DENVER – A novel oral, once-daily, tissue-selective estrogen complex designed to treat postmenopausal symptoms more safely than traditional estrogen/progestin hormone therapy achieved an overall favorable effect on metabolic parameters in a large phase III clinical trial.
Dr. Hugh S. Taylor
The combination of the selective estrogen receptor modulator (SERM) bazedoxifene and conjugated estrogens produced "very favorable" changes in lipid profiles and no clinically meaningful effects on coagulation parameters, fibrinolytic activity, or carbohydrate metabolism in the phase III SMART-1 trial, Dr. Hugh S. Taylor reported at the annual meeting of the American Society for Reproductive Medicine.
The concept underlying the tissue-selective estrogen complex (TSEC) is that the SERM will serve as an antagonist to estrogen’s adverse effects on the uterus and breast without interfering with its favorable CNS effects on vasomotor symptoms, explained Dr. Taylor of Yale University, New Haven, Conn.
The Selective Estrogens, Menopause, and Response to Therapy (SMART-1) trial was a 2-year, double-blind, multicenter, placebo- and active comparator-controlled study involving 7,492 postmenopausal women aged 40-72 years with an intact uterus and acceptable baseline endometrial biopsy results. They were randomized to one of eight treatment arms: bazedoxifene at 10, 20, or 40 mg, each combined with conjugated estrogens at 0.45 or 0.625 mg; raloxifene at 60 mg/day; or placebo.
There are three large randomized SMART trials in the bazedoxifene/conjugated estrogens development program. Prior reports from SMART-1 showed that the TSEC significantly increased bone mineral density while reducing hot flashes and vulvar/vaginal symptoms compared with placebo (Fertil. Steril. 2009;92:1025-38, 1045-52). TSEC also was associated with low rates of endometrial hyperplasia and cumulative amenorrhea rates comparable to those with placebo (Fertil. Steril. 2009;92:1018-24, 1039-44). In the overall SMART series, the thrombotic event rate in TSEC-treated patients was similar to that of estrogen alone. In other words, there was no synergistic effect on clotting events with the combined therapy. The TSEC had no effect on blood pressure, Dr. Taylor continued.
At the meeting, he presented for the first time the results of the SMART-1 metabolic substudy. Metabolic end points take on particular importance because menopause is often associated with unfavorable effects on the metabolic profile. Dr. Taylor focused on the subset of women treated with bazedoxifene 20 mg/conjugated estrogens 0.45 mg because that’s the regimen going forward in development under the trade name Aprela.
The metabolic substudy included 111 women randomized to Aprela and 108 on placebo. All were 1-5 years postmenopausal, with an average of 3 years since their last menstrual period.
Patients who took Aprela had a mean 11% reduction in LDL cholesterol over a 2-year period compared with baseline, a significantly greater change than with placebo. Other significant lipid changes in the Aprela group included a 4% decrease in total cholesterol, an 11% increase in HDL cholesterol level, a 28% rise in the cardioprotective HDL2 subfraction, an 11% increase in apolipoprotein A-I, and a 19% drop in lipoprotein (a). Most of these favorable changes were significantly greater than with placebo at all time points in the study, with testing done at 6, 12, 18, and 24 months.
The fly in the lipid ointment was the 23% increase in triglyceride levels in the Aprela group, which was significantly greater than the 6% increase in the placebo arm. Most hormonal therapies have this unwelcome effect of boosting triglycerides, Dr. Taylor observed.
In terms of coagulation parameters, the Aprela group showed favorable changes in fibrinogen, antithrombin III activity, and plasminogen activator inhibitor–1 activity that were statistically significantly greater than with placebo, but small in size and not clinically meaningful. Fasting insulin, fasting glucose, plasma homocysteine, C-reactive protein, and thyroid-stimulating hormone levels were unaffected by Aprela, he said.
The SMART-1 trial was funded by Wyeth, which has been acquired by Pfizer Inc. Dr. Taylor declared that he has received research grants from and has been on the speakers bureau for the companies.