Total Daily Dose Research Articles

A large Australian longitudinal cohort registry demonstrates sustained safety and efficacy of oral medicinal cannabis for at least two years.

Oral medicinal cannabis (MC) has been increasingly prescribed for a wide range of clinical conditions since 2016. Despite an exponential rise in prescriptions and publications, high quality clinical efficacy and safety studies are lacking. The outcomes of a large Australian clinical electronic registry cohort are presented. A prospective cannabis-naïve patient cohort prescribed oral MC participated in an ongoing longitudinal registry at a network of specialised clinics. Patient MC dose, safety and validated outcome data were collected regularly over two years and analysed. 3,961 patients (mean age 56.07 years [SD 19.08], 51.0% female) with multimorbidity (mean diagnoses 5.14 [SD 4.08]) and polypharmacy (mean 6.26 medications [SD 4.61]) were included in this analysis. Clinical indications were for: chronic pain (71.9%), psychiatric (15.4%), neurological (2.1%), and other diagnoses (10.7%). Median total oral daily dose was 10mg for Δ9-tetrahydrocannabinol (THC) and 22.5mg for cannabidiol (CBD). A stable dose was observed for over two years. 37.3% experienced treatment related adverse events. These were graded mild (67%), moderate (31%), severe (<2%, n = 23) and two (0.1%) serious adverse events. Statistically significant improvements at a p value of <0.001 across all outcomes were sustained for over two years, including: clinical global impression (CGI-E, +39%: CGI-I, +52%; p<0.001), pain interference and severity (BPI, 26.1% and 22.2%; p<0.001), mental health (DASS-21, depression 24.5%, anxiety 25.5%, stress 27.7%; p<0.001), insomnia (ISI, 35.0%; p<0.001), and health status (RAND SF36: physical function, 34.4%: emotional well-being, 37.3%; p<0.001). Mean number of concomitant medications did not significantly change over 2 years (p = 0.481). Oral MC was demonstrated to be safe and well-tolerated for a sustained period in a large complex cohort of cannabis-naïve, multimorbid patients with polypharmacy. There was significant improvement (p<0.001) across all measured clinical outcomes over two years. Results are subject to limitations of Real World Data (RWD) for causation and generalisability. Future high quality randomised controlled trials are awaited.

Population Pharmacokinetics in Hepatic and Renal Impairment and PBPK Drug-Drug Interaction Simulations of Asciminib, a Novel Tyrosine Kinase Inhibitor in Chronic Myeloid Leukemia in Chronic Phase

Introduction: Asciminib, a first-in-class BCR::ABL1 inhibitor that works by specifically targeting the ABL myristoyl pocket (STAMP), has been recently approved by the FDA for adult patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) treated with ≥2 prior tyrosine kinase inhibitors (TKIs), as well as adult patients with Ph+ CML-CP with the T315I mutation. The recommended asciminib doses for patients with Ph+ CML-CP without the T315I mutation are 40 mg twice daily (BID), which is the dose tested in the pivotal phase III study (ASCEMBL), and a more patient-centric dose of 80 mg once daily (QD). For patients with the T315I mutation, the approved dose of asciminib is 200 mg BID. All asciminib drug-drug interaction (DDI) and hepatic and renal impairment studies were conducted at single or multiple doses of 40 mg. Here, we aim to assess the clinical impact of hepatic and renal impairment and of DDIs on the pharmacokinetics (PK) of asciminib and provide recommendations for eventual necessary dose adjustments. Methods: Organ impairment effect was quantified using population pharmacokinetics (PopPK), while DDIs were predicted using physiologically-based pharmacokinetics (PBPK). A 2-compartment PopPK model with a delayed first-order absorption and first-order elimination was developed for asciminib (Li et al. Clin Pharmacokinet, 2022). The original analysis included pooled PK data from patients receiving asciminib at 10−200 mg BID (in the phase I dose-finding study, NCT02081378) or 40 mg BID (in the phase III study ASCEMBL, NCT03106779), and identified baseline absolute glomerular filtration rate (aGFR), nominal total daily dose, body weight and formulation as significant covariates affecting asciminib PK. The model has been further extended to describe patients with renal (based on aGFR) or hepatic (based on Child-Pugh class) impairment, using data from two phase I PK studies in patients with renal (NCT03605277) or hepatic (NCT02857868) impairment. A PBPK model was developed and validated for asciminib using SimCYP v19.1. A stepwise "middle out” approach was used leveraging in vitro, in silico and in vivo data. The PBPK model was validated using single and multiple dose PK at 20‒400 mg daily dose as well as clinical DDI and PK data in patients with organ impairment. Comprehensive DDI scenarios and PK in patients with hepatic and renal impairment, which had not been clinically tested, were simulated at the different recommended doses of asciminib (40 mg BID, 80 mg QD, 200 mg BID). Results: There was no significant impact of hepatic function on asciminib exposure; a non-significant trend to lower clearance was observed in patients with severe hepatic impairment. The PopPK derived steady-state exposures (measured as area under the curve [AUC]0-24h) for patients with severe hepatic impairment were almost identical for both dosing regimens (40 mg BID: 13,018 ng*h/mL, 80 mg QD: 13,020 ng*h/mL), and only marginally higher than those of patients with normal hepatic function (12,638 ng*h/mL and 12,646 ng*h/mL, respectively), well within the therapeutic window of asciminib. Renal function assessment showed that clearance was slightly decreased in patients with renal impairment, although this was not clinically relevant. For both 80 mg QD and 40 mg BID, the median predicted AUC0-24h and maximum plasma concentration (Cmax) for severe renal impairment were 60% and 40% higher, respectively, than those of a typical individual with normal renal function. However, this difference is not considered to be clinically relevant given the relatively flat exposure-safety relationship over a 5-fold difference in exposure. The PBPK model predicted no drug interaction that would significantly impact the PK of asciminib (as a victim) or of other substrates (as a perpetrator). Overall, asciminib exposure was weakly affected by interactions with inducers and inhibitors as a victim (Figure 1B) and was predicted to be a weak inhibitor of CYP3A4 and P-gp at all tested doses and a weak to moderate inhibitor of CYP2C9 as a perpetrator (Figure 1A). Conclusions: Hepatic or renal impairment does not have a clinically significant impact on the PK of asciminib. Hence, dose adaptations for patients with hepatic or renal impairment are not warranted. Overall, asciminib has a manageable DDI risk at all recommended doses. Sponsor: Novartis. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abstract 13395: Truth in Advertising? Health Claims and Contents of Fish Oil Supplements

Background: Fish oil supplement use continues to rise. Although prescription eicosapentaenoic acid (EPA) at 4 gm/day did lower cardiovascular risk, the vast majority of randomized trials have shown no benefit to fish oil dietary supplements. Information on health claims and contents of fish oil supplements is limited. Methods: Label information for on-market fish oil supplements was obtained from the National Institute of Health Dietary Supplement Label Database as of February 2022. Label text was analyzed to categorize health claims by type and organ system referenced. The total daily dose of EPA and docosahexaenoic acid (DHA) was evaluated for supplements made by 16 of the leading retailers and manufacturers of fish oil. Results: We evaluated 2,192 fish oil supplement labels, among which 1,647 (75.1%) made at least one health claim. Of these, only 22.0% (n=362) used from the FDA-approved qualified health claim for fish oil. The remaining 78.0% of labels made “structure &amp; function” claims (e.g., “promotes heart health”, “supports brain and vision function”, etc.) across a variety of organ systems (Figure). Heart-health related claims were the most common (n=1,390, 63.4% of labels). Across 16 different brands/manufacturers, 239 product labels were reviewed for dose information. Wide variation in the doses of EPA and DHA was observed (median EPA+DHA dose 600 mg, interquartile range 250-1100 mg). Only 9.2% of supplements reviewed contained at least 2 gm of EPA+DHA, the minimum recommended for triglyceride lowering, and none contained an EPA dose shown to prevent cardiovascular events (≥4 gm/day). Conclusions: Fish oil supplement labels commonly make vaguely worded claims that imply a range of health benefits, almost none of which are supported by randomized trial data. The doses of EPA and DHA available in commonly used fish oil supplements vary substantially, yet none contain levels shown to reduce cardiovascular risk.

Prevalence of polymyxin-induced nephrotoxicity and its predictors in critically ill adult patients: A meta-analysis.

Polymyxin-induced nephrotoxicity is a major safety concern in clinical practice due to long-term adverse outcomes and high mortality. To conducted a systematic review and meta-analysis of the prevalence and potential predictors of polymyxin-induced nephrotoxicity in adult intensive care unit (ICU) patients. PubMed, EMBASE, the Cochrane Library and Reference Citation Analysis database were searched for relevant studies from inception through May 30, 2022. The pooled prevalence of polymyxin-induced nephrotoxicity and pooled risk ratios of associated factors were analysed using a random-effects or fixed-effects model by Stata SE ver. 12.1. Additionally, subgroup analyses and meta-regression were conducted to assess heterogeneity. A total of 89 studies involving 12234 critically ill adult patients were included in the meta-analysis. The overall pooled incidence of polymyxin-induced nephrotoxicity was 34.8%. The pooled prevalence of colistin-induced nephrotoxicity was not higher than that of polymyxin B (PMB)-induced nephrotoxicity. The subgroup analyses showed that nephrotoxicity was significantly associated with dosing interval, nephrotoxicity criteria, age, publication year, study quality and sample size, which were confirmed in the univariable meta-regression analysis. Nephrotoxicity was significantly increased when the total daily dose was divided into 2 doses but not 3 or 4 doses. Furthermore, older age, the presence of sepsis or septic shock, hypoalbuminemia, and concomitant vancomycin or vasopressor use were independent risk factors for polymyxin-induced nephrotoxicity, while an elevated baseline glomerular filtration rate was a protective factor against colistin-induced nephrotoxicity. Our findings indicated that the incidence of polymyxin-induced nephrotoxicity among ICU patients was high. It emphasizes the importance of additional efforts to manage ICU patients receiving polymyxins to decrease the risk of adverse outcomes.

GLIMMER: A Randomized Phase 2b Dose-Ranging Trial of Linerixibat in Primary Biliary Cholangitis Patients With Pruritus

GLIMMER assessed dose-response, efficacy, and safety of linerixibat, an ileal bile acid transporter inhibitor in development for cholestatic pruritus associated with primary biliary cholangitis (PBC). GLIMMER was a Phase 2b, multicenter, randomized, parallel-group study in adults with PBC and moderate-to-severe pruritus (≥4 on 0-10 numerical rating scale [NRS]). After 4 weeks of single-blind placebo, patients with NRS ≥3 were randomized (3:1) to double-blind linerixibat/placebo for 12 weeks (to week 16), followed by single-blind placebo (to week 20). The primary objective was to investigate dose-related changes in mean worst daily itch (MWDI) score. One hundred forty-seven patients received placebo (n= 36) or linerixibat (once daily: 20 mg, n= 16; 90 mg, n= 23; 180 mg, n= 27; twice daily: 40 mg, n= 23; 90 mg, n= 22). Linerixibat groups exhibited ≥2-point mean reductions in MWDI from baseline at week 16; however, differences from placebo were not significant. Post hoc analysis of change from baseline in monthly itch score over the treatment period (Phase 3 endpoint) showed significant differences between placebo and linerixibat 180 mg once daily (P= .0424), 40 mg twice daily (P= .0105), and 90 mg twice daily (P= .0370). A significant relationship between total daily dose and response was observed post hoc in the per protocol population (P= .0542). Consistent with mechanism of action, diarrhea was the most frequent adverse event, and incidence increased with dose. Linerixibat effect on itch was not significantly different versus placebo in the primary intent-to-treat analysis but was associated with a significant dose-dependent reduction in itch in the per protocol population. A well-tolerated dose was identified for Phase 3 investigation for cholestatic pruritus in PBC. gov ID: NCT02966834.

RF09 | PSAT84 Management of Adrenal Insufficiency with Continuous Subcutaneous Hydrocortisone Infusion: Long-Term Experience in 27 Patients

Abstract Background Conventional management of adrenal insufficiency (AI) includes lifelong oral glucocorticoid replacement therapy. Currently, no glucocorticoid regimens adequately mimic the circadian rhythm of cortisol secretion. In some patients, this causes persistence of severe symptoms. Continuous subcutaneous hydrocortisone infusion (CSHI) is an alternative delivery method using an insulin pump. Previous studies have confirmed CSHI's potential to re-establish the diurnal cortisol profile and reduce total daily dose (TDD) of hydrocortisone. To date no reports are available regarding the long-term usage (&amp;gt;2 years) of CSHI in adults. Methods We report the use of CSHI in 27 patients seen at the Scottsdale Endocrinology Institute from 05/2012 to present. CSHI inclusion criteria were persistence of severe symptoms, high steroid dosage, or gastrointestinal intolerance, malabsorption or bleeding in willing and able patients. Individual basal rates were set using a novel method to re-establish patients’ diurnal cortisol profiles. Patients were educated on pump basics including bolusing and temporary basal rates, allowing them to control their dosing during symptomatic and stressful periods and procedures, and using subcutaneous shots during pump failures. Quality of life (QOL) was assessed using the AddiQOL questionnaire periodically. Data was gathered from patient charts and surveys. We report patient preference of CSHI over oral therapy, and changes in QOL, TDD of hydrocortisone, and crises during pump therapy. Results In our patient sample, there were 2 males and 25 females, 9 had primary AI, 15 had secondary AI, and 3 had steroid-induced AI. Ages ranged from 26 to 78 years. 1 patient had 1 year of CSHI, 19 patients had 2-5 years of CSHI, and 7 patients had &amp;gt;5 years of CSHI. After at least 2 years of CSHI, 24/26 patients preferred CSHI over oral therapy, 25/26 patients continued to report improved symptoms and QOL, and average TDD reduction of hydrocortisone was 22 mg (2.5-55.8). 4 patients previously deemed disabled returned to a productive lifestyle. 2 patients underwent successful pregnancies without untoward events. Only 2 patients were hospitalized due to near adrenal crises. 4 chose to discontinue CSHI, 2 for a high out of pocket expense, and 2 for local skin reactions at infusion sites. Conclusion Our method of calculating basal rates and implementing CSHI was associated with improvement in symptoms and QOL and reduced TDD of hydrocortisone and hospitalizations over treatment duration. We expect this to reduce cumulative side effects of steroids and overall cost of treatment of these patients. Autonomy of dose regulation offered by pump therapy improves patient's ability to handle stressful situations and symptoms, including sleep quality and quantity. In summary, we found CSHI to be a safe and effective method to treat patients with AI experiencing problems with oral treatment over an extended period of time. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Saturday, June 11, 2022 1:12 p.m. - 1:17 p.m.

Assessment of Glucagon-like Peptide-1 Receptor Agonists in Veterans Taking Basal/Bolus Insulin Regimens.

Clinical use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) is well established as add-on therapy to oral medications and basal insulin. However, there is little published data regarding the use of GLP-1 RAs for longer than 12 months in patients taking basal/bolus insulin regimens. The primary goal of our study was to assess the long-term efficacy of GLP-1 RAs as add-on therapy to basal/bolus insulin regimens. This study was a retrospective record review of all patients on basal/bolus insulin regimens who received additional therapy with a GLP-1 RA. The primary outcome was the change in glycosylated hemoglobin A1c (HbA1c) at 3, 6, 12, 18, and 24 months after initiation of the GLP-1 RA. Secondary outcomes included change in weight and total daily dose (TDD) of insulin and incidence of hypoglycemia and other adverse effects (AEs). Ninety-two patient records were reviewed. Mean glycemic control changed from baseline -1.1% (95% CI, -1.3 to -0.8; P < .001) at 3 months; -1.0% (95% CI, -1.3 to -0.7; P < .001) at 6 months; -0.9% (95% CI, 1.3 to -0.6; P < .001) at 12 months; -0.9% (95% CI, -1.4 to -0.3; P = .002) at 18 months; and -0.7 (95% CI, -1.4 to 0.1; P = .07) at 24 months. A significant decrease in weight was also observed from baseline through 18 months, and a significant decrease in TDD of insulin was identified from baseline through 12 months. Hypoglycemia was documented in 29.8% of patients at any point during GLP-1 RA therapy, and gastrointestinal AEs were documented in 18.3% of patients. Adding GLP-1 RAs to complex insulin regimens may help achieve glycemic control while decreasing insulin requirements and mitigating undesirable AEs, such as weight gain.

LBSUN209 A Novel Algorithm For The Management Of Inpatient Covid-19 Steroid-induced Hyperglycemia

Abstract Objective/Background Hyperglycemia in hospitalized patients with COVID-19 is linked to increased morbidity and mortality. With increasing use of glucocorticoid (GC) therapy for COVID-19 hypoxemia, clinicians are challenged with an increased prevalence of hyperglycemia. Methods We developed an insulin protocol to aid front line providers in the management of GC-induced hyperglycemia for hospitalized adults with COVID-19. The protocol was based on expert opinion and was available from March 2021 onward. Glycemic and clinical outcomes were obtained for patients treated with GC and retrospectively compared to historical controls treated with GC admitted up to 6 months prior to protocol implementation. Glycemic parameters for finger stick glucose values (FSG) were defined as hypoglycemia &amp;lt;70 mg/dL, euglycemia 70-180 mg/dL, mild hyperglycemia 180-250 mg/dL and severe hyperglycemia &amp;gt;250 mg/dL. To account for differences in the quantity of total FSG between groups, we adjusted for length of stay and calculated the proportion of FSG per patient. Results 130 patients with COVID-19 and GC induced hyperglycemia from before (n=65) and after (n=65) protocol implementation were matched 1: 1 based on age, weight, and sex. There were no significant differences in other baseline patient characteristics. Significantly more patients in the protocol group had mean FSG in the euglycemic range (16.9% vs 38.5%, p=0. 006), and there was a decrease in patients with mean glucose in the mild hyperglycemia range that trended toward significance (50.8% vs 35.4%, p=0. 076). The protocol group had a significantly lower proportion of hypoglycemic FSG per patient (0. 003 vs 0. 008, p=0. 044). Patients in the protocol group had more euglycemic FSG per patient, but this did not reach significance (0.413 vs 0.350, p=0.239). Similarly, the proportion of mild hyperglycemic FSG per patient trended lower in the protocol group (0.315 vs 0.272, p=0.291). There were no significant differences in severe hyperglycemia per patient (0.311 vs 0.328, p=0.828). The protocol group had a significantly higher utilization of basal-bolus insulin regimen (n=43 vs n=63, p&amp;lt;0. 0001) with an increase percentage of bolus insulin utilization in peak total daily dose (70.2% vs. 62.4%, p=0. 08). Total peak day insulin dose trended lower in the protocol group (0.25 vs 0.32 U/kg, p=0.36). Conclusion A novel insulin protocol for the management of GC-induced hyperglycemia in hospitalized COVID-19 patients is an effective tool to achieve reductions in hypoglycemic events and higher utilization of standard of care basal-bolus insulin regimens without increased hyperglycemia or total daily dose of insulin. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

ODP232 Postoperative Glycemic Management of Children Undergoing Pancreatectomy with Islet Autotransplantation

Abstract Background Children with severe pancreatitis may require pancreatectomy, resulting in insulin-dependent diabetes. Our center has provided pediatric pancreatectomy with islet autotransplantation (PIAT) since 2003 to preserve pancreatic endocrine function and potentially prevent diabetes. We describe our experience with postoperative glycemic management after pediatric PIAT to provide guidance for future management. Method: We reviewed inpatient records for children who underwent PIAT. Data collected included age, indication for pancreatectomy, islet mass infused and details on insulin and nutritional support requirements. Descriptive analysis was performed. Results Twelve pediatric patients have undergone PIAT at our centre, with mean age 12.4 years (range 2.5-18.9) and mean duration of post-operative hospitalization 25 days (range 9-60). Indications for pancreatectomy included ten patients with chronic pancreatitis due to mutations in PRSS1, SPINK1, or CFTR, 1 patient due to trauma, and 1 patient due to tumor. Ten patients underwent total pancreatectomy, and 2 had partial pancreatectomies. Mean islet mass infused per body weight was 5867 IEQ/kg (range 1630-10276). Two patients did not receive insulin during hospitalization. The remaining ten required insulin, with mean maximum total daily dose of 0.9 u/kg/day (range 0.14-1.88). Total daily doses were higher while on parenteral nutrition (mean 0.75 versus 0.27 u/kg/day on days without parenteral nutrition). Duration of insulin therapy was also longer in patients who received parenteral nutrition (mean 25 versus 4 days). Six of the insulin-treated patients were able to discontinue insulin prior to discharge, with mean duration of insulin therapy 13 days (range 1-40). Four remained on insulin at discharge, with a mean total daily dose of 0.46 u/kg/day (range 0.12-0.82). Patients who were on insulin at discharge all had total pancreatectomies, were older (mean 17 versus 9 years), and had smaller islet mass per kilogram infused (mean 2718 versus 8116 IEQ/kg) compared to those not on insulin. Discussion We report our center's experience with PIAT. Seven of twelve patients were insulin-independent at discharge, and the remainder needed modest doses. Previous publications on islet autotransplantation have also demonstrated favourable outcomes in children, with insulin independence rates up to 82%1. Younger age and larger islet mass infused per kilogram predicted insulin independence in our cohort, similar to the findings of Chinnakotla et al2. In addition, our study suggests that feeding difficulties requiring parenteral nutrition increase daily insulin requirements and prolong the need for insulin therapy.

PSUN188 Evaluating Response to GLP-1 Receptor Agonists in Patients with Type 2 Diabetes Mellitus Managed at a Veterans Affairs Hospital

Abstract Type 2 diabetes mellitus (T2DM) is a leading cause of morbidity and mortality in people of all ages worldwide. Glucagon-like peptide-1 receptor agonists (GLP-1 RA) offer an innovative and unique advancement in treatment for T2DM by not only benefiting blood glucose control but also potentially impacting other diabetes-related complications. However, clinical response to GLP-1 RA is not seen in all patient populations. Our goal was to determine the response rate of GLP-1 RA add-on therapy. We performed a retrospective study of veterans with T2DM initiated on any GLP-1 RA from January 1, 2015, to December 31, 2019, for a duration of at least 6 months to assess the response in terms of hemoglobin A1c (A1c), weight, and total daily insulin dose. Baseline characteristics of 332 patients were reviewed to evaluate response rate. Treatment response thresholds included an A1c reduction of at least 0.5%, weight loss of ≥ 3% of pretreatment body weight, and a ≥ 10% reduction in total daily insulin dose (TDD). We then classified veterans into those without a response, or with 1, 2, or all 3 responses based on data 6-12 months after initiating treatment. We considered it a complete response if all 3 categories were fulfilled. Semaglutide (n=141): 10.64% showed a response to A1c alone, 3.55% had weight reduction alone, and 2.84% had insulin reduction alone. 7.09% showed A1c and weight response, 24.82% had A1c and insulin response, and 13.48% had weight and insulin response. A complete response was seen in 33.33% of veterans. Liraglutide (n=131): 18.32% showed a response to A1c alone, 4.58% had weight reduction alone, and 11.45% had insulin reduction alone. 6.11% showed A1c and weight response, 19.08% had A1c and insulin response, and 8.40% had weight and insulin response. A complete response was seen in 25.19% of veterans. Dulaglutide (n=57): 22.81% showed a response to A1c alone, 3.51% had weight reduction alone, and 12.28% had insulin reduction alone. 8.77% showed A1c and weight response, 26.32% had A1c and insulin response, and 1.75% had weight and insulin response. A complete response was seen in 15.79% of veterans. In conclusion, semaglutide's most common response, in 33.33% of patients, was having a complete response, followed by a reduction in A1c and insulin reduction for 24.82% of patients, and then weight and insulin reduction for 13.48% of patients. Liraglutide's most common response, in 25.19% of patients, was having a complete response, followed by a reduction in A1c and insulin dose for 19.08% of patients, and then reduction in A1c alone for 18.32% of patients. Unlike the others, dulaglutide's most common response was not a complete response, but rather A1c and insulin reduction, for 26.32% patients. Dulaglutide also had 22.81% of patients respond with A1c alone. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

PMON191 Current Management of Acute Adrenal Insufficiency Related Adverse Events in Children with Congenital Adrenal Hyperplasia- Results of an International Survey of Specialist Centres

Abstract Background There is wide variation in the reported rate of acute adrenal insufficiency (AI) related adverse events (sick day episodes and adrenal crises) between centres and the definition of these events as well as their management may vary from one centre to another. A greater standardisation of the definition and management of these events would facilitate the benchmarking and comparison of care across centres. Objective Evaluate the level of consensus on the criteria that should be considered 'essential' for defining and managing acute AI related adverse events in children with Congenital Adrenal Hyperplasia. Methods Active users of the International Congenital Adrenal Hyperplasia &amp; International Disorders of Sex Development (I-CAH/I-DSD) Registries (n=66), non-active users of I-CAH/I-DSD (n=35) and the EuRRECa e-Reporting Registry (n=10) were approached to complete an online survey. Results 56 clinicians from 27 countries responded to the survey; response rates for the three Registry groups were 42 (65%), 11 (31%) and 3 (30%), respectively. Written corticosteroid management plans and one to one patient/parent education were provided by 54 (96%) and 51 (91%) clinicians, respectively; 33 (59%) provided steroid-aware emergency cards. 56 (100%) and 55 (98%) clinicians advised an increase in glucocorticoid dosing (sick day dosing) in the event of fever or severe infection (eg. pneumonia). Less common indications for sick day dosing included vaccination and mild afebrile intercurrent illness, recommended by 17 (30%) and 9 (16%) clinicians, respectively. The most frequently reported sick day dosing regimen was tripling the total daily dose of hydrocortisone and administering 3 times daily, reported by 24 (43%) clinicians. 40 (71%) specified the duration of sick day dosing as ≥48 hours for severe infections. Vomiting and diarrhoea were the most common indications for intramuscular hydrocortisone, reported by 34 (61%) and 25 (45%) clinicians, respectively. Over 50% of respondents indicated that essential clinical criteria for adrenal crisis should include fatigue and nausea or vomiting and over 60% indicated that the criteria should include hypotension, hyponatraemia, hyperkalaemia and clinical improvement following parenteral glucocorticoids. A bolus parenteral injection of hydrocortisone and glucose infusions were the most frequently administered medications, reported by 50 (89%) and 32 (57%) of clinicians, respectively. Conclusions Although there is considerable variation in the definition and management of AI related adverse events in children amongst specialist centres, there is also good evidence of consensus on specific aspects that can be used to develop standardised criteria and lead to greater benchmarking of care. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

RF16 | PSUN335 Clinical Effects of Sodium Glucose Transporter Type 2 Inhibitors in Patients with Severe Insulin Resistance

Abstract Background Severe insulin resistance syndromes including lipodystrophy and pathogenic variants in the insulin receptor (INSR) lead to diabetes that is challenging to control. Oral antidiabetic agents have been used to control hyperglycemia, however the efficacy of these treatments has not been studied systematically. This study explores safety and efficacy of sodium glucose cotransporter 2 inhibitors (SGLT2i) in these patients. Methods This was a retrospective chart-review assessing safety (N=31) and efficacy (N=18) of SGLT2i use in patients with clinically or genetically confirmed diagnosis of lipodystrophy or INSR pathogenic variants at our institute. Efficacy outcomes included HbA1c, insulin dose, C-peptide, fasting insulin and 24-hour urine glucose at 12 months and throughout follow-up from 2 to 24 months. Glycemic parameters were analyzed as change from baseline (prior to SGLT2i) adjusted for baseline values after 12 months of SGLT2i and across all timepoints using linear mixed models with post-hoc Dunnett-adjusted comparison of each time point compared to baseline. For HbA1c, additional models were conducted including change in insulin dose as a covariate. Results HbA1c did not significantly change after 1 year of SGLT2i (baseline 9.5±2.5 [80.3±27.7]; 12 months 8.8±2.3% [72.6±25.3 mmol/mol]; p=0.093), or across all time points (p=0.11). However, most patients (83%) were taking insulin, and SGLT2i treatment led to 35% reduction in total daily dose of insulin after 12 months (baseline 186 [100,1010]; 12 months 120 [75,260] units/day; p=0.07) and across all visits (p=0.035), which may have mitigated the reduction in HbA1c. Reduction in HbA1c was significant after adjustment for changes in insulin dose over time (p=0.0498). No significant change was noted in C-peptide, however fasting insulin decreased after 12 months (p=0.021) and across all visits (p=0.005). Urinary glucose excretion increased greater than 5-fold after 12 months of SGLT2i, to over 80 grams per day after 1 year (p=0.04). Adverse effects occurring in &amp;gt;1 subject included hypoglycemia, fungal infections, and extremity pain. Conclusions SGLT2i reduced insulin dose, insulinemia, and insulin dose-adjusted HbA1c in patients with severe insulin resistance, with a similar safety profile compared to type 2 diabetes. SGLT2i use may lead to overall better glycemic control and should be considered as part of the treatment armamentarium for these rare forms of diabetes, but larger trials are needed to confirm these findings. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Sunday, June 12, 2022 12:36 p.m. - 12:41 p.m.

PSAT045 Spontaneous Adrenal Hemorrhage with Partial Adrenal Insufficiency in a Patient Anticoagulated with Apixaban for Antiphospholipid Syndrome

Abstract Background Addison's disease secondary to adrenal hemorrhage is a rare complication of antiphospholipid syndrome (APLS). Anticoagulation with a direct oral anticoagulant (DOAC) might increase the risk of adrenal hemorrhage. We report a patient who developed bilateral adrenal hemorrhage after starting apixaban for deep venous thrombosis (DVT) and pulmonary embolism (PE) in the setting of latent APLS. Clinical Case A 45-year-old man without significant past medical history presented with a left lower extremity DVT and PE. He had no personal or family history of previous trauma, bleeding or clotting events. He was discharged on apixaban. Three days later he was readmitted with bilateral flank pain. Computerized tomography (CT) imaging showed bilateral adrenal gland edema. He was hemodynamically stable. Due to persistent right flank pain and concern for ileus, CT was repeated and revealed findings concerning for adrenal hemorrhage. He subsequently complained of asthenia. Further testing revealed a reduced morning cortisol of 1.4 ug/dL (reference: 6.0 - 18.4 ug/dL) and an elevated morning ACTH of 149 pg/mL (7.2-63.3 pg/mL). Plasma dehydroepiandrosterone sulphate (DHEA-S) was reduced at 39 mcg/dL (70 - 495 mcg/dL), and epinephrine and norepinephrine were undetectable. Morning plasma aldosterone was undetectable and renin activity was 0.76 ng/mL/h (0.25 - 5.82 ng/mL/h). He was started on stress dose steroids and discharged on maintenance hydrocortisone without reinitiating anticoagulation. Two weeks later, he re-presented with a right lower extremity DVT. An APLS panel revealed elevated anti-beta2 glycoprotein 1 IgG and anti-cardiolipin IgG. Laboratory work-up for other causes of thrombosis, including inherited and acquired thrombophilias, anatomical vascular obstruction, paroxysmal nocturnal hemoglobinuria (PNH), heparin-induced thrombocytopenia (HIT), and myeloproliferative neoplasms (MPN), was unrevealing. Warfarin was started with an international normalized ratio (INR) target range of 2-3. Hydrocortisone was continued at a total daily dose of 30mg. Since discharge, his morning cortisol levels have been low at 4.4-4.9 ug/dL and ACTH has remained high at 92-137 pg/mL, but aldosterone has been variable at &amp;lt;1 to 9 ng/dL, and renin has been normal at 0.35 ng/mL/h. This suggests what transpired had been microthrombi-associated intra-adrenal hemorrhage involving the zona fasciculata with sparing of the glomerulosa. Conclusion This case highlights DOAC-associated adrenal hemorrhage in a patient with underlying APLS, an under-appreciated complication. The extent to which the various layers of the adrenal gland are affected may vary. Since guidelines on the management of patients with partial adrenal insufficiency are lacking, further reporting is needed on long term outcomes and adrenal function of these patients. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

PSUN266 A Case of Ipilimumab Induced New-Onset type1 Diabetes Mellitus in a Patient With Renal Cell Carcinoma.

Abstract A 50-year-old female with a recent diagnosis of Renal cell cancer (RCC) with hepatic metastasis and hypothyroidism was referred to the clinic for management of Diabetes Mellitus (DM). The patient was diagnosed with RCC in 2017 and was treated with immunotherapy Ipilimumab for two years. No family history of Diabetes Mellitus and denies history of corticosteroid usage. No previous episodes of Diabetic Ketoacidosis. She was diagnosed with GAD65 negative type 1 Diabetes Mellitus one year after starting Ipilimumab and was managed on a basal-bolus insulin regimen. She was on levothyroxine for the last two years for hypothyroidism and remained clinically and biochemically euthyroid. She attained menopause 10years ago. Physical examination is unremarkable with normal monofilament tests. Initial labs showed a Complete blood count within normal. The comprehensive metabolic panel showed Glucose 104mg/dl (74-106 mg/dl), Potassium 4.2 mmol/L (3.5 -5.0 mmol/L), Bicarb 25mmol/L (21-33 mmol/L).Hb A1C 6.5%, C-peptide 0.3ng/ml(0.8-3.85ng/ml), GAD 65, ia2 and insulin antibodies negative,TSH 3.420uIU/L (0.5-4.5 uIU/L), Free T4 1.16ng/dl (0.79-2.35 ng/dL), Total T3 78 (71-180ng/dl),Thyroid Peroxidase Antibodies(TPO) negative.Pituitary hormone analysis ruled out possible central, which showed FSH &amp;gt;200 IU/L, LH 78.6 IU/L, ACTH 31pg/mL(10-60pg/mL), Serum AM cortisol within normal. Her DM1 was well controlled with an insulin pump with DEXCOM for continuous glucose monitoring, requiring a total daily dose of around 15-20 units/day. The patient currently remains asymptomatic and will be followed in the clinic with labs. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

OR03-4 Efficacy and Safety of Avexitide for Treatment of Hypoglycemia after Gastrointestinal Surgery; Assessment of Novel Dosing Regimens in an Expanded Indication

Abstract Post-bariatric hypoglycemia (PBH) is a rare disease characterized by recurrent episodes of severe, symptomatic hyperinsulinemic hypoglycemia (HH). The predominant form occurs after Roux-en-Y gastric bypass (RYGB). However, severe cases also present after other upper-gastrointestinal procedures. The mechanisms mediating PBH have long been debated, though a critical role for excessive postprandial secretion of glucagon-like peptide-1 (GLP-1) has been established. Avexitide (exendin 9-39) is a first-in-class GLP-1 receptor antagonist in development for treatment of PBH. Prior studies with avexitide administration have shown normalization of postprandial insulin concentrations and reductions in the occurrence of symptomatic hypoglycemia. In the Phase 2 multicenter PREVENT trial, avexitide administered to post-RYGB patients at a total daily dose of 60 mg [30mg twice daily (BID) or 60mg once daily (QD)] for 28 days was well-tolerated and demonstrated significant reductions in the rates of hypoglycemia, symptoms, and percent time in hypoglycemia. Based on the favorable safety and tolerability profile and dose-response relationship observed, we sought to evaluate whether higher doses of avexitide may further enhance the pharmacodynamic response. In addition, we sought to extend the evaluation to patients with HH after vertical sleeve gastrectomy, esophagectomy, gastrectomy or Nissen fundoplication. In this Phase 2b, open label, cross over study (NCT04652479), eligible patients included males and females (&amp;gt;18 years of age; BMI ≤40 kg/m2) with a history of recurrent hypoglycemia refractory to medical nutrition therapy (MNT) and exhibiting at least two severe hypoglycemia events while adhering to MNT over a 14-day period. Metabolic and symptomatic parameters were assessed by self-monitoring of blood glucose (SMBG), e-Diary, and blinded continuous glucose monitor (CGM) during 14 days of MNT as compared to 14 days of MNT + avexitide administered by subcutaneous injection at a dose of 45mg BID and 90mg QD in crossover design and random order, for a total of 28-days of treatment. An interim analysis (mixed-effect model) at ∼50% completion was conducted (n=8). The primary and secondary endpoints were met with statistical significance. Compared with MNT alone, avexitide 45mg BID and 90mg QD reduced the rate of Level 1 hypoglycemia (SMBG&amp;lt;70 mg/dL) by 66% (p=0.022) and 74% (p=0.010); Level 2 hypoglycemia (SMBG &amp;lt;54 mg/dL) by 70% (p=0.003) and 93% (p=0.001); and Level 3 hypoglycemia (severe event characterized by altered mental and/or physical function requiring assistance) by 77% (p=0.002) and 93% (p=0.001), respectively. Objective assessment by blinded CGM corroborated SMBG/e-Diary results, demonstrating significant reductions in the rates of hypoglycemia and improvements in percent time in hypoglycemia. Responses were comparable across surgical subtypes. Greater improvements were consistently observed with once daily (90 mg QD) than twice daily (45 mg BID) dosing and exceeded those reported in the PREVENT trial. Avexitide was well-tolerated, with no serious adverse events. Complete study results will be presented. Presentation: Saturday, June 11, 2022 12:15 p.m. - 12:30 p.m.

PSUN193 Comparing Long-Term Outcomes of Children Diagnosed with New-Onset Type 2 Diabetes in an Outpatient vs Inpatient Setting

Abstract Background Early identification and treatment of children and adolescents with Type 2 Diabetes (T2DM) is thought to improve long-term outcomes. However, it is unclear if severity of T2DM at presentation affects long-term clinical outcomes. Using the location of treatment initiation (inpatient compared to outpatient) as a proxy for severity of illness, we aimed to assess changes in dysglycemia and insulin requirements at diagnosis and after 3 years of follow-up. Methods We performed a retrospective chart review of children 8-18 years of age diagnosed with new onset type 2 diabetes and receiving diabetes care within a large tertiary care center between 1/1/2010 and 11/1/2021 for three consecutive years. Children were identified by ICD codes (ICD9 250.00, ICD10 E13.9 or E11.9). Charts were reviewed to confirm diagnosis. Exclusion criteria included medication induced diabetes, MODY, &amp;gt;1 positive diabetes autoantibody, BMI&amp;lt;85%, complicated medical history (genetic disorders, transplant, cancer, etc.), and &amp;lt; 3 visits in the study time frame. Chi-squared, t-tests, ANOVA, and linear regression were used for analyses. Results A total of 513 patients were identified by ICD code and, after exclusions, 116 were included in the analysis: 69 initially treated in an inpatient setting and 47 initially treated in an outpatient setting. The average A1C at presentation was higher in the inpatient group (11.02% ± 1.77) than the outpatient group (7.19% ± 0.72) (p&amp;lt;0.001). The BMI z-score at presentation was lower in the inpatient group (2.17%±0.58) than the outpatient group (2.41% ±0.35) (p=0.015), but at three years of follow-up the BMI z-score between the groups was not significantly different (2.05%±0.60) compared to (2.12% ±0.50) (p = 0.536). The average A1C remained higher in the inpatient group (9.58%±2.92) compared to the outpatient group (8.43% ±2.44) (p = 0.031). At treatment initiation the average total daily dose of insulin in the inpatient group (0.68±0.36 units/kg/day) was higher than the outpatient group (0.05±0.18 units/kg/day) (p&amp;lt;0.001). At three years of follow-up the average total daily dose of insulin remained higher in the inpatient group (0.50±0.46 units/kg/day) compared to the outpatient (0.29±0.36) (p=0.008 units/kg/day) group. Conclusion In conclusion, pediatric patients initially treated in the inpatient setting had poorer glycemic control and higher insulin requirements at baseline that persisted after three years of follow-up. These findings suggest that initial presentation may predict long-term clinical outcomes in children with T2DM. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

ODP490 Levothyroxine Dosing Based on BMI and Different Causes of Hypothyroidism

Abstract While several approaches can be used when initiating levothyroxine therapy, it is commonly stated that total levothyroxine dose can be calculated as a function of the person's body weight. 1.6 mcg/kg of body weight. But studies have suggested that other factors must be assessed when trying to calculate a total daily dose. The cause of a patient's hypothyroidism may have an effect on their actual replacement needs. It is not the same to consider a patient with postsurgical hypothyroidism who has had all thyroid tissue completely removed versus Hashimoto's or Radioactive Iodine ablation where some thyroid function may be preserved. It is also important to consider a patient's ideal body weight as studies have shown that ideal body weight rather than actual body weight may be more useful in determining a patient's ultimate levothyroxine requirements. As the prevalence of obesity is increasing in the United States and worldwide, factors such as BMI may start playing a more important role when deciding initiation dosage in these patients. We conducted a retrospective chart review with a total of 260 hypothyroid patients on levothyroxine and with two stable TSH values on the same dose. We divided the patient into three BMI categories. &amp;lt;= 24.9, 25-29.9 and &amp;gt;=30. Patients with BMI &amp;lt;= 24.9 had a levothyroxine mean (SD) dose of 1.5 MCG/KG (0.63), those with a BMI 25-29.9: 1.3MCG/KG (0.44), and those with a BMI &amp;gt;=30: 1.1MCG/KG (0.45). P Value &amp;lt;0. 001. When further subdivided into the cause of hypothyroidism (Hashimoto's, post surgical and radioactive iodine), the effects of BMI on levothyroxine dose seem to also be affected. In postsurgical hypothyroidism, patients with BMI &amp;lt;= 24.9 had a levothyroxine mean (SD) dose of 1.8 MCG/KG (0.47), BMI 25-29.9: 1.5MCG/KG (0.21) and BMI &amp;gt;=30: 1.4MCG/KG (0.38). P Value &amp;lt;0. 001. Patients with Hashimoto's with BMI &amp;lt;= 24.9 had a levothyroxine mean (SD) dose of 1.3 MCG/KG (0.65), BMI 25-29.9: 1.1MCG/KG (0.50) and BMI &amp;gt;=30: 0.9MCG/KG (0.44). P Value &amp;lt;0. 001. In patients with hypothyroidism due to radioactive iodine therapy, the levothyroxine dose for those with BMI &amp;lt;= 24. was 1.4 MCG/KG, BMI 25-29.9: 1.2MCG/KG (0.53) and BMI &amp;gt;=30: 1.2MCG/KG (0.39). P Value 0.883 These results suggest that when initiating levothyroxine therapy, a starting dose of 1.6 MCG/KG is not adequate for all patients and that BMI and cause of hypothyroidism should be considered before making this decision. Presentation: No date and time listed

Impact of Dose Reduction of Topical Steroids to Manage Adrenal Insufficiency in Pediatric Eosinophilic Esophagitis.

To evaluate the impact of type and dose of swallowed topical steroids (STS) and concurrent steroid therapy on the development and resolution of adrenal insufficiency (AI) in pediatric eosinophilic esophagitis (EoE). We performed a retrospective case-control study of pediatric EoE subjects in a single tertiary care center, who were treated with STS for at least 3 months and diagnosed with AI based on a peak stimulated cortisol level of <18 µg/dL (500 nmol/L). Steroid forms and doses, and endoscopy data were collected at the time of AI diagnosis and AI resolution or the last known evaluation. Steroid formulations were converted to a fluticasone-equivalent dose for analysis. Thirty-two EoE subjects with AI were identified, and 20 had AI resolution, including 12 who remained on lower dose STS. Eight of the 32 patients were also treated with extended-release budesonide (ER budesonide), which resulted in a 7-fold higher total daily steroid dose, and thus were analyzed separately. When the 24 cases that were not on ER budesonide were compared to the 81 controls, no difference was found in the STS dose nor total daily steroid dose, although the inhaled steroid dose had marginal significance. Peak eosinophil counts tended to increase when STS doses were decreased, except in subjects on ER budesonide at AI diagnosis. Altering the total daily steroid regimen can lead to resolution of AI in patients with EoE, though this may come at the expense of disease control.

Vancomycin dosing required to achieve a therapeutic level in children post-surgical correction of congenital heart disease.

The vancomycin dosing range for safe and effective treatment remains uncertain for children who had corrective surgery for a congenital heart disease (CHD). We aimed to determine the vancomycin dosing requirements for this subgroup of patients.This prospective cohort study included children younger than 14 years old with CHD who received intravenous vancomycin for at least 3 days at the Pediatric Cardiology section of King Abdulaziz Medical City, Riyadh.In total, 140 pediatric patients with CHD were included with a median age of 0.57 years (interquartile range 0.21–2.2). The mean vancomycin total daily dose (TDD), 37.71 ± 6.8 mg/kg/day, was required to achieve a therapeutic trough concentration of 7–20 mg/L. The patient’s age group and the care setting were significant predictors of the vancomycin dosing needs. Neonates required significantly lower doses of 34 ± 6.03 mg/kg/day (P = .002), and young children higher doses of 43.97 ± 9.4 mg/kg/day (P = .003). The dosage requirements were independent of the type of cardiac lesion, cardiopulmonary surgery exposure, sex, and BMI percentile. However, the patients in the pediatric cardiac ward required higher doses of vancomycin 41.08 ± 7.06 mg/kg/day (P = .039). After the treatment, 11 (8.5%) patients had an elevated Scr, and 3 (2.3%) patients developed AKI; however, none of the patients’ sociodemographic factors or clinical variables, or vancomycin therapy characteristics was significantly associated with the renal dysfunction.Overall, the vancomycin TDD requirements are lower in pediatric post-cardiac surgery compared to non-cardiac patients and are modulated by several factors.

Weight gain in type 1 diabetes during the SARS-CoV-2 pandemic. Does lockdown affect the metabolic control of pediatric patients?

Background and aimsDue to the severe acute respiratory syndrome coronavirus 2 pandemic, governments of many countries decided to implement lockdowns, which included school closures. This major lifestyle change also applied to people with diabetes. The aim of this paper was to analyze how the COVID-19 pandemic and related restrictions influenced the metabolic compensation of diabetes in the pediatric population.MethodsPatients with type 1 diabetes (T1D), treated by one therapeutic team, who in 2020 and 2021 paid at least two in-person visits in the outpatient clinic, were included in the study. The time in range (TIR) and HbA1c, as well as the total daily dose (TDD) of insulin and BMI from the visit before the announcement of the pandemic restrictions (March 2020) and during the lockdown (second visit after 6 months) and within the period of loosened restrictions (two visits in 2021) were analyzed.ResultsA total of 185 patients with T1D were included in the study (96 boys), aged 2–18 years (11.5 ± 3.5); 135 of them (72.9%) use CSII and 142 (76.8%) use CGM or FGM. During the first months of the studied period, despite comparable (p>0.05) TIR (57.5 ± 21.4% vs. 59.9 ± 20.5%), improvement of HbA1c was noticed (7.9 ± 1.6% vs. 7.5 ± 1.4%, p=0.0336), whereas in the following months, both HbA1c and TIR were comparable. Also, the TDD increased significantly (from 37.3 ± 18.9 units/day on the first visit up to 46.8 ± 22.7 units/day on the last visit, p=0.0003); however, TDD/kg remained constant (p>0.05) (0.8 ± 0.2 units/kg/day vs. 0.8 ± 0.3 units/kg/day) possibly due to an increased BMI (19.1 ± 3.7 kg/m2 vs. 20.9 ± 4.1 kg/m2, p=0.0001). The percentage of basal insulin in the TDD remained stable (p>0.05) (39.7 ± 11.3% vs. 39.3 ± 13.6%). Furthermore, a significant (p=0.0001) change in the BMI percentile was noticed [from 58.9 ± 26.2 percentiles (%iles) before lockdown vs. 64.6 ± 26.0%iles on the second visit]. However, the BMI percentile returned to baseline (58.1 ± 28.4%iles) at the visit at the end of the observation period.ConclusionsThe parameters of metabolic control in pediatric patients with T1D during the pandemic period remained stable; however, weight gain and an increase in daily insulin dose have been observed, possibly due to reduced physical activity.