Comparative effect of tumour necrosis factor inhibitors versus other biological agents on cardiovascular risk-associated biomarkers in patients with rheumatoid arthritis.

Background: To comparatively investigate the differential effect of second-line tumour necrosis factor inhibitors (TNFis) versus other biological agents on cardiovascular disease (CVD) risk-associated biomarkers in patients with rheumatoid arthritis (RA). Methods: We evaluated the serum levels of lipoprotein-associated apoproteins ApoA1 and ApoB100 and lipoprotein(a) (Lp(a)) and the leptin/adiponectin ratio (LAR) as an insulin resistance proxy in patients with RA from the Rotation Or Change (ROC) trial treated with either a second-line TNFi or another biologic (tocilizumab (TCZ), rituximab or abatacept) at baseline and week 24. We compared the changes in biomarker levels in each group and according to the EULAR response. Results: Of the 300 patients enrolled in the ROC trial, 203 were included in the study, including 96 in the second-line TNFi group and 107 in the other biological group. The measured biomarkers did not deteriorate between baseline and week 24 regardless of the group. A greater improvement in the LAR was noted in the other biological group (median (IQR) -0.12 ng/µg (-0.58 to 0.31) vs 0.04 (-0.19 to 0.43), p=0.033), and a greater improvement in the Lp(a) level was observed following treatment with TCZ than with a TNFi (-0.05 g/L (-0.11 to -0.01) vs -0.01 g/L (-0.02 to 0.01), p<0.001). When considering the patients' responses to treatment, improved biomarkers were mainly observed in the EULAR responders in each treatment group. Conclusions: TNFis and non-TNFis were neutral on improved CVD risk-associated biomarkers in patients with RA insufficiently controlled by TNFis. TCZ could be associated with a better improvement concerning Lp(a) and LAR than TNFis. This improvement could be related to a good therapeutic response, thereby supporting the need of good control of RA. Trial registration number: ClinicalTrials.gov Identifier NCT01000441, registered on 22 October 2009.

Baseline and on-statin treatment lipoprotein(a) levels for prediction of cardiovascular events: individual patient-data meta-analysis of statin outcome trials.

BACKGROUND: Elevated lipoprotein(a) is a genetic risk factor for cardiovascular disease in general population studies. However, its contribution to risk for cardiovascular events in patients with established cardiovascular disease or on statin therapy is uncertain. METHODS: Patient-level data from seven randomised, placebo-controlled, statin outcomes trials were collated and harmonised to calculate hazard ratios (HRs) for cardiovascular events, defined as fatal or non-fatal coronary heart disease, stroke, or revascularisation procedures. HRs for cardiovascular events were estimated within each trial across predefined lipoprotein(a) groups (15 to <30 mg/dL, 30 to <50 mg/dL, and ≥50 mg/dL, vs <15 mg/dL), before pooling estimates using multivariate random-effects meta-analysis. FINDINGS: Analyses included data for 29 069 patients with repeat lipoprotein(a) measurements (mean age 62 years [SD 8]; 8064 [28%] women; 5751 events during 95 576 person-years at risk). Initiation of statin therapy reduced LDL cholesterol (mean change -39% [95% CI -43 to -35]) without a significant change in lipoprotein(a). Associations of baseline and on-statin treatment lipoprotein(a) with cardiovascular disease risk were approximately linear, with increased risk at lipoprotein(a) values of 30 mg/dL or greater for baseline lipoprotein(a) and 50 mg/dL or greater for on-statin lipoprotein(a). For baseline lipoprotein(a), HRs adjusted for age and sex (vs <15 mg/dL) were 1·04 (95% CI 0·91-1·18) for 15 mg/dL to less than 30 mg/dL, 1·11 (1·00-1·22) for 30 mg/dL to less than 50 mg/dL, and 1·31 (1·08-1·58) for 50 mg/dL or higher; respective HRs for on-statin lipoprotein(a) were 0·94 (0·81-1·10), 1·06 (0·94-1·21), and 1·43 (1·15-1·76). HRs were almost identical after further adjustment for previous cardiovascular disease, diabetes, smoking, systolic blood pressure, LDL cholesterol, and HDL cholesterol. The association of on-statin lipoprotein(a) with cardiovascular disease risk was stronger than for on-placebo lipoprotein(a) (interaction p=0·010) and was more pronounced at younger ages (interaction p=0·008) without effect-modification by any other patient-level or study-level characteristics. INTERPRETATION: In this individual-patient data meta-analysis of statin-treated patients, elevated baseline and on-statin lipoprotein(a) showed an independent approximately linear relation with cardiovascular disease risk. This study provides a rationale for testing the lipoprotein(a) lowering hypothesis in cardiovascular disease outcomes trials. FUNDING: Novartis Pharma AG.

Treatment with the natural FXR agonist chenodeoxycholic acid reduces clearance of plasma LDL whilst decreasing circulating PCSK9, lipoprotein(a) and apolipoprotein C-III.

BACKGROUND: The natural farnesoid X receptor (FXR) agonist chenodeoxycholic acid (CDCA) suppresses hepatic cholesterol and bile acid synthesis and reduces biliary cholesterol secretion and triglyceride production. Animal studies have shown that bile acids downregulate hepatic LDL receptors (LDLRs); however, information on LDL metabolism in humans is limited. METHODS: Kinetics of autologous 125 I-LDL were determined in 12 male subjects at baseline and during treatment with CDCA (15 mg kg-1 day-1 ). In seven patients with gallstones treated with CDCA for 3 weeks before cholecystectomy, liver biopsies were collected and analysed for enzyme activities and for specific LDLR binding. Serum samples obtained before treatment and at surgery were analysed for markers of lipid metabolism, lipoproteins and the LDLR modulator proprotein convertase subtilisin/kexin type 9 (PCSK9). RESULTS: Chenodeoxycholic acid treatment increased plasma LDL cholesterol by ~10% as a result of reduced clearance of plasma LDL-apolipoprotein (apo)B; LDL production was somewhat reduced. The reduction in LDL clearance occurred within 1 day after initiation of treatment. In CDCA-treated patients with gallstones, hepatic microsomal cholesterol 7α-hydroxylase and HMG-CoA reductase activities were reduced by 83% and 54%, respectively, and specific LDLR binding was reduced by 20%. During treatment, serum levels of fibroblast growth factor 19 and total and LDL cholesterol increased, whereas levels of 7α-hydroxy-4-cholesten-3-one, lathosterol, PCSK9, apoA-I, apoC-III, lipoprotein(a), triglycerides and insulin were reduced. CONCLUSIONS: Chenodeoxycholic acid has a broad influence on lipid metabolism, including reducing plasma clearance of LDL. The reduction in circulating PCSK9 may dampen its effect on hepatic LDLRs and plasma LDL cholesterol. Further studies of the effects of other FXR agonists on cholesterol metabolism in humans seem warranted, considering the renewed interest for such therapy in liver disease and diabetes.

The effect of various menopausal hormone therapies on markers of inflammation, coagulation, fibrinolysis, lipids, and lipoproteins in healthy postmenopausal women.

OBJECTIVE: Androgenic progestins such as norethisterone acetate (NETA) may influence the effect of estradiol (E(2)) therapy. We compared the influence of oral E(2), with and without NETA, and transdermal E(2) on markers of coagulation, fibrinolysis, and inflammation and on lipids and lipoproteins in healthy postmenopausal women. DESIGN: A total of 112 healthy postmenopausal women were randomized to receive treatment with either oral E(2), with or without NETA, transdermal E(2), or placebo. At baseline and after 28 weeks, levels of serum lipids and lipoproteins and markers of coagulation, fibrinolysis, and inflammation were determined. RESULTS: Of the fibrinolytic parameters, oral E(2) (P < 0.05) and E(2) with NETA (P < 0.01) shortened euglobulin clot lysis time. Oral E(2) decreased plasminogen activator inhibitor-1 activity (P < 0.05). Oral E(2) with NETA reduced plasminogen activator inhibitor-1 antigen levels (P < 0.01) and increased D-dimer antigen levels (P < 0.001). All three modes of menopausal hormone therapy reduced tissue type plasminogen activator antigen. Of the coagulation parameters, both routes of E(2) therapy decreased fibrinogen levels (P = 0.002 for oral and P = 0.007 for transdermal E(2)), whereas E(2) with NETA showed no effect. The decrease of fibrinogen was larger after oral E(2) (P = 0.02). Oral E(2) with NETA reduced antithrombin III (P < 0.001) and protein C (P < 0.001) activity. Oral E(2) (P = 0.04) and E(2) with NETA (P < 0.01) increased C-reactive protein (CRP). Transdermal E(2) showed no influence on CRP. The addition of NETA influenced the change in CRP, as the increase in CRP was more pronounced after E(2) without NETA (P = 0.005). The levels of serum amyloid A, interleukin-6, and tumor necrosis factor-alpha did not change significantly after any of the modes of hormone therapy. Of the lipids and lipoproteins, oral E2 decreased low-density lipoprotein cholesterol (P < 0.01), lipoprotein (a) (P < 0.05), and increased high-density lipoprotein cholesterol (P < 0.05). Transdermal E(2) decreased triglycerides (P < 0.02) and increased high-density lipoprotein cholesterol (P < 0.03). Oral E(2) with NETA decreased total cholesterol (P < 0.01) and high-density lipoprotein cholesterol (P < 0.005). CONCLUSIONS: Oral E(2), with or without NETA, produced no net activation of coagulation but improved fibrinolysis. Both modes of oral menopausal hormone therapy have a greater impact on markers of inflammation, coagulation, fibrinolysis, lipids, and lipoproteins than transdermal E(2). NETA attenuates some E(2) effects. Further studies are needed to elucidate the impact of these effects on clinical endpoints.

The effects of 17 beta-oestradiol plus dydrogesterone compared with conjugated equine oestrogens plus medroxyprogesterone acetate on lipids, apolipoproteins and lipoprotein(a).

OBJECTIVE: To compare the effects of 17 beta-oestradiol plus dydrogesterone with conjugated equine oestrogens plus medroxyprogesterone acetate on serum lipids, apolipoproteins and lipoprotein(a) in postmenopausal women. METHODS: A multi-centre, prospective, randomised, double-blind, comparative one-year study in 362 healthy postmenopausal women aged 39-74 years with an intact uterus. Fasting blood samples were taken at baseline and after 28 and 52 weeks of treatment. Participants received daily oral treatment with continuous combined 1 mg micronised 17 beta-oestradiol/5 mg dydrogesterone (E/D: n=180) or 0.625 mg conjugated equine oestrogens/5 mg medroxyprogesterone acetate (CEE/MPA: n=182). RESULTS: Significant differences between the two groups after 52 weeks were observed for total cholesterol (E/D: -1.7%; CEE/MPA: -7.3%), LDL-cholesterol (E/D: -4.5%; CEE/MPA: -11.3%), HDL-cholesterol (E/D: +15.3%; CEE/MPA: +7.5%), triglycerides (E/D: +9.8%; CEE/MPA: +16.6%), VLDL-triglycerides (E/D: -3.3%; CEE/MPA: +10.0%), lipoprotein(a) (E/D: 0.0%; CEE/MPA: -25.2%) and for the ratio apolipoprotein B/LDL-cholesterol (E/D: +0.9%; CEE/MPA +5.9%). CONCLUSIONS: E/D and CEE/MPA differ in their anti-atherogenic effects on lipids and lipoproteins. This however can not easily be translated to differences in clinical cardiovascular outcomes.

Effects of intranasal estradiol treatment on serum lipoprotein(a) and lipids in hysterectomized women.

The aim of the present study was to evaluate the effects of intranasal estradiol on lipid metabolism and lipoprotein(a) [Lp(a)] levels. A prospective comparative study was designed: 49 hysterectomized, healthy postmenopausal women received intranasal 17beta-estradiol (E2; 300 microg/day). Blood samples were collected at baseline and at the end of the 3 and 6 months of therapy. After 6 months, the serum levels of total cholesterol, LDL-cholesterol and triglycerides did not show any significant change with intranasal 17beta-E2 therapy. HDL-cholesterol levels at 3 and 6 months of treatment were significantly increased compared with baseline levels (p = 0.031, p = 0.000, respectively). There was a significant change in serum Lp(a) levels at the 6th month (p = 0.003) but not at the 3rd month (p = 0.183) compared with the baseline levels. Further studies are needed to detect whether these changes are significant and permanent or not.

Oral, more than transdermal, estrogen therapy improves lipids and lipoprotein(a) in postmenopausal women: a randomized, placebo-controlled study.

OBJECTIVE: To assess the effects of low-dose oral and transdermal estrogen therapy on the lipid profile and lipoprotein(a) [Lp(a)] levels in healthy, postmenopausal women and to study the additional influence of gestodene administration. DESIGN: In a multicenter, randomized, double-blind, placebo-controlled study, 152 healthy, hysterectomized, postmenopausal women received daily either placebo (n = 49), 50 microg transdermal 17beta-estradiol (tE2, n = 33), 1 mg oral 17beta-estradiol (oE2, n = 37), or 1 mg oE2 combined with 25 microg gestodene (oE2 + G, n = 33) for 13 cycles of 28 days, followed by 4 cycles of placebo in each group. Fasting serum concentrations of total, high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol, triglycerides, and Lp(a) were measured at baseline and in cycles 4, 13, and 17. RESULTS: In cycle 13, a significant mean percentage decrease from baseline was found in all treatment groups compared with placebo in total cholesterol (tE2, -4.7%; oE2, -6.9%; oE2 + G, -10.5%) and LDL cholesterol (tE2, -5.8%; oE2, -12.6%; oE2 + G, -13.6%). For both oral groups, the reductions were already significant in cycle 4. None of the treatment groups showed a significant change in HDL cholesterol or triglycerides. In cycle 13, Lp(a) was decreased compared with placebo in the oE2 group (-6.6%) and the oE2 + G group (-8.2%). After washout, all observed changes had returned to baseline level, except for the decreases in total and LDL cholesterol in the oE2 + G group. CONCLUSIONS: Oral E2 and E2 + G, and to a lesser extent transdermal E2, decreased total and LDL cholesterol. Lp(a) was lowered only by the oral treatments.

Hormone replacement therapy does not affect plasma homocysteine in postmenopausal women with coronary artery disease. Free tissue factor pathway inhibitor antigen, a circulating anticoagulant, is related to plasma homocysteine.

OBJECTIVE: The objective was to evaluate the effect of hormone replacement therapy (HRT) on plasma homocysteine levels in postmenopausal women with coronary artery disease (CAD) and to investigate associations of homocysteine to other cardiovascular risk factors. METHODS: The women in this single-center, controlled, and randomized study were examined at baseline, and after 3 and 12 months, after they had been recruited consecutively from patients referred for investigational coronary angiography. All analyses were performed examiner blind. They were randomized to HRT consisting of transdermal application of continuous 17beta-estradiol with cyclic medroxyprogesterone acetate (MPA) tablets for 14 days every 3rd month, or to a control group. RESULTS: After 3 months of unopposed 17beta-estradiol, no significant effect on homocysteine was observed compared to the control group. The absolute decrease of 5% in median plasma homocysteine levels after 12-month HRT did not reach statistical significance. Plasma homocysteine seemed slightly higher in women with three- or four-vessel disease, but the difference was not significant. With increasing homocysteine levels, free tissue factor pathway inhibitor (TFPI) antigen increased, whereas E-selectin decreased. In women with diabetes or elevated blood glucose >6.0 mmol/l, plasma homocysteine was correlated to body mass index, C-peptide and insulin as well as age. CONCLUSION: Transdermal application of 17beta-estradiol and sequential MPA do not affect plasma homocysteine in women with established CAD. Plasma homocysteine is stable in women with CAD over time, and unless special intervention is undertaken, repetitive measurements are not necessary in this particular group of high-risk individuals. The circulating anticoagulant TEPI is related to plasma homocysteine.

Effect of hormone replacement therapy on lipids in perimenopausal and early postmenopausal women.

OBJECTIVE: To determine the effects of oral sequential hormone replacement therapy (HRT) on lipid-profile in perimenopausal and early postmenopausal women. METHODS: We performed a single-center, randomized, placebo-controlled trial. The trial was double blind with respect to 17beta-estradiol/desogestrel (17beta-E-D) and placebo and open with respect to conjugated estrogens/norgestrel (CEE-N). A total of 125 healthy perimenopausal and early postmenopausal women, aged 43-58 years, were recruited from the general population in Zoetermeer, the Netherlands. The intervention consisted of 6 months treatment with 1.5 mg 17beta-estradiol/0.15 mg desogestrel (n=53), 0.625 mg conjugated estrogens/0.15 mg norgestrel (n=36) or placebo (n=36). At baseline, cycle 1, 3 and 6, overnight fasting blood samples were obtained in which lipids were determined. We used linear regression analysis to calculate differences in mean change from baseline in lipids in the active treatment groups compared to placebo. RESULTS: In both treatment groups significant (P<0.05) falls in low-density-lipoprotein (LDL)-cholesterol (17beta-E-D: -7.8% and CEE-N: -8.4%) and lipoprotein(a) (17beta-E-D: -11.7% and CEE-N: -28.3%) were found compared to placebo. Apolipoprotein A1 (17beta-E-D: 6.8% and CEE-N: 7.3%) and HDL-cholesterol (17beta-E-D: 6.4% and CEE-N: 8.0%) significantly increased compared to placebo. No significant changes were found in the other lipids. Mean changes from baseline in total cholesterol, LDL-cholesterol and apolipoprotein B were significantly more pronounced in postmenopausal women compared to perimenopausal women, adjustment for age-differences did not change the results. CONCLUSION: Treatment of perimenopausal and early postmenopausal women with 17beta-E-D or CEE-N changes their lipid-profile in a potentially anti-atherogenic direction. Changes appear to be more pronounced in postmenopausal women compared to perimenopausal women.

The effect of atorvastatin on serum lipids, lipoprotein(a) and plasma fibrinogen levels in primary dyslipidaemia--a pilot study involving serial sampling.

We conducted an open-label study to test the effects of atorvastatin on serum lipids, lipoprotein(a) [Lp(a)] and plasma fibrinogen levels. A total of 90 dyslipidaemic, non-smoking patients (45 patients with primary hypercholesterolaemia and 45 patients with primary mixed hyperlipidaemia) aged 48 +/- 11 years were studied. The patients were treated with 20 mg of atorvastatin for 24 weeks, in a single nocturnal dose. At baseline and every eight weeks, the fasting lipid profile, together with serum Lp(a) and plasma fibrinogen levels (Clauss method), were measured. Atorvastatin was highly effective in normalising the serum lipid profile. No significant change in median serum Lp(a) levels was observed in the whole group of patients (0.14 g/l before, vs. 0.16 g/l after, treatment) as well as in patients with raised (> 0.30 g/l) baseline levels (n = 32). A small non-significant increase of plasma fibrinogen was found (3.04 g/l vs. 3.14 g/l) after 24 weeks of atorvastatin administration. The effects of atorvastatin on both these variables did not differ in patients with hypercholesterolaemia or mixed hyperlipidaemia. In conclusion, our findings suggest that the effect of atorvastatin on plasma fibrinogen levels in dyslipidaemic patients without evident vascular disease is not clinically relevant. Furthermore, any rise in fibrinogen levels that may occur is likely to be transient in nature. Further studies are necessary to clarify this issue. There was no evidence that atorvastatin influences serum Lp(a) levels.

Determinants of human apolipoprotein [a] secretion from mouse hepatocyte cultures.

Efforts to develop an in vitro model system to analyze apolipoprotein [a] (apo[a]) gene transcription, mRNA translation, and protein secretion have been complicated by the limited tissue and species distribution of apo[a] and the presence of regulatory DNA sequences remote from the apo[a] transcription start site. In the current study we examined primary hepatocytes cultured from apo[a] transgenic mice as a model system for analyzing apo[a] biogenesis. Hepatocytes from mice transgenic for a yeast artificial chromosome (YAC) encoding the entire apo[a] gene in its own genomic context (YAC-apo[a] hepatocytes) were unable to maintain apo[a] expression beyond 48 h of culture. This suggests that the apo[a] promoter was not active in cultured YAC-apo[a] hepatocytes. In contrast, apo[a] expression was maintained for at least 7 days in hepatocytes cultured from mice transgenic for an apo[a] cDNA under control of the mouse transferrin promoter (transferrin-apo[a] hepatocytes). Pulse-chase experiments established that more than 80% of apo[a] synthesized by both transferrin-apo[a] and YAC-apo[a] hepatocytes was degraded prior to secretion, independently of the coexpression of human apoB.Thus, low secretion efficiency appears to be a general characteristic of human apo[a] proteins in mouse liver. Apo[a] secretion was increased somewhat (from 18% to 32%) in the presence of lipoprotein-containing serum. Transformed cell lines derived from transferrin apo[a] hepatocytes retained characteristics of apo[a] secretion similar to those observed in primary cells. Primary and transformed apo[a] transgenic hepatocytes may provide valuable additional models with which to study posttranslational mechanisms regulating apo[a] secretion. - Wang, J., J. Boedeker, H. H. Hobbs, and A. L. White. Determinants of human apolipoprotein [a] secretion from mouse hepatocyte cultures. J. Lipid Res. 2001. 42: 60;-69.

Etofibrate but not controlled-release niacin decreases LDL cholesterol and lipoprotein (a) in type IIb dyslipidemic subjects

Etofibrate is a hybrid drug which combines niacin with clofibrate. After contact with plasma hydrolases, both constituents are gradually released in a controlled-release manner. In this study, we compared the effects of etofibrate and controlled-release niacin on lipid profile and plasma lipoprotein (a) (Lp(a)) levels of patients with triglyceride levels of 200 to 400 mg/dl, total cholesterol above 240 mg/dl and Lp(a) above 40 mg/dl. These patients were randomly assigned to a double-blind 16-week treatment period with etofibrate (500 mg twice daily, N = 14) or niacin (500 mg twice daily, N = 11). In both treatment groups total cholesterol, VLDL cholesterol and triglycerides were equally reduced and high-density lipoprotein cholesterol was increased. Etofibrate, but not niacin, reduced Lp(a) by 26 percent and low-density lipoprotein (LDL) cholesterol by 23 percent. The hybrid compound etofibrate produced a more effective reduction in plasma LDL cholesterol and Lp(a) levels than controlled-release niacin in type IIb dyslipidemic subjects

Fibrinolysis and lipoprotein(a) in women with coronary artery disease. Influence of hormone replacement therapy.

BACKGROUND AND OBJECTIVES: The incidence of coronary artery disease (CAD) is higher in post-menopausal than in pre-menopausal women. Epidemiological studies suggest that hormone replacement therapy (HRT) decreases the risk of cardiovascular disease in post-menopausal women. HRT could modify the cardiovascular risk via several mechanisms, including modifications in the fibrinolytic system and lipoprotein (a) levels. Our study was aimed at investigating some of these modifications. DESIGN AND METHODS: In the cross-sectional part of the study we evaluated several components of the fibrinolytic system, coagulation inhibitors and lipid profile in premenopausal (n=15) and post-menopausal women (n=64) with CAD and compared these parameters with those of healthy pre-menopausal (n=31) and post-menopausal women (n=88). The prospective part of the study analyzed the effect of HRT with transdermal estrogen with or without progestogen in post-menopausal women with CAD. RESULTS: Pre- and postmenopausal women with CAD showed significant lower fibrinolytic activity and higher plasminogen activator inhibitor type 1 (PAI-1) levels than their control groups. Lp(a) levels were higher in premenopausal women with CAD than in healthy premenopausal women. In post-menopausal women with CAD, HRT induced a significant decrease in PAI-1 and Lp(a) levels. No significant differences were observed in any parameter studied between the groups treated with transdermal estrogen with and without progestogen. INTERPRETATION AND CONCLUSIONS: CAD is associated with a decrease in fibrinolytic activity, possibly due to an increase in PAI-1 levels. An increase in fibrinolytic activity and a decrease in PAI-1 and Lp(a) levels were observed in CAD women receiving transdermal HRT and these changes may have a favorable impact on the risk of new cardiovascular events in post-menopausal CAD women.

Continuous versus cyclical transdermal oestrogen replacement therapy in postmenopausal women: effects on lipoprotein(a) and nitric oxide levels.

The purpose of our study was to compare the effects of cyclical versus continuous transdermal oestrogen replacement therapy on lipoprotein (a) (Lp(a)) and nitric oxide levels. The patients were randomly assigned into two groups. The first group received transdermal 17-beta oestradiol 50 microg/day for 21 days and the second group the same treatment on a continuous basis. Medroxyprogesterone acetate (10 mg/day orally) was added between the 14th and 25th days to each group. Lipoprotein (a) and nitric oxide levels were measured before the study and after six months. These values were compared using the Wilcoxon rank test within the groups and the unpaired t-test between the groups. Lipoprotein (a) levels decreased significantly in each group at the sixth month (p < 0.05). When compared between the groups, the decrease of lipoprotein (a) levels in the second group was more prominent at the sixth month (p < 0.05). Nitric oxide levels increased in each group after six months (p < 0.05). No difference in nitric oxide levels was observed between the groups before and after the therapy (p > 0.05). Continuous transdermal estradiol had a better effect on lipoprotein (a) levels than cyclical therapy The seven day pause in the 21-day administration did not affect nitric oxide levels negatively after six months.

Changes in HDL-cholesterol and lipoprotein Lp(a) after 6-month treatment with finasteride in males affected by benign prostatic hyperplasia (BPH).

Androgen effects on lipoproteins, mainly high density lipoprotein (HDL), could be exerted by a direct interaction of testosterone (T) or dihydrotestosterone (DHT) with liver androgen receptors. To assess if T needs to be converted into DHT to affect lipid metabolism, 13 patients were studied, affected with benign prostatic hyperplasia (BPH) and treated with an inhibitor of 5 alpha-reductase (finasteride). They were compared with 15 untreated controls. At baseline and after 3 and 6 months of therapy, each patient was evaluated as for lipoprotein and hormone concentrations, as well as for nutritional status. Body composition was assessed by anthropometry and bio-impedance analysis (BIA). Treatment was associated with a significant increase of HDL-cholesterol (HDL-C), mainly HDL3 subclass, and lipoprotein(a) (Lp(a)), as well as a decline of DHT, whereas no significant changes were apparent for T, estradiol (E2), sex hormone binding hormone (SHBG) and body composition indexes. However, no significant associations between DHT and lipid relative changes were apparent at bivariate correlation analysis. This finding was confirmed by comparing patient subsets identified by cluster analysis, according to HDL subclass individual responses. Rather, a slight association with E2 for HDL2 (positive) and HDL3 (negative) was found. In conclusion, finasteride can modify HDL and Lp(a) concentrations. However, by the data, these effects cannot be definitively attributed to the changes in DHT synthesis induced by finasteride, since a direct and non-specific interference of the drug on liver metabolism cannot be excluded.

Insulin-like growth factor binding protein-1 (IGFBP-1) and IGF-I during oral and transdermal estrogen replacement therapy: relation to lipoprotein(a) levels.

Low levels of insulin-like growth factor binding protein-1 (IGFBP-1) have recently been associated with several risk factors for cardiovascular disease. The effects of estrogen replacement therapy (ERT) on plasma IGFBP-1 levels are, however, unclear. A double-blind, placebo-controlled study for 6 months was conducted in 73 hysterectomized postmenopausal women randomized into two groups: oral estradiol (E2) valerate, 2 mg/day (n = 35) and transdermal E2 gel, 1 mg/day (n=38). Plasma IGFBP-1, insulin-like growth factor-I (IGF-I) and lipoprotein(a) (Lp(a)) were determined at baseline, 3 and 6 months. The groups were similar for age and BMI. The baseline levels of estrone (E1), E2, IGFBP-1, IGF-I and Lp(a) did not differ between the groups. During treatment, serum estradiol concentrations increased in both groups. During oral ERT, IGFBP-1 levels increased by 104% (P<0.001), whereas IGF-I levels decreased by 13% (mean, P<0.05). IGF-I and IGFBP-1 levels remained unchanged in the transdermal group. Lp(a) levels decreased by 23% (median, P<0.001) in the oral group, but were unaffected by transdermal therapy. The change in IGFBP-1 concentrations during oral ERT showed an inverse correlation to that in Lp(a) (r = -0.40, P<0.05, Spearman correlation). In conclusion, oral ERT seems to enhance plasma levels of IGFBP-1, which may be one reason for the reduced Lp(a) levels.

Effect of tamoxifen on lipoprotein(a) and insulin-like growth factor-I (IGF-I) in healthy women.

Studies in breast cancer patients have shown that tamoxifen decreases circulating levels of lipoprotein(a) (Lp(a)), an independent risk factor for premature coronary heart disease, and insulin-like growth factor-I (IGF-I), a promising surrogate biomarker for breast cancer. Since a common hormone regulatory pathway has been suggested for both biomarkers, we measured Lp(a) levels for 6 months in 68 healthy women participating in a chemoprevention trial of tamoxifen and correlated its changes with IGF-I. After 1 month, mean Lp(a) levels decreased by 23% with tamoxifen and increased by 6% with placebo (P = 0.033). No further change was observed after 2 and 6 months. Women with abnormal values at baseline (i.e. > 30 mg/dl) showed the highest reduction. The mean levels of IGF-I decreased by 23.5% with tamoxifen and remained stable with placebo, but the changes induced by tamoxifen in Lp(a) and IGF-I levels were uncorrelated. Our results support the observation that tamoxifen may be a suitable preventive option for women with multiple disease risk factors.