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Background The cancer‐anorexia‐cachexia syndrome (CACS) is a common and debilitating wasting disorder characterized by loss of skeletal muscle and worse morbidity and mortality. In pre‐clinical studies, CACS is associated with loss of peroxisome proliferator‐activated receptor alpha (PPAR‐α) dependent ketone production in the liver. Fibrates are PPAR‐α agonists that are commonly used to treat dyslipidemia. Treating mice with fibrates was found to prevent skeletal muscle loss. We examine whether patients with cancer treated with PPAR‐α agonists experience less CACS. Methods We performed a retrospective cohort study of patients (N = 6922) at Memorial Sloan Kettering Cancer Center who were diagnosed with non‐small cell lung cancer (NSCLC) between 2002 and 2017 and were incidentally prescribed fenofibrate or gemfibrozil at the time of diagnosis. These patients were compared to a propensity score‐matched control set who were not taking either drug. The primary outcome included a composite outcome of CACS, which included significant weight loss before or after the time of diagnosis. Secondary outcomes included change in cross‐sectional skeletal muscle area over time as measured in serial CT imaging studies and overall survival. Descriptive statistics, Kaplan–Meier analysis and multivariable logistic regression were performed to compare outcomes between the two groups. Results Among patients with NSCLC, 149 were taking fenofibrate or gemfibrozil at the time of diagnosis. A 2:1 propensity score‐matched cohort of 298 patients was created that was well‐matched with regard to baseline characteristics. Regarding the primary composite outcome, there was no significant difference in the prevalence of CACS between those taking fibrates and propensity‐matched controls (49.7 vs. 46.6%). When skeletal muscle mass was measured directly using cross‐sectional imaging, patients on fibrates were found to have lost significantly less muscle area over time (−3.3 vs.−4.2%, p = 0.03). There was no difference in overall survival between groups. Conclusion Patients with NSCLC taking fibrates at the time of diagnosis lost less muscle area over time. In a secondary analysis, this change was not associated with a change in overall survival, though this study was likely underpowered for this analysis.

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 β‐, 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. Phosphoinositide 3‐kinase (PI3K)/protein kinase B (AKT) inhibitor induced hyperglycemia is particularly likely to happen in patients with baseline diabetes, pre‐diabetes, or elevated body mass index. It is manageable with dose interruption, dose modification and/or pharmacologic management; and that sodium‐glucose transport protein 2 inhibitors are a promising second‐line option after metformin.

ObjectivePrior studies demonstrate that some untoward clinical outcomes vary by outdoor temperature. This is true of some endpoints common among persons with diabetes, a population vulnerable to climate change-associated health risks. Yet, prior work has been agnostic to the antidiabetes drugs taken by such persons. We examined whether relationships between ambient temperature and adverse health outcomes among persons with type 2 diabetes (T2D) varied by exposure to different antidiabetes drugs.DesignRetrospective cohort.SettingHealthcare and meteorological data from five US states, 1999–2010.ParticipantsUS Medicaid beneficiaries with T2D categorised by use of antidiabetes drugs.ExposureMaximum daily ambient temperature (t-max).OutcomesHospital presentation for serious hypoglycaemia, diabetic ketoacidosis (DKA) or sudden cardiac arrest (examined separately).MethodsWe linked US Medicaid to US Department of Commerce data that permitted us to follow individuals longitudinally and examine health plan enrolment, healthcare claims, and meteorological exposures—all at the person-day level. We mapped daily temperature from weather stations to Zone Improvement Plan (ZIP) codes, then assigned a t-max to each person-day based on the residential ZIP code. Among prespecified subcohorts of users of different pharmacologic classes of antidiabetes drugs, we calculated age and sex-adjusted occurrence rates for each outcome by t-max stratum. We used modified Poisson regression to assess relationships between linear and quadratic t-max terms and each outcome. We examined effect modification between t-max and a covariable for current exposure to a specific antidiabetes drug and assessed significance via Wald tests.ResultsWe identified ∼3 million persons with T2D among whom 713 464 used sulfonylureas (SUs), dipeptidyl peptidase-4 inhibitors (DPP-4is), meglitinides, or glucagon-like peptide 1 receptor agonists (GLP1RAs). We identified a positive linear association between t-max and serious hypoglycaemia among non-insulin users of glimepiride and of glyburide but not glipizide (Wald p value for interaction among SUs=0.048). We identified an inverse linear association between t-max and DKA among users of the DPP-4i sitagliptin (p=0.016) but not the GLP1RA exenatide (p=0.080). We did not identify associations between t-max and sudden cardiac arrest among users of SUs, meglitinides, exenatide, or DPP-4is.ConclusionsWe identified some antidiabetes drug class-specific and agent-specific differences in the relationship between ambient temperature and untoward glycaemic but not arrhythmogenic, safety outcomes.

BackgroundThe association between nonadherence to chronic medications and potentially preventable healthcare utilization and spending is largely unknown.ObjectivesTo examine the associations of chronic medication nonadherence with potentially preventable utilization and spending among patients who were prescribed diabetic medications, renin-angiotensin system antagonists (RASA) for hypertension, or statins for high cholesterol, and compare the associations by patient race/ethnicity and socioeconomic status.DesignRetrospective cohort study. Medicare fee-for-service claims data from 2013 to 2016 for 177,881 patients.MeasuresMedication nonadherence was defined as having a below 80% proportion of days covered in each 6-month interval after the index prescription. Potentially preventable utilization was measured by preventable emergency department visits and preventable hospitalizations. Potentially preventable spending was calculated as the geographically adjusted spending associated with preventable encounters.ResultsAfter adjustment for other patient characteristics, medication nonadherence was associated with a 1.7-percentage-point increase (95% confidence interval [CI]: 1.4 to 2.0 percentage points, p < 0.001) in the probability of preventable utilization among the diabetic medication cohort, a 1.7-percentage-point increase (95% CI: 1.5 to 1.9 percentage points, p < 0.001) among the RASA cohort, and a 1.0-percentage-point increase (95% CI: 0.8 to 1.1 percentage points, p < 0.001) among the statin cohort. Among patients with at least one preventable encounter, medication nonadherence was associated with $679–$898 increased preventable spending. The incremental probability of preventable utilization and incremental spending associated with nonadherence were higher among racial/ethnic minority and low socioeconomic groups.ConclusionsImproving medication adherence is a potential avenue to reducing preventable utilization and spending. Interventions are needed to address racial/ethnic and socioeconomic disparities.

Major depressive disorder (MDD) is a common psychiatric and behavioral disorder. To discover novel variants conferring risk to MDD, we conducted a whole-genome scan of copy number variation (CNV), including 1,693 MDD cases and 4,506 controls genotyped on the Perlegen 600K platform. The most significant locus was observed on 5q35.1, harboring the SLIT3 gene (P = 2×10(-3)). Extending the controls with 30,000 subjects typed on the Illumina 550 k array, we found the CNV to remain exclusive to MDD cases (P = 3.2×10(-9)). Duplication was observed in 5 unrelated MDD cases encompassing 646 kb with highly similar breakpoints. SLIT3 is integral to repulsive axon guidance based on binding to Roundabout receptors. Duplication of 5q35.1 is a highly penetrant variation accounting for 0.7% of the subset of 647 cases harboring large CNVs, using a threshold of a minimum of 10 SNPs and 100 kb. This study leverages a large dataset of MDD cases and controls for the analysis of CNVs with matched platform and ethnicity. SLIT3 duplication is a novel association which explains a definitive proportion of the largely unknown etiology of MDD.

The coronavirus disease 2019 (COVID-19) is heterogeneous and our understanding of the biological mechanisms of host response to the viral infection remains limited. Identification of meaningful clinical subphenotypes may benefit pathophysiological study, clinical practice, and clinical trials. Here, our aim was to derive and validate COVID-19 subphenotypes using machine learning and routinely collected clinical data, assess temporal patterns of these subphenotypes during the pandemic course, and examine their interaction with social determinants of health (SDoH). We retrospectively analyzed 14418 COVID-19 patients in five major medical centers in New York City (NYC), between March 1 and June 12, 2020. Using clustering analysis, 4 biologically distinct subphenotypes were derived in the development cohort ( N  = 8199). Importantly, the identified subphenotypes were highly predictive of clinical outcomes (especially 60-day mortality). Sensitivity analyses in the development cohort, and rederivation and prediction in the internal ( N  = 3519) and external ( N  = 3519) validation cohorts confirmed the reproducibility and usability of the subphenotypes. Further analyses showed varying subphenotype prevalence across the peak of the outbreak in NYC. We also found that SDoH specifically influenced mortality outcome in Subphenotype IV, which is associated with older age, worse clinical manifestation, and high comorbidity burden. Our findings may lead to a better understanding of how COVID-19 causes disease in different populations and potentially benefit clinical trial development. The temporal patterns and SDoH implications of the subphenotypes may add insights to health policy to reduce social disparity in the pandemic.

Background The low cost of thiazolidinediones makes them a potentially valuable therapeutic option for the > 300 million economically disadvantaged persons worldwide with type 2 diabetes mellitus. Differential selectivity of thiazolidinediones for peroxisome proliferator-activated receptors in the myocardium may lead to disparate arrhythmogenic effects. We examined real-world effects of thiazolidinediones on outpatient-originating sudden cardiac arrest (SCA) and ventricular arrhythmia (VA). Methods We conducted population-based high-dimensional propensity score-matched cohort studies in five Medicaid programs (California, Florida, New York, Ohio, Pennsylvania | 1999–2012) and a commercial health insurance plan (Optum Clinformatics | 2000–2016). We defined exposure based on incident rosiglitazone or pioglitazone dispensings; the latter served as an active comparator. We controlled for confounding by matching exposure groups on propensity score, informed by baseline covariates identified via a data adaptive approach. We ascertained SCA/VA outcomes precipitating hospital presentation using a validated, diagnosis-based algorithm. We generated marginal hazard ratios (HRs) via Cox proportional hazards regression that accounted for clustering within matched pairs. We prespecified Medicaid and Optum findings as primary and secondary, respectively; the latter served as a conceptual replication dataset. Results The adjusted HR for SCA/VA among rosiglitazone (vs. pioglitazone) users was 0.91 (0.75–1.10) in Medicaid and 0.88 (0.61–1.28) in Optum. Among Medicaid but not Optum enrollees, we found treatment effect heterogeneity by sex (adjusted HRs = 0.71 [0.54–0.93] and 1.16 [0.89–1.52] in men and women respectively, interaction term p-value = 0.01). Conclusions Rosiglitazone and pioglitazone appear to be associated with similar risks of SCA/VA.

Alpelisib is a α-selective phosphatidylinositol 3-kinase (PI3K) inhibitor approved for treatment of postmenopausal women, and men, with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2–), PIK3CA-mutated, advanced breast cancer (ABC). Hyperglycemia is a common, on-target adverse effect that impairs treatment efficacy and increases the rate of treatment delays, dose reductions, and discontinuation. Currently, there are no clear guidelines on how to manage hyperglycemia due to alpelisib when metformin is not effective. In this case series, we review 3 subjects with ABC that developed hyperglycemia during alpelisib-fulvestrant therapy and were successfully managed with dietary and pharmacologic interventions. These cases provide anecdotal evidence to support the use of sodium-glucose co-transporter-2 inhibitors (SGLT2i) and very low carbohydrate diets to minimize hyperglycemia during alpelisib therapy.

Aims To compare rates of use and adherence for newer versus older second‐line diabetes drug classes in commercially insured, Medicare Advantage and dual‐eligible (covered by both Medicare and Medicaid) patients. Materials and Methods Longitudinal cohort study using insurance claims data from 1/1/2012 to 12/31/2016 to identify patients with a first prescription, after metformin, of a second‐line diabetes drug (eg sulphonylurea, DPP‐4 inhibitor, thiazolidinedione, SGLT‐2 inhibitor or GLP‐1 receptor agonist) and to estimate their adherence to that drug class. Univariate analysis and multivariable logistic regression were used to examine the association between insurance type and use of each drug class, and between insurance type and adherence to each drug class. Results The study population included 96,663 patients. Trends in drug use differed by insurance type. For example, sulphonylurea use declined among the commercially insured (from 46% to 39%, p < .001) but not among Medicare Advantage or dual‐eligible patients. Patterns of adherence also differed between insurance groups. For example, compared to commercial insurance, Medicare Advantage was associated with higher adherence to sulphonylurea (odds ratio [OR] 1.32, 95% CI 1.21–1.43)) but lower adherence to SGLT‐2 inhibitors (OR 0.43 (95% CI 0.33–0.56)). Conclusions This study finds differences in utilization and adherence for diabetes drugs across insurance types. Older medications such as sulphonylureas appear to be more used and better adhered to among Medicare Advantage recipients, while the opposite is true for newer medication classes. These findings suggest a need to personalize selection of diabetes drugs according to insurance status, particularly when adherence needs optimization. Patients with Medicare Advantage coverage are less likely to adhere to expensive new diabetes drugs than patients with commercial insurance. Older, less expensive diabetes drugs may continue to play an important role in the care of these patients.

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.