Sodium-glucose cotransporter-2 inhibitors for hypergycemia in phosphoinositide 3-kinase pathway inhibition.

PURPOSE: Phosphoinositide 3-kinase (PI3K) inhibition is used for the treatment of certain cancers, but can cause profound hyperglycemia and insulin resistance, for which sodium-glucose cotransporter-2 (SGLT2) inhibitors have been proposed as a preferred therapy. The objective of this research is to assess the effectiveness and safety of SGLT2 inhibitors for hyperglycemia in PI3K inhibition. METHODS: We conducted a single-center retrospective review of adults initiating the PI3K inhibitor alpelisib. Exposure to different antidiabetic drugs and adverse events including diabetic ketoacidosis (DKA) were assessed through chart review. Plasma and point-of-care blood glucoses were extracted from the electronic medical record. Change in serum glucose and the rate of DKA on SGLT2 inhibitor versus other antidiabetic drugs were examined as co-primary outcomes. RESULTS: We identified 103 patients meeting eligibility criteria with median follow-up of 92 days after starting alpelisib. When SGLT2 inhibitors were used to treat hyperglycemia, they were associated with a decrease in mean random glucose by -46 mg/dL (95% CI - 77 to - 15) in adjusted linear modeling. Five cases of DKA were identified, two occurring in patients on alpelisib plus SGLT2 inhibitor. Estimated incidence of DKA was: alpelisib plus SGLT2 inhibitor, 48 DKA cases per 100 patient-years (95% CI 6, 171); alpelisib with non-SGLT2 inhibitor antidiabetic drugs, 15 (95% CI 2, 53); alpelisib only, 4 (95% CI 0.1, 22). CONCLUSIONS: SGLT2 inhibitors are effective treatments for hyperglycemia in the setting of PI3K inhibition.

Loss of hepatocyte ERBB3 but not EGFR impairs hepatocarcinogenesis.

Epidermal growth factor receptor (EGFR) and ERBB3 have been implicated in hepatocellular carcinogenesis (HCC). However, it is not known whether altering the activity of either EGFR or ERBB3 affects HCC development. We now show that Egfr(Dsk5) mutant mice, which have a gain-of-function allele that increases basal EGFR kinase activity, develop spontaneous HCC by 10 mo of age. Their tumors show increased activation of EGFR, ERBB2, and ERBB3 as well as AKT and ERK1,2. Hepatocyte-specific models of EGFR and ERBB3 gene ablation were generated to evaluate how the loss of these genes affected tumor progression. Loss of either receptor tyrosine kinase did not alter liver development or regenerative liver growth following carbon tetrachloride injection. However, using a well-characterized model of HCC in which N-nitrosodiethylamine is injected into 14-day-old mice, we discovered that loss of hepatocellular ERBB3 but not EGFR, which occurred after tumor initiation, retarded liver tumor formation and cell proliferation. We found no evidence that this was due to increased apoptosis or diminished phosphatidylinositol-3-kinase activity in the ERBB3-null cells. However, the relative amount of phospho-STAT3 was diminished in tumors derived from these mice, suggesting that ERBB3 may promote HCC through STAT3 activation.

Third-Line Overactive Bladder Therapies on TikTok: What Does the Public Learn?

IMPORTANCE: Millions of people rely on social media platforms, including TikTok, for health-related information. TikTok has not yet been evaluated as an information source for overactive bladder (OAB) third-line therapies. OBJECTIVES: Our aim was to assess TikTok videos on third-line therapies for OAB for misinformation and quality. STUDY DESIGN: In this cross-sectional analysis, we abstracted the top 50 TikTok videos for keywords: "Axonics," "sacral neuromodulation," "Interstim," "PTNS," "posterior tibial nerve stimulation," and "bladder Botox." Videos were scored for quality by 3 independent reviewers using the Medical Quality Video Evaluation Tool (MQ-VET). Two reviewers determined if videos contained misinformation. RESULTS: Of 300 videos screened, 119 videos were included. Twenty-four (21%) were created by medical professionals (MPs). Medical professional videos were more frequently shared (5 vs 1, P < 0.01) but had similar views, likes, comments, and length. Although MP videos had significantly higher MQ-VET scores (43 vs 27, P < 0.01), there was no difference in the rate of misinformation between MP and non-MP videos (21% vs 18%). Twenty-two videos (18.4%) contained misinformation, which were 3 times longer (50.5 vs 15 seconds, P < 0.01) and had higher MQ-VET scores (34.5 vs 27, P = 0.03) than those without misinformation. Common themes of misinformation pertained to therapy indication, mechanism of action, and patient limitations after undergoing therapy. CONCLUSIONS: Many TikTok videos on OAB third-line therapies contain misinformation. Most of these videos were not of high quality and created by the public. Medical professionals should be aware of misinformation permeating TikTok, given its large audience, and aim to promote or offer educational material of better accuracy and quality.

Sodium-Glucose Cotransporter-2 Inhibitors for Hyperglycemia in Phosphoinositide 3-kinase Pathway Inhibition.

Purpose Phosphoinositide 3-kinase (PI3K) inhibition is used for the treatment of certain cancers, but can cause profound hyperglycemia and insulin resistance, for which sodium-glucose cotransporter-2 (SGLT2) inhibitors have been proposed as a preferred therapy. The objective of this research is to assess the effectiveness and safety of SGLT2 inhibitors for hyperglycemia in PI3K inhibition. Methods We conducted a single-center retrospective review of adults initiating the PI3k inhibitor alpelisib. Exposure to different antidiabetic drugs and adverse events including diabetic ketoacidosis (DKA) were assessed through chart review. Plasma and point-of-care blood glucoses were extracted from the electronic medical record. Change in serum glucose and the rate of DKA on SGLT2 inhibitor versus other antidiabetic drugs were examined as co-primary outcomes. Results We identified 103 patients meeting eligibility criteria with median follow-up of 85 days after starting alpelisib. When SGLT2 inhibitors were used to treat hyperglycemia, they were associated with a decrease in mean random glucose by -54 mg/dL (95% CI -99 to -8) in adjusted linear modeling. Five cases of DKA were identified, two occurring in patients on alpelisib plus SGLT2 inhibitor. Estimated incidence of DKA was: alpelisib plus SGLT2 inhibitor, 24 DKA cases per 100 patient-years (95% CI 6, 80); alpelisib with non-SGLT2 inhibitor antidiabetic drugs, 7 (95% CI 0.1, 34); alpelisib only, 4 (95% CI 0.1, 21). Conclusions SGLT2 inhibitors are effective treatments for hyperglycemia in the setting of PI3K inhibition, but given possible adverse events, SGLT2 inhibitors should be used with caution.

Five-year Weight Loss Maintenance With Obesity Pharmacotherapy.

CONTEXT: Long-term treatment of obesity with lifestyle changes alone is unsustainable for most individuals because of several factors including adherence and metabolic adaptation. Medical management of obesity has proven efficacy for up to 3 years in randomized controlled trials. However, there is a dearth of information regarding real-world outcomes beyond 3 years. OBJECTIVE: This work aimed to assess long-term weight loss outcomes over a 2.5- to 5.5-year period with US Food and Drug Administration (FDA)-approved and off-label antiobesity medications (AOMs). METHODS: A cohort of 428 patients with overweight or obesity were treated with AOMs at an academic weight management center with an initial visit between April 1, 2014, and April 1, 2016. Intervention included FDA-approved and off-label AOMs. The primary outcome was percentage weight loss from initial to final visit. Key secondary outcomes included weight reduction targets as well as demographic and clinical predictors of long-term weight loss. RESULTS: The average weight loss was 10.4% at a mean follow-up duration of 4.4 years. The proportions of patients who met the weight reduction targets of 5% or greater, 10% or greater, 15% or greater, and 20% or greater were 70.8%, 48.1%, 29.9%, and 17.1%, respectively. On average, 51% of maximum weight loss was regained, while 40.2% of patients maintained their weight loss. In a multivariable regression analysis, a higher number of clinic visits was associated with more weight loss. Metformin, topiramate, and bupropion were associated with increased odds of maintaining 10% or greater weight loss. CONCLUSION: Clinically significant long-term weight loss of 10% or more beyond 4 years is achievable in clinical practice settings with obesity pharmacotherapy.

Characterization, management, and risk factors of hyperglycemia during PI3K or AKT inhibitor treatment.

PURPOSE: The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway controls insulin sensitivity and glucose metabolism. Hyperglycemia is one of the most common on-target adverse effects (AEs) of PI3K/AKT inhibitors. As several PI3K and AKT inhibitors are approved by the United States Food and Drug Administration or are being studied in clinical trials, characterizing this AE and developing a management strategy is essential. METHODS: Patients with hematologic or solid malignancies treated at Memorial Sloan Kettering Cancer Center with a PI3K or AKT inhibitor were included in this retrospective analysis. A search for patients experiencing hyperglycemia was performed. The frequency, management interventions and outcomes were characterized. RESULTS: Four hundred and ninety-one patients with 10 unique cancer types who received a PI3K or AKT inhibitor were included. Twelve percent of patients required a dose interruption, 6% of patients required a dose reduction and 2% of patients were hospitalized to manage hyperglycemia. No events occurred among patients receiving ß-, γ-, or δ- specific PI3K inhibitor. There was one case where the PI3K or AKT inhibitor was permanently discontinued due to hyperglycemia. Metformin was the most commonly used antidiabetic medication, followed by insulin, sodium-glucose transport protein 2 (SGLT2) inhibitors, and sulfonylurea. SGLT2 inhibitors were associated with the greatest reductions in blood sugar, followed by metformin. At least one case of euglycemic diabetic ketoacidosis (DKA) occurred in a patient on PI3K inhibitor and SGLT2 inhibitor. Body mass index ≥ 25 and HbA1c  ≥ 5.7 are were independently significant predictors of developing hyperglycemia. CONCLUSION: Hyperglycemia is one of the major on-target side effects of PI3K and AKT inhibitors. It is manageable with antidiabetic medications, treatment interruption and/or dose modification. We summarize pharmacological interventions that may be considered for PI3K/AKT inhibitor induced hyperglycemia. SGLT2-inhibitor may be a particularly effective second-line option after metformin but there is a low risk of euglycemic DKA, which can be deadly. To our knowledge, our report is the largest study of hyperglycemia in patients receiving PI3K/AKT inhibitors.

Graves Disease Following the SARS-CoV-2 Vaccine: Case Series.

Widespread vaccination is a principal strategy to mitigate the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and lessen the global burden of coronavirus disease 2019 (COVID-19). Information is rapidly evolving about the impact of SARS-CoV-2 vaccines on the immune and endocrine systems. This case series heightens clinical awareness of possible thyroid effects and conveys knowledge of what to monitor, which are fundamental components of public health and pharmacovigilance. We present a case series of Graves disease following mRNA SARS-CoV-2 vaccination, with symptoms and altered thyroid function tests developing within 7 days of the first dose in 2 women aged 38 and 63 years, and 28 days after the second dose in a 30-year-old man. New-onset Graves disease occurred following administration of mRNA vaccines against SARS-CoV-2. Based on the timing of signs and symptoms relative to administration of the vaccine and the absence of other probable causes, we consider the vaccine as a potential contributor to the diagnosis. The viral spike protein, delivered indirectly through an encoded mRNA vaccine, may be capable of triggering an inflammatory cascade and immune response triggering thyroid dysfunction.

Dosing Common Medications in Hospitalized Pediatric Patients with Obesity: A Review.

Medication management in children and adolescents with obesity is challenging because both developmental and pathophysiological changes may impact drug disposition and response. Evidence to date indicates an effect of obesity on drug disposition for certain drugs used in this population. This work identified published studies evaluating drug dosing, pharmacokinetics (PK), and effect in pediatric patients with obesity, focusing on 70 common medications used in a pediatric network of 42 US medical centers. A PubMed search revealed 33 studies providing PK and/or effectiveness data for 23% (16 of 70) of medications, 44% of which have just one study and can be considered exploratory. This work appraising 4 decades of literature shows several promising approaches: greater use of PK models applied to prospective clinical studies, dosing recommendations derived from both PK and safety, and multiyear effectiveness data on drugs for chronic conditions (e.g., asthma). Most studies make dose recommendations but are weakened by retrospective study design, small study populations, and no controls or historic controls. Dosing decisions continue to rely on extrapolating knowledge, including targeting systemic drug exposure typically achieved in adults. Optimal weight-based dosing strategies vary by drug and warrant prospective, controlled studies incorporating PK and modeling and simulation to complement clinical assessment.

Metastatic retroperitoneal paraganglioma: Case report and review of the literature.

Paragangliomas are rare neuroendocrine tumors with 500 to 1600 new cases in the United States each year (1). The clinical presentation may range from asymptomatic to the classic triad of episodic diaphoresis, headache, and palpitations. Surgery is the hallmark of treatment when tumors are amenable to resection. When patients are found to have metastases, systemic therapies may be employed. In this case report, we present a patient found to have a large retroperitoneal paraganglioma with nodal metastases.

Pediatric Obesity: Influence on Drug Dosing and Therapeutics.

Obesity is an ongoing global health concern and has only recently been recognized as a chronic disease of energy homeostasis and fuel partitioning. Obesity afflicts 17% of U.S. children and adolescents. Severe obesity (≥120% of the 95th percentile of body mass index (BMI) for age, or a BMI ≥ 35 kg/m2 ) is the fastest-growing subgroup and now approaches 6% of all U.S. youth. Health consequences (eg, type 2 diabetes, coronary heart disease) are related in a dose-dependent manner to severity of obesity. Because therapeutic interventions are less effective in severe obesity, prevention is a high priority. Treatment plans involving combinations of behavioral therapy, nutrition, and exercise achieve limited success. Only one drug, orlistat, is U.S. Food and Drug Administration approved for long-term obesity management in adolescents 12 years and older. As part of comprehensive medication management, clinicians should consider the propensity for a given drug to aggravate weight gain and to consider alternatives that minimize weight impact. Medication management must take into account developmental changes as well as the pathophysiology of obesity and comorbidities. Despite expanding insight into obesity pathophysiology, there are gaps in its translation to therapeutic application. The historical construct of obesity as simply a fat-storage disorder is fundamentally inaccurate. The approach to adjusting doses based solely on body size and extrapolating from therapeutic knowledge of adult obesity may be based on assumptions that are not fully substantiated. Classes of drugs commonly prescribed for comorbidities associated with obesity should be prioritized for clinical research evaluations aimed at optimizing dosing regimens in pediatric obesity.