Blended e-learning and certification for medicines development professionals: results of a 7-year collaboration between King's College, London and the GMDP Academy, New York.

Introduction: The field of Medicines Development faces a continuous need for educational evolution to match the interdisciplinary and global nature of the pharmaceutical industry. This paper discusses the outcomes of a 7-year collaboration between King's College London and the Global Medicines Development Professionals (GMDP) Academy, which aimed to address this need through a blended e-learning program. Methods: The collaboration developed a comprehensive curriculum based on the PharmaTrain syllabus, delivered through a combination of asynchronous and synchronous e-learning methods. The program targeted a diverse range of professionals serving in areas related to Medical Affairs. Results: Over seven annual cohorts, 682 participants from eighty-six countries were enrolled in the program. The program's effectiveness was assessed using Kirkpatrick's model, showing elevated levels of satisfaction (over 4.0 on a five-point scale), suggesting significant gains in competence at the cognitive level and leveraged performance. Notably, 70% of responding alumni reported significant improvement in their functions, corroborated by 30% of their supervisors. The further long-term impact of the program on their respective organization has not been established. Discussion: The GMDP Academy's program has significantly contributed to life-long learning in Medicines Development, addressing educational gaps and fostering interdisciplinary collaboration. Its success highlights the importance of continuous education in keeping pace with the industry's evolving demands and underscores the potential of blended learning in achieving educational objectives in pharmaceutical medicine.

Estimating prevalence of classical homocystinuria in the United States using Optum's de-identified market clarity data.

Background and objectives: Prevalence estimates for classical homocystinuria (HCU) are variable and likely underestimated due to underdiagnosis. Claims data represent a strong but seldom used resource to analyze prevalence of HCU. The aim of this study was to estimate a prevalence range of HCU in the US utilizing a combination of diagnosis codes, total homocysteine levels, and clinical presentations indicative of HCU. Methods: This was a non-interventional retrospective cohort study, using Optum's de-identified Market Clarity Data, with a patient identification period from January 01, 2016, through September 30, 2021. An algorithm was developed to identify 2 cohorts of patients using broad and strict definitions of HCU. The index date was the date within the identification period on which the first criterion was met for the inclusion criteria. Baseline demographics, clinical characteristics, and complications were assessed and summarized using descriptive statistics. Crude and standardized prevalence estimates were calculated. Results: There were 3880 and 633 patients that met the relevant inclusion criteria for the broad and strict cohorts, respectively. The projected US prevalence of HCU was calculated to be 17,631 and 3466 based on the broad and strict definitions, respectively. The average annual standardized prevalence across 2016-2020 was 5.29 and 1.04 per 100,000 people for the broad and strict cohorts, respectively. Conclusions: Prevalence estimates of HCU vary depending on databases or datasets used and identification criteria. Many patients with clinical presentations suggesting a diagnosis of HCU did not have an associated diagnosis, potentially indicating underdiagnosis or underreporting. Future research should study alternative methods, such as the identification algorithm in our analysis, to better diagnose and understand the true prevalence of HCU.

Cardiovascular, Kidney Failure, and All-Cause Mortality Events in Patients with Focal Segmental Glomerulosclerosis in a U.S. Real-World Database.

BACKGROUND: Focal segmental glomerulosclerosis (FSGS) leads to proteinuria and progressive decline in glomerular filtration rate which correlates with kidney failure and increased cardiovascular risk. The purpose of this study was to estimate the effects of proteinuria on kidney failure status/all-cause mortality and cardiovascular disease events/all-cause mortality, as well as the relationship between progression to kidney failure and occurrence of cardiovascular disease/mortality events among adult patients (≥18 years old) with FSGS. METHODS: This was an observational, retrospective cohort study utilizing Optum® de-identified Market Clarity Data and proprietary Natural Language Processing (NLP) data. The study period was from January 1, 2007 through March 31, 2021, with patients in the overall cohort being identified from July 1, 2007 through March 31, 2021. The index date was the first FSGS ICD-10 diagnosis code or FSGS-related NLP term within the identification period. RESULTS: Elevated proteinuria >1.5 g/g and ≥3.5 g/g increased risk for kidney failure/all-cause mortality (adjusted hazard ratio [95% CI]: 2.34 [1.99-2.74] and 2.44 [2.09-2.84], respectively) and cardiovascular disease/all-cause mortality (adjusted hazard ratio [95% CI]: 2.11 [1.38-3.22] and 2.27 [1.44-3.58], respectively). Progression to kidney failure was also associated with a higher risk of cardiovascular disease/all-cause mortality (adjusted hazard ratio [95% CI]: 3.04 [2.66-3.48]. CONCLUSIONS: A significant proportion of FSGS patients experience kidney failure and cardiovascular disease events. Elevated proteinuria and progression to kidney failure were associated with a higher risk of cardiovascular disease/all-cause mortality events, and, elevated pre-kidney failure proteinuria was associated with progression to kidney failure/all-cause mortality events. Treatments that meaningfully reduce proteinuria and slow the decline in glomerular filtration rate have the potential to reduce the risk of cardiovascular disease, kidney failure and early mortality in patients with FSGS.

Impact of Proteinuria and Kidney Function Decline on Health Care Costs and Resource Utilization in Adults With IgA Nephropathy in the United States: A Retrospective Analysis.

Rationale & Objective: Among patients with IgA nephropathy (IgAN), proteinuria and decline in kidney function may be associated with increased economic burden. This study aimed to provide current information on the epidemiology and economic burden of IgAN in the United States. Study Design: Retrospective cohort study. Setting & Study Population: Overall, 9,984 patients in the Optum's Market Clarity database identified by the presence of at least 2 natural language processing-derived IgAN signs and disease and symptoms terms; 813 with linked claims data included in a health care resource utilization/cost subcohort. Predictor: High-risk proteinuria (≥1 g/d), chronic kidney disease (CKD) stage. Outcomes: Standardized prevalence, health care resource utilization, costs. Analytical Approach: Descriptive statistics for categorical and continuous variables. Direct standardization for prevalence estimation. Generalized linear models for health care resource utilization/costs, reported as per-patient-per-month (PPPM) costs in 2020 US dollars. Results: The estimated standardized US prevalence of IgAN (2016-2020) was 329.0 per 1,000,000 persons. High-risk proteinuria (≥1 vs <1 g/d) was associated with a higher mean PPPM number of outpatient visits (3.49 vs 1.74; P = 0.01) and pharmacy claims (3.79 vs 2.41; P = 0.01), contributing to higher mean total costs PPPM ($3,732 vs $1,457; P = 0.01). Furthermore, higher CKD stage was also associated with higher health care resource utilization (number of outpatient visits PPPM, number of pharmacy claims PPPM, proportion of patients with inpatient visits and emergency department visits; P < 0.001) and mean total cost PPPM (from $2,111 CKD stage 1 to $10,703 CKD stage 5/kidney failure; P < 0.001). Limitations: Generalizability outside of the catchment group for the database, missing data/errors inherent in retrospective database studies, relatively small sample size, use of Optum Market Clarity standardized pricing algorithms, exclusion of out-of-pocket costs. Conclusions: Health care resource utilization and costs were higher for IgAN patients with high-risk proteinuria and worsening kidney function. Treatments that reduce proteinuria and slow CKD disease progression may reduce the economic burden associated with IgAN. Plain-Language Summary: Immunoglobulin A nephropathy (IgAN) is a rare kidney disease. Over time, the kidneys may leak protein into the urine (proteinuria). IgAN can lead to kidney failure. Because IgAN is rare, it is hard to know how many people have it. This study used electronic health records to estimate the number of patients with IgAN in the United States, describe the characteristics of patients, and understand their treatments and the costs. The number of patients with IgAN increased between 2016 and 2020. The researchers think this is because doctors learned more about IgAN. Patients with severe disease used more health care resources and had higher costs. The authors believe treatments that slow kidney damage may reduce the cost of treating IgAN.

Baseline very low-density lipoprotein cholesterol is associated with the magnitude of triglyceride lowering on statins, fenofibric acid, or their combination in patients with mixed dyslipidemia.

Fibric acid derivatives like fenofibric acid (FA) decrease hepatic production of very low-density lipoprotein (VLDL)-associated triglycerides (TG). Hepatic VLDL production can be estimated from VLDL-associated cholesterol (VLDL-C). We assessed if the degree of TG reduction observed with FA, statins, or their combination is associated with baseline VLDL-C. Overall, 2,715 patients with mixed dyslipidemia in three randomized, controlled studies were assigned to one of six treatment strategies: FA, low-dose statin (LDS), FA + LDS, moderate-dose statin (MDS), FA + MDS, and high-dose statin (HDS). Patients were dichotomized into low- or high-baseline VLDL-C groups. Pooled data were used to compare the degree of TG reduction in patients with low- vs. high-baseline VLDL-C for each treatment arm, using unpaired, two-sided t test. Additionally, the association between baseline VLDL-C level and percentage TG reduction from baseline was evaluated by linear regression. Diagnostic performance of baseline VLDL-C levels in predicting 5, 10, 15, and 20% TG reduction was assessed by receiver operating characteristics (ROC) analysis. In all treatment groups, following 12 weeks of therapy, a significantly greater percent change from baseline in TG was observed in the high-baseline VLDL-C group as compared with the low-baseline VLDL-C group. Linear regression analysis indicated that approximately 6 to 13% of the decrease in TG could be explained by baseline VLDL-C. ROC-derived cut points for baseline VLDL-C were obtained for 5, 10, 15, and 20% TG reduction. Baseline VLDL-C levels are associated with the degree of TG lowering using FA, statins, or their combination, thereof.

Niacin extended-release/simvastatin combination therapy produces larger favorable changes in high-density lipoprotein particles than atorvastatin monotherapy.

BACKGROUND: The purpose of this research was to compare the effects of niacin extended-release in combination with simvastatin (NER/S) versus atorvastatin monotherapy on high-density lipoprotein (HDL) particle number and size in patients with hyperlipidemia or dyslipidemia from the SUPREME study. METHODS: This was a post hoc analysis of patients (n = 137) who completed the SUPREME study and who had lipid particle number and size measurements at both baseline and at week 12 by nuclear magnetic resonance spectroscopy. Following ≥4 weeks without lipid-modifying therapy (washout period), the patients received NER/S 1000/40 mg/day for 4 weeks followed by NER/S 2000/40 mg/day for 8 weeks, or atorvastatin 40 mg/day for 12 weeks. Median percent changes in HDL particle number and size from baseline to week 12 were compared between the NER/S and atorvastatin treatment groups using the Wilcoxon rank-sum test. Distribution of HDL particle subclasses at week 12 was compared between the treatment groups using the Cochran-Mantel-Haenszel test. RESULTS: Treatment with NER/S resulted in a significantly greater percent reduction in small HDL particle number at week 12 compared with atorvastatin monotherapy (-1.8% versus 4.2%, P = 0.014), and a numerically greater percent increase in large HDL particle number (102.4% versus 39.2%, P = 0.078) compared with atorvastatin monotherapy. A significantly greater percent increase in HDL particle size from baseline at week 12 was observed with NER/S compared with atorvastatin (6.0% versus 1.3%, P < 0.001). NER/S treatment also resulted in a significant shift in HDL particle size from small and medium at baseline to large at week 12 (P < 0.0001). CONCLUSION: Treatment with NER/S resulted in larger favorable changes in number and size of HDL particle subclasses compared with atorvastatin monotherapy, including a numerically greater increase in number of large HDL particles, and a significantly greater decrease in number of small HDL particles compared with atorvastatin monotherapy. In addition, NER/S treatment resulted in a significant change in HDL particle size distribution from small and medium to large.

Attainment of goal/desirable lipid levels in patients with mixed dyslipidemia after 12 weeks of treatment with fenofibric acid and rosuvastatin combination therapy: a pooled analysis of controlled studies.

BACKGROUND: Goal/desirable lipid levels are underachieved in patients with mixed dyslipidemia. These patients may have substantial residual risk of cardiovascular disease even while receiving optimal LDL-C-lowering therapy and may require additional therapy to improve multiple lipid/lipoprotein levels. OBJECTIVE: To evaluate attainment of goal/desirable levels of lipids/lipoproteins after 12-week treatment with combination rosuvastatin + fenofibric acid versus rosuvastatin monotherapy. METHODS: This was a post hoc analysis of patients with mixed dyslipidemia who enrolled in one of two randomized controlled trials, and were treated (N = 2066) with rosuvastatin (5, 10, or 20 mg), fenofibric acid 135 mg, or rosuvastatin + fenofibric acid for 12 weeks. Data were pooled across doses of rosuvastatin as monotherapy and combination therapy. RESULTS: Compared with rosuvastatin monotherapy, combination therapy had comparable effects in achieving risk-stratified LDL-C goals; however, measures of total atherogenic burden were improved because significantly greater percentages of patients attained non-HDL-C goal in high- (62.9% vs 50.4%, P = .006) and moderate-risk groups (87.6% vs 80.4%, P = .016) and apolipoprotein B (ApoB) <90 mg/dL in high-risk group (59.8% vs 43.8%, P < .001). In the overall population, more patients treated with the combination therapy achieved desirable levels of HDL-C >40/50 mg/dL in men/women (P < .001), triglycerides <150 mg/dL (P < .001), and ApoB <90 mg/dL (P < .001), compared with rosuvastatin monotherapy. Furthermore, combination therapy resulted in significantly greater percentages of patients achieving simultaneous specified levels of LDL-C + non-HDL-C (P < .015); LDL-C + HDL-C + TG (P < .001); and LDL-C + HDL-C + triglycerides + non-HDL-C + ApoB (P < .001), compared with rosuvastatin monotherapy. CONCLUSION: Rosuvastatin + fenofibric acid may be more efficacious than rosuvastatin alone in patients with mixed dyslipidemia.

Prevalence of dyslipidemia and lipid goal attainment in statin-treated subjects from 3 data sources: a retrospective analysis.

BACKGROUND: Evidence-based randomized clinical trials have shown significant benefit of statin treatment with regard to cardiovascular disease. In anticipation of the National Cholesterol Education Program Adult Treatment Panel IV guidelines, we wanted to assess the current state of lipid goal attainment in the high-risk secondary prevention population in the United States. The objectives of the study were to estimate the proportion of high-risk patients treated with statin monotherapy who achieved Adult Treatment Panel III-recommended low-density lipoprotein cholesterol (LDL-C) goals (<100 mg/dL; optional <70 mg/dL) as well as non-high-density lipoprotein cholesterol goals (<130 mg/dL; optional <100 mg/dL). METHODS AND RESULTS: This is a cross-sectional, retrospective study of 3 data sources: electronic medical records (2003-September 2010), administrative claims data (2003-2010), and National Health and Nutrition Examination Survey data (2007-2008). High-risk patients (≥ 18 years of age) were defined as those with a history of coronary heart disease or coronary heart disease risk equivalent who had the latest complete lipid panel measurement and had been treated with statin monotherapy for >90 days at the time of the lipid panel. Cardiovascular disease, coronary heart disease, and coronary heart disease risk equivalents were defined on the basis of availability, specific to each data source. Across the 3 data sources, 20% to 26% of high-risk patients treated with statin monotherapy for >90 days had LDL-C <70 mg/dL, and 67% to 77% had LDL-C <100 mg/dL. The percentages of those attaining both LDL-C goals and non-high-density lipoprotein cholesterol goals were quantitatively smaller (13.5% to 19.0% and 46% to 70%). CONCLUSIONS: Across the 3 data sources, there was consistency in the proportion of high-risk patients treated with statin monotherapy who were at LDL-C goal. A significant number of these statin-treated patients had additional dyslipidemias.

Long-term efficacy of adding fenofibric acid to moderate-dose statin therapy in patients with persistent elevated triglycerides.

OBJECTIVE: The objective of this study was to evaluate the long-term efficacy of adding fenofibric acid to moderate-dose statin therapy in patients at goal for low-density lipoprotein cholesterol (LDL-C) but with persistent hypertriglyceridemia. METHODS: This is a post hoc analysis of a subset of patients (N = 92) with mixed dyslipidemia treated with moderate-dose statin (rosuvastatin 20 mg, simvastatin 40 mg, or atorvastatin 40 mg) for 12 weeks in three controlled trials who had achieved LDL-C <100 mg/dL but whose triglycerides remained >200 mg/dL, and had fenofibric acid 135 mg added to the moderate-dose statin in a 52-week open-label extension study. Lipid and apolipoprotein (Apo) values and the proportion of patients meeting individual and combined treatment targets with combination therapy were determined at scheduled visits during the 52-week study and compared with baseline (start of extension study). RESULTS: Addition of fenofibric acid to moderate-dose statin for 52 weeks resulted in significant (P < 0.001) improvements in non-high-density lipoprotein cholesterol (non-HDL-C; -9.0%), ApoB (-9.8%), HDL-C (14.9%), and triglycerides (-37.6%) compared with baseline. At final visit, greater proportions of patients achieved optimal levels of individual parameters as well as combined targets of LDL-C + non-HDL-C (60.0% vs 52.2%), LDL-C + non-HDL-C + ApoB (53.3% vs 37.8%, P = 0.007), and LDL-C + non-HDL-C + ApoB + HDL-C + triglycerides (25.6% vs 0.0%) than at baseline. CONCLUSIONS: The addition of fenofibric acid to moderate-dose statin in patients whose LDL-C was optimal but whose triglycerides remained >200 mg/dL led to additional improvements in non-HDL-C, ApoB, HDL-C, and triglycerides that resulted in greater proportions of patients attaining optimal levels of the individual parameters as well as simultaneously achieving optimal levels of these parameters and LDL-C.

Evaluating optimal lipid levels in patients with mixed dyslipidemia following short- and long-term treatment with fenofibric acid and statin combination therapy: a post hoc analysis.

OBJECTIVE: To evaluate the achievement of individual and combined lipid and lipoprotein/biomarker targets as specified by treatment guidelines with the combination of fenofibric acid and statin therapy in patients with mixed dyslipidemia. METHODS: Data for the post hoc analyses were derived from three 12-week controlled studies and a 52-week extension study. Patients were treated with fenofibric acid 135 mg; low-, moderate-, or high-dose statin (rosuvastatin 10, 20, or 40 mg; atorvastatin 20, 40, or 80 mg; or simvastatin 20, 40, or 80 mg); or fenofibric acid + low- or moderate-dose statin in the controlled studies; and with fenofibric acid + moderate-dose statin in the extension study. Achievement of risk-stratified low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), and apolipoprotein B (ApoB) targets; and optimal levels of ApoB <90 mg/dL, HDL-C >40/50 mg/dL in men/women, triglycerides (TG) < 150 mg/dL, and high-sensitivity C-reactive protein <2 mg/L were assessed. RESULTS: In the controlled studies, significantly lower percentage of high-risk patients treated with fenofibric acid + moderate-dose statin, and significantly higher percentage of high-risk patients treated with fenofibric acid + low-dose statin, compared with corresponding-dose statin monotherapies, achieved their LDL-C (51.3% vs. 72.9%, p < 0.001) and non-HDL-C targets (53% vs. 38%, p = 0.02), respectively. Among all patients, optimal levels of ApoB, HDL-C, TG, and the combined target of LDL-C + non-HDL-C + ApoB + HDL-C + TG were achieved by higher percentage of patients treated with fenofibric acid + low- and moderate-dose statin versus corresponding dose-statin monotherapies (p ≤ 0.04 for all comparisons). In the extension study, significantly (p < 0.001 for all comparisons) higher percentage of patients had achieved individual and combined targets at final visit, compared with baseline. CONCLUSIONS: In patients with mixed dyslipidemia, short-term treatment with the combination of fenofibric acid and low- or moderate-dose statin resulted in comparable or more patients achieving individual targets of non-HDL-C, ApoB, HDL-C, and TG, and combined targets for these parameters and LDL-C, compared with corresponding-dose statin monotherapy. In the long-term study, the proportion meeting these targets was significant, compared with baseline. Limitations include the post hoc nature of the analysis, and the fact that all patients had mixed dyslipidemia and majority were white, which limits generalization to other populations.

Efficacy of fenofibric acid plus statins on multiple lipid parameters and its safety in women with mixed dyslipidemia.

The combination of fibrate and statin therapies may be a treatment option for women with multiple lipid abnormalities. We, therefore, initiated the present safety and efficacy analysis to address the paucity of such data in women with mixed dyslipidemia. A total of 1,393 women with mixed dyslipidemia (low-density lipoprotein [LDL] cholesterol ≥ 130 mg/dl, triglycerides [TG] ≥ 150 mg/dl, high-density lipoprotein [HDL] cholesterol <50 mg/dl), who had enrolled in any 1 of 3 randomized clinical trials, were evaluated. The eligible women were randomized to receive fenofibric acid plus a low- or moderate-dose statin (combination treatment); or low-, moderate-, or high-dose statin monotherapy; or fenofibric acid monotherapy. With low-dose combination treatment, the baseline HDL cholesterol level increased 20% and TG decreased 46% compared to an 8% HDL cholesterol increase and 20% TG decrease with low-dose statins alone. With the moderate-dose combination, the baseline HDL cholesterol increased 21% and TG decreased 44% compared to an 8% HDL cholesterol increase and 26% TG decrease with moderate-dose statins alone. The reduction in baseline LDL cholesterol with low-dose and moderate-dose combinations (37% and 39%, respectively) was comparable to the reduction with corresponding-dose statins (36% and 43%, respectively). High-dose statins decreased the baseline LDL cholesterol 47%; however, the increase in HDL cholesterol (9%) and decrease in TG (25%) were similar to the changes observed with lower doses of statins. The safety profiles of the combinations were comparable to those of the component therapies. In conclusion, these data suggest that a combination of fenofibric acid and a statin could be considered safe and efficacious for treating women with mixed dyslipidemia.

The effects of fenofibric acid alone and with statins on the prevalence of metabolic syndrome and its diagnostic components in patients with mixed dyslipidemia.

OBJECTIVE: To compare fenofibric acid (FA) + statin to respective monotherapies on the prevalence of metabolic syndrome and its diagnostic components in patients with mixed dyslipidemia. RESEARCH DESIGN AND METHODS: Post hoc analysis of over 2,000 metabolic syndrome patients administered either FA + low- or moderate-dose statin; FA alone; or low-, moderate-, or high-dose statin alone. RESULTS: FA + low- or moderate-dose statin combination therapy reduced the presence of metabolic syndrome (35.7 or 35.9%, respectively) more than low-, moderate-, or high-dose statin monotherapy (15.5, 16.6, or 13.8%, respectively), mostly due to improvements in triglycerides and HDL cholesterol levels. Mean glucose levels slightly decreased with FA monotherapy, slightly increased with statin monotherapy, and were essentially unchanged with FA + statin. FA with or without statin also reduced non-HDL cholesterol, apolipoprotein B, total cholesterol, VLDL cholesterol, and high-sensitivity C-reactive protein. CONCLUSIONS: FA + statin in patients with mixed dyslipidemia reduces the prevalence of metabolic syndrome.

Efficacy and safety of fenofibric acid co-administered with low- or moderate-dose statin in patients with mixed dyslipidemia and type 2 diabetes mellitus: results of a pooled subgroup analysis from three randomized, controlled, double-blind trials.

BACKGROUND: Monotherapy with lipid-modifying medication is frequently insufficient to normalize lipid abnormalities in patients with mixed dyslipidemia and type 2 diabetes mellitus. OBJECTIVE: To evaluate the efficacy and safety of fenofibric acid + statin combination therapy in this population. STUDY DESIGN: A pooled, subgroup analysis of three randomized, controlled, double-blind, 12-week trials. SETTING: Multiple clinical research facilities in the US and Canada. PATIENTS: Patients with mixed dyslipidemia and type 2 diabetes (n = 586). INTERVENTION: Fenofibric acid (Trilipix) 135 mg monotherapy; low-, moderate-, or high-dose statin monotherapy (rosuvastatin [Crestor] 10, 20, or 40 mg; simvastatin [Zocor] 20, 40, or 80 mg; or atorvastatin [Lipitor] 20, 40, or 80 mg); or fenofibric acid + low- or moderate-dose statin. MAIN OUTCOME MEASURE: Mean percentage changes in lipid parameters, percentages of patients achieving optimal serum lipid/apolipoprotein levels, and incidence of adverse events. RESULTS: Fenofibric acid + low-dose statin resulted in significantly (p < 0.001) greater mean percentage changes in high-density lipoprotein cholesterol (HDL-C) [16.8%] and triglycerides (-43.9%) than low-dose statin monotherapy (4.7% and -18.1%, respectively) and significantly (p < 0.001) greater reductions in low-density lipoprotein cholesterol (LDL-C) [-34.0%] than fenofibric acid monotherapy (-5.3%). Similarly, fenofibric acid + moderate-dose statin resulted in significantly (p < or = 0.011) greater mean percentage changes in HDL-C (16.3%) and triglycerides (-43.4%) than moderate-dose statin monotherapy (8.7% and -24.2%, respectively) and significantly (p < 0.001) greater reductions in LDL-C (-32.6%) than fenofibric acid monotherapy (-5.3%). Compared with low- or moderate-dose statin, fenofibric acid + low- or moderate-dose statin resulted in over 5-fold higher percentages of patients achieving optimal levels of LDL-C, non-HDL-C, apolipoprotein B, HDL-C, and triglycerides simultaneously. Incidence of adverse events was generally similar among treatments. CONCLUSION: Fenofibric acid + statin combination therapy in patients with mixed dyslipidemia and type 2 diabetes was well tolerated and resulted in more comprehensive improvement in the lipid/apolipoprotein profile than either monotherapy. [Clinical trials are registered at www.clinicaltrials.gov: NCT00300482, NCT00300456, and NCT00300469].

Blood pressure control with amlodipine add-on therapy in patients with hypertension and diabetes: results of the Amlodipine Diabetic Hypertension Efficacy Response Evaluation Trial.

BACKGROUND: Attainment of blood pressure (BP) goals in patients with diabetes is critical both to reduce the risk of cardiovascular events and to delay the progression of renal disease. While therapeutic guidelines advise initial therapy with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, monotherapy with these agents may not be sufficient to attain target BP. OBJECTIVE: The ADHT (Amlodipine Diabetic Hypertension Efficacy Response Evaluation Trial) evaluated the efficacy and safety of adding amlodipine to the treatment regimen of patients with hypertension and diabetes who were already receiving either quinapril or losartan as monotherapy. METHODS: ADHT was a double-blind, double-dummy, 22-week trial conducted in the US. After a washout period of 7-13 days, patients (aged 30-75 y) with hypertension and diabetes were randomized to receive quinapril 20 mg/day plus placebo or losartan 50 mg/day plus placebo for 4 weeks, titrated to 40 mg or 100 mg (if required), respectively, for an additional 4 weeks to achieve their BP goals (<130/80 mm Hg). At week 8, either amlodipine 5 mg/day or placebo was added for an additional 12 weeks, with titration to 10 mg at week 14 if the BP goal was not achieved. RESULTS: Efficacy of add-on therapy was evaluated in 411 patients (amlodipine 211, placebo 200). BP goal was reached by 27.5% of patients when amlodipine was added to quinapril or losartan monotherapy, compared with 12.5% when placebo was added (OR 2.73; 95% CI 1.61 to 4.64; p < 0.001). When added to quinapril or losartan monotherapy, amlodipine reduced BP by 8.1/5.4 mm Hg, compared with a 1.6/0.7 mm Hg decrease with add-on placebo (p < 0.001). Amlodipine, quinapril, and losartan were well tolerated. CONCLUSIONS: Amlodipine is safe and effective when added to quinapril or losartan monotherapy to help lower BP toward therapeutic targets in patients with hypertension and diabetes.

Impact of systemic hypertension on the cardiovascular benefits of statin therapy--a meta-analysis.

The ASCOT-LLA and ALLHAT-LLT trials provide conflicting evidence of the efficacy of statins in decreasing cardiovascular (CV) morbidity and mortality in hypertensive patients. We performed a meta-analysis to compare the overall efficacy of statins in hypertensive and nonhypertensive patients enrolled in major randomized clinical trials. We systematically reviewed PubMed publications from 1985 onward for placebo-controlled randomized trials that examined the effect of statins on cardiac morbidity and mortality. Only trials that followed >or=1,000 patients for >or=2 years were included in the meta-analysis. Outcomes included cardiac or CV death, major coronary events, or major CV events. Pooled estimates of relative risk (RR) were calculated separately for hypertensive and nonhypertensive patients. The moderating effect of the percentage of hypertensive patients at baseline was tested using meta-regression. Besides the ASCOT-LLA and ALLHAT-LLT, 12 trials enrolling 69,984 patients met inclusion criteria. Overall, in these 12 trials, statin therapy decreased cardiac death by 24% (RR 0.76, 95% confidence interval [CI] 0.71 to 0.82). There was no evidence of difference in RR estimates for hypertensive (RR 0.78, 95% CI 0.72 to 0.84) and nonhypertensive (RR 0.76, 95% CI 0.72 to 0.80) patients. Similarly, meta-regression showed that the efficacy of statins was not moderated by the percentage of hypertensive patients at baseline (Q estimate 1.51, p=0.22). In conclusion, statin therapy effectively decreases CV morbidity and mortality to the same extent in hypertensive and nonhypertensive patients.

Cost analysis of amlodipine versus enalapril in patients with coronary artery disease and normal blood pressure: findings from the CAMELOT economic substudy.

OBJECTIVES: To analyse 2-year hospitalization and cost data collected during a prospective, double-blind, randomized, controlled trial comparing amlodipine, enalapril and placebo in normotensive patients with coronary artery disease (CAD). METHODS: All patients who were enrolled in the CAMELOT study were included in this economic substudy. Patients with CAD and normal blood pressure were randomized to amlodipine, enalapril or placebo, and followed up for 24 months (between 1999 and 2004). Data on hospitalizations and medication use were obtained from the clinical trial. Costs were assigned from secondary sources. Total costs ($US, year 2004 values) were estimated as the sum of costs associated with cardiovascular hospitalizations, study medications and concomitant cardiovascular medications. Costs and resource use were analysed by treatment arm overall and for selected patient subgroups. Cost differences were evaluated using nonparametric bootstrap techniques. RESULTS: Of 1991 patients enrolled, 663 were treated with amlodipine, 673 were treated with enalapril and 655 were treated with placebo. Significantly fewer patients were hospitalized for cardiovascular reasons in the amlodipine group (16.4%) than in the placebo group (22.7%; p < 0.01), but not compared with the enalapril group (20.1%; p = 0.09). The amlodipine group also had numerically fewer days in hospital per patient (1.1) than the enalapril (1.3) and placebo (1.5) groups. Mean 2-year per-patient costs in the amlodipine group were estimated to be $US 609 and $US 717 lower than for the placebo and enalapril groups, respectively. CONCLUSIONS: These results suggest that use of amlodipine may reduce costs of care among CAD patients with normal blood pressure.

Influence of a 3-day regimen of azithromycin on the disposition kinetics of cyclosporine A in stable renal transplant patients.

Some macrolide antibiotics have been shown to produce significant drug-drug interactions through the inhibition of cytochrome P450 (CYP) enzymes. In renal transplant patients these interactions pose potentially serious problems for the safe administration of cyclosporine A (CSA), a substrate of CYP3A4. The effects of azithromycin on CSA disposition kinetics were evaluated in eight stable renal transplant patients. Patients had been stabilized on individualized doses of CSA which remained unchanged throughout the study. Azithromycin was administered for 3 days. Baseline measurements of CSA disposition kinetics were taken prior to azithromycin treatment (study day 2) and after 3 days (study day 5) of azithromycin treatment (500mg/day, orally). The key parameters of interest were the area under the CSA blood concentration versus time curve (AUC) measured for 24h after the morning dose of CSA on both days 2 and 5, and the C(max) values of CSA. The geometric mean ratios (GMRs) of those parameters (day 5/day 2) and their 90% confidence intervals (90% CI) were 107 (98,116) and 119 (104,136), respectively. The 7% increase in exposure level and 19% increase in peak plasma concentration are not likely to be clinically significant. It is concluded that azithromycin (500mg/dayx3 days) does not alter the disposition kinetics of CSA in a clinically significant way, and that CSA dosage adjustments are not warranted in renal transplant patients taking these two drugs together.