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.

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.

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.

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.

The risk of sudden cardiac arrest and ventricular arrhythmia with rosiglitazone versus pioglitazone: real-world evidence on thiazolidinedione safety.

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.

Twelve-year trends in pharmacologic treatment of type 2 diabetes among patients with heart failure in the United States.

We conducted a cross-sectional analysis using a database from commercial health plans in the United States to describe trends in the use of antidiabetic medications among patients with type 2 diabetes and heart failure (HF) from 2006 through 2017. We used loop diuretic dose as a surrogate for HF severity (mild HF 0-40 mg/day, moderate-severe HF >40 mg/day). We assessed antidiabetic medication dispensing in the 90 days following HF diagnosis. Over the 12-year period, we identified an increase in the use of metformin (39.2% vs. 62.6%), dipeptidyl peptidase-4 inhibitors (DPP-4i) (0.5% vs. 17.1%) and sodium-glucose co-transporter-2 inhibitors (SGLT-2i) (0.0% vs. 9.0%), but a decrease in the use of sulphonylureas (47.8% vs. 27.8%) and thiazolidinediones (TZDs) (31.7% vs. 5.3%). In 2017, patients with moderate-severe HF more commonly used insulin (43.1%); a majority of mild HF patients used metformin (62.8%). A proportion of patients with moderate-severe HF used TZDs (4.4%). Among patients with diabetes and HF, the use of metformin and DPP-4i rapidly increased, but a proportion of patients with moderate-severe HF continued to use TZDs. Despite their promising cardiovascular safety profile, SGLT-2i use remains limited.

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.

Comparative risk of serious hypoglycemia with oral antidiabetic monotherapy: A retrospective cohort study.

PURPOSE: To examine and compare risks of serious hypoglycemia among antidiabetic monotherapy-treated adults receiving metformin, a sulfonylurea, a meglitinide, or a thiazolidinedione. METHODS: We performed a retrospective cohort study of apparently new users of monotherapy with metformin, glimepiride, glipizide, glyburide, pioglitazone, rosiglitazone, nateglinide, or repaglinide within a dataset of Medicaid beneficiaries from California, Florida, New York, Ohio, and Pennsylvania. We did not include users of dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 agonists, or sodium-glucose co-transporter 2 inhibitors. We identified serious hypoglycemia outcomes within 180 days following new use using a validated, diagnosis-based algorithm. We calculated age- and sex-standardized outcome occurrence rates for each drug and generated propensity score-adjusted hazard ratios vs metformin using Cox proportional hazards regression. RESULTS: The ranking of standardized occurrence rates of serious hypoglycemia was glyburide > glimepiride > glipizide > repaglinide > nateglinide > rosiglitazone > pioglitazone > metformin. Rates were increased for all study drugs at higher average daily doses. Adjusted hazard ratios (95% confidence intervals) vs metformin were 3.95 (3.66-4.26) for glyburide, 3.28 (2.98-3.62) for glimepiride, 2.57 (2.38-2.78) for glipizide, 2.03 (1.64-2.52) for repaglinide, 1.21 (0.89-1.66) for nateglinide, 0.90 (0.75-1.07) for rosiglitazone, and 0.80 (0.68-0.93) for pioglitazone. CONCLUSIONS: Sulfonylureas were associated with the highest rates of serious hypoglycemia. Among all study drugs, the highest rate was seen with glyburide. Pioglitazone was associated with a lower adjusted hazard for serious hypoglycemia vs metformin, while rosiglitazone and nateglinide had hazards similar to that of metformin.

Instrumental Variable Methods for Continuous Outcomes That Accommodate Nonignorable Missing Baseline Values.

Instrumental variable (IV) methods provide unbiased treatment effect estimation in the presence of unmeasured confounders under certain assumptions. To provide valid estimates of treatment effect, treatment effect confounders that are associated with the IV (IV-confounders) must be included in the analysis, and not including observations with missing values may lead to bias. Missing covariate data are particularly problematic when the probability that a value is missing is related to the value itself, which is known as nonignorable missingness. In such cases, imputation-based methods are biased. Using health-care provider preference as an IV method, we propose a 2-step procedure with which to estimate a valid treatment effect in the presence of baseline variables with nonignorable missing values. First, the provider preference IV value is estimated by performing a complete-case analysis using a random-effects model that includes IV-confounders. Second, the treatment effect is estimated using a 2-stage least squares IV approach that excludes IV-confounders with missing values. Simulation results are presented, and the method is applied to an analysis comparing the effects of sulfonylureas versus metformin on body mass index, where the variables baseline body mass index and glycosylated hemoglobin have missing values. Our result supports the association of sulfonylureas with weight gain.

A tutorial on the use of instrumental variables in pharmacoepidemiology.

PURPOSE: Instrumental variable (IV) methods are used increasingly in pharmacoepidemiology to address unmeasured confounding. In this tutorial, we review the steps used in IV analyses and the underlying assumptions. We also present methods to assess the validity of those assumptions and describe sensitivity analysis to examine the effects of possible violations of those assumptions. METHODS: Observational studies based on regression or propensity score analyses rely on the untestable assumption that there are no unmeasured confounders. IV analysis is a tool that removes the bias caused by unmeasured confounding provided that key assumptions (some of which are also untestable) are met. RESULTS: When instruments are valid, IV methods provided unbiased treatment effect estimation in the presence of unmeasured confounders. However, the standard error of the IV estimate is higher than the standard error of non-IV estimates, e.g., regression and propensity score methods. Sensitivity analyses provided insight about the robustness of the IV results to the plausible degrees of violation of assumptions. CONCLUSIONS: IV analysis should be used cautiously because the validity of IV estimates relies on assumptions that are, in general, untestable and difficult to be certain about. Thus, assessing the sensitivity of the estimate to violations of these assumptions is important and can better inform the causal inferences that can be drawn from the study. Copyright © 2017 John Wiley & Sons, Ltd.

Proposals to Conduct Randomized Controlled Trials Without Informed Consent: a Narrative Review.

BACKGROUND: Individual informed consent from all participants is required for most randomized clinical trials (RCTs). However, some exceptions-for example, emergency research-are widely accepted. METHODS: The literature on various approaches to randomization without consent (RWOC) has never been systematically reviewed. Our goal was to provide a survey and narrative synthesis of published proposals for RWOC. We focused on proposals to randomize at least some participants in a study without first obtaining consent to randomization. This definition included studies that omitted informed consent entirely, omitted informed consent for selected patients (e.g., the control group), obtained informed consent to research but not to randomization, or only obtained informed consent to randomization after random assignment had already occurred. It omitted oral and staged consent processes that still obtain consent to randomization from all participants before randomization occurs. RESULTS: We identified ten different proposals for RWOC: two variants of cluster randomization, two variants of the Zelen design, consent to postponed information, two-stage randomized consent, cohort multiple RCT, emergency research, prompted optional randomization trials, and low-risk pragmatic RCTs without consent. CONCLUSION: Of all designs discussed here, only cluster randomized designs and emergency research are routinely used, with the justification that informed consent is infeasible in those settings. Other designs have raised concerns that they do not appropriately respect patient autonomy. Recent proposals have emphasized the importance for RWOC of demonstrating such respect through systematic patient engagement, transparency, and accountability, potentially in the context of learning health care systems.

Novel Anti-glycemic Drugs and Reduction of Cardiovascular Risk in Diabetes: Expectations Realized, Promises Unmet.

PURPOSE OF REVIEW: The purpose is to review evidence on cardiovascular risks and benefits of new treatments for type 2 diabetes mellitus. RECENT FINDINGS: In response to guidance issued by the Food and Drug Administration, thousands of patients have been enrolled in large randomized trials evaluating the cardiovascular effects of the three newest diabetes drug classes: glucagon-like peptide-1 (GLP-1) receptor agonists, sodium glucose cotransporter 2 (SGLT-2) inhibitors, and dipeptidyl peptidase-4 (DPP-4) inhibitors. Two studies of GLP-1 receptor agonists-one of liraglutide and one of semaglutide-have shown cardiovascular benefit relative to placebo, and one study of the SGLT-2 inhibitor empagliflozin has shown benefit. The other published cardiovascular outcome studies of the newest drug classes have generally supported safety, apart from an as-yet unresolved safety concern about increased rates of heart failure with DPP-4 inhibitors. Recent research suggests the thiazolidinedione pioglitazone may have beneficial effects on some cardiovascular outcomes as well, but these are counterbalanced by a known increase of the risk of heart failure with this drug. In general, more prospective randomized trial data is now available regarding the cardiovascular effects of the newer diabetes drugs than on the older drug classes. New evidence suggests that the newest diabetes drugs are safe from a cardiovascular perspective. Evidence on benefit from at least some members of the GLP-1 receptor agonist and SGLT-2 inhibitor classes is encouraging but not yet decisive.

The Large Language Model GPT-4 Compared to Endocrinologist Responses on Initial Choice of Antidiabetic Medication under Conditions of Clinical Uncertainty.

OBJECTIVE: To explore how the commercially available large language model (LLM) GPT-4 compares to endocrinologists when addressing medical questions when there is uncertainty regarding the best answer. RESEARCH DESIGN AND METHODS: This study compared responses from GPT-4 to responses from 31 endocrinologists using hypothetical clinical vignettes focused on diabetes, specifically examining the prescription of metformin versus alternative treatments. The primary outcome was the choice between metformin and other treatments. RESULTS: With a simple prompt, GPT-4 chose metformin in 12% (95% CI 7.9-17%) of responses, compared with 31% (95% CI 23-39%) of endocrinologist responses. After modifying the prompt to encourage metformin use, the selection of metformin by GPT-4 increased to 25% (95% CI 22-28%). GPT-4 rarely selected metformin in patients with impaired kidney function, or a history of gastrointestinal distress (2.9% of responses, 95% CI 1.4-5.5%). In contrast, endocrinologists often prescribed metformin even in patients with a history of gastrointestinal distress (21% of responses, 95% CI 12-36%). GPT-4 responses showed low variability on repeated runs except at intermediate levels of kidney function. CONCLUSIONS: In clinical scenarios with no single right answer, GPT-4's responses were reasonable, but differed from endocrinologists' responses in clinically important ways. Value judgments are needed to determine when these differences should be addressed by adjusting the model. We recommend against reliance on LLM output until it is shown to align not just with clinical guidelines but also with patient and clinician preferences, or it demonstrates improvement in clinical outcomes over standard of care.

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.

Strong synaptic transmission impact by copy number variations in schizophrenia.

Schizophrenia is a psychiatric disorder with onset in late adolescence and unclear etiology characterized by both positive and negative symptoms, as well as cognitive deficits. To identify copy number variations (CNVs) that increase the risk of schizophrenia, we performed a whole-genome CNV analysis on a cohort of 977 schizophrenia cases and 2,000 healthy adults of European ancestry who were genotyped with 1.7 million probes. Positive findings were evaluated in an independent cohort of 758 schizophrenia cases and 1,485 controls. The Gene Ontology synaptic transmission family of genes was notably enriched for CNVs in the cases (P = 1.5 x 10(-7)). Among these, CACNA1B and DOC2A, both calcium-signaling genes responsible for neuronal excitation, were deleted in 16 cases and duplicated in 10 cases, respectively. In addition, RET and RIT2, both ras-related genes important for neural crest development, were significantly affected by CNVs. RET deletion was exclusive to seven cases, and RIT2 deletions were overrepresented common variant CNVs in the schizophrenia cases. Our results suggest that novel variations involving the processes of synaptic transmission contribute to the genetic susceptibility of schizophrenia.