonography. Hypoglycaemia disappeared within 5 days to 8 months after withdrawing ALA alone or using corticosteroid treatment. IAA turned negative in 7 months (median; range 2-36). Follow-up showed no recurrent hypoglycaemic episodes at 7.25 months (median; range 1-36). WHAT IS NEW AND CONCLUSION: ALA-induced IAS is a clinically rare autoimmune disease with hypoglycaemia that occurs during medication treatment or after drug withdrawal that should be treated promptly.

[Analysis on the impact of the introduction of a quality management plan of the diabetes care process in a Health Area of Galicia (Spain)]. / Análisis del impacto de la implantación del plan de gestión de calidad del proceso asistencial de diabetes en un Área Sanitaria de Galicia.

OBJECTIVE: To analyse the impact of a management plan for the diabetes process on the level of control of HbA1c and the rate of hypoglycaemia. MATERIAL AND METHODS: The Health Area had a catchment population of 446,603. An anti-diabetic drug prescription (29,705 patients) was used to select diabetic patients. The variables recorded were: percentage of patients with HbA1c <8% and the hypoglycaemia rate before and after implementation of the quality program. RESULTS: The prevalence of diabetes was 11.8%, with 71.3% of them receiving some pharmacological treatment. In the year 2016, in the Integrated Health Area of Santiago de Compostela (Spain), 59.6% (95% CI: 57.9% -61.2%) of the patients had an HbA1c of less than 8%. After the implementation of the quality program, there was an increase in the number of controlled patients, reaching 63.6% (IRQ: 16.0%) in 2017, and 63.8% (95% CI: 62.5% - 65.2%) in 2018. The annual rate of hypoglycaemia increased non-significantly from 2.8 (95% CI: 2.22-3.35) in 2016, to 2.94 (95% CI: 2.35-2.35) in 2017 (P=.083), and 3.0 (95% CI: 2.44-3.56) in 2018 (P=.399). CONCLUSIONS: The implementation of the diabetes process management program enabled the level of control of HbA1c to be improved, as well as increase the percentage of patients who undergo regular check-ups, without increasing hypoglycaemia.

Outbreak of Severe Hypoglycemia After Ingestion of a Male Enhancement Supplement - Virginia, August-November 2019.

In August 2019, the Virginia Poison Center (VPC) and the Blue Ridge Poison Center (BRPC) were contacted concerning patients experiencing repeated episodes of marked hypoglycemia following ingestion of a male enhancement supplement tablet marketed as "V8" in convenience stores in central Virginia. Over the following 3 months, the Virginia Department of Agriculture and Consumer Services (VDACS) and the Virginia Department of Health (VDH) conducted an investigation and identified 17 patients meeting the case definition (severe hypoglycemia within 48 hours of consuming an over-the-counter male enhancement supplement in a man with no history of use of insulin or other medication used to control blood glucose). Analysis of the V8 tablets revealed that most contained glyburide, a sulfonylurea oral hypoglycemic used in the treatment of diabetes and associated with prolonged hypoglycemia following overdose (1). To stem this outbreak, V8 was removed from stores when found, and public service announcements were released. The public health implications of V8 use include the potential for substantial morbidity from hypoglycemic episodes and the potential for mortality if health care services are not accessed in a timely manner when hypoglycemia occurs. The presence of V8 in the market poses a serious threat to public health because of its potentially life-threatening adverse effects.

Use of Antihyperglycemic Medications in U.S. Adults: An Analysis of the National Health and Nutrition Examination Survey.

OBJECTIVE: 1) To examine trends in the use of diabetes medications and 2) to determine whether physicians individualize diabetes treatment as recommended by the American Diabetes Association (ADA). RESEARCH DESIGN AND METHODS: We conducted a retrospective, cross-sectional analysis of 2003-2016 National Health and Nutrition Examination Survey (NHANES) data. We included people ≥18 years who had ever been told they had diabetes, had an HbA1c >6.4%, or had a fasting plasma glucose >125 mg/dL. Pregnant women and patients aged <20 years receiving only insulin were excluded. We assessed trends in use of ADA's seven preferred classes from 2003-2004 to 2015-2016. We also examined use by hypoglycemia risk (sulfonylureas, insulin, and meglitinides), weight effect (sulfonylureas, thiazolidinediones [TZDs], insulin, and meglitinides), cardiovascular benefit (canagliflozin, empagliflozin, and liraglutide), and cost (brand-name medications and insulin analogs). RESULTS: The final sample included 6,323 patients. The proportion taking any medication increased from 58% in 2003-2004 to 67% in 2015-2016 (P < 0.001). Use of metformin and insulin analogs increased, while use of sulfonylureas, TZDs, and human insulin decreased. Following the 2012 ADA recommendation, the choice of drug did not vary significantly by older age, weight, or presence of cardiovascular disease. Patients with low HbA1c, or HbA1c <6%, and age ≥65 years were less likely to receive hypoglycemia-inducing medications, while older patients with comorbidities were more likely. Insurance, but not income, was associated with the use of higher-cost medications. CONCLUSIONS: Following ADA recommendations, the use of metformin increased, but physicians generally did not individualize treatment according to patients' characteristics. Substantial opportunities exist to improve pharmacologic management of diabetes.

Decreasing Hypoglycemia following Insulin Administration for Inpatient Hyperkalemia.

BACKGROUND: Acute hyperkalemia (serum potassium ≥ 5.1 mEq/L) is often treated with a bolus of IV insulin. This treatment may result in iatrogenic hypoglycemia (glucose < 70 mg/dl). OBJECTIVES: The aims of this study were to accurately determine the frequency of iatrogenic hypoglycemia following insulin treatment for hyperkalemia, and to develop an electronic health record (EHR) orderset to decrease the risk for iatrogenic hypoglycemia. DESIGN: This study was an observational, prospective study. SETTING: The setting for this study was a university hospital. PATIENTS: All nonobstetric adult inpatients in all acute and intensive care units were eligible. INTERVENTION: Implementation of a hyperkalemia orderset (Orderset 1.1) with glucose checks before and then one, two, four, and six hours after regular intravenous insulin administration. Based on the results from Orderset 1.1, Orderset 1.2 was developed and introduced to include weight-based dosing of insulin options, alerts identifying patients at higher risk of hypoglycemia, and tools to guide decision-making based on the preinsulin blood glucose level. MEASUREMENTS: Patient demographics, weight, diabetes history, potassium level, renal function, and glucose levels were recorded before, and then glucose levels were measured again at one, two, four, and six hours after insulin was administered. RESULTS: The iatrogenic hypoglycemia rate identified with mandatory glucose checks in Orderset 1.1 was 21%; 92% of these occurred within three hours posttreatment. Risk factors for hypoglycemia included decreased renal function (serum creatinine >2.5 mg/dl), a high dose of insulin (>0.14 units/kg), and re-treatment with blood glucose < 140 mg/dl. After the introduction of Orderset 1.2, the rate of iatrogenic hypoglycemia decreased to 10%. CONCLUSIONS: The use of an EHR orderset for treating hyperkalemia may reduce the risk of iatrogenic hypoglycemia in patients receiving insulin while still adequately lowering their potassium.

Lessening Organ dysfunction with VITamin C (LOVIT): protocol for a randomized controlled trial.

BACKGROUND: Sepsis is a health problem of global importance; treatments focus on controlling infection and supporting failing organs. Recent clinical research suggests that intravenous vitamin C may decrease mortality in sepsis. We have designed a randomized controlled trial (RCT) to ascertain the effect of vitamin C on the composite endpoint of death or persistent organ dysfunction at 28 days in patients with sepsis. METHODS: LOVIT (Lessening Organ dysfunction with VITamin C) is a multicenter, parallel-group, blinded (participants, clinicians, study personnel, Steering Committee members, data analysts), superiority RCT (minimum n = 800). Eligible patients have sepsis as the diagnosis for admission to the intensive care unit (ICU) and are receiving vasopressors. Those admitted to the ICU for more than 24 h are excluded. Eligible patients are randomized to high-dose intravenous vitamin C (50 mg/kg every 6 h for 96 h) or placebo. The primary outcome is a composite of death or persistent organ dysfunction (need for vasopressors, invasive mechanical ventilation, or new and persisting renal replacement therapy) at day 28. Secondary outcomes include persistent organ dysfunction-free days to day 28, mortality and health-related quality of life at 6 months, biomarkers of dysoxia, inflammation, infection, endothelial function, and adverse effects (hemolysis, acute kidney injury, and hypoglycemia). Six subgroup analyses are planned. DISCUSSION: This RCT will provide evidence of the effect of high-dose intravenous vitamin C on patient-important outcomes in patients with sepsis. TRIAL REGISTRATION: clinicaltrials.gov, NCT03680274, first posted 21 September 2018.

Impact of the Diabetes Inpatient Care and Education (DICE) project on length of stay and mortality.

AIM: To determine whether the Diabetes Inpatient Care and Education (DICE) programme, a whole-systems approach to managing inpatient diabetes, reduces length of stay, in-hospital mortality and readmissions. RESEARCH DESIGN AND METHODS: Diabetes Inpatient Care and Education initiatives included identification of all diabetes admissions, a novel DICE care-pathway, an online system for prioritizing referrals, use of web-linked glucose meters, an enhanced diabetes team, and novel diabetes training for doctors. Patient administration system data were extracted for people admitted to Ipswich Hospital from January 2008 to June 2016. Logistic regression was used to compare binary outcomes (mortality, 30-day readmissions) 6 months before and after the intervention; generalized estimating equations were used to compare lengths of stay. Interrupted time series analysis was performed over the full 7.5-year period to account for secular trends. RESULTS: Before-and-after analysis revealed a significant reduction in lengths of stay for people with and without diabetes: relative ratios 0.89 (95% CI 0.83, 0.97) and 0.93 (95% CI 0.90, 0.96), respectively; however, in interrupted time series analysis the change in long-term trend for length of stay following the intervention was significant only for people with diabetes (P=0.017 vs P=0.48). Odds ratios for mortality were 0.63 (0.48, 0.82) and 0.81 (0.70, 0.93) in people with and without diabetes, respectively; however, the change in trend was not significant in people with diabetes, while there was an apparent increase in those without diabetes. There was no significant change in 30-day readmissions, but interrupted time series analysis showed a rising trend in both groups. CONCLUSION: The DICE programme was associated with a shorter length of stay in inpatients with diabetes beyond that observed in people without diabetes.

Combination therapy with SGLT-2 inhibitors and GLP-1 receptor agonists as complementary agents that address multi-organ defects in type 2 diabetes.

Type 2 diabetes (T2D) has a complex pathophysiology composed of multiple underlying defects that lead to impaired glucose homeostasis and the development of macrovascular and microvascular complications. Of the currently available glucose-lowering therapies, sodium-glucose cotransporter-2 inhibitors (SGLT-2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) both provide effective glycemic control and have been shown to reduce cardiovascular (CV) events in patients with T2D and a high CV risk or established CV disease. Because these agents have complementary mechanisms of action, they are able to act on multiple defects of T2D when used in combination. This review discusses the rationale for and potential benefits of SGLT-2i plus GLP-1RA combination therapy in patients with T2D. A search of the PubMed database was conducted for studies and reviews describing the combined use of SGLT-2is and GLP-1RAs, with a specific focus on identifying clinical studies of combination therapy in patients with T2D. In clinical studies, glycated hemoglobin (A1c) was significantly reduced over 28-52 weeks with SGLT-2i plus GLP-1RA therapy versus the individual agents or baseline. Several CV risk factors, including body weight, blood pressure, and lipid parameters, were also improved. SGLT-2i plus GLP-1RA therapy was generally well tolerated, with a low risk of hypoglycemia and no unexpected findings. Taken together with results from large CV outcomes trials of SGLT-2is and GLP-1RAs, combination therapy with these agents potentially provides effective durable glycemic control and CV benefits due to their complementary actions on the defects of T2D.

Blood glucose levels in diabetic patients undergoing hyperbaric oxygen therapy.

INTRODUCTION: To determine if hyperbaric oxygen (HBO2) therapy has an effect on diabetic blood glucose levels (BGL) and, if so, the extent of this effect. Also, to examine factors that exacerbate any observed effect. METHODS: This was a retrospective review of prospectively collected quality data on diabetics undergoing HBO2. Pre- and post-treatment BGL were recorded. Pre-treatment BGL ⟨120 mg/dL received glucose supplementation. Hypoglycemia was defined as BGL ⟨70 mg/dL. BGL ⟨90 mg/dL was included as an elevated hypoglycemia threshold. RESULTS: 77 patients representing 1,825 treatments were included for analysis. No patient had deleterious side effects or required emergency care. BGL decreased in 75.4% of treatments in this group, with a median decrease of 25 mg/dL (IQR=54 mg/dL; range of decreased 374 mg/dL to increased 240 mg/dL). A statistically significant greater percentage of treatments of patients with type 2 diabetes resulted in a decrease in BGL (1598 or 77.5%) compared to treatments of patients with type 1 diabetes (169 or 51.5%) (χ2(1, N=1767) =55.37, p⟨0.001). 1.1% of treatments had post-HBO2 serum glucose ⟨90 mg/dL, and 0.2% of treatments had post-HBO2 serum glucose ⟨70 mg/dL. The majority (70%) of patients with post-HBO2 BGL ⟨90 mg/dL were maintained on insulin alone (χ2(2, N=20) =12.4, p=0.002). Well-controlled diabetics (i.e., those with all BGLs within 50 mg/dL over all pre-HBO2 treatments) had no post-HBO2 BGL ⟨70 mg/dL or ⟨90 mg/dL. CONCLUSION: Our results suggest that HBO2 does not cause a clinically significant decrease in diabetic patient BGL. No patient in our study had deleterious side effects or required emergency care. We found that glucose level of ⟨90 mg/dL occurred more often in those who use insulin. Hyperbaric patients who exhibit consistent BGL values may represent a group who could be managed similarly to the non-diabetic population.

Hindbrain lactoprivic regulation of hypothalamic neuron transactivation and gluco-regulatory neurotransmitter expression: Impact of antecedent insulin-induced hypoglycemia.

Hindbrain energy state shapes hypothalamic control of glucostasis. Dorsal vagal complex (DVC) L-lactate deficiency is a potent glucose-stimulatory signal that triggers neuronal transcriptional activation in key hypothalamic metabolic loci. The energy gauge AMPK is activated in DVC metabolic-sensory A2 noradrenergic neurons by hypoglycemia-associated lactoprivation, but sensor reactivity is diminished by antecedent hypoglycemia (AH). Current research addressed the premise that AH alters hindbrain lactoprivic regulation of hypothalamic metabolic transmitter function. AH did not modify reductions in A2 dopamine-beta-hydroxylase and monocarboxylate-2 (MCT2) protein expression elicited by caudal fourth ventricular delivery of the MCT inhibitor alpha-cyano-4-hydroxycinnamic acid (4CIN), but attenuated 4CIN activation of A2 AMPK. 4CIN constraint of hypothalamic norepinephrine (NE) activity was averted by AH in a site-specific manner. 4CIN induction of Fos immunolabeling in hypothalamic arcuate (ARH), ventromedial (VMN), dorsomedial (DMN) and paraventricular (PVN) nuclei and lateral hypothalamic area (LHA) was avoided by AH. AH affected reactivity of select hypothalamic metabolic neurotransmitter/enzyme marker proteins, e.g. ARH neuropeptide Y, VMN glutamate decarboxylase, DMN RFamide-related peptide-1 and -3, and LHA orexin-A profiles to 4CIN, but did not alleviate drug inhibition of ARH proopiomelanocortin. AH prevented 4CIN augmentation of circulating glucagon, but did not alter hyperglycemic or hypocorticosteronemic responses to that treatment. Results identify hindbrain lactate deficiency as a stimulus for glucagon secretion, and imply that habituation of this critical counter-regulatory hormone to recurring hypoglycemia may involve one or more hypothalamic neurotransmitters characterized here by acclimation to this critical sensory stimulus.