Application of a data continuity prediction algorithm to an electronic health record-based pharmacoepidemiology study.

BACKGROUND AND OBJECTIVES: Use of algorithms to identify patients with high data-continuity in electronic health records (EHRs) may increase study validity. Practical experience with this approach remains limited. METHODS: We developed and validated four algorithms to identify patients with high data continuity in an EHR-based data source. Selected algorithms were then applied to a pharmacoepidemiologic study comparing rates of COVID-19 hospitalization in patients exposed to insulin versus noninsulin antidiabetic drugs. RESULTS: A model using a short list of five EHR-derived variables performed as well as more complex models to distinguish high- from low-data continuity patients. Higher data continuity was associated with more accurate ascertainment of key variables. In the pharmacoepidemiologic study, patients with higher data continuity had higher observed rates of the COVID-19 outcome and a large unadjusted association between insulin use and the outcome, but no association after propensity score adjustment. DISCUSSION: We found that a simple, portable algorithm to predict data continuity gave comparable performance to more complex methods. Use of the algorithm significantly impacted the results of an empirical study, with evidence of more valid results at higher levels of data continuity.

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.

Prescriber Uncertainty as Opportunity to Improve Care of Type 2 Diabetes with Chronic Kidney Disease: Mixed Methods Study.

BACKGROUND: Over 5 million patients in the United States have type 2 diabetes mellitus (T2D) with chronic kidney disease (CKD); antidiabetic drug selection for this population is complex and has important implications for outcomes. OBJECTIVE: To better understand how providers choose antidiabetic drugs in T2D with CKD DESIGN: Mixed methods. Interviews with providers underwent qualitative analysis using grounded theory to identify themes related to antidiabetic drug prescribing. A provider survey used vignettes and direct questions to quantitatively assess prescribers' knowledge and preferences. A retrospective cohort analysis of real-world prescribing data assessed the external validity of the interview and survey findings. PARTICIPANTS: Primary care physicians, endocrinologists, nurse-practitioners, and physicians' assistants were eligible for interviews; primary care physicians and endocrinologists were eligible for the survey; prescribing data were derived from adult patients with serum creatinine data. MAIN MEASURES: Interviews were qualitative; for the survey and retrospective cohort, proportion of patients receiving metformin was the primary outcome. KEY RESULTS: Interviews with 9 providers identified a theme of uncertainty about guidelines for prescribing antidiabetic drugs in patients with T2D and CKD. The survey had 105 respondents: 74 primary care providers and 31 endocrinologists. Metformin was the most common choice for patients with T2D and CKD. Compared to primary care providers, endocrinologists were less likely to prescribe metformin at levels of kidney function at which it is contraindicated and more likely to correctly answer a question about metformin's contraindications (71% versus 41%) (p < .05). Real-world data were consistent with survey findings, and further showed low rates of use of sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists (<10%) in patients with eGFR below 60 ml/min/1.73m2. CONCLUSIONS: Providers are unsure how to treat T2D with CKD and incompletely informed as to existing guidelines. This suggests opportunities to improve care.

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.

Impact of a Provider Tele-mentoring Learning Model on the Care of Medicaid-enrolled Patients With Diabetes.

BACKGROUND: Project ECHO (Extension for Community Healthcare Outcomes), a tele-mentoring program for health care providers, has been shown to improve provider-reported outcomes, but there is insufficient research on patient-level outcomes. OBJECTIVES: To evaluate the impact of primary care provider (PCP) participation in Project ECHO on the care of Medicaid enrollees with diabetes. RESEARCH DESIGN: New Jersey Medicaid claims and encounter data and difference-in-differences models were used to compare utilization and spending between Medicaid patients seen by PCPs participating in a Project ECHO program to those of matched nonparticipating PCPs. SUBJECTS: A total of 1776 adult Medicaid beneficiaries (318 with diabetes), attributed to 25 participating PCPs; and 9126 total (1454 diabetic) beneficiaries attributed to 119 nonparticipating PCPs. MEASURES: Utilization and spending for total inpatient, diabetes-related inpatient, emergency department, primary care, and endocrinologist services; utilization of hemoglobin A1c tests, eye exams, and diabetes prescription medications among diabetics, and total Medicaid spending. RESULTS: Participation in Project ECHO was associated with decreases of 44.3% in inpatient admissions (P=0.001) and 61.9% in inpatient spending (P=0.021) among treatment relative to comparison patients. Signs of most other outcome estimates were consistent with hypothesized program effects but without statistical significance. Sensitivity analyses largely confirmed these findings. CONCLUSIONS: We find evidence that Project ECHO participation was associated with large and statistically significant reductions of inpatient hospitalization and spending. The study was observational and limited by a small sample of participating PCPs. This study demonstrates the feasibility and potential value of quasi-experimental evaluation of Project ECHO patient outcomes using claims data.

Baseline haemoglobin A1c and the risk of COVID-19 hospitalization among patients with diabetes in the INSIGHT Clinical Research Network.

AIMS: To examine the association between baseline glucose control and risk of COVID-19 hospitalization and in-hospital death among patients with diabetes. METHODS: We performed a retrospective cohort study of adult patients in the INSIGHT Clinical Research Network with a diabetes diagnosis and haemoglobin A1c (HbA1c) measurement in the year prior to an index date of March 15, 2020. Patients were divided into four exposure groups based on their most recent HbA1c measurement (in mmol/mol): 39-46 (5.7%-6.4%), 48-57 (6.5%-7.4%), 58-85 (7.5%-9.9%), and ≥86 (10%). Time to COVID-19 hospitalization was compared in the four groups in a propensity score-weighted Cox proportional hazards model adjusting for potential confounders. Patients were followed until June 15, 2020. In-hospital death was examined as a secondary outcome. RESULTS: Of 168,803 patients who met inclusion criteria; 50,016 patients had baseline HbA1c 39-46 (5.7%-6.4%); 54,729 had HbA1c 48-57 (6.5-7.4%); 47,640 had HbA1c 58-85 (7.5^%-9.9%) and 16,418 had HbA1c ≥86 (10%). Compared with patients with HbA1c 48-57 (6.5%-7.4%), the risk of hospitalization was incrementally greater for those with HbA1c 58-85 (7.5%-9.9%) (adjusted hazard ratio [aHR] 1.19, 95% confidence interval [CI] 1.06-1.34) and HbA1c ≥86 (10%) (aHR 1.40, 95% CI 1.19-1.64). The risk of COVID-19 in-hospital death was increased only in patients with HbA1c 58-85 (7.5%-9.9%) (aHR 1.29, 95% CI 1.06, 1.61). CONCLUSIONS: Diabetes patients with high baseline HbA1c had a greater risk of COVID-19 hospitalization, although association between HbA1c and in-hospital death was less consistent. Preventive efforts for COVID-19 should be focused on diabetes patients with poor glucose control.

Comparative Safety of Sodium-Glucose Cotransporter 2 Inhibitors Versus Dipeptidyl Peptidase 4 Inhibitors and Sulfonylureas on the Risk of Diabetic Ketoacidosis.

OBJECTIVE: To assess the association of sodium-glucose cotransporter 2 (SGLT2) inhibitors with diabetic ketoacidosis compared with dipeptidyl peptidase 4 (DPP-4) inhibitors and sulfonylureas in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: We conducted a new-user active comparator cohort study to examine two pairwise comparisons: 1) SGLT2 inhibitors versus DPP-4 inhibitors and 2) SGLT2 inhibitors versus sulfonylureas. The main outcome was diabetic ketoacidosis present on hospital admission. We adjusted for confounders through propensity score matching. We used Cox proportional hazards regression with a robust variance estimator to estimate hazard ratios (HRs) and corresponding 95% CIs while adjusting for calendar time. RESULTS: In cohort 1 (n = 85,125 for SGLT2 inhibitors and n = 85,125 for DPP-4 inhibitors), the incidence rates of diabetic ketoacidosis per 1,000 person-years were 6.0 and 4.3 for SGLT2 inhibitors and DPP4 inhibitors, respectively. In cohort 2 (n = 72,436 for SGLT2 inhibitors and n = 72,436 for sulfonylureas), the incidence rates of diabetic ketoacidosis per 1,000 person-years were 6.3 and 4.5 for SGLT2 inhibitors and sulfonylureas, respectively. In Cox proportional hazards regression models, the use of SGLT2 inhibitors was associated with a higher rate of diabetic ketoacidosis compared with DPP-4 inhibitors (adjusted HR [aHR] 1.63; 95% CI 1.36, 1.96) and sulfonylureas (aHR 1.56; 95% CI 1.30, 1.87). CONCLUSIONS: In this comparative safety study using real-world data, patients with type 2 diabetes who were newly prescribed SGLT2 inhibitors had a higher rate of diabetic ketoacidosis compared with DPP-4 inhibitors and sulfonylureas. Clinicians should be vigilant about this association.

Chronic Medication Nonadherence and Potentially Preventable Healthcare Utilization and Spending Among Medicare Patients.

BACKGROUND: The association between nonadherence to chronic medications and potentially preventable healthcare utilization and spending is largely unknown. OBJECTIVES: To 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. DESIGN: Retrospective cohort study. Medicare fee-for-service claims data from 2013 to 2016 for 177,881 patients. MEASURES: Medication 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. RESULTS: After 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. CONCLUSIONS: Improving medication adherence is a potential avenue to reducing preventable utilization and spending. Interventions are needed to address racial/ethnic and socioeconomic disparities.

Comparative Safety of Dipeptidyl Peptidase-4 Inhibitors and Sudden Cardiac Arrest and Ventricular Arrhythmia: Population-Based Cohort Studies.

In vivo studies suggest that arrhythmia risk may be greater with less selective dipeptidyl peptidase-4 inhibitors, but evidence from population-based studies is missing. We aimed to compare saxagliptin, sitagliptin, and linagliptin with regard to risk of sudden cardiac arrest (SCA)/ventricular arrhythmia (VA). We conducted high-dimensional propensity score (hdPS) matched, new-user cohort studies. We analyzed Medicaid and Optum Clinformatics separately. We identified new users of saxagliptin, sitagliptin (both databases), and linagliptin (Optum only). We defined SCA/VA outcomes using emergency department and inpatient diagnoses. We identified and then controlled for confounders via a data-adaptive, hdPS approach. We generated marginal hazard ratios (HRs) via Cox proportional hazards regression using a robust variance estimator while adjusting for calendar year. We identified the following matched comparisons: saxagliptin vs. sitagliptin (23,895 vs. 96,972) in Medicaid, saxagliptin vs. sitagliptin (48,388 vs. 117,383) in Optum, and linagliptin vs. sitagliptin (36,820 vs. 78,701) in Optum. In Medicaid, use of saxagliptin (vs. sitagliptin) was associated with an increased rate of SCA/VA (adjusted HR (aHR), 2.01, 95% confidence interval (CI) 1.24-3.25). However, in Optum data, this finding was not present (aHR, 0.79, 95% CI 0.41-1.51). Further, we found no association between linagliptin (vs. sitagliptin) and SCA/VA (aHR, 0.65, 95% CI 0.36-1.17). We found discordant results regarding the association between SCA/VA with saxagliptin compared with sitagliptin in two independent datasets. It remains unclear whether these findings are due to heterogeneity of treatment effect in the different populations, chance, or unmeasured confounding.

Angiotensin-Converting Enzyme Inhibitors Used Concomitantly with Insulin Secretagogues and the Risk of Serious Hypoglycemia.

Serious hypoglycemia is a major adverse event associated with insulin secretagogues. Previous studies have suggested a potential relationship between angiotensin-converting enzyme inhibitors (ACEIs) used with sulfonylureas and serious hypoglycemia, and widely used drug compendia warn of this potential drug-drug interaction. We investigated the association between serious hypoglycemia and concomitant use of ACEIs in patients receiving insulin secretagogues, using the self-controlled case series design and Medicaid claims data from 5 US states linked to Medicare claims from 1999-2011. The exposure of interest was active prescription for ACEIs during insulin secretagogue or metformin (negative control object drug) episodes. The outcome was hospital presentation for serious hypoglycemia, identified by discharge diagnosis codes in inpatient and emergency department claims (positive predictive value ~ 78-89%). We calculated confounder-adjusted rate ratios (RRs) and 95% confidence internals (CIs) of outcome occurrence during ACEI-exposed vs. ACEI-unexposed time using conditional Poisson regression. The RRs for ACEIs were not statistically elevated during observation time of glipizide (RR, 1.06; CI, 0.98-1.15), glyburide (RR, 1.05; CI, 0.96-1.15), repaglinide (RR, 1.15; CI, 0.94-1.41), or metformin (RR, 1.02; CI, 0.97-1.06); but was modestly elevated with glimepiride (RR, 1.23; CI, 1.11-1.37) and modestly reduced with nateglinide (RR, 0.73; CI, 0.56-0.96). The overall pattern of results do not suggest that ACEIs used with insulin secretagogues were associated with increased rates of serious hypoglycemia, with the possible exception of glimepiride.

Compared to commercially insured patients, Medicare advantage patients adopt newer diabetes drugs more slowly and adhere to them less.

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.

Clinical subphenotypes in COVID-19: derivation, validation, prediction, temporal patterns, and interaction with social determinants of health.

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.

Treating Alpelisib-Induced Hyperglycemia with Very Low Carbohydrate Diets and Sodium-Glucose Co-Transporter 2 Inhibitors: A Case Series.

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.

Trial of restarting and tolerating metformin (TreatMet).

This randomized, double-blind, placebo-controlled, n-of-1 crossover study assessed whether metformin's side effects are reproducible in patients with a history of metformin intolerance. Participants completed up to four cycles of 2 weeks of metformin exposure and 2 weeks of placebo exposure. Participants completed surveys based on the Gastrointestinal Symptom Rating Scale and the Treatment Satisfaction Questionnaire for Medication. The primary hypotheses were that treatment satisfaction would be equal for placebo and metformin and that more than 30% of the study enrollees would be able to adhere to a higher dose of metformin 6 months after participation. Thirteen patients (all women, mean age 52.4 years) enrolled, three of whom were lost to follow-up or were non-adherent to study protocol. Metformin was associated with significantly lower global treatment satisfaction scores compared with placebo (39.58 vs. 53.75, P < .05 ) but participants could not distinguish metformin from placebo and did not report higher rates of gastrointestinal side effects on metformin. Two out of 10 participants adhered to a higher dose of metformin after trial completion. Metformin appears to have barriers to use beyond its classic gastrointestinal side effects.