Risk of incident dementia following metformin initiation compared with noninitiation or delay of antidiabetic medication therapy.
Ontology highlight
ABSTRACT: Purpose
Emerging evidence suggests metformin compared with sulfonylurea is associated with an 8% to 10% lower risk for dementia. Guidelines recommend metformin as initial diabetes treatment, but there is still the question of treatment timing. Thus, the risk of dementia associated with initiating metformin compared with not initiating or delaying treatment was examined.Methods
A retrospective cohort study (1996 to 2015) was conducted with electronic health records from Veteran Health Affairs (VHA; n = 112 845) and Kaiser Permanente Washington (KPW; n = 14 333) healthcare systems. Patients were aged ≥50 years, had a hemoglobin A1c (HbA1c) between 6.5 and <9.5 mg/dL, and did not have dementia or fills for antidiabetic medications before cohort entry. Initiators started metformin monotherapy and noninitiators used no antidiabetic medications in the 6 months after the first qualifying HbA1c. The primary outcome was incident dementia. Propensity scores and inverse probability of treatment weighting (IPTW) controlled for confounding in Cox proportional hazards models.Results
During a median follow-up of 6.2 years in VHA and 6.8 years in KPW, there were 7547 new dementia cases in VHA and 1090 in KPW. After IPTW, there was no association between initiation of metformin (vs no initial treatment) and incident dementia in VHA (HR = 1.04; 95% confidence interval [CI]: 0.95-1.13) or KPW (HR = 0.81; 95% CI: 0.51-1.28). Results did not differ by age, baseline HbA1c, or race.Conclusions
Results do not support initiating metformin earlier to prevent cognitive decline and, thus, may dampen enthusiasm for metformin as a potential antidementia drug. Randomized clinical trials could help clarify the relationship between metformin and cognitive decline.
SUBMITTER: Salas J
PROVIDER: S-EPMC8457517 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:ObjectiveTo compare incident dementia risk among patients who initiated treatment with metformin or sulfonylurea in Veterans Health Affairs (VHA) patients with replication in Kaiser Permanente Washington (KPW) patients to determine whether first-choice antidiabetic medications are associated with reduced risk of dementia.Patients and methodsCohorts contained 75,187 VHA patients and 10,866 KPW patients, 50 years and older, who initiated monotherapy with metformin or sulfonylurea. Patients were free of dementia diagnoses and any diabetes treatment for 2 years before cohort entry. Variables were extracted from electronic health data from VHA (1999-2015) and KPW (1996-2015), which included diagnosis codes, pharmacy data, laboratory values, and demographic characteristics. Propensity scores and inverse probability of treatment weighting controlled for confounding.ResultsVeterans Health Affairs patients were 60.8±6.8 years of age on average, and KPW patients were 63.1±9.5 years of age. In the VHA sample, 72,769 (96.8%) were male; and in the KPW sample, 5480 (50.4%). After adjusting for confounding, metformin initiation was associated with a significantly (P=.02) lower risk of dementia in VHA (hazard ratio, 0.9; 95% CI, 0.9-1.0), with a similar point estimate in KPW (hazard ratio, 0.9; 95% CI, 0.7-1.1). Metformin was not associated with dementia risk in patients 75 years and older.ConclusionExisting epidemiological studies of metformin and incident dementia have been inconsistent. Using a similar study design in 2 patient populations that differed in clinical and demographic characteristics, our results provide robust evidence that metformin use is associated with a modestly lower risk of incident dementia.
| S-EPMC7029783 | biostudies-literature
Project description:Ibrutinib is associated with dramatic efficacy against B-cell malignancies. Yet, it has been linked with potentially limiting cardiotoxicity, including emerging reports of profound hypertension (HTN). The long-term incidence, severity, and impact of HTN development with ibrutinib are unknown. Therefore, in 562 consecutive patients treated with ibrutinib for B-cell malignancies from 2009 through 2016, we assessed the new/incident or worsened HTN (systolic blood pressure [BP] cutoff, 130 mm Hg). Observed incident HTN rates were compared with Framingham-heart-predicted incident HTN rates. We also evaluated the relationship of HTN to the development of other major adverse cardiovascular events (MACEs), including arrhythmia, myocardial infarction, stroke, heart failure, and cardiovascular death. Further, we assessed the effects of different antihypertensive classes on ibrutinib-related HTN. Overall, 78.3% of ibrutinib users developed new or worsened HTN over a median of 30 months. New HTN developed in 71.6% of ibrutinib users, with a time to 50% cumulative incidence of 4.2 months. Among those without preceding HTN, 17.7% developed high-grade HTN (BP >160/100 mm Hg). In multivariate regression, new or worsened HTN was associated with increased MACEs (hazard ratio [HR], 2.17; 95% confidence interval [CI], 1.08-4.38). No single antihypertensive class was associated with prevention or control of ibrutinib-related HTN. However, antihypertensive initiation was associated with a lower risk of a MACE (HR, 0.40; 95% CI, 0.24-0.66). Collectively, these data suggest that ibrutinib is associated with a substantial increase in the incidence and severity of HTN, and that HTN development carries a higher risk of subsequent cardiotoxic events.
| S-EPMC6887116 | biostudies-literature
Project description:BackgroundStudies suggest that anticholinergic medication or benzodiazepine use could increase dementia risk. We tested this hypothesis using data from a UK cohort study.MethodsWe used data from the baseline (Y0), 2-year (Y2) and 10-year (Y10) waves of the Medical Research Council Cognitive Function and Ageing Study. Participants without dementia at Y2 were included (n = 8216). Use of benzodiazepines (including nonbenzodiazepine Z-drugs), anticholinergics with score 3 (ACB3) and anticholinergics with score 1 or 2 (ACB12) according to the Anticholinergic Cognitive Burden scale were coded as ever use (use at Y0 or Y2), recurrent use (Y0 and Y2), new use (Y2, but not Y0) or discontinued use (Y0, but not Y2). The outcome was incident dementia by Y10. Incidence rate ratios (IRR) were estimated using Poisson regression adjusted for potential confounders. Pre-planned subgroup analyses were conducted by age, sex and Y2 Mini-Mental State Examination (MMSE) score.ResultsDementia incidence was 9.3% (N = 220 cases) between Y2 and Y10. The adjusted IRRs (95%CI) of developing dementia were 1.06 (0.72, 1.60), 1.28 (0.82, 2.00) and 0.89 (0.68, 1.17) for benzodiazepines, ACB3 and ACB12 ever-users compared with non-users. For recurrent users the respective IRRs were 1.30 (0.79, 2.14), 1.68 (1.00, 2.82) and 0.95 (0.71, 1.28). ACB3 ever-use was associated with dementia among those with Y2 MMSE> 25 (IRR = 2.28 [1.32-3.92]), but not if Y2 MMSE≤25 (IRR = 0.94 [0.51-1.73]).ConclusionsNeither benzodiazepines nor ACB12 medications were associated with dementia. Recurrent use of ACB3 anticholinergics was associated with dementia, particularly in those with good baseline cognitive function. The long-term prescribing of anticholinergics should be avoided in older people.
| S-EPMC6802337 | biostudies-literature
Project description:BackgroundAnticholinergic medications may increase risk of dementia and stroke, but prospective studies in healthy older people are lacking.ObjectiveCompare risk of incident dementia and stroke by anticholinergic burden among initially healthy older people.DesignProspective cohort study.SettingPrimary care (Australia and USA).Participants19,114 community-dwelling participants recruited for the ASPREE trial, aged 70+ years (65+ if US minorities) without major cardiovascular disease, dementia diagnosis, or Modified Mini-Mental State Examination score below 78/100.MeasurementsBaseline anticholinergic exposure was calculated using the Anticholinergic Cognitive Burden (ACB) score. Dementia was adjudicated using Diagnostic and Statistical Manual of Mental Disorders volume IV criteria, and stroke using the World Health Organization definition.ResultsAt baseline, 15,000 participants (79%) had an ACB score of zero, 2930 (15%) a score of 1-2, and 1184 (6%) a score of ≥ 3 (indicating higher burden). After a median follow-up of 4.7 years and adjusting for baseline covariates, a baseline ACB score of ≥ 3 was associated with increased risk of ischemic stroke (adjusted HR 1.58, 95% CI 1.06, 2.35), or dementia (adjusted HR 1.36, 95% CI 1.01, 1.82), especially of mixed etiology (adjusted HR 1.53, 95% CI 1.06, 2.21). Results were similar for those exposed to moderate/highly anticholinergic medications.LimitationsResidual confounding and reverse causality are possible. Assessment of dose or duration was not possible.ConclusionsHigh anticholinergic burden in initially healthy older people was associated with increased risk of incident dementia and ischemic stroke. A vascular effect may underlie this association. These findings highlight the importance of minimizing anticholinergic exposure in healthy older people.
| S-EPMC8175463 | biostudies-literature
Project description:Background Post-market analyses revealed unanticipated links between first-generation Bruton’s tyrosine kinase inhibitor (BTKi) therapy, ibrutinib, and profound early hypertension. Yet, whether this is seen with novel selective second (next)-generation BTKi therapy, acalabrutinib, is unknown. Methods Leveraging a large cohort of consecutive B cell cancer patients treated with acalabrutinib from 2014 to 2020, we assessed the incidence and ramifications of new or worsened hypertension [systolic blood pressure (SBP) ≥ 130 mmHg] after acalabrutinib initiation. Secondary endpoints were major cardiovascular events (MACE: arrhythmias, myocardial infarction, stroke, heart failure, cardiac death) and disease progression. Observed incident hypertension rates were compared to Framingham heart-predicted and ibrutinib-related rates. Multivariable regression and survival analysis were used to define factors associated with new/worsened hypertension and MACE, and the relationship between early SBP increase and MACE risk. Further, the effect of standard antihypertensive classes on the prevention of acalabrutinib-related hypertension was assessed. Results Overall, from 280 acalabrutinib-treated patients, 48.9% developed new/worsened hypertension over a median of 41 months. The cumulative incidence of new hypertension by 1 year was 53.9%, including 1.7% with high-grade (≥ 3) hypertension. Applying the JNC 8 cutoff BP of ≥ 140/90 mmHg, the observed new hypertension rate was 20.5% at 1 year, > eightfold higher than the Framingham-predicted rate of 2.4% (RR 8.5, P < 0.001), yet 34.1% lower than ibrutinib (12.9 observed-to-expected ratio, P < 0.001). In multivariable regression, prior arrhythmias and Black ancestry were associated with new hypertension (HR 1.63, HR 4.35, P < 0.05). The degree of SBP rise within 1 year of treatment initiation predicted MACE risk (42% HR increase for each + 5 mmHg SBP rise, P < 0.001). No single antihypertensive class prevented worsened acalabrutinib-related hypertension. Conclusions Collectively, these data suggest that hypertension may be a class effect of BTKi therapies and precedes major cardiotoxic events. Supplementary Information The online version contains supplementary material available at 10.1186/s13045-022-01302-7.
| S-EPMC9281099 | biostudies-literature
Project description:The use of all-trans retinoic acid (ATRA) combined with arsenic trioxide (ATO) with or without cytotoxic chemotherapy is highly effective in acute promyelocytic leukemia (APL) but incident chronic adverse events (AEs) after initiation of therapy are not well understood. We retrospectively analyzed adult patients with newly diagnosed APL from 2004 through 2014 to identify incident AEs following treatment and contributing risk factors. Cardiac and neurologic AEs were more common and characterized in detail. Cardiac AEs such as the development of coronary artery disease (CAD), arrhythmias, and heart failure had a cumulative incidence of 6.4% (CI95 1.8-11.1%), 2.9% (CI95 0.0-6.4%), 5.8% (CI95 1.2-10.3%) at 4 years from diagnosis, respectively. In multivariate analyses of factors influencing heart failure, the presence of clinical or radiographic CAD (HR 4.25; P?=?0.011) or troponin elevation prior to completion of therapy (HR 8.86; P?=?0.0018) were associated with increased heart failure incidence, but not anthracycline use or dose. Neurological AEs were common following therapy; at 4 years, the cumulative incidence of vision changes was 12.4% (CI95 6.0-18.7%), peripheral neuropathy 10.3% (CI95 4.5-16.1%), and memory or cognitive change 7.6% (CI95 2.5-12.7%). We did not identify any association between specific therapies and the development of cardiac and neurologic AEs. APL is a highly curable leukemia; further efforts are needed to address incident chronic AEs, with particular focus on cardiac and neurological care.
| S-EPMC5993355 | biostudies-literature
Project description:IntroductionHIV and antiretroviral therapy (ART) have been associated with increased cardiovascular disease and important changes in lipid metabolism. Advances in mass-spectrometry technology allow for the detailed assessment of individual lipid species which may illuminate the mechanisms underlying increased cardiovascular risk. We describe the change in plasma lipidome with initiation of antiretroviral therapy and compare these by regimen.MethodsPlasma lipid profiling (by electrospray isonisation-tandem mass spectrometry) was performed on ARV-naive HIV positive participants randomised to one of three regimens; tenofovir/emtricitabine with efavirenz, ritonavir-boosted atazanavir (atazanavir/r) or zidovudine/abacavir. Participants (n = 115) who remained on their randomised regimen with complete samples available at baseline, week 12 and 48 were included. 306 lipid species from 22 lipid classes were analysed.ResultsInitiation of ART led to significant changes in lipidome which were partly dependent on the randomised regimen received. This led to significant differences in 72 lipid species and 7 classes (cholesterol ester, free cholesterol, phosphatidylcholine, GM3 ganglioside, trihexosylceramide, monohexosylceramide, and ceramides) by arm at week 48. Consistently higher lipid concentrations were seen with efavirenz compared with atazanavir/r or zidovudine/abacavir. Twelve of the lipid species and two lipid classes (cholesterol esters and ceramides) that were significantly increased in the efavirenz arm compared with the atazanavir/r or zidovudine/abacavir arms have previously been associated with future cardiovascular events in HIV positive patients. Change in HIV viral load was predictive of change in 3 lipid species.ConclusionsInitiation of ART lead to significant changes in the plasma lipidome that were greatest in those receiving efavirenz.
| S-EPMC6114786 | biostudies-literature
Project description:AIMS:Type 2 diabetes mellitus (DM2) affects 10% of the population, but little is known about how DM2 and antidiabetic medication impact glioblastoma (GBM) patients. PATIENTS & METHODS:We retrospectively reviewed GBM patients with DM2 seen at a single institution from 1998 to 2010. RESULTS:Of 988 GBMs, 124 (12.6%) were affected by DM2. Thirty-four developed DM2 after steroid use and 89 had pre-existing DM2. Median overall survival among diabetic GBMs was 10 months compared with 13 months among nondiabetics. Only 15% of diabetic patients achieved sustained steroid taper. Sixty-seven (54%) were managed with a single antidiabetic medication and, within this monotherapy group, Karnofsky Performance Score, resection status, steroid dependency and metformin use were the most important predictors of survival on multivariate analysis. CONCLUSION:The prevalence of DM2 among GBMs is similar to that of the general population. A more aggressive approach to steroid tapering and the choice of antidiabetic drug may improve survival within this patient population.
| S-EPMC6166491 | biostudies-literature
Project description:ImportancePrior 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.ObjectiveTo investigate the association of terminating metformin treatment for reasons unrelated to kidney dysfunction with dementia incidence.Design, setting, and participantsThis 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.ExposuresA 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 measuresThe 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.ResultsThe 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 relevanceIn 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.
| S-EPMC10600586 | biostudies-literature
Project description:ObjectiveThe use of electroconvulsive therapy (ECT) in the treatment of bipolar disorder (BD) remains poorly described. Based on data from Danish registries with complete nationwide coverage, this study of patients with incident BD aimed to describe when, how, and for whom ECT is used in the context of BD.MethodsWe identified patients receiving their first diagnosis of BD in the period from 2008 to 2018, who subsequently received ECT. Descriptive statistics were used to clarify when, how, and for whom ECT is used.ResultsWe identified 1338 patients with incident BD who subsequently received ECT. The median age at the first ECT session was 50.6 years (interquartile range [IQR]: 26.4), and 62% of those treated with ECT were female. The median time from the diagnosis of BD to the first ECT treatment was 0.6 years (IQR: 2.6), and 58% of the patients receiving ECT had the first treatment within the first year after being diagnosed with BD. The most common indication for the first ECT treatment was depression (mainly non-psychotic depression), followed by mania (mainly psychotic mania). The first ECT session was typically provided to inpatients (97%), upon patient consent (98%) and with bilateral electrode placement (60%).ConclusionsA substantial proportion of the patients with incident BD who receive ECT require this treatment within the first year after the diagnosis. The most common indication for ECT is depression followed by (psychotic) mania. Inpatient voluntary ECT using bilateral electrode placement is the most common form of administration.
| S-EPMC10087321 | biostudies-literature