Background: Risk of severe hypoglycemia increases markedly with age in type 2 diabetes (T2D) . For many older patients, discussion of safe de-prescribing strategies is indicated to reduce iatrogenic ...overtreatment. We examined differences in insulin and sulfonylurea (SU) prescription prevalence among older adults (age ≥ 75 years) by race/ethnicity. Because race/ethnic disparities among Black patients have been attributed to doctor-patient communication barriers, we tested the hypothesis that older Black patients were more likely to be prescribed medicines that can induce severe hypoglycemia.
Methods: We studied 18,149 adults (≥75 years) with T2D and a last measured HbA1c ≤ 8.0% between 2019-2021 in Kaiser Permanente Northern California. Electronic health records were used to identify prescription of insulin, SUs, or both. Medication treatment prevalence was stratified by race/ethnicity (Non-Latino White NLW, Black, Latino, Asian, Other) and compared using chi-square tests.
Results: Mean age was 80.5 (±4.8) years; 54% were women; mean HbA1c was 6.9% (±0.7%) , with 42% prescribed insulin, 72% prescribed SUs and 13% prescribed both. Elderly Black and NLW patients had a higher insulin prevalence (both at 45%, p<0.001) , while Asians had the lowest (31%, p=<0.001) . Conversely, Blacks had the lowest SU prevalence (66%, p<0.001) , and Asians had the highest (79%, p<0.001) . A similar pattern was observed in patients with the tightest HbA1c control (< 7.0%; n=8,794) : Black patients had the highest insulin (39%, p<0.001) and lowest SU prevalence (69% p<0.001) , while Asians had the lowest insulin (26%, p<0.001) and highest SU prevalence (81%, p<0.001) .
Conclusion We found significant variation in use of high-risk medicines by race/ethnicity. Older Black patients had higher insulin use while older Asian patients had the highest SU use. Efforts to promote safe de-prescribing practices in older adults may need to be tailored to the unique physiologic and cultural needs of different patient groups.
Disclosure
D.Abdelgadir: None. C.Board: None. D.K.Ranatunga: None. R.W.Grant: None.
Funding
National Institute on Aging (R01AG068133-S1)
Genetic substudies of randomized controlled trials demonstrate that high coronary heart disease (CHD) polygenic risk score modifies statin CHD relative risk reduction; it is unknown if the ...association extends to statin users undergoing routine care. We sought to determine how statin effectiveness is modified by CHD polygenic risk score in a real‐world cohort of participants without previous myocardial infarction. We determined CHD polygenic risk scores in participants of the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. Covariate‐adjusted Cox regression models were used to compare the risk of cardiovascular outcomes between statin users and matched nonusers. Statin effectiveness on incident myocardial infarction showed no gradient with increasing 10‐year Pooled Cohort Equations atherosclerotic cardiovascular disease (ASCVD) risk across low, borderline, intermediate, and high ASCVD risk score groups. In contrast, statin effectiveness by polygenic risk was largest in the high polygenic risk score group (hazard ratio (HR) 0.41, 95% confidence interval (CI), 0.31–0.53; P = 1.5E‐11), intermediate in the intermediate polygenic risk score group (HR 0.56, 95% CI, 0.47–0.66; P = 8.4E‐12), and smallest in the low polygenic risk score group (HR 0.67, 95% CI, 0.47–0.97; P = 0.03; P for high vs. low = 0.01). ASCVD risk and statin low‐density lipoprotein cholesterol (LDL‐C) lowering did not differ across polygenic risk score groups. In patients undergoing routine care, CHD polygenic risk modified statin relative risk reduction of incident myocardial infarction independent of LDL‐C lowering. Our findings extend prior work by identifying a subset (i.e., self‐identified White individuals with low CHD polygenic risk scores) with attenuated clinical benefit from statins.
To assess the impact of CYP2C9 variation on phenytoin patient response and clinician prescribing practice where genotype was unknown during treatment.
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.
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.
CYP2C9 variation was associated with clinically meaningful differences in clinician prescribing practice and patient response, with potential implications for healthcare utilization and treatment efficacy.
The role of cytochrome P450 (CYP)2C9 and CYP2C19 genetic variation in risk for phenytoin‐induced cutaneous adverse drug events is not well understood independently of the human leukocyte antigen B ...(HLA‐B)*15:02 risk allele. In the multi‐ethnic resource for Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort, we identified 382 participants who filled a phenytoin prescription between 2005 and 2017. These participants included 21 people (5%) who self‐identified as Asian, 18 (5%) as black, 29 (8%) as white Hispanic, and 308 (81%) as white non‐Hispanic. We identified 264 (69%) CYP2C9*1/*1, 77 (20%) CYP2C9*1/*2, and 29 (8%) CYP2C9*1/*3. We also determined CYP2C19 genotypes, including 112 with the increased activity CYP2C19*17 allele. Using electronic clinical notes, we identified 32 participants (8%) with phenytoin‐induced cutaneous adverse events recorded within 100 days of first phenytoin dispensing. Adjusting for age, sex, daily dose, and race/ethnicity, participants with CYP2C9*1/*3 or CYP2C9*2/*2 genotypes were more likely to develop cutaneous adverse events compared with CYP2C9*1/*1 participants (odds ratio 4.47; 95% confidence interval 1.64–11.69; P < 0.01). Among participants with low‐intermediate and poor CYP2C9 metabolizer genotypes, eight (22%) who also had extensive and rapid CYP2C19 metabolizer genotypes experienced cutaneous adverse events, compared with none of those who also had intermediate CYP2C19 metabolizer genotypes (P = 0.17). Genetic variation reducing CYP2C9 metabolic activity may increase risk for phenytoin‐induced cutaneous adverse events in the absence of the HLA‐B*15:02 risk allele.
Prostate-specific antigen (PSA) levels have been used for detection and surveillance of prostate cancer (PCa). However, factors other than PCa-such as genetics-can impact PSA. Here we present ...findings from a genome-wide association study (GWAS) of PSA in 28,503 Kaiser Permanente whites and 17,428 men from replication cohorts. We detect 40 genome-wide significant (P<5 × 10
) single-nucleotide polymorphisms (SNPs): 19 novel, 15 previously identified for PSA (14 of which were also PCa-associated), and 6 previously identified for PCa only. Further analysis incorporating PCa cases suggests that at least half of the 40 SNPs are PSA-associated independent of PCa. The 40 SNPs explain 9.5% of PSA variation in non-Hispanic whites, and the remaining GWAS SNPs explain an additional 31.7%; this percentage is higher in younger men, supporting the genetic basis of PSA levels. These findings provide important information about genetic markers for PSA that may improve PCa screening, thereby reducing over-diagnosis and over-treatment.
A genome-wide association study (GWAS) of prostate cancer in Kaiser Permanente health plan members (7,783 cases, 38,595 controls; 80.3% non-Hispanic white, 4.9% African-American, 7.0% East Asian, and ...7.8% Latino) revealed a new independent risk indel rs4646284 at the previously identified locus 6q25.3 that replicated in PEGASUS (N = 7,539) and the Multiethnic Cohort (N = 4,679) with an overall P = 1.0 × 10(-19) (OR, 1.18). Across the 6q25.3 locus, rs4646284 exhibited the strongest association with expression of SLC22A1 (P = 1.3 × 10(-23)) and SLC22A3 (P = 3.2 × 10(-52)). At the known 19q13.33 locus, rs2659124 (P = 1.3 × 10(-13); OR, 1.18) nominally replicated in PEGASUS. A risk score of 105 known risk SNPs was strongly associated with prostate cancer (P < 1.0 × 10(-8)). Comparing the highest to lowest risk score deciles, the OR was 6.22 for non-Hispanic whites, 5.82 for Latinos, 3.77 for African-Americans, and 3.38 for East Asians. In non-Hispanic whites, the 105 risk SNPs explained approximately 7.6% of disease heritability. The entire GWAS array explained approximately 33.4% of heritability, with a 4.3-fold enrichment within DNaseI hypersensitivity sites (P = 0.004).
Taken together, our findings of independent risk variants, ethnic variation in existing SNP replication, and remaining unexplained heritability have important implications for further clarifying the genetic risk of prostate cancer. Our findings also suggest that there may be much promise in evaluating understudied variation, such as indels and ethnically diverse populations.
To identify rare variants associated with prostate cancer susceptibility and better characterize the mechanisms and cumulative disease risk associated with common risk variants, we conducted an ...integrated study of prostate cancer genetic etiology in two cohorts using custom genotyping microarrays, large imputation reference panels, and functional annotation approaches. Specifically, 11,984 men (6,196 prostate cancer cases and 5,788 controls) of European ancestry from Northern California Kaiser Permanente were genotyped and meta-analyzed with 196,269 men of European ancestry (7,917 prostate cancer cases and 188,352 controls) from the UK Biobank. Three novel loci, including two rare variants (European ancestry minor allele frequency < 0.01, at 3p21.31 and 8p12), were significant genome wide in a meta-analysis. Gene-based rare variant tests implicated a known prostate cancer gene (
), as well as a novel candidate gene (
), which encodes a receptor highly expressed in prostate tissue and is related to the B7/CD28 family of T-cell immune checkpoint markers. Haplotypic patterns of long-range linkage disequilibrium were observed for rare genetic variants at
and other loci, reflecting their evolutionary history. In addition, a polygenic risk score (PRS) of 188 prostate cancer variants was strongly associated with risk (90th vs. 40th-60th percentile OR = 2.62,
= 2.55 × 10
). Many of the 188 variants exhibited functional signatures of gene expression regulation or transcription factor binding, including a 6-fold difference in log-probability of androgen receptor binding at the variant rs2680708 (17q22). Rare variant and PRS associations, with concomitant functional interpretation of risk mechanisms, can help clarify the full genetic architecture of prostate cancer and other complex traits. SIGNIFICANCE: This study maps the biological relationships between diverse risk factors for prostate cancer, integrating different functional datasets to interpret and model genome-wide data from over 200,000 men with and without prostate cancer.
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Elevated lipoprotein(a) levels are a risk factor for aortic stenosis (AS). However, a large-scale replication of associations between LPA variants and AS, their interactions with risk factors, and ...the effect of multiple risk alleles is not well established.
To replicate the association between LPA variants with AS and identify subgroups who are at higher risk of developing AS.
This case-control study of AS included 44 703 individuals (3469 cases) 55 years or older who were enrolled in the Genetic Epidemiology Research on Aging cohort and who were members of the Kaiser Permanente Northern California health care delivery system. The study leveraged the linkage of administrative health data, electronic medical records, genotypes, and self-reported questionnaire data. The 3469 AS cases were diagnosed between January 1996 and December 2015. Individuals with valvular congenital heart disease were excluded.
Two single-nucleotide polymorphisms in the LPA locus, rs10455872 and rs3798220, that are known to associate with circulating plasma lipoprotein(a) levels and an LPA risk score.
Aortic stenosis or aortic valve replacement.
The 44 703 participants were of European ancestry,of whom 22 019 (49.3%) were men. The mean (SD) age for the control group was 69.3 (8.3) years and the mean (SD) age for AS cases was 74.6 (8.5) years. Both LPA variants were associated with AS, with a per risk allele odds ratio of 1.34 (95% CI, 1.23-1.47; P = 1.7 × 10-10) for rs10455872 and 1.31 (95% CI, 1.09-1.58; P = 3.6 × 10-3) for rs3798220 after adjusting for age, age2, and sex. The results remained significant after adjusting for risk factors. The estimates were similar for an LPA risk score. Individuals with 2 risk alleles had a 2-fold or greater odds of AS compared with individuals with no risk alleles (for rs10455872, homozygous odds ratio, 2.05; 95% CI, 1.37-3.07; P = 5.3 × 10-4; for rs3798220, homozygous odds ratio, 3.74; 95% CI, 1.03-13.6; P = .05; and for compound heterygotes, odds ratio, 2.00; 95% CI, 1.17-3.44; P = .01). For rs10455872, the odds ratio for AS was greatest in individuals aged 55 to 64 years and declined with age (interaction P = .03). Each rs10455872 risk allele was also associated with AS that was diagnosed 0.71 years earlier (95% CI, -1.42 to 0; P = .05).
We provide a large-scale confirmation of the association between 2 LPA variants and AS, reaching genome-wide significance. In addition, individuals with 2 risk alleles have 2-fold or greater odds of developing AS. Age may modify these associations and identify subgroups who are at greater risk of developing AS.
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.
To investigate the association of terminating metformin treatment for reasons unrelated to kidney dysfunction with dementia incidence.
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.
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.
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.
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.
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.
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