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1.  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 
The 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.
Metabolic 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.
During 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).
Long-term treatment by bezafibrate was not associated with longitudinal ProBNP changes in patients with pre-existing CAD and advanced functional capacity impairment.
PMCID: PMC2645368  PMID: 19173749
2.  Does the lipid-lowering peroxisome proliferator-activated receptors ligand bezafibrate prevent colon cancer in patients with coronary artery disease? 
Epidemiologic 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.
Our 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.
Development 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.
Our data, derived from patients with coronary artery disease, support the hypothesis regarding a possible preventive effect of bezafibrate on the development of colon cancer.
PMCID: PMC2440374  PMID: 18565233
3.  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.
PMCID: PMC1592077  PMID: 17002798
4.  Statins research unfinished saga: desirability versus feasibility 
Drugs in the same class are generally thought to be therapeutically equivalent because of similar mechanisms of action (the so-called "class effect"). However, statins differ in multiple characteristics, including liver and renal metabolism, half-life, effects on several serum lipid components, bioavailability and potency. Some are fungal derivatives, and others are synthetic compounds. The percentage absorption of an oral dose, amount of protein binding, degree of renal excretion, hydrophilicity, and potency on a weight basis is variable. These differences may be even greater in diabetic patients, who may present diabetes-induced abnormalities in P450 isoforms and altered hepatic metabolic pathways. Thus, it is obvious that head-to-head comparisons between different statins are preferable than trial-to-trial comparisons. Such assessments are of utmost importance, especially in cases in which specific populations with a distinct lipid profile and altered metabolic pathways, like diabetics, are studied. It should be specially pinpointed that patients with metabolic syndrome and diabetes constitute also a special population regarding their atherogenic dyslipidemia, which is usually associated with low HDL-cholesterol, hypertriglyceridemia and predominance of small dense LDL-cholesterol. Therefore, these patients may benefit from fibrates or combined statin/fibrate treatment. This policy is not accomplished since in the real world things are more complex. Trials would require very large sample sizes and long-term follow-up to detect significant differences in myocardial infarction or death between two different statins. Moreover, the fact that new compounds are under several phases of research and development represents an additional drawback for performing the trials. Ideally, head-to-head trials regarding clinically important outcomes should be conducted for all drugs. Nonetheless, the desirability of performing such trials, which epitomize modern evidence-based medicine, is frequently superseded by the feasibility dictated by pragmatic and economic circumstances. In the latter case, in absence of solid systematic documentation of comparable health benefits and long-term safety, both researchers and practicing physicians should allude to the weight of scientific endorsement behind the arguments and seek for the possible strengths and weaknesses intrinsic to each specific study. In any case, conclusions based on surrogate endpoints cannot completely substitute head-to-head comparisons regarding patients' outcome.
PMCID: PMC1156921  PMID: 15941471
coronary artery disease; diabetes; hyperlipidemia; statins; trials
5.  Increased prevalence of left ventricular hypertrophy in hypertensive women with type 2 diabetes mellitus 
Left ventricular hypertrophy (LVH) is a powerful independent risk factor for cardiovascular morbidity and mortality among hypertensive patients. Data regarding relationships between diabetes and LVH are controversial and inconclusive, whereas possible gender differences were not specifically investigated. The goal of this work was to investigate whether gender differences in left heart structure and mass are present in hypertensive patients with type 2 diabetes.
Five hundred fifty hypertensive patients with at least one additional cardiovascular risk factor (314 men and 246 women, age 52 to 81, mean 66 ± 6 years), were enrolled in the present analysis. In 200 (36%) of them – 108 men and 92 women – type 2 diabetes mellitus was found upon enrollment. End-diastolic measurements of interventricular septal thickness (IVS), LV internal diameter, and posterior wall thickness were performed employing two-dimensionally guided M-mode echocardiograms. LVH was diagnosed when LV mass index (LVMI) was >134 g/m2 in men and >110 g/m2 in women.
Mean LVMI was significantly higher among diabetic vs. nondiabetic women (112.5 ± 29 vs. 105.6 ± 24, p = 0.03). In addition, diabetic women presented a significantly higher prevalence of increased IVS thickness, LVMI and left atrial diameter on intra-gender comparisons. The age adjusted relative risk for increased LVMI in diabetics vs. nondiabetics was 1.47 (95% CI: 1.0–2.2) in females and only 0.8 (0.5–1.3) in males.
Type 2 diabetes mellitus was associated with a significantly higher prevalence of LVH and left atrial enlargement in hypertensive women.
PMCID: PMC317343  PMID: 14633284
Diabetes mellitus; Echocardiography; Hypertension; Left ventricular hypertrophy

Results 1-5 (5)