Genetic drivers of heterogeneity in type 2 diabetes pathophysiology.

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.

Multi-ancestry genome-wide study in >2.5 million individuals reveals heterogeneity in mechanistic pathways of type 2 diabetes and complications.

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes. To characterise the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study (GWAS) data from 2,535,601 individuals (39.7% non-European ancestry), including 428,452 T2D cases. We identify 1,289 independent association signals at genome-wide significance (P<5×10-8) that map to 611 loci, of which 145 loci are previously unreported. We define eight non-overlapping clusters of T2D signals characterised by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial, and enteroendocrine cells. We build cluster-specific partitioned genetic risk scores (GRS) in an additional 137,559 individuals of diverse ancestry, including 10,159 T2D cases, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned GRS are more strongly associated with coronary artery disease and end-stage diabetic nephropathy than an overall T2D GRS across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings demonstrate the value of integrating multi-ancestry GWAS with single-cell epigenomics to disentangle the aetiological heterogeneity driving the development and progression of T2D, which may offer a route to optimise global access to genetically-informed diabetes care.

Multiancestry Genome-Wide Association Study of Aortic Stenosis Identifies Multiple Novel Loci in the Million Veteran Program.

BACKGROUND: Calcific aortic stenosis (CAS) is the most common valvular heart disease in older adults and has no effective preventive therapies. Genome-wide association studies (GWAS) can identify genes influencing disease and may help prioritize therapeutic targets for CAS. METHODS: We performed a GWAS and gene association study of 14 451 patients with CAS and 398 544 controls in the Million Veteran Program. Replication was performed in the Million Veteran Program, Penn Medicine Biobank, Mass General Brigham Biobank, BioVU, and BioMe, totaling 12 889 cases and 348 094 controls. Causal genes were prioritized from genome-wide significant variants using polygenic priority score gene localization, expression quantitative trait locus colocalization, and nearest gene methods. CAS genetic architecture was compared with that of atherosclerotic cardiovascular disease. Causal inference for cardiometabolic biomarkers in CAS was performed using Mendelian randomization and genome-wide significant loci were characterized further through phenome-wide association study. RESULTS: We identified 23 genome-wide significant lead variants in our GWAS representing 17 unique genomic regions. Of the 23 lead variants, 14 were significant in replication, representing 11 unique genomic regions. Five replicated genomic regions were previously known risk loci for CAS (PALMD, TEX41, IL6, LPA, FADS) and 6 were novel (CEP85L, FTO, SLMAP, CELSR2, MECOM, CDAN1). Two novel lead variants were associated in non-White individuals (P<0.05): rs12740374 (CELSR2) in Black and Hispanic individuals and rs1522387 (SLMAP) in Black individuals. Of the 14 replicated lead variants, only 2 (rs10455872 [LPA], rs12740374 [CELSR2]) were also significant in atherosclerotic cardiovascular disease GWAS. In Mendelian randomization, lipoprotein(a) and low-density lipoprotein cholesterol were both associated with CAS, but the association between low-density lipoprotein cholesterol and CAS was attenuated when adjusting for lipoprotein(a). Phenome-wide association study highlighted varying degrees of pleiotropy, including between CAS and obesity at the FTO locus. However, the FTO locus remained associated with CAS after adjusting for body mass index and maintained a significant independent effect on CAS in mediation analysis. CONCLUSIONS: We performed a multiancestry GWAS in CAS and identified 6 novel genomic regions in the disease. Secondary analyses highlighted the roles of lipid metabolism, inflammation, cellular senescence, and adiposity in the pathobiology of CAS and clarified the shared and differential genetic architectures of CAS with atherosclerotic cardiovascular diseases.

Prognostic value of tumor-infiltrating immune cells and immune checkpoints in elderly head-and-neck squamous cell carcinoma patients undergoing definitive (chemo)radiotherapy.

BACKGROUND AND PURPOSE: Tumor-infiltrating lymphocytes (TILs) are associated with locoregional control (LRC) in head-and-neck squamous cell carcinoma (HNSCC) patients undergoing (chemo)radiotherapy. As immunosenescence results in reduced immune activity, the role of TILs in elderly HNSCC patients may differ compared to younger patients, providing a rationale to study the prognostic role of TILs and immune checkpoints (ICs) in this population. MATERIAL AND METHODS: Sixty-three HNSCC patients aged ≥ 65 years undergoing definitive (chemo)radiotherapy between 2010 and 2019 with sufficient material from pre-treatment biopsies were included in the analysis. Immunohistochemical stainings of CD3, CD4, CD8, PD-L1, TIM3, LAG3, TIGIT and CD96, and of osteopontin as an immunosenescence-associated protein were performed. Overall survival (OS) and progression-free survival (PFS) were determined using the Kaplan-Meier method, and Fine-Gray's models were used for locoregional failure (LRF) analyses. RESULTS: While there was no correlation between patient age and IC expression, osteopontin levels correlated with increasing age (r = 0.322, p < 0.05). Two-year OS, PFS, and LRC were 44%, 34%, and 71%, respectively. Increased LAG3 expression, both intraepithelial (SHR = 0.33, p < 0.05) and stromal (SHR = 0.38, p < 0.05), and elevated stromal TIM3 expression (SHR = 0.32, p < 0.05) corresponded with reduced LRFs. Absent tumoral PD-L1 expression (TPS = 0%) was associated with more LRFs (SHR = 0.28, p < 0.05). There was a trend towards improved LRF rates in elderly patients with increased intraepithelial CD3 + (SHR = 0.52, p = 0.07) and CD8 + (SHR = 0.52, p = 0.09) TIL levels. CONCLUSION: LAG3, TIM3 and TPS are promising biomarkers in elderly HNSCC patients receiving (chemo)radiotherapy. Considering the frequency of non-cancer related deaths in this population, the prognostic value of these biomarkers primarily relates to LRC.

Neuroendocrine tumours of the breast: a genomic comparison with mucinous breast cancers and neuroendocrine tumours of other anatomic sites.

AIMS: Breast neuroendocrine tumours (NETs) constitute a rare histologic subtype of oestrogen receptor (ER)-positive breast cancer, and their definition according to the WHO classification was revised in 2019. Breast NETs display histologic and transcriptomic similarities with mucinous breast carcinomas (MuBCs). Here, we sought to compare the repertoire of genetic alterations in breast NETs with MuBCs and NETs from other anatomic origins. METHODS: On histologic review applying the new WHO criteria, 18 breast tumours with neuroendocrine differentiation were reclassified as breast NETs (n=10) or other breast cancers with neuroendocrine differentiation (n=8). We reanalysed targeted sequencing or whole-exome sequencing data of breast NETs (n=10), MuBCs type A (n=12) and type B (n=11). RESULTS: Breast NETs and MuBCs were found to be genetically similar, harbouring a lower frequency of PIK3CA mutations, 1q gains and 16q losses than ER-positive/HER2-negative breast cancers. 3/10 breast NETs harboured the hallmark features of ER-positive disease (ie, PIK3CA mutations and concurrent 1q gains/16q losses). Breast NETs showed an enrichment of oncogenic/likely oncogenic mutations affecting transcription factors compared with common forms of ER-positive breast cancer and with pancreatic and pulmonary NETs. CONCLUSIONS: Breast NETs are heterogeneous and are characterised by an enrichment of mutations in transcription factors and likely constitute a spectrum of entities histologically and genomically related to MuBCs. While most breast NETs are distinct from ER-positive/HER2-negative IDC-NSTs, a subset of breast NETs appears to be genetically similar to common forms of ER-positive breast cancer, suggesting that some breast cancers may acquire neuroendocrine differentiation later in tumour evolution.

The genomic landscape of metastatic histologic special types of invasive breast cancer.

Histologic special types of breast cancer (BC) account for ~20% of BCs. Large sequencing studies of metastatic BC have focused on invasive ductal carcinomas of no special type (IDC-NSTs). We sought to define the repertoire of somatic genetic alterations of metastatic histologic special types of BC. We reanalyzed targeted capture sequencing data of 309 special types of BC, including metastatic and primary invasive lobular carcinomas (ILCs; n = 132 and n = 127, respectively), mixed mucinous (n = 5 metastatic and n = 14 primary), micropapillary (n = 12 metastatic and n = 8 primary), and metaplastic BCs (n = 6 metastatic and n = 5 primary), and compared metastatic histologic special types of BC to metastatic IDC-NSTs matched according to clinicopathologic characteristics and to primary special type BCs. The genomic profiles of metastatic and primary special types of BC were similar. Important differences, however, were noted: metastatic ILCs harbored a higher frequency of genetic alterations in TP53, ESR1, FAT1, RFWD2, and NF1 than primary ILCs, and in CDH1, PIK3CA, ERBB2, TBX3, NCOR1, and RFWD2 than metastatic IDC-NSTs. Metastatic ILCs displayed a higher mutational burden, and more frequently dominant APOBEC mutational signatures than primary ILCs and matched metastatic IDC-NSTs. ESR1 and NCOR mutations were frequently detected in metastatic mixed mucinous BCs, whereas PIK3CA and TP53 were the most frequently altered genes in metastatic micropapillary and metaplastic BCs, respectively. Taken together, primary and metastatic BCs histologic special types have remarkably similar repertoires of somatic genetic alterations. Metastatic ILCs more frequently harbor APOBEC mutational signatures than primary ILCs and metastatic IDC-NSTs.

Clinical patterns and genomic profiling of recurrent 'ultra-low risk' endometrial cancer.

OBJECTIVE: Despite good prognosis for patients with low-risk endometrial cancer, a small subset of women with low-grade/low-stage endometrial cancer experience disease recurrence and death. The aim of this study was to characterize clinical features and mutational profiles of recurrent, low-grade, non-myoinvasive, 'ultra-low risk' endometrioid endometrial adenocarcinomas. METHODS: We retrospectively identified patients with International Federation of Gynecology and Obstetrics (FIGO) stage IA endometrioid endometrial cancers who underwent primary surgery at our institution, between January 2009 and February 2017, with follow-up of ≥12 months. 'Ultra-low risk' was defined as FIGO tumor grade 1, non-myoinvasive, and lacking lymphovascular space invasion. Tumor-normal profiling using massively parallel sequencing targeting 468 genes was performed. Microsatellite instability was assessed using MSIsensor. DNA mismatch repair (MMR) protein proficiency was determined by immunohistochemistry. RESULTS: A total of 486 patients with ultra-low risk endometrioid endometrial cancers were identified: 14 (2.9%) of 486 patients developed a recurrence. Median follow-up for non-recurrent endometrioid endometrial cancers: 34 (range 12-116) months; for recurrent endometrioid endometrial cancers: 50.5 (range 20-116) months. Patients with recurrent disease were older, had lower body mass index, and were most commonly non-White (p=0.025, p<0.001, and p<0.001, respectively). Other clinical characteristics did not differ. MMR immunohistochemistry was obtained for 211 (43%) tumors: 158 (75%) MMR-proficient and 53 (25%) MMR-deficient. Primary tumors of 9 recurrent and 27 non-recurrent endometrioid endometrial cancers underwent mutational profiling. Most were microsatellite stable (6/9, 67% recurrent; 25/27, 93% non-recurrent). Recurrent PTEN and PIK3CA mutations were present in both groups. Exon 3 CTNNB1 hotspot mutations were found in 4/9 (44%) recurrent and 8/27 (30%) non-recurrent (p=0.44). CONCLUSIONS: Patients diagnosed with ultra-low risk endometrioid endometrial cancers have an overall excellent prognosis. However, in our study, 2.9% of patients with no identifiable clinical or pathologic risk factors developed recurrence. Further work is warranted to elucidate the mechanism for recurrence in this population.

Erratum: Publisher Correction: Homologous recombination DNA repair defects in PALB2-associated breast cancers.

[This corrects the article DOI: 10.1038/s41523-019-0115-9.].

Homologous recombination DNA repair defects in PALB2-associated breast cancers.

Mono-allelic germline pathogenic variants in the Partner And Localizer of BRCA2 (PALB2) gene predispose to a high-risk of breast cancer development, consistent with the role of PALB2 in homologous recombination (HR) DNA repair. Here, we sought to define the repertoire of somatic genetic alterations in PALB2-associated breast cancers (BCs), and whether PALB2-associated BCs display bi-allelic inactivation of PALB2 and/or genomic features of HR-deficiency (HRD). Twenty-four breast cancer patients with pathogenic PALB2 germline mutations were analyzed by whole-exome sequencing (WES, n = 16) or targeted capture massively parallel sequencing (410 cancer genes, n = 8). Somatic genetic alterations, loss of heterozygosity (LOH) of the PALB2 wild-type allele, large-scale state transitions (LSTs) and mutational signatures were defined. PALB2-associated BCs were found to be heterogeneous at the genetic level, with PIK3CA (29%), PALB2 (21%), TP53 (21%), and NOTCH3 (17%) being the genes most frequently affected by somatic mutations. Bi-allelic PALB2 inactivation was found in 16 of the 24 cases (67%), either through LOH (n = 11) or second somatic mutations (n = 5) of the wild-type allele. High LST scores were found in all 12 PALB2-associated BCs with bi-allelic PALB2 inactivation sequenced by WES, of which eight displayed the HRD-related mutational signature 3. In addition, bi-allelic inactivation of PALB2 was significantly associated with high LST scores. Our findings suggest that the identification of bi-allelic PALB2 inactivation in PALB2-associated BCs is required for the personalization of HR-directed therapies, such as platinum salts and/or PARP inhibitors, as the vast majority of PALB2-associated BCs without PALB2 bi-allelic inactivation lack genomic features of HRD.

Whole-exome sequencing and RNA sequencing analyses of acinic cell carcinomas of the breast.

AIMS: Acinic cell carcinoma (ACC) of the breast is a rare histological form of triple-negative breast cancer (TNBC). Despite its unique histology, targeted sequencing analysis has failed to identify recurrent genetic alterations other than those found in common forms of TNBC. Here we subjected three breast ACCs to whole-exome and RNA sequencing to determine whether they would harbour a pathognomonic genetic alteration. METHODS AND RESULTS: DNA and RNA samples from three breast ACCs were subjected to whole-exome sequencing and RNA-sequencing, respectively. Somatic mutations, copy number alterations, mutational signatures and fusion genes were determined with state-of-the-art bioinformatics methods. Our analyses revealed TP53 hotspot mutations associated with loss of heterozygosity of the wild-type allele in two cases. Mutations affecting homologous recombination DNA repair-related genes were found in two cases, and an MLH1 pathogenic germline variant was found in one case. In addition, copy number analysis revealed the presence of a somatic BRCA1 homozygous deletion and focal amplification of 12q14.3-12q21.1, encompassing MDM2, HMGA2, FRS2, and PTPRB. No oncogenic in-frame fusion transcript was identified in the three breast ACCs analysed. CONCLUSIONS: No pathognomonic genetic alterations were detected in the breast ACCs analysed. These tumours have somatic genetic alterations similar to those of common forms of TNBC, and may show homologous recombination deficiency or microsatellite instability. These findings provide further insights into why breast ACCs, which are usually clinically indolent, may evolve into or in parallel with high-grade TNBC.

Promotion- and prevention-focused coping: A meta-analytic examination of regulatory strategies in the work stress process.

We provide a meta-analytic examination of the regulatory strategies that employees adopt to cope with different types of stressors in the workplace and how these strategies are linked to work and personal outcomes. Drawing from regulatory focus theory, we introduce a new taxonomy of promotion- and prevention-focused coping that complements the traditional taxonomy of problem- and emotion-focused coping in the transactional theory of stress. In addition, we propose that challenge stressors tend to evoke promotion-focused coping, whereas hindrance stressors tend to evoke prevention-focused coping. As a pair of important coping mechanisms in the work stress process, promotion-focused coping is positively related to employees' job performance, job attitudes, and personal well-being, whereas prevention-focused coping is negatively related to these outcomes. We conducted an original meta-analysis of coping strategies in the workplace and tested the hypotheses with 550 effect sizes drawn from 156 samples that involved a total of 75,344 employees. We also tested the tenability of the proposed stressor-coping-outcome processes using meta-analytic path models and further examined the robustness of these models using full-information bootstrapping technique. The results converge to show that promotion- and prevention-focused coping serve as important intervening mechanisms that account for the relationships between work stressors and individual outcomes. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

A retrospective cohort study of the potency of lipid-lowering therapy and race-gender differences in LDL cholesterol control.

BACKGROUND: Reasons for race and gender differences in controlling elevated low density lipoprotein (LDL) cholesterol may be related to variations in prescribed lipid-lowering therapy. We examined the effect of lipid-lowering drug treatment and potency on time until LDL control for black and white women and men with a baseline elevated LDL. METHODS: We studied 3,484 older hypertensive patients with dyslipidemia in 6 primary care practices over a 4-year timeframe. Potency of lipid-lowering drugs calculated for each treated day and summed to assess total potency for at least 6 and up to 24 months. Cox models of time to LDL control within two years and logistic regression models of control within 6 months by race-gender adjust for: demographics, clinical, health care delivery, primary/specialty care, LDL measurement, and drug potency. RESULTS: Time to LDL control decreased as lipid-lowering drug potency increased (P < 0.001). Black women (N = 1,440) received the highest potency therapy (P < 0.001) yet were less likely to achieve LDL control than white men (N = 717) (fully adjusted hazard ratio [HR] 0.66 [95% CI 0.56-0.78]). Black men (N = 666) and white women (N = 661) also had lower adjusted HRs of LDL control (0.82 [95% CI 0.69, 0.98] and 0.75 [95% CI 0.64-0.88], respectively) than white men. Logistic regression models of LDL control by 6 months and other sensitivity models affirmed these results. CONCLUSIONS: Black women and, to a lesser extent, black men and white women were less likely to achieve LDL control than white men after accounting for lipid-lowering drug potency as well as diverse patient and provider factors. Future work should focus on the contributions of medication adherence and response to treatment to these clinically important differences.

Cognition-based and affect-based trust as mediators of leader behavior influences on team performance.

We develop a model in which cognitive and affective trust in the leader mediate the relationship between leader behavior and team psychological states that, in turn, drive team performance. The model is tested on a sample of 191 financial services teams in Hong Kong and the U.S. Servant leadership influenced team performance through affect-based trust and team psychological safety. Transformational leadership influenced team performance indirectly through cognition-based trust. Cognition-based trust directly influenced team potency and indirectly (through affect-based trust) influenced team psychological safety. The effects of leader behavior on team performance were fully mediated through the trust in leader variables and the team psychological states. Servant leadership explained an additional 10% of the variance in team performance beyond the effect of transformational leadership. We discuss implications of these results for research on the relationship between leader behavior and team performance, and for efforts to enhance leader development by combining knowledge from different leadership theories.

Psychological contract breaches, organizational commitment, and innovation-related behaviors: a latent growth modeling approach.

This study examined the relationships among psychological contract breaches, organizational commitment, and innovation-related behaviors (generating, spreading, implementing innovative ideas at work) over a 6-month period. Results indicate that the effects of psychological contract breaches on employees are not static. Specifically, perceptions of psychological contract breaches strengthened over time and were associated with decreased levels of affective commitment over time. Further, increased perceptions of psychological contract breaches were associated with decreases in innovation-related behaviors. We also found evidence that organizational commitment mediates the relationship between psychological contract breaches and innovation-related behaviors. These results highlight the importance of examining the nomological network of psychological contract breaches from a change perspective.

Does a single-pill antihypertensive/lipid-lowering regimen improve adherence in US managed care enrolees? A non-randomized, observational, retrospective study.

BACKGROUND: A previous study in 4703 patients suggested that a single-pill combination of amlodipine and atorvastatin is associated with greater adherence to therapy than a two-pill calcium channel antagonist (calcium channel blocker [CCB]) and HMG-CoA reductase inhibitor (statin) regimen. However, the impact of prior medication use on the potential adherence benefits of single-pill amlodipine/atorvastatin has not been studied. OBJECTIVE: To compare adherence to single-pill amlodipine/atorvastatin versus two-pill CCB + statin regimens in a large managed care population, stratified according to prior CCB and statin use. METHODS: This retrospective study was conducted among managed care enrolees in the US. Patients included in the analysis had to have a pharmacy claim for single-pill amlodipine/atorvastatin or claims for both a CCB and a statin within any 30-day window between April 2004 and April 2005. Adherence was measured over 6 months following the index date (the date of the first single-pill amlodipine/atorvastatin claim or of the claim for the second medication class for any two-pill CCB + statin regimen) as the proportion of days covered (PDC) by both CCB and statin therapy; patients were considered 'adherent' if PDC was > or =80%. Patients were divided into four cohorts based on pre-index CCB and statin use: (i) naive (CCB)/naive (statin); (ii) experienced (CCB)/naive (statin); (iii) naive (CCB)/experienced (statin); and (iv) experienced (CCB)/experienced (statin). Within each cohort, adherence was compared for patients receiving single-pill amlodipine/atorvastatin versus two-pill amlodipine + atorvastatin or other two-pill CCB + statin regimens (including amlodipine or atorvastatin but not both) at index. Multivariable logistic regression with propensity score weighting was used to adjust for covariates, including age, sex and co-morbidities. RESULTS: In total, 35,430 patients were included in the analysis. At month 6 (after adjusting for covariates), patients in the experienced (CCB)/naive (statin) cohort receiving single-pill amlodipine/atorvastatin were more than twice as likely to be adherent as those receiving two-pill amlodipine + atorvastatin (odds ratio [OR] 2.20; p < 0.0001) or other two-pill CCB + statin regimens (OR 2.75; p < 0.0001). Similarly, patients in the naive (CCB)/experienced (statin) cohort receiving single-pill amlodipine/atorvastatin were more likely to be adherent than those receiving two-pill amlodipine + atorvastatin (OR 1.72; p < 0.0001) or other two-pill CCB + statin regimens (OR 2.81; p < 0.0001). In contrast, in the naive (CCB)/naive (statin) cohort there was no significant difference in adherence between patients receiving single-pill amlodipine/atorvastatin versus two-pill amlodipine + atorvastatin (OR 1.00), although patients receiving single-pill amlodipine/atorvastatin were slightly more likely to be adherent than those receiving other two-pill CCB + statin regimens (OR 1.29; p < 0.01). In the experienced (CCB)/experienced (statin) cohort there was also no significant difference between patients receiving single-pill amlodipine/atorvastatin versus two-pill amlodipine + atorvastatin (OR 1.08), and only a slightly greater likelihood of achieving adherence to single-pill amlodipine/atorvastatin versus other two-pill CCB + statin regimens (OR 1.19; p < 0.01). CONCLUSIONS: This large retrospective study confirms previous observations that single-pill amlodipine/atorvastatin can help improve adherence versus two-pill CCB + statin regimens. However, greater improvements in adherence are likely to be observed in patients with prior experience of either CCB or statin therapy than in those either naive to, or experienced with, both therapies.

Racial disparities in hypertension control, but not treatment intensification.

BACKGROUND: Racial disparities in hypertension control are well documented, yet the contribution of providers to these disparities remains unclear. The objective of this study was to examine whether provider management of uncontrolled hypertension differed by patient race. METHODS: In a retrospective cohort of 16,881 hypertensive adults in six academic primary care practices from 1/2004 to 12/2006, we evaluated hypertension control in black vs. white patients according to expert guidelines and, among those with uncontrolled hypertension, whether antihypertensive drugs were intensified by providers. Generalized estimating equations accounted for clustering and adjusted sequentially and additively for patient, provider, and practice characteristics, as well as health-care utilization and antihypertensive medication potency. RESULTS: Black patients' visits (55.5% of 132,730 visits) had a higher unadjusted odds (1.63, 95% confidence interval (CI) 1.57-1.69) of uncontrolled hypertension than white patients' visits; the fully adjusted odds ratio remained significant (1.40, CI 1.33-1.48, P < 0.001). Among 66,327 visits with uncontrolled hypertension, no intensification of antihypertensive drugs was less likely for blacks' visits before adjustment (0.80, CI 0.76-0.83, P < 0.001) but moderated in the fully adjusted model (adjusted odds ratio 0.93, CI 0.87-0.99, P < 0.05) compared with whites' visits. Accounting for provider race, intensification was more likely at black patients' visits compared with white patients' visits. CONCLUSIONS: In our study, black patients had poorer hypertension control, and providers were more likely to intensify antihypertensive drugs at visits of black compared with white patients as appropriate. These data suggest that more research is needed to understand racial disparities in hypertension control.

Are high-risk hypertensive patients being prescribed concomitant statin therapy?: a retrospective cohort study.

BACKGROUND: Treatment guidelines for dyslipidemic patients have focused on lipid levels and risk assessments. However, normolipidemic patients who have multiple risk factors for cardiovascular disease may also benefit from HMG-CoA reductase inhibitor (statin) therapy. OBJECTIVE: We examined the frequency of statin prescriptions in patients initiating antihypertensive drug treatment in a US managed-care setting. STUDY DESIGN AND PATIENT: This retrospective cohort study used the PharMetrics' Patient-Centric Database to identify enrollees initiating antihypertensive treatment (September 2001 to February 2004). Patients newly treated with antihypertensives and with various levels of coronary heart disease (CHD) risk (including dyslipidemia, established CHD, type 2 diabetes mellitus, and no CHD but three or more cardiovascular risk factors) were included in the study. MAIN OUTCOME MEASURE: Cumulative probability of receiving statin therapy each month after antihypertensive initiation. Multivariable logistic regression was used to identify factors associated with receiving concomitant statin therapy. RESULTS: Of 142 389 patients (mean age 51.7 years) newly treated with antihypertensives, 32 056 (22.5%) were prescribed statins within 1 year. The cumulative probability of being prescribed a statin increased with increasing numbers of CHD risk factors, irrespective of dyslipidemia status. After adjusting for age, sex, and other potential predictors, patients were more likely to receive statin therapy if they had a history of dyslipidemia (adjusted odds ratio [AOR] 5.68 [95% CI 5.52, 5.85]), established CHD/congestive heart failure (AOR 3.39 [95% CI 3.16, 3.63]), or three or more additional cardiovascular risk factors but no CHD (AOR 3.01 [95% CI 2.74, 3.30]). CONCLUSION: Among patients beginning antihypertensive treatment, those with established CHD or CHD risk factors were more likely to receive statins, but a substantial fraction did not fill any statin prescription. The increased use of statin therapy could benefit many hypertensive patients with additional CHD risk factors.

Association between prescription burden and medication adherence in patients initiating antihypertensive and lipid-lowering therapy.

PURPOSE: The association between prescription burden and medication adherence in patients initiating antihypertensive and lipid-lowering therapy was studied. METHODS: Patients enrolled in managed care organizations who initiated antihypertensive therapy coincident with lipid-lowering therapy (no more than 90 days apart) between January 1, 1997, and April 30, 2000, were eligible for inclusion. Analysis was limited to new users of antihypertensive and lipid-lowering therapy. The proportion of days covered (PDC) by antihypertensive and lipid-lowering therapy was calculated for the first year after therapy initiation; patients with a PDC of > or =80% for both drug classes were considered adherent. Prescription burden was defined as the number of prescription medications taken in the year prior to starting antihypertensive and lipid-lowering therapy. Demographic, clinical, and health-service-use variables associated with both prescription burden and medication adherence were measured using medical and pharmacy claims data from the year before initiation of antihypertensive and lipid-lowering therapy. RESULTS: Among 5759 patients, the mean +/- S.D. prescription burden was 3.6 +/- 3.7 (median, 3) medications, and the mean +/- S.D. PDC with antihypertensive and lipid-lowering therapy was 53.9% +/- 31.9% (median, 58.5%). Among patients with 0, 1, and 2 prior medications, 41%, 35%, and 30% of patients were adherent, respectively, to antihypertensive and lipid-lowering therapy. Among patients with 10 or more prior medications, 20% were adherent. CONCLUSION: Among patients in a managed care database taking antihypertensive and lipid-lowering medications, adherence to those regimens became less likely as the number of prescription medications increased. The reduction in adherence with additional prescription medications was greatest in patients with the fewest preexisting prescriptions.

Transition probabilities and predictors of adherence in a California Medicaid population using antihypertensive and lipid-lowering medications.

OBJECTIVES: To determine adherence rates, transition probabilities, and factors associated with transition from higher to lower adherence in antihypertensive (AH) and lipid-lowering (LL) medications. METHODS: California Medicaid data (1995-2003) were used to identify hypertensive patients with prescriptions for both AH and LL medications. Proportion of days covered (PDC) was used to define three adherence classifications: fully adherent (FA, PDC >or= 0.8), partially adherent (PA, 0.2