Descriptions and interpretations of the ACCORD-Lipid trial in the news and biomedical literature: a cross-sectional analysis.

The lipid component of the Action to Control Cardiovascular Risk in Diabetes (ACCORD-Lipid) trial was a landmark, publicly funded study demonstrating that fenofibrate, when added to statin therapy, was not associated with improved cardiovascular outcomes among patients with diabetes mellitus. We performed a cross-sectional study of all articles describing the results of ACCORD-Lipid in the news and biomedical literature in the 15 months following its publication. For articles published in biomedical journals, we determined whether there was an association between authors' conflicts of interest and trial interpretation. We identified 67 news articles and 141 biomedical journal articles discussing ACCORD-Lipid. Approximately 30% of news and biomedical journal articles described fenofibrate as ineffective, whereas nearly 20% concluded it was effective. Among articles making a recommendation, approximately 50% of news and 67% of biomedical journal articles supported continued fibrate use. Authors with conflicts of interest were more likely to describe fenofibrate as effective (27.1% vs 8.9%; relative risk, 3.03; 95% CI, 1.22-7.50; P = .008) and support continued fibrate use (77.4% vs 45.8%; 1.69; 1.07-2.67; P = .006). The ACCORD-Lipid trial was described inconsistently in news and biomedical journal articles, possibly creating uncertainty among patients and physicians. In addition, conflicts of interest were associated with more favorable trial interpretation.

Avoidance of generic competition by Abbott Laboratories' fenofibrate franchise.

The ongoing debate concerning the efficacy of fenofibrate has overshadowed an important aspect of the drug's history: Abbott Laboratories, the maker of branded fenofibrate, has produced several bioequivalent reformulations that dominate the market, although generic fenofibrate has been available for almost a decade. This continued use of branded formulations, which cost twice as much as generic versions of fenofibrate, imposes an annual cost of approximately $700 million on the US health care system. Abbott Laboratories maintained its dominance of the fenofibrate market in part through a complex switching strategy involving the sequential launch of branded reformulations that had not been shown to be superior to the first-generation product and patent litigation that delayed the approval of generic formulations. The small differences in dose of the newer branded formulations prevented their substitution with generics of older-generation products. As soon as direct generic competition seemed likely at the new dose level, where substitution would be allowed, Abbott would launch another reformulation, and the cycle would repeat. Based on the fenofibrate example, our objective is to describe how current policy can allow pharmaceutical companies to maintain market share using reformulations of branded medications, without demonstrating the superiority of next-generation products.

Use of fibrates in the United States and Canada.

CONTEXT: Interest in the role of fibrates intensified after the publication of the negative results from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, which assessed therapy with fenofibrate plus statins. The evidence for clinical benefit in outcomes with the use of fibrates is heavily weighted on the use of the older fibrates such as gemfibrozil and clofibrate. OBJECTIVES: To examine trends in the current use of fibrates and to examine the relationship between differences in the availability and use of brand-name vs generic formulations of fenofibrate and the economic implications in the United States compared with Canada. DESIGN, SETTING, AND PATIENTS: Population-level, observational cohort study using IMS Health data from the United States and Canada of patients prescribed fibrates between January 2002 and December 2009. MAIN OUTCOME MEASURES: Fibrate prescriptions dispensed and expenditures. RESULTS: In the United States, fibrate prescriptions dispensed increased from 336 prescriptions/100,000 population in January 2002 to 730 prescriptions/100,000 population in December 2009, an increase of 117.1% (95% confidence interval [CI], 116.0%-117.9%), whereas in Canada, fibrate prescriptions increased from 402 prescriptions/100,000 population in January 2002 to 474 prescriptions/100,000 population in December 2009, an increase of 18.1% (95% CI, 17.9%-18.3%) (P <.001). In the United States, fenofibrate prescriptions dispensed increased from 150 prescriptions/100,000 population in January 2002 to 440 prescriptions/100,000 population in December 2009, an increase of 159.3% (95% CI, 157.7%-161.0%), comprising 47.9% of total fibrate prescriptions in 2002 and 65.2% in 2009. In Canada, fenofibrate prescriptions increased from 321 prescriptions/100,000 population in January 2002 to 429 prescriptions/100,000 population in December 2009. The annual ratio of generic to brand-name fenofibrate use in the United States ranged from 0:1 to 0.09:1 between 2002 and 2008, while the ratio in Canada steadily increased from 0.51:1 to 1.89:1 between 2005 and 2008. In the United States, crude fenofibrate expenditures increased from $11,535/100,000 population/month in 2002 to $44,975/100,000 population/month in 2009, while the rates in Canada declined from $17,695/100,000 population/month in 2002 to $16,112/100,000 population/month in 2009. Fibrate expenditures per 100,000 population were 3-fold higher in 2009 in the United States compared with Canada. CONCLUSION: During the past decade, prescriptions for fibrates (particularly fenofibrate) increased in the United States, while prescriptions for fibrates in Canada remained stable.

Is fenofibrate a cost-saving treatment for middle-aged individuals with type 2 diabetes? A South African private-sector perspective.

INTRODUCTION: This project was based on the FIELD trial. It is a localisation of the study by Carrington and Stewart. The aim of the original study was to determine the impact of fenofibrate therapy on healthcare costs of middle-aged patients with type 2 diabetes at high risk of future cardiovascular events. METHODS: The methodology used in the Carrington article was adopted for this study. The clinical foundation for the analysis was derived from the findings of the FIELD study. All costs were sourced from electronic databases obtained from private-sector South African funders of healthcare. Event costs for the cardiovascular events were determined and added to the treatment costs for the individual treatment arms. The cost saving was determined as the difference between the event costs saved and the additional treatment costs associated with fenofibrate treatment. All costs were reported as 2008 ZAR and a discount rate of 10% was used. The study adopted a South African private-sector funder perspective. RESULTS: If the same approach is followed as in the Carrington and Stewart study, a cost saving of 18% results. This is the difference between the total costs associated with the placebo and fenofibrate arms, respectively (R3 480 471 compared to R2 858 598 per 1 000 patient years for the placebo and fenofibrate arms, respectively). The total costs were determined as the sum of associated event costs and treatment costs for each of the comparators. CONCLUSIONS: Based on this exploratory analysis, it seems that Lipanthyl treatment in middle-aged patients resulted in a cost saving due to the prevention of cardiovascular events when it was used in the treatment of type 2 diabetics, as in the FIELD study. It should therefore be considered to be cost effective, even when just the cardiovascular risk reduction effect is considered.

Preventing diabetic complications: a primary care perspective.

While controlling cardiometabolic risk factors remains central to diabetes management, substantial disease burden persists despite intensive targeting of blood glucose, blood pressure and lipids. Data from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study provide some new insights. As well as significant reduction in total cardiovascular disease events, especially among patients with marked atherogenic dyslipidaemia (low high-density lipoprotein (HDL) cholesterol and hypertriglyceridaemia), fenofibrate had preventive effects on microvascular outcomes, reducing laser treatment for retinopathy, progression of albuminuria, and non-traumatic amputations. These findings suggest re-evaluation of fenofibrate as an option for reducing the risk of diabetic vascular complications.

Pharmacoeconomic analysis of hypertriglyceridemia treatment at medical institutions.

It has been demonstrated that HMG-CoA reductase inhibitors effectively decrease low density lipoprotein and total cholesterol levels, and presently, HMG-CoA reductase inhibitors are most widely used in hyperlipidemia treatment. On the other hand, it has been demonstrated that fibrate agents decrease triglyceride levels more effectively compared to HMG-CoA reductase inhibitors. A cost-effectiveness study comparing fenofibrate, a fibrate agent, and atorvastatin was therefore conducted in hypertriglyceridemia patients. Referring to an analytical method published in the UK, the percentage of patients received fenofibrate and atorvastatin treatments at each dose level was estimated from prescription records at the medical institutions investigated. Changes in the total cholesterol and triglyceride values after the drug administration were investigated examining published reports. Based on the said data, the treatment effectiveness was measured by the percentage of patients who achieved the target lipid levels. The treatment costs were estimated based on the number of patients investigated and reimbursement prices of the drugs. The incremental cost-effectiveness ratio of fenofibrate in decreasing triglyceride levels was dominant over atorvastatin. The incremental cost-effectiveness ratio of atorvastatin in decreasing low density lipoprotein cholesterol levels was JPY 69911. This provides a model for choosing drug treatments that reflects clinical practices at medical institutions by substituting figures for individual cases.

Is fenofibrate a cost-saving treatment for middle-aged individuals with type II diabetes? An economic analysis of the FIELD Study.

BACKGROUND: The aim of this study was to determine the impact of fenofibrate therapy on health care costs in middle-aged patients with type II diabetes at high risk of future cardiovascular events. METHODS: We undertook an economic analysis of the FIELD study conducted from the perspective of the third party payer (direct costs) with all "within trial" health care costs derived from reported clinical outcomes using pooled data from all 9795 study participants. All analyses were performed on an intention-to-treat-basis and items of expenditure were derived from 2001/2002 health economic data: comparing Diagnostic Related Groupings (DRG) costs of major morbid events from an average of unit costs derived from three European countries (UK, France and Germany). RESULTS: Despite the additional cost of applying fenofibrate therapy, that was off-set slightly by a reduced need for supplementary lipid-lowering therapy (a net cost increase of 20,495 Euros per 1000 person years to apply combined lipid-lowering therapy), fenofibrate was associated with a net saving of 23,607 Euros in health care costs per 1000 person years of follow-up. This represents an approximate 10% net saving in health care costs (total of 227,111 versus 203,415 Euros for the placebo and treatment groups, respectively). As such, based on the 95% CI calculated for observed event rates per 1000 person years at risk, the cost impact of fenofibrate therapy ranged from a 24% net saving to a 4% net increase in health care costs relative to treatment with placebo. When the highest compared to lowest DRG unit costs were applied to observed event rates, the cost impact of fenofibrate therapy varied from a 5% to 12% net saving (low versus high cost health care models) in health care costs relative to usual care. CONCLUSION: The robust nature of these analyses suggest potential cost advantages in the longer-term by applying fenofibrate in this type of patient cohort (quite possibly in combination with statin therapy) via a marked reduction in costly cardiac events and procedures.

Comparison of fluvastatin + fenofibrate combination therapy and fluvastatin monotherapy in the treatment of combined hyperlipidemia, type 2 diabetes mellitus, and coronary heart disease: a 12-month, randomized, double-blind, controlled trial.

BACKGROUND: Diabetes risk is often complicated by a mixed hyperlipoproteinemia not sufficiently controlled by a single antihyperlipidemic drug; however, there are some concerns about the safety of combined statin and fibrate treatments. OBJECTIVE: The aim of this study was to compare the efficacy and safety profile of fluvastatin + fenofibrate combination therapy and those of fluvastatin monotherapy in the treatment of combined hyperlipidemia, type 2 diabetes mellitus (DM), and coronary heart disease (CHD) (ie, high risk for cardiovascular disease [CVD]). METHODS: This 12-month, randomized, double-blind, controlled trial was conducted at the University of Pavia, Pavia, Italy. Patients aged 18 to 80 years with combined hyperlipidemia, type 2 DM, and CHD were randomly assigned to receive combination therapy with extended-release fluvastatin 80 mg + micronized fenofibrate 200 mg or monotherapy with extended-release fluvastatin 80 mg. All treatments were given in tablet form, once daily with the evening meal, for 12 months. Lipid variables (low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], total cholesterol [TC], and triglycerides [TG]) at 6 and 12 months were the primary efficacy variables, and glycemic status (glycosylated hemoglobin [HbA(1c)], fasting plasma glucose, and postprandial plasma glucose levels) at 6 and 12 months was the secondary efficacy variable. Tolerability was assessed using physical examination, including vital-sign assessment, body-weight measurement, electrocardiography, adverse events, and laboratory tests. A pharmacoeconomic analysis of both treatment regimens was also carried out using the incremental cost-effectiveness ratio (ICER). RESULTS: A total of 48 patients (24 men, 24 women; mean [SD] age, 60 [5] years) were enrolled. After 6 months, all primary efficacy variables, except for TG level, showed significant improvements from baseline only in the combination-therapy group (changes: LDL-C, -25%; HDL-C, +12%; and TC, -19%; all, P < 0.05 vs baseline). After 12 months, lipid variables showed significant improvements over baseline in both groups (all, P < 0.05), except for TG in the monotherapy group. Significant changes in LDL-C, HDL-C, and TG were found in the combination-therapy group (-35%, +34%, -32%, respectively) versus the monotherapy group (-25%, +14%, -17%, respectively; all, P < 0.05 between groups). The change from baseline in HbA(1c) level was significant with combination therapy (-12% vs -7%; P < 0.05). Both treatments were well tolerated, with no significant differences in the incidences of adverse events between the 2 groups. The ICER showed that each 1% decrease in LDL-C level achieved with the fenofibrate + fluvastatin combination added a cost of 14.97 Euros/y (US 12.25 US dollars/y), and each 1% increase in HDL-C level added a cost of 7.48 Euros/y (6.12/y US dollars), over the cost of monotherapy. CONCLUSIONS: In this selected sample of patients with combined hyperlipidemia, type 2 DM, and CHD, the combination of extended-release fluvastatin + micronized fenofibrate was associated with a more improved lipid profile than fluvastatin monotherapy, and was a well-tolerated and cost-effective therapeutic choice to treat these patients at high risk for CVD.

Update on fenofibrate.

Fenofibrate is a fibric acid derivative that has been marketed since the mid-1970's (1998 in the United States). Its active metabolite, fenofibric acid, is responsible for the primary pharmacodynamic effects of the drug: reductions in total plasma cholesterol, low density lipoprotein cholesterol, triglycerides, and very low-density lipoprotein concentrations and increases in high-density lipoprotein cholesterol and apolipoproteins AI and AII concentrations. These effects are mediated by activation of peroxisome proliferator-activated receptor-alpha (PPAR(alpha)). The drug has broad spectrum utility, with documented efficacy in Fredrickson types IIa, IIb, III, IV, and V hyperlipidemias. Fenofibrate is well tolerated, with digestive and musculoskeletal side effects similar to those of other fibrates. Results of the initial cardiovascular morbidity/mortality outcomes study with fenofibrate (known as DAIS [Diabetes Atherosclerosis Intervention Study]) were encouraging vis-à-vis slowing of atherosclerotic progression in the coronary vasculature of type II diabetics. The results of other ongoing outcome trials are eagerly awaited. These results will help to establish the overall place of fenofibrate in the hypolipidemic armamentarium.

Fenofibrate in the treatment of dyslipidemia: a review of the data as they relate to the new suprabioavailable tablet formulation.

BACKGROUND: The fibric acid derivative fenofibrate is indicated as an adjunct to dietary modification in adults with primary hypercholesterolemia or mixed dyslipidemia (types IIa and IIb hyperlipidemia, Fredrickson classification) to reduce levels of low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglycerides (TG), and apolipoprotein (apo) B, and to increase levels of high-density lipoprotein cholesterol (HDL-C) and apo A. It is also indicated as adjunctive therapy to diet for the treatment of hypertriglyceridemia (types IV and V hyperlipidemia). Initially approved in the United States in a micronized capsule formulation, fenofibrate is now available in a new "suprabioavailable" tablet formulation that has increased bioavailability, achieving equivalent plasma concentrations at lower doses. The 67- and 200-mg micronized capsules can be considered equivalent to the 54- and 160-mg suprabioavailable tablets, respectively. OBJECTIVE: This paper reviews the pharmacologic properties, clinical usefulness, and safety profile of fenofibrate in the management of dyslipidemias. METHODS: Recent studies, abstracts, reviews, and consensus statements published in the English-language literature were identified through searches of MEDLINE (1966-January 2002), International Pharmaceutical Abstracts (1970-January 2002), and PharmaProjects (1990-January 2002) using the search terms fenofibrate, fibrates, hyperlipidemia, hypertriglyceridemia, and dyslipidemia. RESULTS: Fenofibrate is well absorbed after oral administration, with peak plasma levels attained in 6 to 8 hours. The absolute bioavailability of fenofibrate cannot be determined due to its being virtually insoluble in aqueous media suitable for injection; however, after oral administration of a single dose of radiolabeled fenofibrate, approximately 60% of the dose appeared in urine, primarily as fenofibric acid and its glucuronated conjugate, and approximately 25% was excreted in the feces. The apparent volume of distribution is 0.89 L/kg in healthy volunteers, and protein binding is approximately 99% in healthy and hyperlipidemic patients. Neither fenofibrate nor fenofibric acid appears to undergo significant oxidative metabolism in vivo. Fenofibric acid has a half-life of 20 hours. Fenofibrate is effective in lowering TG levels and increasing HDL-C levels. Its LDL-C-lowering effect is greater than that of gemfibrozil. Adverse effects of fenofibrate appear to be similar to those of other fibrates, including gastrointestinal symptoms, cholelithiasis, hepatitis, myositis, and rash. Fenofibrate therapy has been associated with increases in serum aminotransferase levels, and clinical monitoring of these markers of liver function should be performed regularly. CONCLUSIONS: Fenofibrate is effective in reducing levels of TG, TC, and LDL-C, and increasing levels of HDL-C in patients with dyslipidemias. Its efficacy and tolerability in the treatment of hypertriglyceridemia and combined hyperlipidemia have been demonstrated in numerous clinical trials. Its use is accompanied by a low incidence of adverse effects and laboratory abnormalities. Fenofibrate protects against coronary heart disease not only through its effects on lipid parameters but also by producing alterations in LDL structure and, possibly, alterations in the various hemostatic parameters. Its uricosuric property may prove to be a useful adjunctive attribute.

Pharmacoeconomic evaluation of anti-hyperlipidemic agent fenofibrate.

We evaluated the economic efficiency as well as the clinical effectiveness on serum lipid levels of a change in drug therapy from bezafibrate or a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor to fenofibrate. Subjects were 26 outpatients suffering from type IIb or type IV hyperlipidemia who visited our hospital between October 2000 and January 2001. Medication doses, and serum lipid levels were recorded prior to the change to fenofibrate and at 6 months after the change. Medical costs were also calculated at the same time points. A significant reduction in medical costs of 14.9% was observed following the change to fenofibrate. Serum lipid levels were not significantly different, although an increase in low density lipoprotein-cholesterol (LDL-cholesterol) was observed in patients changing from the HMG-CoA reductase inhibitor. The actual drug costs were reduced by 21.8% in the bezafibrate to fenofibrate group and by 23.7% in the HMG-CoA reductase inhibitor to fenofibrate group. Although the drug costs of changing to fenofibrate decreased significantly, other costs remained almost unchanged.

Cost effectiveness of micronised fenofibrate and simvastatin in the short-term treatment of type IIa and type IIb hyperlipidaemia.

The aim of this study was to compare the cost effectiveness of micronised fenofibrate 200 mg and simvastatin 20 mg in the treatment of type IIa and IIb hyperlipidaemia. In a retrospective analysis, data from 2 randomised controlled clinical trials were evaluated. The results show that micronised fenofibrate has a better short term cost effectiveness than simvastatin. The costs per successfully treated patient with hyperlipidaemia over a 12-week period were [in Deutschmarks (DM); DMI = $US0.66, April 1995] DM537 for fenofibrate and DM809 for simvastatin. When the data were analysed according to type of hyperlipidaemia (classification of Frederickson), there were only small differences between both test drugs (DM450 for fenofibrate, DM517 for simvastatin) in patients with type IIa because simvastatin had higher response rates which, in part, compensated for the higher acquisition cost. However, response rates in patients with type IIb hyperlipidaemia were higher for fenofibrate, which led to a substantial cost advantage for this agent (DM768 for fenofibrate, DM2080 for simvastatin). These results were confirmed by various sensitivity analyses, including the assessment of drug monitoring programmes (postmarketing surveillance) to validate response rates and the total costs of the therapy. In this study, we evaluated the total costs of a 12-week period of therapy, not the costs per day. The results are based on actual clinical data and not just on theoretical models. The study underlines the necessity to differentiate between the types of hyperlipidaemia when performing a pharmacoeconomic analysis of lipid-lowering treatments.

Cost-effectiveness study of a lipid-lowering therapy in hyperlipoproteinaemia type IIb and type IV (Frederickson).

We performed a cost-effectiveness simulation of acipimox, bezafibrate, fenofibrate and gemfibrozil in patients with hyperlipoproteinaemia type IIb and IV (Frederickson). A distinction was made between patients with HLP type IIb and IV and HLP associated with diabetes mellitus type II (NIDDM). Direct costs were assessed as those incurred by social security for the treatment, and indirect costs were not taken into account. In appropriate dosages, all 4 substances can be considered equally efficacious in lowering lipid levels, although gallstones occur 3 times more frequently in patients treated with fibrates than in those treated with acipimox. Acquisition costs of the 4 drugs under consideration are comparable. Thus, when hospitalisation costs for treatment of gallstones are taken into account, therapy with acipimox is more cost effective than fibrate therapy.