Effect of Dosage Reduction of Hypoglycemic Multidrug Regimens on the Incidences of Acute Glycemic Complications in People With Type 2 Diabetes Who Fast During Ramaḍān: A Randomized Controlled Trial

ObjectiveWe aimed to investigate the effect of dosage reduction of four hypoglycemic multidrug regimens on the incidences of acute glycemic complications in people with type 2 diabetes who fast during Ramaḍān.MethodsWe conducted an open-label, parallel-group, randomized controlled trial at a tertiary care center in Amman, Jordan. We recruited adults with type 2 diabetes who expressed an intention to fast during Ramaḍān and were adherent to one of four regimens—namely: metformin and glimepiride; metformin and vildagliptin; metformin and insulin glargine U100; or, metformin, insulin glargine U100, and human regular insulin. We randomly assigned participants in a 2:1 ratio to low- or regular-dosage therapy. The primary outcomes were the incidences of hypoglycemia and hyperglycemia during the 29 days of Ramaḍān 2017, and the secondary outcomes were the incidences of diabetic ketoacidosis and hyperosmolar hyperglycemic state during the same period.ResultsWe randomly assigned 687 participants to low-dosage therapy (n = 458) or regular-dosage therapy (n = 229) and included 678 (452 and 226, respectively) in the final analysis. The incidence of hypoglycemia was lower in the low-dosage group compared with the regular-dosage group (19 [4.2%] vs. 52 [23.0%], respectively; OR, 0.15 [95% CI, 0.08–0.26]; P < 0.001). The incidence of hyperglycemia did not differ between the low- and regular-dosage groups (319 [70.6%] vs. 154 [68.1%], respectively; OR, 1.12 [95% CI, 0.79–1.58]; P = 0.5). No participants experienced diabetic ketoacidosis or hyperosmolar hyperglycemic state. Each 1% decrease in the baseline HbA1c concentration was associated with a 19.9-fold (95% CI, 9.6–41.5; P < 0.001) increase in the odds of hypoglycemia, and each 1% increase in the baseline HbA1c concentration was associated with a 15.7-fold (95% CI, 10.0–24.6; P < 0.001) increase in the odds of hyperglycemia.ConclusionDosage reduction decreases the incidence of hypoglycemia without a concomitant increase in the incidences of hyperglycemia, diabetic ketoacidosis, and hyperosmolar hyperglycemic state in people with type 2 diabetes who fast during Ramaḍān.Clinical Trial Registrationwww.ClinicalTrials.gov, identifier NCT04237493.

Treatment-related side effects and views about dosage assessment to sustain quality of life: Results of an advocate-led survey of patients with metastatic breast cancer (MBC).

1005 Background: Metastatic breast cancer (MBC) is generally incurable and the majority of patients with MBC will remain on treatment indefinitely. Patients usually begin each new treatment at the Recommended Starting Dose (RSD) on the FDA-approved label based on results from clinical trials. However, patients’ ability to tolerate the RSD in the real-world may differ from the clinical trial setting. While the importance of patient reported outcomes is recognized, understanding tolerability from the patient’s perspective is lacking and patients’ willingness to discuss individualized doses for MBC therapy has not been evaluated. Methods: Patient advocates from the Patient-Centered Dosing Initiative distributed a confidential online survey to patients with MBC via social media groups, organizational newsletters, and online support forums. The survey was developed by patients and medical oncologists to ascertain the prevalence and impact of patients’ treatment-related side effects, quality of patient-physician communication, management of side effects, and interest in alternative approaches to the RSD when a new treatment is initiated or adverse side effects are experienced. Results: 1,221 patients with MBC completed the survey within 15 days. The median number of lines of MBC therapy was 2.5 (range 1 - ≥5) and 46% (n = 564) of patients received their MBC diagnosis within two years of taking the survey. 86% (n = 1,051) reported experiencing at least one significant treatment-related side effect, and of these, 20% (n = 213) visited the Emergency Room/hospital and 43% (n = 454) missed at least one treatment. 98% (n = 1,026) of patients with side effects discussed them with their doctors and 82% (n = 838) were helped by their physicians. The most common (non-exclusive) mitigation strategies were dosage reductions (66%, n = 556) and prescription medications (59%, n = 494). Of the 556 patients given a dosage reduction, 83% (n = 459) reported feeling better. Notably, 92% (n = 1,127) of patients expressed willingness to discuss alternative dosing options with their physicians based upon their personal characteristics and individual preferences. Conclusions: Given that 86% of patients with MBC experienced at least one significant treatment-related side effect and 83% improved after dosage reduction, innovative dosage-related strategies are warranted to sustain Quality of Life. Patient-physician discussions in which the patient’s physical attributes and circumstances are periodically assessed may determine the right dose for the patient upon treatment initiation and afterwards, and the vast majority of patients would be receptive to such discussions.

Efficacy and Tolerability of Nintedanib in Idiopathic-Inflammatory-Myopathy-Related Interstitial Lung Disease: A Pilot Study

Objectives: To initially clarify the efficacy and tolerability of nintedanib in patients with idiopathic-inflammatory-myopathy-related interstitial lung disease (IIM-ILD).Methods: A retrospective, real-world analysis was conducted in IIM-ILD patients who regularly received outpatient visit or hospitalization from January 2018 to March 2020 in three centers. And the patients were divided into two groups depending on presence or absence of nintedanib therapy. Comparisons, Kaplan-Meier survival analysis and propensity score matching were made to identify difference in time to death from any cause, incidence of rapidly progressive interstitial lung disease (RP-ILD) and comorbidity of pulmonary infection between the two groups. The following logistic regression analyses and Cox proportional-hazard regression analyses were used to verify the therapeutic value of nintedanib as well as clinical significance of other factors. Adverse events were descriptively recorded.Results: Thirty-six patients receiving nintedanib therapy and 115 patients without use of nintedanib were included. Before and after propensity score matching, the primary comparisons revealed better survival (P = 0.015, P = 0016, respectively) and lower incidence of RP-ILD (P = 0.017, P = 0.014, respectively) in patients with nintedanib therapy. Logistic regression analysis identified that disease activity (P < 0.001), percent-predicted diffusing capacity of the lung for carbon monoxide (DLCO%, P = 0.036), nintedanib therapy (P = 0.004, OR value = 0.072) and amyopathic dermatomyositis (ADM, P = 0.012) were significantly correlated with RP-ILD. Cox proportional hazards regression analysis suggested that disease activity (P < 0.001), anti-MDA5 antibody (P < 0.001) and nintedanib therapy (P = 0.013, HR value=0.268) were significantly associated with survival of IIM-ILD patients. Similar results can also be seen in analyses after propensity score matching. In the 36 patients with nintedanib therapy, diarrhea was the most common adverse event (44.4%) and hepatic insufficiency contributed to most dosage reduction (44.4% of nine patients) or therapy discontinuation (60.0% of five patients).Conclusions: Nintedanib was found to reduce incidence of RP-ILD and improve survival in IIM-ILD patients in a real-world setting. Anti-MDA5 antibody could be taken as a risk factor for unfavorable outcome. ADM was significantly correlated with occurrence of RP-ILD. In addition to the most frequent diarrhea, hepatic insufficiency was closely related to dosage reduction or therapy discontinuation.

752. Management of 20 Patients Diagnosed with Posaconazole-Induced Pseudohyperaldosteronism

Background Posaconazole-induced pseudohyperaldosteronism (PIPH) has been associated with elevated posaconazole serum concentrations. Clinicians are faced with the difficult task of managing patients with PIPH while not compromising the efficacy of antifungal prophylaxis or treatment. Commonly, modifications to posaconazole therapy are utilized in managing PIPH including dosage reduction of posaconazole or therapeutic switch to an alternative antifungal. Methods We retrospectively reviewed 20 consecutive adult patients diagnosed with PIPH in this case series. Patient data including blood pressure, electrolytes, endocrine laboratory values, and posaconazole serum concentrations collected before and after therapeutic intervention. Results Out of 20 patients included, 17 patients (85%) underwent therapeutic modification with posaconazole dose reduction (N=11) as the most common change. Other modifications included posaconazole discontinuation (N=3), switch to an alternative antifungal (N=2), and addition of spironolactone (N=1). Clinical improvement (a decrease in systolic blood pressure and increase in serum potassium) was observed in 9 of 17 patients (52.9%). Table 1. Management of Posaconazole-Induced Pseudohyperaldosteronism - p1 Table 1. Management of Posaconazole-Induced Pseudohyperaldosteronism - p2 Table 1. Management of Posaconazole-Induced Pseudohyperaldosteronism - p3 Conclusion We report our experience with PIPH management, for which there is currently no universally effective strategy. We suggest a stepwise approach for PIPH management, starting with posaconazole dose reduction and repeat assessment of clinical and laboratory parameters. If resolution of PIPH is not achieved, an alternative triazole antifungal or the addition of an aldosterone antagonist are additional potential interventions. Even with this approach, it is possible for PIPH to persist after therapeutic modification. Thus, early diagnosis and continuous, close monitoring of patients is warranted. Disclosures All Authors: No reported disclosures

A Genotyping/Phenotyping Approach with Careful Clinical Monitoring to Manage the Fluoropyrimidines-Based Therapy: Clinical Cases and Systematic Review of the Literature

Fluoropyrimidines (FP) are mainly metabolised by dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene. FP pharmacogenetics, including four DPYD polymorphisms (DPYD-PGx), is recommended to tailor the FP-based chemotherapy. These polymorphisms increase the risk of severe toxicity; thus, the DPYD-PGx should be performed prior to starting FP. Other factors influence FP safety, therefore phenotyping methods, such as the measurement of 5-fluorouracil (5-FU) clearance and DPD activity, could complement the DPYD-PGx. We describe a case series of patients in whom we performed DPYD-PGx (by real-time PCR), 5-FU clearance and a dihydrouracil/uracil ratio (as the phenotyping analysis) and a continuous clinical monitoring. Patients who had already experienced severe toxicity were then identified as carriers of DPYD variants. The plasmatic dihydrouracil/uracil ratio (by high-performance liquid chromatography (HPLC)) ranged between 1.77 and 7.38. 5-FU clearance (by ultra-HPLC with tandem mass spectrometry) was measured in 3/11 patients. In one of them, it reduced after the 5-FU dosage was halved; in the other case, it remained high despite a drastic dosage reduction. Moreover, we performed a systematic review on genotyping/phenotyping combinations used as predictive factors of FP safety. Measuring the plasmatic 5-FU clearance and/or dihydrouracil/uracil (UH2/U) ratio could improve the predictive potential of DPYD-PGx. The upfront DPYD-PGx combined with clinical monitoring and feasible phenotyping method is essential to optimising FP-based chemotherapy.

Real-world Experience of Nintedanib Therapy in Idiopathic-inflammatory-myopathy-related Interstitial Lung Disease: Efficacy and Tolerability

Background Interstitial lung disease (ILD) is a common and frequently fatal extra-muscular complication in patients with idiopathic inflammatory myopathy (IIM), and is refractory to the conventional immunosuppressive medications. Nintedanib has previously been proven to be effective and tolerable in idiopathic pulmonary fibrosis, systemic-sclerosis-related ILD, etc. However, the efficacy and safety of nintedanib in idiopathic-inflammatory-myopathy-related ILD (IIM-ILD) remain unknown. The purpose of this study was to initially explore the efficacy and tolerability of nintedanib in IIM-ILD patients. Methods A real-world analysis was conducted to explore the efficacy and tolerability of nintedanib in IIM-ILD patients who regularly received outpatient visit or hospitalization from January 2018 to October 2019 in one medical center. The primary end point was occurrence of rapid progression of interstitial lung disease (RP-ILD) in the follow-up. And time to death from any cause, complication of pulmonary infection and difference in immunosuppressive regimen were taken as secondary end points in this study. Adverse events were descriptively recorded. Results 22 patients receiving nintedanib therapy and 82 patients under conventional medications were included. After propensity score matching, the primary comparison revealed that better survival (P = 0.036) and prominently less RP-ILD (P = 0.031) in patients with nintedanib therapy. Logistic regression analysis identified that disease activity (P = 0.032), anti-PM-Scl75 antibody (P = 0.027) and nintedanib therapy (P = 0.023, OR value = 0.063) were significantly correlated with RP-ILD. Cox proportional hazards regression analysis demonstrated that disease activity (P = 0.007), anti-MDA5 antibody (P = 0.004) and nintedanib therapy (P = 0.027, HR value = 0.190) were significantly associated with survival of IIM-ILD patients. Similar results can also be seen in analyses before propensity score matching. In the 22 patients with nintedanib therapy, diarrhea was the most common adverse event (54.5%) and hepatic insufficiency contributed to most dosage reduction (50%) or therapy discontinuation (50%). Conclusion Nintedanib therapy might reduce incidence of RP-ILD and improve survival in IIM-ILD patients. Anti-PM-Scl75 and anti-MDA5 antibodies could predict RP-ILD and survival respectively. In addition to the most frequent diarrhea, hepatic insufficiency was closely related to dosage reduction or therapy discontinuation. Trial registration: ISRCTN.com, ISRCTN 10507540. Retrospectively registered.