Conjugated Estrogens and Bazedoxifene Improve β Cell Function in Obese Menopausal Women

Dragana Lovre; Erin Peacock; Bonnie Katalenich; Cynthia Moreau; Beibei Xu; Chandra Tate; Kristina M. Utzschneider; Jean-François Gautier; Vivian Fonseca; Franck Mauvais-Jarvis

Disclosures

J Endo Soc. 2019;3(8):1583-1594. 

In This Article

Abstract and Introduction

Abstract

Context: Studies suggest that menopausal hormone therapy (MHT) prevents type 2 diabetes (T2D). The combination of conjugated estrogens (CE) with the selective estrogen receptor modulator bazedoxifene (BZA) is an MHT that improves obesity and T2D in preclinical models of menopausal metabolic syndrome. The effect of CE/BZA on adiposity and glucose homeostasis in obese postmenopausal women is unknown.

Objective: To investigate the effect of CE/BZA on body composition, glucose homeostasis, and markers of inflammation in obese postmenopausal women.

Research Design, Intervention, and Participants: Randomized, double-blind, placebo-controlled pilot trial of 12 obese menopausal women assigned to 12-week treatment with CE 0.45 mg/BZA 20 mg (n = 7) or placebo (n = 5). At baseline and after 12 weeks, we assessed body composition (dual-energy X-ray absorptiometry), glucose homeostasis (IV glucose tolerance test), and inflammation biomarkers.

Results: Women treated with CE/BZA exhibited increased β cell function using homeostatic model assessment-B [median (interquartile range) CE/BZA vs placebo: 18.5 (−0.9 to 320.6) μU/mM vs −25.5 (−39.9 to −0.1) μU/mM; P = 0.045], and decreased basal glucose concentrations (Gb) [−5.2 (−9.2 to −1.7) mg/dL vs 2.7 (0.9 to 4.9) mg/dL; P = 0.029]. Insulin sensitivity was higher in the placebo arm [1.35 (1.12 to 1.82) (μU/mL) min−1 vs −0.24 (−1.50 to 0.19) (μU/mL) min−1; P = 0.029]. No changes between treatment groups were observed for the acute insulin response to glucose (AIRg), the disposition index (DI), body composition, and inflammatory biomarkers.

Conclusions: A 12-week treatment of obese postmenopausal women with CEs/BZA improves fasting β cell function and glucose concentrations without change in AIRg, HOMA-IR, DI, body composition, or markers of inflammation.

Introduction

Observational studies and large randomized controlled trials suggest that menopausal hormone therapy (MHT) reduces adiposity, improves insulin resistance (IR), and delays the incidence of type 2 diabetes (T2D).[1–6] However, using general estrogen therapy to prevent diabetes in women is neither recommended nor approved by the Food and Drug Administration (FDA). Therefore, treatments that provide the beneficial effects of estrogens on glucose homeostasis without adverse effects are needed. Selective estrogen receptor modulators (SERMs) are compounds that exert tissue-selective estrogen receptor agonist or antagonist activity. For example, bazedoxifene (BZA) is a SERM that exhibits estrogen agonist activity in bone but estrogen antagonist activity in breast and uterus. The combination of conjugated estrogens (CE) with BZA is approved by the FDA for treatment of postmenopausal vasomotor symptoms and prevention of osteoporosis.[7,8] The combination CE and BZA (CE/BZA) provides the benefits of estrogen therapy such as reducing hot flashes and vulvar–vaginal atrophy, preventing menopausal osteoporosis while simultaneously protecting the endometrium and breast from estrogen stimulation and without the need of a progestin.[9–15] Using a mouse model of postmenopausal metabolic syndrome, we reported that CE/BZA prevents estrogen deficiency-induced obesity, T2D, and nonalcoholic fatty liver disease as efficiently as CE alone.[16] We found that CE/BZA increased fat oxidation and energy expenditure, thus preventing ectopic fat accumulation in liver and skeletal muscle and improving IR and glucose intolerance. In addition, in female diabetic mouse models of insulin deficiency, CE/BZA prevents β cell failure and delays diabetes.[17] The current randomized, double-blind, placebo-controlled pilot trial was designed to assess the effect of a 12-week treatment with CE/BZA vs placebo on body composition, glucose homeostasis, and markers of inflammation in obese postmenopausal women.

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