Metformin Cessation and Dementia Incidence.

Importance: Prior studies suggested that metformin may be associated with reduced dementia incidence, but associations may be confounded by disease severity and prescribing trends. Cessation of metformin therapy in people with diabetes typically occurs due to signs of kidney dysfunction but sometimes is due to less serious adverse effects associated with metformin. Objective: To investigate the association of terminating metformin treatment for reasons unrelated to kidney dysfunction with dementia incidence. Design, Setting, and Participants: This cohort study was conducted at Kaiser Permanente Northern California, a large integrated health care delivery system, among a cohort of metformin users born prior to 1955 without history of diagnosed kidney disease at metformin initiation. Dementia follow-up began with the implementation of electronic health records in 1996 and continued to 2020. Data were analyzed from November 2021 through September 2023. Exposures: A total of 12 220 early terminators, individuals who stopped metformin with normal estimated glomerular filtration rate (eGFR), were compared with routine metformin users, who had not yet terminated metformin treatment or had terminated (with or without restarting) after their first abnormal eGFR measurement. Early terminators were matched with routine users of the same age and gender who had diabetes for the same duration. Main outcomes and measures: The outcome of interest was all-cause incident dementia. Follow-up for early terminators and their matched routine users was started at age of termination for the early terminator. Survival models adjusted for sociodemographic characteristics and comorbidities at the time of metformin termination (or matched age). Mediation models with HbA1c level and insulin usage 1 and 5 years after termination tested whether changes in blood glucose or insulin usage explained associations between early termination of metformin and dementia incidence. Results: The final analytic sample consisted of 12 220 early terminators (5640 women [46.2%]; mean [SD] age at start of first metformin prescription, 59.4 [9.0] years) and 29 126 routine users (13 582 women [46.6%]; mean [SD] age at start of first metformin prescription, 61.1 [8.9] years). Early terminators had 1.21 times the hazard of dementia diagnosis compared with routine users (hazard ratio, 1.21; 95% CI, 1.12 to 1.30). In mediation analysis, contributions to this association by changes in HbA1c level or insulin use ranged from no contribution (0.00 years; 95% CI, -0.02 to 0.02 years) for insulin use at 5 years after termination to 0.07 years (95% CI, 0.02 to 0.13 years) for HbA1c level at 1 year after termination, suggesting that the association was largely independent of changes in HbA1c level and insulin usage. Conclusions and Relevance: In this study, terminating metformin treatment was associated with increased dementia incidence. This finding may have important implications for clinical treatment of adults with diabetes and provides additional evidence that metformin is associated with reduced dementia risk.

Development and application of an algorithm for statin-induced myopathy based on electronic health record-derived structured elements.

Objective: Considering the non-specific nature of muscle symptoms, studies of statin-induced myopathy (SIM) in electronic health records require accurate algortihms that can reliably identify true statin-related cases. However, prior algorithms have been constructed in study populations that preclude broad applicability. Here we developed and validated an algorithm that accurately defines SIM from electronic health records using structured data elements and conducted a study of determinants of SIM after applying the algorithm. Materials and Methods: We used electronic records from an integrated health care delivery system (including comprehensive pharmacy dispensing records) and defined SIM as elevated creatine kinase (CK) ≥4 x upper limit of normal. A diverse cohort of participants receiving a variety of statin regimens met the criteria for study inclusion. Results: We identified multiple conditions strongly associated with elevated CK independent of statin use. A 2-step algorithm was developed using these all-cause conditions as secondary causes (step 1) along with evidence of a statin regimen change (step 2). We identified 1,262 algorithm-derived statin-induced elevated CK cases. Gold standard SIM cases determined from manual chart reviews on a random subset of the all-cause elevated CK cases were used to validate the algorithm, which had a 76% sensitivity and 77% specificity for detecting the most certain cases. Pravastatin use was associated with a 2.18 odds (95% confidence interval 1.39-3.40, P=0.0007) for statin-induced CK elevation compared to lovastatin use after adjusting for dose and other factors. Conclusions: We have produced an efficient, easy-to-apply methodological tool that can improve the quality of future research on statin-induced myopathy.

Torsade de pointes: A nested case-control study in an integrated healthcare delivery system.

BACKGROUND: TdP is a form of polymorphic ventricular tachycardia which develops in the setting of a prolonged QT interval. There are limited data describing risk factors, treatment, and outcomes of this potentially fatal arrhythmia. OBJECTIVE: Our goals were as follows: (1) to validate cases presenting with Torsade de Pointes (TdP), (2) to identify modifiable risk factors, and (3) to describe the management strategies used for TdP and its prognosis in a real-world healthcare setting. METHODS: Case-control study (with 2:1 matching on age, sex, and race/ethnicity) nested within the Genetic Epidemiology Research on Aging (GERA) cohort. Follow-up of the cohort for case ascertainment was between January 01, 2005 and December 31, 2018. RESULTS: A total of 56 cases of TdP were confirmed (incidence rate = 3.6 per 100,000 persons/years). The average (SD) age of the TdP cases was 74 (13) years, 55 percent were female, and 16 percent were non-white. The independent predictors of TdP were potassium concentration <3.6 mEq/L (OR = 10.6), prior history of atrial fibrillation/flutter (OR = 6.2), QTc >480 ms (OR = 4.4) and prior history of coronary artery disease (OR = 2.6). Exposure to furosemide and amiodarone was significantly greater in cases than in controls. The most common treatment for TdP was IV magnesium (78.6%) and IV potassium repletion (73.2%). The in-hospital and 1-year mortality rates for TdP cases were 10.7% and 25.0% percent, respectively. CONCLUSIONS: These findings may inform quantitative multivariate risk indices for the prediction of TdP and could guide practitioners on which patients may qualify for continuous ECG monitoring and/or electrolyte replacement therapy.

QT Interval Dynamics and Cardiovascular Outcomes: A Cohort Study in an Integrated Health Care Delivery System.

Background Long QT has been associated with ventricular dysrhythmias, cardiovascular disease (CVD) mortality, and sudden cardiac death. However, no studies to date have investigated the dynamics of within-person QT change over time in relation to risk of incident CVD and all-cause mortality in a real-world setting. Methods and Results A cohort study among members of an integrated health care delivery system in Northern California including 61 455 people (mean age, 62 years; 60% women, 42% non-White) with 3 or more ECGs (baseline in 2005-2009; mean±SD follow-up time, 7.6±2.6 years). In fully adjusted models, tertile 3 versus tertile 1 of average QT corrected (using the Fridericia correction) was associated with cardiac arrest (hazard ratio [HR], 1.66), heart failure (HR, 1.62), ventricular dysrhythmias (HR, 1.56), all CVD (HR, 1.31), ischemic heart disease (HR, 1.28), total stroke (HR, 1.18), and all-cause mortality (HR, 1.24). Tertile 3 versus tertile 2 of the QT corrected linear slope was associated with cardiac arrest (HR, 1.22), ventricular dysrhythmias (HR, 1.12), and all-cause mortality (HR, 1.09). Tertile 3 versus tertile 1 of the QT corrected root mean squared error was associated with ventricular dysrhythmias (HR, 1.34), heart failure (HR, 1.28), all-cause mortality (HR, 1.20), all CVD (HR, 1.14), total stroke (HR, 1.08), and ischemic heart disease (HR, 1.07). Conclusions Our results demonstrate improved predictive ability for CVD outcomes using longitudinal information from serial ECGs. Long-term average QT corrected was more strongly associated with CVD outcomes than the linear slope or the root mean squared error. This new evidence is clinically relevant because ECGs are frequently used, noninvasive, and inexpensive.

Assessing the clinical impact of CYP2C9 pharmacogenetic variation on phenytoin prescribing practice and patient response in an integrated health system.

OBJECTIVE: To assess the impact of CYP2C9 variation on phenytoin patient response and clinician prescribing practice where genotype was unknown during treatment. METHODS: A retrospective analysis of Resource on Genetic Epidemiology Research on Adult Health and Aging cohort participants who filled a phenytoin prescription between 1996 and 2017. We used laboratory test results, medication dispensing records, and medical notes to identify associations of CYP2C9 genotype with phenytoin blood concentration, neurologic side effects, and medication dispensing patterns reflecting clinician prescribing practice and patient response. RESULTS: Among 993 participants, we identified 69% extensive, 20% high-intermediate, 10% low-intermediate, and 2% poor metabolizers based on CYP2C9 genotypes. Compared with extensive metabolizer genotype, low-intermediate/poor metabolizer genotype was associated with increased dose-adjusted phenytoin blood concentration [21.3 pg/mL, 95% confidence interval (CI): 13.6-29.0 pg/mL; P < 0.01] and increased risk of neurologic side effects (hazard ratio: 2.40, 95% CI: 1.24-4.64; P < 0.01). Decreased function CYP2C9 genotypes were associated with medication dispensing patterns indicating dose decrease, use of alternative anticonvulsants, and worse adherence, although these associations varied by treatment indication for phenytoin. CONCLUSION: CYP2C9 variation was associated with clinically meaningful differences in clinician prescribing practice and patient response, with potential implications for healthcare utilization and treatment efficacy.