Detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III)

The protective effects of estrogen on the cardiovascular system

Summary Guidance is provided in a European setting on the assessment and treatment of postmenopausal women with or at risk from osteoporosis. Introduction The European Foundation for Osteoporosis and Bone disease (subsequently the International Osteopo- rosis Foundation) published guidelines for the diagnosis and management of osteoporosis in 1997. This manuscript updates these in a European setting. Methods The following areas are reviewed: the role of bone mineral density measurement for the diagnosis of osteoporo- sis and assessment of fracture risk; general and pharmaco- logical management of osteoporosis; monitoring of treatment; assessment of fracture risk; case finding strategies; investigation of patients; health economics of treatment. Results and conclusions A platform is provided on which specific guidelines can be developed for national use.

/pdf/european-guidance-for-the-diagnosis-and-management-of-bexvs3o205.pdf

European guidance for the diagnosis and management of osteoporosis in postmenopausal women

http://hwmaint.circ.ahajournals.org/cgi/reprint/110/9/e82.pdf

ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction

ContextRaloxifene hydrochloride is a selective estrogen
receptor modulator that has antiestrogenic effects on breast and
endometrial tissue and estrogenic effects on bone, lipid metabolism,
and blood clotting.ObjectiveTo determine whether women taking raloxifene have a
lower risk of invasive breast cancer.Design and SettingThe Multiple Outcomes of Raloxifene Evaluation
(MORE), a multicenter, randomized, double-blind trial, in which women
taking raloxifene or placebo were followed up for a median of 40 months
(SD, 3 years), from 1994 through 1998, at 180 clinical centers composed
of community settings and medical practices in 25 countries, mainly in
the United States and Europe.ParticipantsA total of 7705 postmenopausal women, younger than 81
(mean age, 66.5) years, with osteoporosis, defined by the presence of
vertebral fractures or a femoral neck or spine T-score of at least 2.5
SDs below the mean for young healthy women. Almost all participants
(96%) were white. Women who had a history of breast cancer or who were
taking estrogen were excluded.InterventionRaloxifene, 60 mg, 2 tablets daily; or raloxifene, 60
mg, 1 tablet daily and 1 placebo tablet; or 2 placebo tablets.Main Outcome MeasuresNew cases of breast cancer, confirmed by
histopathology. Transvaginal ultrasonography was used to assess the
endometrial effects of raloxifene in 1781 women. Deep vein thrombosis
or pulmonary embolism were determined by chart review.ResultsThirteen cases of breast cancer were confirmed among the
5129 women assigned to raloxifene vs 27 among the 2576 women assigned
to placebo (relative risk [RR], 0.24; 95% confidence interval
[CI], 0.13-0.44; P<.001). To prevent 1 case of breast
cancer, 126 women would need to be treated. Raloxifene decreased the
risk of estrogen receptor–positive breast cancer by 90% (RR, 0.10;
95% CI, 0.04-0.24), but not estrogen receptor–negative invasive
breast cancer (RR, 0.88; 95% CI, 0.26-3.0). Raloxifene increased the
risk of venous thromboembolic disease (RR, 3.1; 95% CI, 1.5-6.2), but
did not increase the risk of endometrial cancer (RR, 0.8; 95% CI,
0.2-2.7).ConclusionAmong postmenopausal women with osteoporosis, the
risk of invasive breast cancer was decreased by 76% during 3 years of
treatment with raloxifene.

https://jamanetwork.com/journals/jama/articlepdf/190420/joc90196.pdf

The Effect of Raloxifene on Risk of Breast Cancer in Postmenopausal Women: Results From the MORE Randomized Trial

Context.—Raloxifene is a selective estrogen receptor modulator that has estrogen-agonistic
effects on bone and estrogen-antagonistic effects on breast and uterus.Objective.—To identify the effects of raloxifene on markers of cardiovascular risk
in postmenopausal women, and to compare them with those induced by hormone
replacement therapy (HRT).Design.—Double-blind, randomized, parallel trial.Setting.—Eight sites in the United States.Participants.—390 healthy postmenopausal women recruited by advertisement.Intervention.—Participants were randomized to receive 1 of 4 treatments: raloxifene,
60 mg/d; raloxifene, 120 mg/d; HRT (conjugated equine estrogen, 0.625 mg/d,
and medroxyprogesterone acetate, 2.5 mg/d); or placebo.Main Outcome Measures.—Change and percent change from baseline of lipid levels and coagulation
parameters after 3 months and 6 months of treatment.Results.—At the last visit completed, compared with placebo, both dosages of
raloxifene significantly lowered low-density lipoprotein cholesterol (LDL-C)
by 12% (P<.001), similar to the 14% reduction
with HRT (P<.001). Both dosages of raloxifene
significantly lowered lipoprotein(a) by 7% to 8% (P<.001),
less than the 19% decrease with HRT (P<.001).
Raloxifene increased high-density lipoprotein-2 cholesterol (HDL2-C)
by 15% to 17% (P<.05), less than the 33% increase
with HRT (P<.001). Raloxifene did not significantly
change high-density lipoprotein cholesterol (HDL-C), triglycerides, or plasminogen
activator inhibitor-1 (PAI-1); whereas HRT increased HDL-C by 11% and triglycerides
by 20%, and decreased PAI-1 by 29% (for all, P<
.001). Raloxifene significantly lowered fibrinogen by 12% to 14% (P<.001), unlike HRT, which had no effect. Neither treatment changed
fibrinopeptide A or prothrombin fragment 1 and 2.Conclusions.—Raloxifene favorably alters biochemical markers of cardiovascular risk
by decreasing LDL-C, fibrinogen, and lipoprotein(a), and by increasing HDL2-C without raising triglycerides. In contrast to HRT, raloxifene had
no effect on HDL-C and PAI-1, and a lesser effect on HDL2-C and
lipoprotein(a). Further clinical trials are necessary to determine whether
these favorable biochemical effects are associated with protection against
cardiovascular disease.

https://jamanetwork.com/journals/jama/articlepdf/187517/JOC72104.pdf

Effects of Raloxifene on Serum Lipids and Coagulation Factors in Healthy Postmenopausal Women

ContextRaloxifene, a selective estrogen receptor modulator, improves cardiovascular
risk factors, but its effect on cardiovascular events is unknown.ObjectiveTo determine the effect of raloxifene on cardiovascular events in osteoporotic
postmenopausal women.DesignSecondary analysis of data from the Multiple Outcomes of Raloxifene
Evaluation trial, a randomized, double-blind, placebo-controlled trial conducted
between November 1994 and September 1999.SettingOutpatient and community settings at 180 sites in 25 countries.ParticipantsA total of 7705 osteoporotic postmenopausal women (mean age, 67 years).InterventionPatients were randomly assigned to receive raloxifene, 60 mg/d (n =
2557), or 120 mg/d (n = 2572), or placebo (n = 2576) for 4 years.Main Outcome MeasuresCardiovascular events, including coronary events (myocardial infarction,
unstable angina, or coronary ischemia) and cerebrovascular events (stroke
or transient ischemic attack), collected as safety end points and subsequently
adjudicated by a cardiologist blinded to therapy. Cardiovascular risk at study
entry was determined by the presence of multiple cardiovascular risk factors
or prior coronary events or revascularization procedure.ResultsIn the overall cohort, there were no significant differences between
treatment groups in the number of combined coronary and cerebrovascular events:
96 (3.7%) with placebo, 82 (3.2%) with 60 mg/d of raloxifene, and 94 (3.7%)
with 120 mg/d of raloxifene. Relative risks (RRs) were 0.86 (95% confidence
interval [CI], 0.64-1.15) and 0.98 (95% CI, 0.74-1.30) for 60 mg/d and 120
mg/d of raloxifene, respectively. Similar results were obtained when coronary
and cerebrovascular events were analyzed separately. Among the subset of 1035
women with increased cardiovascular risk at baseline, those assigned to raloxifene
had a significantly lower risk of cardiovascular events compared with placebo
(RR, 0.60; 95% CI, 0.38-0.95 for both raloxifene groups). The number of cardiovascular
events during the first year was not significantly different across groups
in the overall cohort (P = .94), or among women at
increased cardiovascular risk (P = .86) or with evidence
of established coronary heart disease (P = .60).ConclusionsRaloxifene therapy for 4 years did not significantly affect the risk
of cardiovascular events in the overall cohort but did significantly reduce
the risk of cardiovascular events in the subset of women with increased cardiovascular
risk. There was no evidence that raloxifene caused an early increase in risk
of cardiovascular events. Before raloxifene is used for prevention of cardiovascular
events, these findings require confirmation in trials with evaluation of cardiovascular
outcomes as the primary objective.

https://jamanetwork.com/journals/jama/articlepdf/194654/joc11015.pdf

Raloxifene and Cardiovascular Events in Osteoporotic Postmenopausal Women: Four-Year Results From the MORE (Multiple Outcomes of Raloxifene Evaluation) Randomized Trial

C-Reactive protein and homocysteine are independent risk factors for the development of cardiovascular disease. This study compared the effects of hormone replacement therapy (HRT) and raloxifene on serum C-reactive protein and homocysteine levels as markers of cardiovascular risk in healthy postmenopausal women. Healthy postmenopausal women (n = 390) were enrolled in a double blind, randomized, placebo-controlled, 6-month trial at eight out-patient sites in the United States. Women were randomly assigned to receive continuous combined HRT (0.625 mg/day conjugated equine estrogen and 2.5 mg/day medroxyprogesterone acetate), raloxifene (60 or 120 mg/day), or placebo for 6 months. C-Reactive protein and homocysteine were measured in baseline and 6-month serum samples. HRT increased C-reactive protein levels by 84% (P 0.2). Raloxifene (60 and 120 mg/day) significantly lowered serum levels of homocystein...

The effects of hormone replacement therapy and raloxifene on C-reactive protein and homocysteine in healthy postmenopausal women: a randomized, controlled trial.

OBJECTIVE —Ruboxistaurin selectively inhibits protein kinase C-β and ameliorates kidney disease in animal models of diabetes. The purpose of this study was to evaluate the effects of ruboxistaurin on diabetic nephropathy in humans. RESEARCH DESIGN AND METHODS —A randomized, double-blind, placebo-controlled, multicenter, pilot study was performed to evaluate the effects of 32 mg/day ruboxistaurin for 1 year in persons ( n = 123) with type 2 diabetes and persistent albuminuria (albumin-to-creatinine ratio [ACR] 200-2,000 mg/g), despite therapy with renin-angiotensin system inhibitors. The primary end point was a change in the ACR. Estimated glomerular filtration rate (eGFR) (four-component equation from the Modification of Diet in Renal Disease study) was also calculated. RESULTS —At baseline, urinary ACR was 764 ± 427 mg/g (means ± SD), and eGFR was 70 ± 24 ml/min per 1.73 m 2 . Systolic and diastolic blood pressures were 135 ± 14 and 75 ± 9 mmHg, respectively. HbA 1c was 8.0 ± 1.2%. After 1 year, urinary ACR decreased significantly (−24 ± 9%) in participants treated with ruboxistaurin ( P = 0.020) and nonsignificantly (−9 ± 11%) in the placebo group ( P = 0.430). The ACR-lowering effect of ruboxistaurin appeared by 1 month. eGFR did not decline significantly in the ruboxistaurin group (−2.5 ± 1.9 ml/min per 1.73 m 2 ) ( P = 0.185), whereas the placebo group lost significant eGFR over 1 year (−4.8 ± 1.8 ml/min per 1.73 m 2 ) ( P = 0.009). Between-group differences for changes in ACR and eGFR were not statistically significant, but this pilot study was underpowered to determine such differences. CONCLUSIONS —In persons with type 2 diabetes and nephropathy, treatment with ruboxistaurin reduced albuminuria and maintained eGFR over 1 year. Ruboxistaurin may add benefit to established therapies for diabetic nephropathy.

https://care.diabetesjournals.org/content/diacare/28/11/2686.full.pdf

Pamela W. Anderson

Papers

Effects of Raloxifene on Serum Lipids and Coagulation Factors in Healthy Postmenopausal Women

Raloxifene and Cardiovascular Events in Osteoporotic Postmenopausal Women: Four-Year Results From the MORE (Multiple Outcomes of Raloxifene Evaluation) Randomized Trial

The effects of hormone replacement therapy and raloxifene on C-reactive protein and homocysteine in healthy postmenopausal women: a randomized, controlled trial.

The effect of ruboxistaurin on nephropathy in type 2 diabetes

Raloxifene and Cardiovascular Events in Osteoporotic Postmenopausal Women