Bezafibrate Infarction Prevention Study Research Articles

Association of Bezafibrate Treatment With Reduced Risk of Cancer in Patients With Coronary Artery Disease

ObjectiveTo evaluate the association between bezafibrate, a drug used to treat hypertriglyceridemia, and long-term cancer incidence in patients with coronary artery disease (CAD). Patients and MethodsThe study comprised 2980 patients with CAD (mean age, 60 years; 2729 [91.6%] men) who were free of cancer and were enrolled in the Bezafibrate Infarction Prevention study, a double-blind trial conducted between May 1, 1990, and January 31, 1993, in 18 cardiology departments in Israel. Patients randomized to receive 400 mg of bezafibrate (n=1486) or placebo (n=1494) daily for a median of 6.2 years (range, 4.7-7.6 years) were followed up for incidence of cancer through the Israeli National Cancer Registry and all-cause death through the Population Registry of the State of Israel until December 31, 2013. Cox proportional hazards and Fine and Gray survival models were used to assess the bezafibrate-cancer association. ResultsClinical characteristics and laboratory values were well balanced between the 2 groups at the study entry. Over a median follow-up of 22.5 years (range, 21.2-23.9 years), cancer developed in 753 patients. With death considered a competing event, the cumulative incidence of cancer at the end of the follow-up was lower in the bezafibrate vs the placebo group (23.9%; 95 CI, 21.9%-26.1% vs 27.2%; 95 CI, 25.1%-29.4%; P=.04). The hazard ratio for cancer in the bezafibrate vs placebo groups was 0.86 (95% CI, 0.74-0.99). In mediation analysis, the association between bezafibrate treatment and cancer incidence was not sensitive to adjustment for on-trial lipid levels but was attenuated on adjustment for on-trial fibrinogen levels. ConclusionBezafibrate treatment is associated with reduced risk of cancer among patients with CAD. Fibrinogen, but not lipid lowering, is linked to this association.

Biochemistry and Molecular Biology of Mechanisms of Action of Fibrates – An Overview

Fibrates are a class of medication that mainly lowers the blood triglyceride levels. They reduce the LDL and increase the levels of HDL C, in the blood. Clofibrate, the first member to be discovered in 1962 , and introduced in USA in 1967, is withdrawn in 2002, due to unexplained hepatomegaly, hepato-toxicity and possible risk of hepatic cancer. Other fibrates are introduced in the late 1970s and early 1980s, such as gemfibrozil in the United States and bezafibrate and ciprofibrate in Europe. Their lipid lowering effects are found to decrease CVS risk , progression of atherosclerosis and metabolic syndrome, macrovascular and microvascular diabetic complications like stroke, myocardial infarction, peripheral vascular disease and diabetic retinopathy .Various clinical trials like VA-HIT trial (Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial) , FIELD trail. (the Fenofibrate Intervention and Event Lowering in Diabetes) Helsinki Heart Study, ACCORD -Lipid trial (The lipid component of the Action to Control Cardiovascular Risk in Diabetes trial ) and BIP (Bezafibrate Infarction Prevention Study) trial and angiography trials, like LOCAT (Lopid Coronary Angiography Trial) and BECLAIT (Bezafibrate Coronary Atherosclerosis Intervention Trial) demonstrated the beneficial effects of gemfibrozil and fenofibrate. Their mechanism of action remained obscure for three decades, ie till 1990s, when their mode of action was found. The Mechanism of action of fibrates include limitation of substrate availability for triglyceride synthesis in the liver, promotion of the action of lipoprotein lipase, (LPL) modulation of low density lipoprotein receptor/ligand interaction and stimulation of reverse cholesterol transport The biochemical and molecular mechanisms involving the various enzymes like LCAT (Lecithin-cholesterol acyl transferase) and CYP7A1 etc. (cholesterol 7-alpha-monooxygenase or cytochrome P450 7A1 (CYP7A1) ) , transporters like ABC , CETP (ATP-binding cassette transporter, Cholesterol ester binding protein) and NTCP, OATP (Na+-dependent taurocholate transporter / organic anion transporters) . These are the.) and nuclear factors like LXR, PPAR alfa etc. (liver orphan receptor α , and peroxisome proliferative nuclear factor) , in relation to the mechanisms of action of fibrates are discussed . Areas of current interests in literature are briefed.

Lipoprotein-associated phospholipase A2, and subsequent cardiovascular events and mortality among patients with coronary heart disease

Objective: The objective of this study is to evaluate the relevance of Lp-PLA2 to risk prediction among coronary heart disease (CHD) patients. Methods: Lp-PLA2 activity was measured in 2538 CHD patients included in the Bezafibrate Infarction Prevention (BIP) study. Results: Adjusting for patient characteristics and traditional risk factors, 1 standard deviation of Lp-PLA2 was associated with a hazard ratio (HR) of 1.12 (95% confidence interval (CI): 1.00–1.25) for mortality and 1.03 (0.93–1.14) for cardiovascular events. Lp-PLA2 did not significantly improve model discrimination, or calibration nor result in noteworthy reclassification. Conclusions: Our results do not support added value of Lp-PLA2 for predicting cardiovascular events or mortality among CHD patients beyond traditional risk factor.

Is Serum Uric Acid Level an Independent Predictor of Heart Failure Among Patients With Coronary Artery Disease?

Uric acid (UA) is elevated in patients with the metabolic syndrome, and there is a possible association with coronary events. Its association with future risk of heart failure (HF) is not clear. Our objective was to evaluate the association between levels of UA and risk of HF in patients with stable coronary artery disease (CAD). Serum UA is associated with HF in CAD patients. A retrospective cohort analysis among 2939 participants of the bezafibrate infarction prevention study, assessing long-term risk of HF incidence over an 8-year of follow-up in relation to baseline UA. Among patients with high levels of UA, there was a larger proportion of men, systolic hypertension, diabetes mellitus, metabolic syndrome, elevated total cholesterol, chronic renal failure, and previous coronary revascularization procedures. The rate of myocardial infarction during the follow-up was 10.9%, 10.3%, and 11.6% in the 1st, 2nd and 3rd tertiles of UA, respectively (P = 0.68). Age-adjusted hazard ratios for HF were 1.16 (95% confidence interval [CI]: 0.94-1.45) and 1.28 (95% CI: 1.04-1.59) in the 2nd and 3rd tertiles, respectively, as compared to the 1st tertile. After adjusting for multiple confounders and myocardial infarction, the hazard ratio for developing HF was 1.18 (95% CI: 0.95-1.47) and 1.25 (95% CI: 1.00-1.56) in the 2nd and 3rd tertiles of UA levels, respectively. UA levels are associated with future risk of HF in patients with stable CAD, but this association is attenuated after adjusting for traditional CAD risk factors.

Effect of the Metabolic Syndrome and Hyperuricemia on Outcome in Patients With Coronary Artery Disease (from the Bezafibrate Infarction Prevention Study)

Hyperuricemia appears to be related to metabolic syndrome (MS), but its impact on cardiovascular risk in patients with MS is unclear. We evaluated the impact of hyperuricemia on cardiovascular risk in patients with MS. Of 2,963 patients with coronary artery disease enrolled in the Bezafibrate Infarction Prevention study, 1,410 had MS, as established by the presence of ≥3 of the following 5 criteria: serum fasting glucose >110 mg/dl, triglycerides >150 mg/dl, high-density lipoprotein cholesterol <40 mg/dl in men and <50 mg/dl in women, systolic and diastolic blood pressures >130 and 80 mm Hg, respectively, and body mass index >28 kg/m². The remaining 1,553 patients had no MS. Primary end points were defined as occurrence of acute myocardial infarction or sudden cardiac death. Hyperuricemia was defined as serum uric acid levels >7.0 mg/dl in men and >6.0 mg/dl in women, respectively. Higher rate of primary end point was noted in hyperuricemic patients (n = 284) versus normouricemic patients (n = 1,126) with MS (20.1% and 15.3%, respectively, p = 0.05). After adjustment for age, gender, smoking, diabetes, previous myocardial infarction, hypertension, New York Heart Association classes II to IV, estimated glomerular filtration rate, body mass index, total cholesterol, triglycerides, diuretics, antiplatelets, angiotensin-converting enzyme inhibitors, β blockers, and bezafibrate treatment, hyperuricemic patients with MS demonstrated significantly higher risk for the primary end point compared to normouricemic patients with MS (hazard ratio 1.45, 95% confidence interval 1.00 to 2.17, p = 0.05). In conclusion, hyperuricemia is associated with increased risk of myocardial infarction and sudden cardiac death in patients with MS.

Serum Uric Acid for Risk Stratification of Patients with Coronary Artery Disease

Objectives: In patients with coronary artery disease (CAD), elevated serum uric acid (SUA) levels may predict worse cardiovascular outcomes. It is known that SUA levels are influenced by renal function. We aimed to assess the predictive value of SUA while taking into account patients’ renal function. Methods: The primary end point (PEP) risk, including fatal or nonfatal myocardial infarction (MI) or sudden death, was assessed by SUA quintiles before and after adjustment for the estimated glomerular filtration rate (eGFR) in 2,796 nondiabetic CAD patients enrolled in the Bezafibrate Infarction Prevention study. Results: The PEP risk increased from the lowest (11.8%) to highest SUA quintile (18.0%), p < 0.005, respectively. After adjustment for age, sex, smoking, prior MI, metabolic syndrome variables, NYHA classes II–IV, heart rate and treatment with bezafibrate, diuretics, angiotensin-converting enzyme inhibitors, β-blockers, calcium channel blockers and antiplatelets, the highest SUA quintile exhibited the highest PEP risk [hazard ratio (HR): 1.47 (95% CI: 1.06–2.04)]. Patients in the highest – compared with those in the lowest – quintiles continued to demonstrate an increased PEP risk [HR: 1.46 (95% CI: 1.04–2.06)], even after additional adjustment for the eGFR. Conclusion: In nondiabetic patients with CAD, elevated SUA levels are associated with an increased risk of cardiac events, independent of renal function.

Metabolic syndrome, diabetes mellitus, and the subsequent development of prostate cancer

5158 Background: The lifetime risk of an American man developing prostate cancer (PC) is one in six. Metabolic syndrome (MS) is a cluster of medical disorders (hypertension, dyslipidaemia, hyperglycaemia, obesity) associated with the subsequent development of diabetes mellitus (DM). DM and MS afflict 11% and 22% of US adults respectively. MS and DM are associated with disturbed lipid homeostasis, and hypogonadism. DM and MS predispose to the development of gastrointestinal and endometrial cancer. DM and MS's influence on PC is less clear; some studies have suggested that whereas DM inhibits PC, MS promotes PC development. Methods: The Bezafibrate Infarction Prevention study was a randomized trial of fibrate therapy for the secondary prevention of ischemic heart disease. Between 1990–2 15524 men and women with ischemic heart disease were screened, of whom 3090 entered the trial. 81% were male. Participants were divided into three groups according to baseline parameters: (A) those with neither MS nor DM, (B) those with MS but no DM, (C) those with DM (with or without MS). MS was defined according to ATPIII guidelines. DM was defined by medical history or fasting glucose &gt; 125 mg/dL. Follow-up for PC incidence and all-cause mortality was obtained through the Israeli cancer registry and the Ministry of the Interior respectively. Analysis accounts for differences in age and non-cancer-related-mortality between groups. Ethics approval was obtained. Results: 1350 participants were excluded due to missing data or previous cancer diagnosis, leaving 11,541 men. Mean age at enrollment 61 years (45–74). Median follow-up was 12 years. There were 6119 (53%), 3,376 (29%), and 2,046 (18%) participants in groups A, B and C respectively. Overall there were 459 cases of PC; 298, 123 and 48 in groups A, B and C. The age adjusted PC rates were 4.30, 3.61 and 2.55 per 1,000 patient years in groups A, B and C respectively (A vs C p = 0.003). Data were also analyzed examining PC incidence as a function of ‘number of components of MS present’ after pooling groups A, B and C. Relative risk of developing PC was 1.00, 0.92, 0.90, 0.69, 0.71, and 0.33 for 0, 1, 2, 3, 4, and 5 components respectively. Conclusions: A baseline diagnosis of DM (highly significant) or MS (trend) was associated with a decreased prostate cancer rate over the subsequent 12 years. No significant financial relationships to disclose.

Long-term effects of peroxisome proliferator-activated receptor ligand bezafibrate on N-terminal pro-B type natriuretic peptide in patients with advanced functional capacity impairment

BackgroundThe effects of pan-peroxisome proliferator-activated receptor (PPAR) ligand bezafibrate on N-terminal pro-B type natriuretic peptide (ProBNP) level in patients with coronary artery disease (CAD) is unknown. The current study aimed to investigate the long-term effects of bezafibrate on ProBNP level in patients with pre-existing CAD and advanced functional capacity impairment.MethodsMetabolic and inflammatory parameters were analyzed from stored frozen serum samples obtained from 108 patients enrolled in the Bezafibrate Infarction Prevention (BIP) Study. They presented with New York Heart Association (NYHA) functional class III, comprising 58 patients in the bezafibrate group and 50 in the placebo groups, and completed a 2-year prospective, double-blind, placebo-controlled follow-up.ResultsDuring follow-up ProBNP level did not change significantly in the placebo group, whereas it increased slightly in the bezafibrate group, which was older and with lower baseline ProBNP values. No significant differences between the groups were found for ProBNP levels after 2 year of follow-up. Analysis-of-covariance (ANCOVA) -taking into account age and baseline ProBNP level- showed that bezafibrate was not associated with longitudinal ProBNP changes during the follow-up period (p = 0.3).ConclusionLong-term treatment by bezafibrate was not associated with longitudinal ProBNP changes in patients with pre-existing CAD and advanced functional capacity impairment.

Apolipoproteins and long-term prognosis in coronary heart disease patients

Apolipoproteins have been recently suggested as an alternative to lipoproteins in prediction of cardiovascular risk. Data regarding their added value in predicting the prognosis of coronary heart disease (CHD) patients are scarce. Our aim was to examine the association between lipoprotein cholesterol and related apolipoproteins with long-term mortality among CHD patients. Patients (4,472 men; 624 women, 40-74 years old) with total cholesterol <270 mg/dL (<7.0 mmol/L), high-density lipoprotein cholesterol (HDL-C) <45 mg/dL (<1.16 mmol/L), and triglycerides <300 mg/dL (< or =3.39 mmol/L); excluded from the Bezafibrate Infarction Prevention study; or included in the placebo arm were followed up for a median of 12.3 years. Among both men and women, the association of apolipoproteins A-I and B with mortality was comparable to their corresponding lipids (HDL-C, non-HDL-C respectively). Adjusting for age, disease history, comorbidities, smoking and baseline glucose, the risk associated with the upper versus the lower tertile (lower vs upper for HDL-C and apolipoprotein A-I) among men were 1.04 (95% CI 0.91-1.19) for non-HDL-C; 1.11 (0.97-1.27) for apolipoprotein B; 1.24 (1.09-1.41) for HDL-C; and 1.30 (1.14-1.49) for apolipoprotein A-I. Atherogenic to nonatherogenic particle ratios (lipids or apolipoproteins) were in line with the results of their individual components pointing to a less atherogenic profile among women. Models including either apolipoprotein or cholesterol subfractions had similar predictive power. Lipoprotein cholesterol and associated apolipoprotein have comparable ability to predict long-term mortality. The measurement of apolipoproteins constitutes an acceptable alternative to the use of blood lipids in assessing prognosis for CHD patients.

Does the lipid-lowering peroxisome proliferator-activated receptors ligand bezafibrate prevent colon cancer in patients with coronary artery disease?

BackgroundEpidemiologic studies have suggested that hypertriglyceridemia and insulin resistance are related to the development of colon cancer. Nuclear peroxisome proliferator-activated receptors (PPAR), which play a central role in lipid and glucose metabolism, had been hypothesized as being involved in colon cancerogenesis. In animal studies the lipid-lowering PPAR ligand bezafibrate suppressed colonic tumors. However, the effect of bezafibrate on colon cancer development in humans is unknown. Therefore, we proposed to investigate a possible preventive effect of bezafibrate on the development of colon cancer in patients with coronary artery disease during a 6-year follow-up.MethodsOur population included 3011 patients without any cancer diagnosis who were enrolled in the randomized, double blind Bezafibrate Infarction Prevention (BIP) Study. The patients received either 400 mg of bezafibrate retard (1506 patients) or placebo (1505 patients) once a day. Cancer incidence data were obtained by matching a subject's identification numbers with the National Cancer Registry. Each matched record was checked for correct identification.ResultsDevelopment of new cancer (all types) was recorded in 177 patients: in 79 (5.25%) patients from the bezafibrate group vs. 98 (6.51%) from the placebo group. Development of colon cancer was recorded in 25 patients: in 8 (0.53%) patients from the bezafibrate group vs. 17 (1.13%) from the placebo group, (Fisher's exact test: one side p = 0.05; two side p = 0.07).A difference in the incidence of cancer was only detectable after a 4 year lag and progressively increased with continued follow-up. On multivariable analysis the colon cancer risk in patients who received bezafibrate tended to be lower with a hazard ratio of 0.47 and 95% confidence interval 0.2–1.1.ConclusionOur data, derived from patients with coronary artery disease, support the hypothesis regarding a possible preventive effect of bezafibrate on the development of colon cancer.

Beta-blockers for coronary heart disease in chronic kidney disease

Limited data exist on whether the cardioprotective benefit of beta-blockers is modified by the presence of chronic kidney disease (CKD). A post hoc analysis of the data from the Bezafibrate Infarction Prevention (BIP) study was performed. CKD was defined according to the Modification of Diet in Renal Disease (MDRD) equation as an estimated glomerular filtration rate (GFR) <60 mL/min/1.73 m(2). The Cox proportional hazard model, including adjustment for propensity score, was used to estimate the hazard ratios (HR) for the composite endpoint combining acute myocardial infarction (AMI) or sudden cardiac death (SCD). In this cohort of 3075 coronary heart disease (CHD) patients, 568 (18.5%) had CKD and 1185 (38.5%) were treated with beta-blockers. A total of 245 (43.1%) CKD patients received beta-blockers at baseline. The mean (+/- SD) estimated GFR in the CKD and non-CKD subgroups was 55 (+/- 4) and 73 (+/- 9) mL/min/1.73 m(2), respectively. After a median follow-up of 6.2 years, the crude incidence rates of AMI or SCD/1000 person years (PY) were 25.6, 21.9, 34.6 and 27.5 for the beta-blockers-/CKD-, beta-blockers+/CKD-, beta-blockers-/CKD+ and beta-blockers+/CKD+ groups, respectively. Compared to patients with beta-blockers-/CKD-, the adjusted HR of AMI or SCD was 0.87 (90% CI 0.71-1.06) for the beta-blockers+/CKD-, 1.35 (90% CI 1.05-1.73) for the beta-blockers-/CKD+ and 1.06 (90% CI 0.76-1.46) for the beta-blockers+/CKD+. These analyses suggest that the use of beta-blockers is associated with a reduction in event risk in patients with CHD regardless of the presence or absence of CKD.

C-Reactive Protein Distribution and Correlates among Men and Women with Chronic Coronary Heart Disease

Background: C-reactive protein (CRP) elevated in inflammation is associated with atherosclerotic disease. We describe the distribution of CRP and its association with coronary heart disease (CHD) risk factors in a large CHD patient group. Methods: This analysis comprises 2,723 male and 256 female CHD patients, included in the Bezafibrate Infarction Prevention (BIP) study. High sensitive CRP levels were determined in frozen plasma samples. Results: CRP distribution, was normalized upon log transformation. Levels among women were higher than in men in the entire group (4.4 vs. 3.5 mg/l) and in each age group. Co-morbidities, smoking, lower education level, and use of cardiovascular drugs, were associated with elevated CRP levels in both sexes. The correlation between CRP and body mass index (BMI), insulin and glucose was stronger among women. The explained variability in CRP level was larger in women (20%) compared to men (13%). Among women, BMI explained 10% of CRP variability, whereas the contribution of each variable among men was significantly smaller. Conclusions: Among men and women with CHD, CRP level was correlated with traditional risk factors and to a lesser degree to manifestation of CHD. BMI is the main contributor to CRP variability, explained by these factors among women.

Effects of Peroxisome Proliferator-Activated Receptor Ligands, Bezafibrate and Fenofibrate, on Adiponectin Level

Adiponectin is adipose-specific secretory protein and acts as anti-diabetic and anti-atherosclerotic molecule. We previously found peroxisome proliferators response element in adiponectin promoter region, suggesting that peroxisome proliferator-activated receptor (PPAR) ligands elevate adiponectin. Fibrates are known to be PPARalpha ligands and were shown to reduce risks of diabetes and cardiovascular disease. Effect of fibrates on adiponectin has not been clarified, whereas thiazolidinediones enhance adiponectin. Thus, we explored the possibility and mechanism that fibrates enhance adiponectin in humans, mice, and cells. Significant increase of serum adiponectin was observed in bezafibrate-treated subjects compared with placebo group in patients enrolled in The Bezafibrate Infarction Prevention study. Higher baseline adiponectin levels were strongly associated with reduced risk of new diabetes. Fibrates, bezafibrate and fenofibrate, significantly elevated adiponectin levels in wild-type mice and 3T3-L1 adipocytes. Such an effect was not observed in PPARalpha-deficient mice and adipocytes. Fibrates activated adiponectin promoter but failed to enhance its activity when the point mutation occurred in peroxisome proliferators response element site and the endogenous PPARalpha was knocked down by PPARalpha-RNAi. Our results suggest that fibrates enhance adiponectin partly through adipose PPARalpha and measurement of adiponectin might be a useful tool for searching subjects at high risk for diabetes.

Atherogenic dyslipidemia in metabolic syndrome and type 2 diabetes: therapeutic options beyond statins

Lowering of low-density lipoprotein cholesterol with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) is clearly efficacious in the treatment and prevention of coronary artery disease. However, despite increasing use of statins, a significant number of coronary events still occur and many of such events take place in patients presenting with type 2 diabetes and metabolic syndrome. More and more attention is being paid now to combined atherogenic dyslipidemia which typically presents in patients with type 2 diabetes and metabolic syndrome. This mixed dyslipidemia (or "lipid quartet"): hypertriglyceridemia, low high-density lipoprotein cholesterol levels, a preponderance of small, dense low-density lipoprotein particles and an accumulation of cholesterol-rich remnant particles (e.g. high levels of apolipoprotein B) – emerged as the greatest "competitor" of low-density lipoprotein-cholesterol among lipid risk factors for cardiovascular disease. Most recent extensions of the fibrates trials (BIP – Bezafibrate Infarction Prevention study, HHS – Helsinki Heart Study, VAHIT – Veterans Affairs High-density lipoprotein cholesterol Intervention Trial and FIELD – Fenofibrate Intervention and Event Lowering in Diabetes) give further support to the hypothesis that patients with insulin-resistant syndromes such as diabetes and/or metabolic syndrome might be the ones to derive the most benefit from therapy with fibrates. However, different fibrates may have a somewhat different spectrum of effects. Other lipid-modifying strategies included using of niacin, ezetimibe, bile acid sequestrants and cholesteryl ester transfer protein inhibition. In addition, bezafibrate as pan-peroxisome proliferator activated receptor activator has clearly demonstrated beneficial pleiotropic effects related to glucose metabolism and insulin sensitivity. Because fibrates, niacin, ezetimibe and statins each regulate serum lipids by different mechanisms, combination therapy – selected on the basis of their safety and effectiveness – may offer particularly desirable benefits in patients with combined hyperlipidemia as compared with statins monotherapy.

Long-term effect of bezafibrate on pancreatic beta-cell function and insulin resistance in patients with diabetes

Objective Development of insulin resistance (IR) and the progressive failure of the pancreatic beta-cell function (BCF) may be important in the pathogenesis of type 2 diabetes. Influence of peroxisome proliferator-activated receptors ligand bezafibrate on BCF and IR in patients with diabetes is unknown. The present study was aimed to investigate the long-term effect of bezafibrate on these parameters in diabetic patients enrolled in the Bezafibrate Infarction Prevention (BIP) Study. Methods Metabolic and inflammatory parameters were analyzed from stored frozen plasma samples obtained from 351 diabetic patients (168 treated by bezafibrate and 183 by placebo) who completed a 2-year of randomized, double-blind, placebo-controlled study period. The homeostatic indexes of BCF (HOMA-BCF) and IR (HOMA-IR) were calculated according to the homeostasis model of assessment. Results Both groups displayed similar baseline characteristics. During follow-up, in the placebo group there was 28% rise of HOMA-IR ( p < 0.001). In contrast, HOMA-IR in patients in the bezafibrate group did not change ( p = 0.99). The intergroup differences in HOMA-IR percentage changes were in favor of bezafibrate ( p = 0.01). HOMA-BCF values have significantly decreased by 13.9% ( p = 0.04) in patients of placebo group, whereas in patients of bezafibrate group HOMA-BCF was stable during follow-up and its alterations (−2.9%) were non-significant ( p = 0.59). Conclusions Diabetic patients from the placebo group demonstrated a progressive declining of BCF and an increasing of IR over 2 years of follow-up. These longitudinal changes were attenuated when patients used bezafibrate.

Decrease in triglyceride level by bezafibrate is related to reduction of recurrent coronary events: a Bezafibrate Infarction Prevention substudy

Fibrates were reported to be effective in reducing recurrent coronary events in coronary heart disease patients with elevated triglycerides. It is not known whether this effect is related to the extent of triglyceride reduction. Participants comprised 3090 coronary heart disease patients enrolled in the Bezafibrate Infarction Prevention study, which showed a nonsignificant reduction (9.4%; P=0.26) in fatal or nonfatal myocardial infarction and sudden death during a mean follow-up time of 6.2 years. Significant reduction in triglyceride serum level was evident only among patients allocated to bezafibrate, ranging between 0.06 mmol/l (5 mg/dl) in the lowest decile of baseline triglycerides level and 0.68 mmol/l (60 mg/dl) in the highest baseline decile. The extent of triglyceride reduction with bezafibrate was significantly associated with the reduction of risk; relative risk reduction of 55% (hazards ratio: 0.45; 95% confidence interval: 0.24-0.84) was observed among patients with baseline triglycerides>or=2.26 mmol/l who reduced triglyceride level to >0.50 mmol/l (>44.3 mg/dl). In contrast, the risk of recurrent events among patients treated with bezafibrate and achieving less triglyceride reduction or failing to reduce triglyceride level was not significantly different from that of patients treated with placebo. Bezafibrate treatment was associated with significant risk reduction among coronary heart disease patients with elevated triglyceride levels that substantially reduced their triglyceride level with treatment.

Serum Homocysteine and Long-Term Risk of Myocardial Infarction and Sudden Death in Patients with Coronary Heart Disease

We have prospectively evaluated the risk of incident coronary events in association with serum total homocysteine in patients with preexisting chronic coronary heart disease. A nested case-control design was used. Total homocysteine concentration was measured in baseline fasting serum samples from patients with chronic coronary heart disease enrolled in the Bezafibrate Infarction Prevention Study (n = 3,090) who developed coronary events during 6.2 years of follow-up (n = 69). They were matched for age and gender with controls without subsequent cardiovascular events. Elevated homocysteine levels were associated with 2.5 times higher risk of subsequent coronary events and each 5 µmol/l increment was associated with a 25% higher risk.

Cardioprotective Properties of Fibrates

Several large intervention trials have investigated the potential of fibrates to reduce cardiovascular events. The results have varied widely: positive, with gemfibrozil in the primary prevention Helsinki Heart Study (HHS)1 and the secondary prevention Veterans Administration High Density Lipoprotein Intervention Trial (VA-HIT)2; positive, with reservations related to an increase in noncardiovascular mortality in the primary prevention World Health Organization trial (clofibrate)3; and mixed, with bezafibrate in the secondary prevention Bezafibrate Infarction Prevention (BIP) study4 and with fenofibrate in the combined primary and secondary prevention FIELD study,5 in which positive outcomes were observed only in certain subgroups. Reasons for the differences between the outcomes of these studies are not immediately apparent. Article p 1556 It emerged in post hoc subgroup analyses of the HHS,6 VA-HIT,7 and BIP8 data that fibrate-induced reductions in cardiovascular events were especially great (of the order of 30% to 50%) in subjects with evidence of insulin resistance or other features of the metabolic syndrome, such as dyslipidemia and increased body weight. However, this finding was not replicated with fenofibrate in the FIELD study.5 In another post hoc analysis of VA-HIT, it was found that diabetics with preexisting cardiovascular disease derived a major reduction in future events when treated with gemfibrozil,7 but again, this was not confirmed with fenofibrate in FIELD.5 The observation that the cardioprotective effects of gemfibrozil in the HHS and VA-HIT studies were substantially greater than those found with other fibrates in the World Health Organization, BIP, and FIELD studies may reflect no more than the play of chance. It may also reflect differences in the populations studied in the trials. However, it is possible that gemfibrozil has protective properties that are lacking in other fibrates or that other fibrates have adverse …

Adiponectin and the development of diabetes in patients with coronary artery disease and impaired fasting glucose

Adiponectin has insulin-sensitizing properties, and high adiponectin levels have been shown to be associated with reduced risk of developing diabetes. Patients with coronary artery disease (CAD) have relatively low adiponectin levels and high prevalence of glucose intolerance. The role of adiponectin in predicting the development of diabetes in this high-risk group has not been determined. The study aimed to determine whether baseline adiponectin levels predict the development of diabetes in a group of patients with CAD and impaired fasting glucose (IFG). A total of 588 patients who participated in the Bezafibrate Infarction Prevention (BIP) study and who had at baseline fasting glucose of 100-125 mg/dl were included and followed for 6.2+/-1.3 years. Adiponectin was determined in frozen plasma samples taken at baseline. Of the patients with IFG at baseline, 256 (44%) developed diabetes during follow-up. The patients who developed diabetes had at baseline higher body-mass index, fasting glucose, C-reactive protein, triglycerides, homeostatic assessment of insulin resistance (HOMA-IR) and diastolic blood pressure than patients who did not develop diabetes. Adiponectin levels at baseline were significantly lower in patients who developed diabetes than in patients who did not develop diabetes (P = 0.009, nonparametric Kruskall-Wallis test). An increase of 1 unit of natural logarithm of adiponectin level was associated with a hazard ratio of 0.77 (95% CI, 0.61-0.96) for diabetes development. Patients with CAD and IFG have a very high rate of conversion to type 2 diabetes. Even in this high-risk group, high adiponectin levels are associated with reduced risk of developing diabetes.

Hypertriglyceridemia—why, when and how should it be treated?

The relationship between serum triglyceride levels and cardiovascular disease has remained enigmatic despite four decades of research. The majority of the available evidence tends to support the role of hypertriglyceridemia as an independent risk factor for cardiovascular disease. However, there are no guidelines recommending a target triglyceride level for prevention of cardiovascular disease. The focus of lipid lowering therapy still remains the reduction of global cardiovascular risk by optimizing LDL cholesterol levels. Therapeutic options for triglyceride-lowering include lifestyle modification and pharmacological agents, such as fibrates, omega 3 fatty acids and niacin. Post-hoc analyses of the Helsinki Heart Study, Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial and Bezafibrate Infarction Prevention Study suggest a beneficial effect of the treatment of hypertriglyceridemia with fibrates, mainly in obese subjects with insulin resistance. However, in order to establish the actual clinical relevance of lowering triglyceride levels, prospective trials need to be conducted with the specific purpose of studying the effects of triglyceride reduction on clinical end points, i. e. coronary events and stroke.