Metabolic Syndrome Traits Increase the Risk of Major Adverse Liver Outcomes in Type 2 Diabetes.

OBJECTIVE: Type 2 diabetes (T2D) increases the risk for major adverse liver outcomes (MALOs), including cirrhosis and its complications. Patients with T2D frequently have other traits of the metabolic syndrome (MetS). It remains uncertain whether there is a synergistic effect of accumulating MetS traits on future MALO risk. RESEARCH DESIGN AND METHODS: Patients with T2D without a history of liver disease were identified from national registers in Sweden from 1998 to 2021. MetS traits included hypertension, low HDL level, hypertriglyceridemia, obesity, and albuminuria, in addition to T2D. MALO events were identified based on administrative coding from national registers until 31 October 2022. Data were analyzed using Cox regression models. RESULTS: In total, 230,992 patients were identified (median age 64 years; 58% male), of whom 3,215 (1.39%) developed MALOs over a median follow-up of 9.9 years. Compared with patients with one MetS trait (only T2D) at baseline, those with more than one MetS trait had a higher rate of MALOs (adjusted hazard ratio [aHR] 2.33, 95% CI 1.53-3.54). The rate of MALOs increased progressively with increasing numbers of MetS traits at baseline (aHR 1.28 per added trait, 95% CI 1.23-1.33). During follow-up, patients who acquired additional MetS traits had a progressively higher rate of MALOs. The MetS trait with the largest association with incident MALOs was hypertension (aHR 2.06, 95% CI 1.57-2.71). CONCLUSIONS: Having or acquiring additional traits of MetS increase the rate of progression to MALOs in patients with T2D. These results could be used to inform screening initiatives for liver disease.

Limitations of Noninvasive Tests-Based Population-Level Risk Stratification Strategy for Nonalcoholic Fatty Liver Disease.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are highly prevalent but underdiagnosed. AIMS: We used an electronic health record data network to test a population-level risk stratification strategy using noninvasive tests (NITs) of liver fibrosis. METHODS: Data were obtained from PCORnet® sites in the East, Midwest, Southwest, and Southeast United States from patients aged [Formula: see text] 18 with or without ICD-10-CM diagnosis codes for NAFLD, NASH, and NASH-cirrhosis between 9/1/2017 and 8/31/2020. Average and standard deviations (SD) for Fibrosis-4 index (FIB-4), NAFLD fibrosis score (NFS), and Hepatic Steatosis Index (HSI) were estimated by site for each patient cohort. Sample-wide estimates were calculated as weighted averages across study sites. RESULTS: Of 11,875,959 patients, 0.8% and 0.1% were coded with NAFLD and NASH, respectively. NAFLD diagnosis rates in White, Black, and Hispanic patients were 0.93%, 0.50%, and 1.25%, respectively, and for NASH 0.19%, 0.04%, and 0.16%, respectively. Among undiagnosed patients, insufficient EHR data for estimating NITs ranged from 68% (FIB-4) to 76% (NFS). Predicted prevalence of NAFLD by HSI was 60%, with estimated prevalence of advanced fibrosis of 13% by NFS and 7% by FIB-4. Approximately, 15% and 23% of patients were classified in the intermediate range by FIB-4 and NFS, respectively. Among NAFLD-cirrhosis patients, a third had FIB-4 scores in the low or intermediate range. CONCLUSIONS: We identified several potential barriers to a population-level NIT-based screening strategy. HSI-based NAFLD screening appears unrealistic. Further research is needed to define merits of NFS- versus FIB-4-based strategies, which may identify different high-risk groups.

NAFLD and NASH are obesity-independent risk factors in COVID-19: Matched real-world results from the large PINC AI™ Healthcare Database.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are potential risk factors for severe pneumonia and other infections. Available data on the role of NAFLD/NASH in worsening outcomes for COVID-19 are controversial and might be confounded by comorbidities. METHODS: We used the PINC AI™ Healthcare Data Special Release (PHD-SR) to identify patients with COVID-19 (ICD-10) at approximately 900 hospitals in the United States. We performed exact matching (age, gender, and ethnicity) for patients with or without NAFLD/NASH, adjusting for demographics (admission type, region) and comorbidities (e.g., obesity, diabetes) through inverse probability of treatment weighting and then analysed hospitalisation-related outcomes. RESULTS: Among 513 623 patients with SARS-CoV-2 (COVID-19), we identified 14 667 with NAFLD/NASH who could be matched to 14 667 controls. Mean age was 57.6 (±14.9) years, 50.8% were females and 43.7% were non-Hispanic whites. After matching, baseline characteristics (e.g., age, ethnicity, and gender) and comorbidities (e.g., hypertension, obesity, diabetes, and cardiovascular disease) were well balanced (standard difference (SD) <.10), except for cirrhosis and malignancies. Patients with COVID-19 and NAFLD/NASH had higher FIB-4 scores, a significantly longer hospital length of stay (LOS) and intensive care LOS than controls (9.4 vs. 8.3 days, and 10.4 vs. 9.3, respectively), even after adjusting for cirrhosis and malignancies. Patients with COVID-19 and NAFLD/NASH also had significantly higher risk of needing invasive mandatory ventilation (IMV) (odds ratio 1.0727; 95% CI 1.0095-1.1400). Other outcomes were similar in both groups. CONCLUSIONS: In this large real-world cohort of patients hospitalised for COVID-19 in the United States, NAFLD/NASH were obesity-independent risk factors for complicated disease courses.

Predicting NAFLD prevalence in the United States using National Health and Nutrition Examination Survey 2017-2018 transient elastography data and application of machine learning.

This cohort analysis investigated the prevalence of nonalcoholic fatty liver disease (NAFLD) and NAFLD with fibrosis at different stages, associated clinical characteristics, and comorbidities in the general United States population and a subpopulation with type 2 diabetes mellitus (T2DM), using the National Health and Nutrition Examination Survey (NHANES) database (2017-2018). Machine learning was explored to predict NAFLD identified by transient elastography (FibroScan® ). Adults ≥20 years of age with valid transient elastography measurements were included; those with high alcohol consumption, viral hepatitis, or human immunodeficiency virus were excluded. Controlled attenuation parameter ≥302 dB/m using Youden's index defined NAFLD; vibration-controlled transient elastography liver stiffness cutoffs were ≤8.2, ≤9.7, ≤13.6, and >13.6 kPa for F0-F1, F2, F3, and F4, respectively. Predictive modeling, using six different machine-learning approaches with demographic and clinical data from NHANES, was applied. Age-adjusted prevalence of NAFLD and of NAFLD with F0-F1 and F2-F4 fibrosis was 25.3%, 18.9%, and 4.4%, respectively, in the overall population and 54.6%, 32.6%, and 18.3% in those with T2DM. The highest prevalence was among Mexican American participants. Test performance for all six machine-learning models was similar (area under the receiver operating characteristic curve, 0.79-0.84). Machine learning using logistic regression identified male sex, hemoglobin A1c, age, and body mass index among significant predictors of NAFLD (P ≤ 0.01). Conclusion: Data show a high prevalence of NAFLD with significant fibrosis (≥F2) in the general United States population, with greater prevalence in participants with T2DM. Using readily available, standard demographic and clinical data, machine-learning models could identify subjects with NAFLD across large data sets.

Do patient characteristics predict which patients with overactive bladder benefit from a higher fesoterodine dose?

INTRODUCTION AND HYPOTHESIS: We sought to determine whether baseline characteristics predict which overactive bladder (OAB) patients benefit from fesoterodine 8 mg versus 4 mg. METHODS: In double-blind, placebo-controlled, flexible-dose trials, baseline characteristics of OAB patients with ≥ 1 urgency urinary incontinence (UUI) episodes/24 h who escalated from fesoterodine 4 mg to 8 mg were evaluated. Possible dose-escalation predictors (age; sex; previous antimuscarinic use; UUI, micturitions, and urgency episodes/24 h; race; body mass index; time to dose escalation; OAB duration) were compared in escalators versus non-escalators. Patients from fixed-dose trials with dose-escalator characteristics were identified (matched dose-escalator sample) to assess changes from baseline with fesoterodine 4 mg, 8 mg, and placebo. RESULTS: In flexible-dose trials, significant predictors of fesoterodine dose escalation were younger age (≤ 65.8 years), greater number of baseline micturitions (≥ 13.1) and urgency episodes/24 h (≥ 10.9), greater OAB duration (≥ 9.1 years), and more frequent previous antimuscarinic use (58.3%), but not baseline UUI episodes/24 h. In the matched dose-escalator sample (fesoterodine 4 mg: n = 215; 8 mg: n = 198; placebo: n = 217), change from baseline in UUI episodes significantly improved with fesoterodine 8 mg versus 4 mg (P = 0.043) and with both doses versus placebo (P < 0.001). Dry mouth and constipation rates were higher with fesoterodine 8 mg. CONCLUSIONS: Dose-escalator patients had a significantly greater UUI response with fesoterodine 8 mg versus 4 mg. Given the potential for adverse events, fesoterodine 4 mg is recommended to start; however, patients with UUI and identified predictors may benefit from initial treatment with fesoterodine 8 mg or rapid dose escalation.

Systematic literature review of clinical trials evaluating pharmacotherapy for overactive bladder in elderly patients: An assessment of trial quality.

AIMS: Overactive bladder (OAB) disproportionately affects older-aged adults, yet most randomized controlled trials (RCTs) underrepresent patients ≥65. This systematic literature review (SLR) identified RCTs evaluating ß-3 adrenergic agonists or muscarinic antagonists in elderly patients with OAB, and compared study quality across trials. METHODS: MEDLINE® , Embase® , and Cochrane Collaboration Central Register of Clinical Trials databases were searched from inception through April 28, 2015 to identify published, peer-reviewed RCT reports evaluating ß-3 adrenergic agonists or muscarinic antagonists in elderly OAB patients (either ≥65 years or study-described as "elderly"). To assess study quality of RCT reports, we focused on internal/external validity, assessed via two scales: the validated Effective Public Health Practice Project [EPHPP]): Quality Assessment Tool for Quantitative Studies, and a tool commissioned by the Agency for Healthcare Research and Quality (AHRQ). RESULTS: Database searches yielded 1380 records that were then screened according to predefined inclusion/exclusion criteria. We included eight papers meeting study criteria. Despite scientific community efforts to improve RCT reporting standards, published reports still include incomplete and inconsistent reporting-of subject attrition, baseline patient characteristics, inclusion/exclusion criteria, and other important details. Only three of the eight OAB RCTs in this review received quality ratings of Strong (EPHPP) or Fair (AHRQ) and were multicenter with large samples. CONCLUSIONS: Despite the prevalence of OAB among older age individuals, relatively few RCTs evaluate OAB treatments explicitly among elderly subjects. The findings from this quality assessment suggest some areas for improvement in both conduct and reporting of future RCTs assessing OAB treatment in elderly.

Patterns of medical management of overactive bladder (OAB) and benign prostatic hyperplasia (BPH) in the United States.

AIMS: Overactive bladder (OAB) and benign prostatic hyperplasia (BPH) are highly prevalent conditions that place a large burden on the United States (US) health care system. We sought to analyze patterns of prescription medication usage for incident OAB in men and women, and for incident BPH in men using US health insurance claims data. MATERIALS AND METHODS: This study used Truven Health MarketScan® Commercial and Medicare Supplemental Research databases. The data were pooled from diverse points of care. BPH subjects included men age 18+ with the first and last two diagnoses of BPH ≥30 days apart and no BPH diagnosis for 1 year prior. OAB subjects included men and women age 18+, who were diagnosed similarly with incident OAB. The type of medication, medication continuation (persistence), and switching to a different medication were analyzed through September 30, 2013. RESULTS: Medication persistence was much higher overall for BPH than OAB (56% vs 34%, respectively, P < 0.0001), and was highest among men with BPH age 65+ (62%). Patients age 18-64 were less likely to continue medication than older adults (age 65+) for both BPH and OAB. A 9.4% of patients in the OAB cohort and 6.9% of men with BPH switched from one medication to another. CONCLUSIONS: Persistence was higher with BPH than OAB medications overall, whereas switching rates were higher in the OAB group. The lower persistence of OAB medication may be due to less efficacy or tolerability. The possibility of under treatment of OAB also warrants future investigations.

Characteristics of antimuscarinic responders versus suboptimal responders in a randomized clinical trial of patients with overactive bladder symptoms.

OBJECTIVE: To assess the characteristics of tolterodine extended-release (ER) 4 mg responders and suboptimal responders (≤50% decrease in UUI episodes/24 h) among patients with overactive bladder (OAB), including urgency urinary incontinence (UUI), and identify predictors of a >50% UUI response with fesoterodine 8 mg in tolterodine suboptimal responders. METHODS: Adult patients with OAB symptoms for ≥6 months and ≥8 micturitions, and ≥2 and <15 UUI episodes/24 h at week -2 received open-label tolterodine ER 4 mg during a 2 week run-in. Suboptimal responders after tolterodine treatment (week 0) were randomized to fesoterodine (4 mg for 1 week, 8 mg for weeks 2-12) or placebo once daily. Post-hoc analyses compared the percentage change from week -2 to week 0 in UUI episodes/24 h in tolterodine responders versus suboptimal responders and identified significant predictors of a UUI response at week 12 with fesoterodine 8 mg among tolterodine suboptimal responders. RESULTS: Of 897 patients, 610 (68%) were UUI suboptimal responders during the run-in period. UUI episodes/24 h at week -2 were similar in tolterodine responders and suboptimal responders (4.2 vs. 4.3), but responders showed a significantly greater median percentage decrease in UUI episodes/24 h after tolterodine treatment at week 0 (80.0% versus 15.3%; p < .0001). During double-blind treatment, the percentage of patients with a UUI response at week 12 was significantly greater with fesoterodine (69.9%) than placebo (57.0%; p = .0027). Fesoterodine (vs. placebo), no previous antimuscarinic use before tolterodine run-in, and less UUI severity at baseline were significant predictors of a UUI response. CONCLUSIONS: For patients with OAB, including UUI, who were treated initially with tolterodine and showed a suboptimal UUI response, nearly 70% demonstrated a UUI response with second-line fesoterodine 8 mg. No antimuscarinic use before tolterodine and fewer baseline UUI episodes were significant predictors of a UUI response with fesoterodine.

A pooled analysis of the efficacy of fesoterodine for the treatment of overactive bladder, and the relationship between safety, co-morbidity and polypharmacy in patients aged 65 years or older.

Background: overactive bladder (OAB) is a common condition in older persons. Antimuscarinic treatment remains the mainstay of treatment of OAB but clinicians have been reluctant to prescribe this to older patients. This study examined efficacy and safety information from patients >65 in fesoterodine trials to reaffirm efficacy and to explore the relationships between treatment emergent adverse events (TEAEs), coexisting medication and co-morbidity. Methods: data from 10 double-blind, placebo-controlled studies were analysed. A logistic regression analysis, where TEAE incidence was predicted by treatment, prior antimuscarinic treatment, number of coexisting medications, number of concomitant diseases and all possible combinations of two-way interaction terms with treatment was conducted. Results: of 4,040 patients who participated in trials; fesoterodine treatment was associated with statistically significant reductions in all disease-related and patient-reported outcomes compared to placebo. There was a significant increase in the likelihood of reporting a TEAE in association with the number of coexistent medications (odds ratio (OR) = 1.028, 95% CI: 1.0143-1.044, P < 0.003). The OR of having a TEAE with increase in the number of concomitant diseases was 1.058 (95% CI: 1.044-1.072, P < 0.0001). Central nervous system (CNS) events were few. Discussion: fesoterodine treatment led to clinically meaningful improvements across all included patient reported outcomes. The number of concomitant conditions had the greatest influence on the likelihood of an adverse event being reported. CNS TEAE were not associated with fesoterodine dose and were low across all categories of concomitant disease and coexisting medication.

Development of a predictive model for urgency urinary incontinence.

The ability to set realistic expectations of treatment response in patients with overactive bladder (OAB) can have an impact on patient engagement and adherence to study medication. In order to help set treatment expectations for OAB, a Physician Predictive Tool has been developed based on predictive modelling. Models have been developed utilizing data from eight Phase 3 and 4 fesoterodine clinical trials and these models enable the prediction of individual treatment response in subjects with OAB, based on various baseline characteristics. The data utilized and covariates that were hypothesized to influence treatment response are described. The model selection and development process are also outlined, and the final model and some example results utilizing this model are presented. Finally, we discuss the potential benefits and limitations of such a predictive tool.

Real-World Patterns of Care for the Overactive Bladder Syndrome in the United States.

OBJECTIVE: To examine the "real-world" overactive bladder (OAB) practice patterns using national data in the United States. MATERIALS AND METHODS: The Humedica EHR database was queried. This database consists of de-identified patient records from a network of organizations treating approximately over 30 million patients across states in the United States. The entire study period was from July 1, 2008, to September 30, 2013. Patients with a diagnosis of OAB between July 1, 2009, and June 30, 2012 were included and followed. Patient comorbidities, demographics, diagnostic testing, and medication usage were analyzed. RESULTS: Of 19,309,600 subjects enrolled during the study period, 46,648 adults had a diagnosis of OAB, with follow-up of at least 6 months, and met the inclusion criteria. There were 35,315 women and 11,333 men. Compared with women, men with OAB were more likely to undergo post-void residual measurement (32% vs 22%) and diagnostic cystoscopy (10% vs 7%). Women were more likely than men to undergo urodynamics (7% vs 3%). Overall, 34% of women and 19% of men diagnosed with OAB were prescribed medication. CONCLUSION: Few patients with OAB underwent invasive diagnostic testing. Anticholinergic medication was prescribed to a minority of patients diagnosed with OAB, indicating possible underuse of a potentially effective therapy. Men were less likely than women to receive medical therapy, despite the fact that OAB is common in both sexes.

Do patient characteristics predict responsiveness to treatment of overactive bladder with antimuscarinic agents?

OBJECTIVE: To determine clinical and demographic characteristics associated with antimuscarinic treatment response using a regression model. METHODS: Adults with overactive bladder (OAB) symptoms for >3 months and ≥ 1 urgency urinary incontinence (UUI) episode and ≥ 8 micturitions per 24 hours at baseline were randomized to fesoterodine (8 mg), tolterodine extended-release (4 mg), or placebo in two 12-week, double-blind, head-to-head studies. Fesoterodine-treated patients received 4 mg/d during the first week and 8 mg/d thereafter. Patients completed 3-day bladder diaries and the Overactive Bladder Questionnaire at baseline and week 12. Pooled data for changes from baseline to week 12 in winsorized UUI episodes, micturitions, and urgency episodes per 24 hours and Overactive Bladder Questionnaire Symptom Bother and health-related quality of life scores were analyzed posthoc using a regression model that selects outcome predictors from baseline values and patient characteristics while retaining baseline values and treatment, with stepwise inclusion of significant covariates and assessment of treatment interactions. Logistic regression was used for analysis of diary-dry rates. RESULTS: Younger age, lack of previous antimuscarinic treatment, shorter duration of OAB diagnosis, and female gender were common predictors of larger changes in outcomes from baseline to week 12. Baseline measures often interacted with treatment, such that poorer baseline outcomes were predictive of larger treatment differences. Longer duration since OAB diagnosis predicted greater treatment differences for UUI episodes and in diary-dry rate, and increased age predicted greater treatment differences for micturitions. CONCLUSION: Symptom severity and duration, age, gender, and previous antimuscarinic pharmacotherapy impact the response to antimuscarinic treatment.

Defining response and non-response to treatment in patients with overactive bladder: a systematic review.

OBJECTIVE: There is currently a lack of formal guidance for assessing treatment response and non-response in patients with overactive bladder (OAB). Such guidance would be useful for both clinical practice and the design of clinical trials. Our purpose was to review and assess definitions of treatment response and non-response used in patients with OAB. METHODS: We conducted a systematic review of articles published between January 1, 2005 and August 8, 2013 using PubMed. Search terms included (overactive bladder) AND ('treatment response' OR responder OR success OR satisfied OR goal OR refractory OR nonresponder OR fail OR persistent OR dissatisfied). Limits were 'humans' and 'English'. Studies conducted in subjects with neurogenic detrusor overactivity, conditions other than OAB, or OAB symptoms following lower urinary tract/pelvic surgery were excluded; case reports and letters were also excluded. RESULTS: The literature search returned 423 articles, of which 75 met the inclusion criteria and defined a specific threshold by which treatment response or non-response was determined for patients receiving behavioral therapy and/or treatment with an antimuscarinic, ß3-agonist, botulinum toxin, or neural stimulation. One published abstract from congress proceedings and three additional articles that were not identified by the search were included; thus, a total of 79 records were included. A wide variety of symptom-based definitions and patient-reported outcomes (PROs) were used. Symptom-based definitions frequently used a threshold of 50-100% improvement in general or specific symptoms; urgency urinary incontinence (UUI) was often used in studies with incontinent patients. Definitions based on PROs frequently used measures of satisfaction, general improvement, or goal achievement. Studies of patients with refractory OAB often referred to a failure to respond to ≥1 other therapy, or to poor efficacy or unacceptable tolerability, without further specification. Limitations of this review are that only English language articles were included and that only the PubMed database was used for the literature search. CONCLUSIONS: There is considerable heterogeneity in the definitions of treatment response and non-response in trials of patients with OAB; some standardization would be beneficial. However, there is also heterogeneity among patients of what constitutes treatment success or failure, and conceptualizations of treatment response and non-response in both clinical trials and clinical practice must take patient characteristics into account. For patients with UUI, it is recommended that the criteria for treatment response include this symptom, as measured by change in the absolute number of UUI episodes or achievement of continence, given its impact on patients' lives and associated bother. PROs provide important information that confirm symptom-based measures by demonstrating that observed changes in symptoms are meaningful to the patient. In clinical practice, measures of treatment satisfaction and goal achievement can be highly useful.

Relationship between biomarkers of oxidized low-density lipoprotein, statin therapy, quantitative coronary angiography, and atheroma: volume observations from the REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) study.

OBJECTIVES: This study was designed to test the hypothesis that circulating biomarkers of oxidized low-density lipoprotein (OxLDL) are affected by statin therapy and predict changes in atheroma volume. BACKGROUND: Oxidative stress is thought to play an important role in atherogenesis but the relationship between OxLDL, statin therapy, and atheroma volume in humans is not known. METHODS: In a subgroup of 214 patients from the REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) trial, oxidized phospholipids (OxPL) and malondialdehyde (MDA) epitopes per apolipoprotein B-100 (apoB), immunoglobin (Ig) G and IgM apoB immune complexes, and OxLDL autoantibodies were measured at baseline and after 18 months of treatment with atorvastatin or pravastatin. Relationships between changes of OxLDL biomarkers and quantitative coronary angiography (QCA), total atheroma volume, and percentage atheroma volume were analyzed. RESULTS: There were no differences in QCA parameters or atheroma volume in the 2 groups at baseline. Compared with baseline values, OxPL/apoB and MDA/apoB, and lipoprotein (a) levels increased 21% to 48% (p < 0.001 for all) in response to atorvastatin and 17% to 39% (p < 0.001 for all) in response to pravastatin. In contrast, IgG apoB immune complexes, IgM apoB immune complexes, and IgM OxLDL autoantibodies were significantly reduced by both atorvastatin and pravastatin (p value range 0.003 to <0.001). There were no significant differences between the atorvastatin and pravastatin groups. In the entire cohort, there were no correlations between changes in any OxLDL biomarkers and changes in QCA parameters or atheroma volume. CONCLUSIONS: Statin therapy results in significant increases in OxPL/apoB, MDA/apoB, and lipoprotein (a) levels and decreases in apoB immune complexes and OxLDL autoantibodies. However, these measures did not correlate with changes in QCA parameters or atheroma volume.

Effects of increasing doses of atorvastatin on the atherogenic lipid subclasses commonly associated with hypertriglyceridemia.

The increased cardiovascular risk associated with hypertriglyceridemia is thought to be due in part to high levels of triglyceride (TG)-rich lipoproteins and small dense low-density lipoprotein (LDL). In this post hoc analysis, effects of increasing doses of atorvastatin (10, 20, 40, and 80 mg) on atherogenic lipid subclasses commonly associated with hypertriglyceridemia were evaluated in 191 men and women who were candidates for lipid-lowering therapy and had baseline TG levels >200 mg/dl (2.3 mmol/L). After 8 weeks of treatment, in addition to significantly decreasing LDL cholesterol and TG levels, atorvastatin significantly increased LDL peak particle diameter (p <0.01) and significantly decreased the concentration of small LDL subclasses IIIa and IIIb (p <0.0001) from baseline at all doses. These effects were more pronounced with higher compared with lower doses of atorvastatin. Each dose of atorvastatin also significantly lowered levels of very LDL, intermediate-density lipoprotein (p <0.0001), and small very LDL subclass 3 (p <0.0001). Greater decreases were achieved by those patients receiving higher doses of atorvastatin (20, 40, and 80 mg). The increase in LDL size correlated with the decrease in TG levels, but not with the decrease in LDL cholesterol levels. However, the decrease in small dense LDL cholesterol concentrations correlated significantly with TG and LDL cholesterol decreases. In conclusion, atorvastatin significantly lowered levels of TG-rich remnant lipoproteins and favorably changed LDL particle size in patients with hypertriglyceridemia. These effects may explain the benefits of statin therapy in high-risk patients with hypertriglyceridemia even when levels of LDL cholesterol are at goal.

Relationship between cardiovascular risk factors and atherosclerotic disease burden measured by intravascular ultrasound.

OBJECTIVES: The goal of this study was to determine the relationship between established cardiovascular risk factors and the extent of coronary atherosclerotic plaque. BACKGROUND: Few data exist correlating cardiovascular risk factors with volumetric measurements of coronary atheroma burden in patients with coronary artery disease. METHODS: Clinical characteristics, quantitative coronary angiography, and intravascular ultrasound (IVUS) were evaluated in subjects enrolled in a study comparing atorvastatin and pravastatin. Plaque areas were measured at 1-mm intervals to compute atheroma volume. The percent of cross sections with an abnormal intimal thickness (>0.5 mm) was determined. Data on cardiovascular risk factors were collected. RESULTS: In 654 subjects, atheroma volume averaged 174.5 mm3 and percent atheroma volume 38.9%. Atherosclerosis was present in 81.2% of 25,897 cross sections. In univariate analysis, there was a strong association between diabetes, male gender, and a history of either prior revascularization or stroke with percent atheroma volume. Hypertension or prior myocardial infarction was also predictive of more severe disease. Low-density lipoprotein and C-reactive protein were not significant predictors of greater disease burden. In multivariate analysis, diabetes, male gender, and a history of a prior interventional procedure remained strong predictors of increased atheroma volume. History of stroke, non-Caucasian race, and smoking status remained significant. Although multiple measures of IVUS disease burden were worse in subjects with diabetes, angiographic stenosis severity was not different. CONCLUSIONS: Male gender, diabetes, and a history of prior revascularization are strong independent predictors of atherosclerotic burden in coronary disease patients. Many risk factors did not predict angiographic disease severity, suggesting different mechanisms drive stenosis development and atheroma accumulation.

Effects of obesity on lipid-lowering, anti-inflammatory, and antiatherosclerotic benefits of atorvastatin or pravastatin in patients with coronary artery disease (from the REVERSAL Study).

The effect of obesity on atherosclerotic burden and its modulation by lipid-lowering therapy is unknown. The Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) study was analyzed to determine the influence of increasing body mass index (BMI) on plasma lipids, C-reactive protein, plaque burden as determined by intravascular ultrasound, and the serial change in these parameters with a moderate or intensive lipid-lowering strategy. Patients with a higher BMI were younger, more likely to be women, and had a greater prevalence of hypertension, diabetes, and the metabolic syndrome. Although a higher BMI was associated with a lower high-density lipoprotein level and higher triglyceride and C-reactive protein levels, there was no apparent influence of BMI on plaque burden. However, with the intensive lipid-lowering strategy, a greater BMI was associated with a lower proportionate decrease in low-density lipoprotein (49.1 +/- 21.4% vs 43.0 +/- 22.4%, p = 0.008) and a greater proportionate decrease in C-reactive protein (39.7% vs 33.3%, p <0.04). Further, although moderate and intensive lipid-lowering strategies halted plaque progression in subjects with a lower BMI (median progression rates +1.5% and +1.2%, respectively), a significant effect on plaque progression rates was seen only with adoption of an intensive lipid-lowering strategy in the most obese subjects (median progression rate -1.88% vs +6.5% with the moderate lipid-lowering strategy, p = 0.01). In conclusion, plaque progression in obese patients is attenuated using an intensive, but not moderate, lipid-lowering strategy. These results highlight the need for aggressive risk factor modification and a decrease in vascular inflammation in obese patients.

beta-Sitosterol stimulates ceramide metabolism in differentiated Caco2 cells.

Previous studies from our laboratory on tumor cells suggest that phytosterols stimulate ceramide production, which was associated with cell growth inhibition and stimulation of apoptosis. The objective of the present study was to examine the effect of phytosterols on ceramide metabolism in small intestinal cells that represent the first cells in contact with dietary phytosterols. Caco(2) cells, an accepted model for human intestinal epithelial cells, were used in this study. Ceramide and ceramide-containing lipids were examined by labeling the ceramide pool with (3)H-serine. Cells were supplemented with 16 microM of sterols (cholesterol, beta-sitosterol or campesterol) for 16 days postconfluence and continued to differentiate. Of the two phytosterols, beta-sitosterol, but not campesterol, induced more than double the serine labeling when compared with cholesterol. This increase was uniform in sphingomyelin (SM), ceramide and sphingosine labeling. Sterols had no effect on SM concentration in the cells. In addition, sterol had no effect on the activity of SM synthase or sphingomyelinases. There was an inhibition of ceramidases with campesterol supplementation. These data suggest that the observed increases in SM and sphingosine labeling were due to an increase in ceramide turnover. The increase in ceramide turnover with beta-sitosterol supplementation was not associated with growth inhibition but was with increases in ceramide glycosylation products such as cerebrosides and gangliosides. It was concluded that beta-sitosterol has no effect on differential Caco(2), a model of normal small intestinal cells. The increase in the glycosylated ceramide products may offer a means to protect the cells from the harmful effect of ceramide by excreting them with lipoproteins.

Effects of various amounts of dietary plant sterol esters on plasma and hepatic sterol concentration and aortic foam cell formation of cholesterol-fed hamsters.

Dietary intake of plant sterol esters (PSE) lowers plasma LDL-cholesterol (LDL-C), but can modestly increase plasma plant sterol concentrations. The objective of the present study was to investigate the impact of increasing doses of dietary PSE on plasma and liver sterol concentrations as well as on aortic foam cell development as a marker of atherogenesis. One-hundred and twenty F(1)B hybrid Syrian golden hamsters (20 per group) were fed a basal atherogenic diet containing 30% of energy as fat and 0.12% (w/w) cholesterol and supplemented with 0, 0.24, 0.48, 0.96, 1.92 and 2.84% (w/w) PSE. After 12 weeks, plasma total cholesterol (TC) and LDL-C were significantly lower in the groups fed PSE compared with control. Plasma plant sterol concentrations increased with increasing dietary PSE intake up to the dietary level of 1.92% and then reached a plateau. On the other hand, hepatic campesterol and sitosterol concentrations plateaued at 0.24% PSE. Foam cell presence in the aortic arch showed an inverse relationship with dietary PSE intake (P<0.0001). Lipid-filled foam cell areas of hamsters receiving 0.24, 0.48 or 2.84% PSE were approximately 70, 90 and 100% smaller than in control hamsters fed no PSE. In summary, dietary PSE lowered plasma TC and LDL-C. Despite an increase in plasma plant sterol concentrations they did not contribute to aortic foam cell development. In fact dietary PSE significantly inhibited aortic foam cell formation. This study supports the concept that PSE through their cholesterol-lowering action prevent development of atherogenesis in this animal model.

A spread enriched with plant sterol-esters lowers blood cholesterol and lipoproteins without affecting vitamins A and E in normal and hypercholesterolemic Japanese men and women.

The objective of the study was to investigate whether different initial baseline cholesterol levels modulate the efficacy of a spread enriched with plant sterol-esters (PS) in lowering blood cholesterol in a Japanese population consuming their usual diet. Healthy adults with a mean age of 45 y and mean plasma total cholesterol (TC) level of 6.5 mmol/L were recruited to participate in a double-blind trial comprised of a run-in period of 1 wk, followed by two intervention periods of 3 wks in a 2 x 2 crossover design and a post-trial follow-up of 3 wk. Volunteers consumed two spreads, one enriched with PS (12 g/100 g plant sterols) and a control spread not fortified with PS. Recommended spread intake was 15 g/d. Effects on plasma lipids, lipoproteins, beta-carotene and vitamins A and E were assessed. Plasma TC and LDL cholesterol (LDL-C) concentrations were 5.8 and 9.1% lower, respectively, when subjects consumed the PS spread than when they consumed the control spread (P < 0.001). Subjects were divided into two groups [normal and mildly cholesterolemic (TC <5.7 mmol/L) and hypercholesterolemic (TC >/= 5.7 mmol/L)]. Reductions (P < 0.001) in TC and LDL-C due to treatment in the former group were 4.9 and 7.9%, respectively. In the hypercholesterolemic group, the reductions (P < 0.001) were 7.1 and 10.6%, respectively. The decreases did not differ between normal/mildly cholesterolemic and hypercholesterolemic subjects. Plasma apolipoprotein B (apoB) and remnant-like particle (RLP) cholesterol (RLP-C) concentrations were lower when subjects consumed the PS spread (44.3 g/L) than the control spread (49.7 g/L). Plasma beta-carotene concentration was lower (P < 0.001) in subjects consuming the PS spread than in the control. Changes in plasma vitamins A and E levels did not differ after intake of the PS and control spreads. In conclusion, consumption of a PS-enriched spread effectively lowered plasma TC, LDL-C, apoB and RLP-C regardless of baseline plasma TC at an intake of 1.8 g/d of plant sterols.