Disclosures Intira Sriprasert, Howard Hodis and Wendy Mack - - PDF document

Effect of Estradiol Dose and Serum Estradiol Levels on Metabolic Measures in Early and Late Postmenopausal Women in the REPLENISH trial Sriprasert I. NAMS 2019 presentation on Sept 27, 2019 1

Effect of Estradiol Dose and Serum Estradiol Levels on Metabolic Measures in Early and Late Postmenopausal Women in the REPLENISH trial

Intira Sriprasert1,2, Howard N. Hodis1,3,4, Brian Bernick5, Sebastian Mirkin5, Wendy J. Mack1,4

1Department of Preventive Medicine, Keck School of Medicine, University of Southern California 2Department of Obstetrics and Gynecology

, Faculty of Medicine, Chiang Mai University , Thailan d,

3Department of Medicine, Keck School of Medicine, University of Southern California 4Atherosclerosis Research Unit, Keck School of Medicine, University of Southern California, 5TherapeuticsMD, Boca Raton, FL.

• Intira Sriprasert, Howard Hodis and Wendy Mack
• Received an unrestricted research grant from TherapeuticsMD
• Brian Bernick and Sebastian Mirkin
• Employees of TherapeuticsMD
• Own company stock/stock options

Disclosures

2

Effect of Estradiol Dose and Serum Estradiol Levels on Metabolic Measures in Early and Late Postmenopausal Women in the REPLENISH trial Sriprasert I. NAMS 2019 presentation on Sept 27, 2019 2

• Hormone therapy (HT) timing hypothesis
• Women who initiate HT at younger age or sooner after menopause

have reduced risk of cardiovascular disease (CVD) and all-cause mortality compared with placebo.

3

Hormone Therapy & Cardiovascular Disease

Boardman HMP , et al. Cochrane Database of Systematic Reviews 2015. Hodis HN, et al. NEJM 2016;374(13):1221-31.

Meta-analysis: Coronary heart disease

< 60 yrs < 10 yrs-since-menopaus e ≥ 60 yrs ≥ 10 yrs-since-menopause

RR=0.52 (0.29, 0.96) RR=1.07 (0.96, 1.20)

Effect of HT compared with placebo

ELITE trial: Atherosclerosis progression rate

< 6 yrs-since-menopause ≥ 10 yrs-since-menopause

• 3.45 um/yr

(-5.99, -0.91) 1.17 um/yr (-0.98, 3.31)

Estrogen in the Prevention of Atherosclerosis (EPAT) trial: Higher HDL and lower LDL explained 30% of E2 therapy benefit

• n atherosclerosis progression
• T
• tal cholesterol (CHOL)
• Low density lipoprotein cholesterol (LDL)
• Fasting blood glucose (GLUC)
• High-density lipoprotein cholesterol (HDL)
• Triglycerides (TRIG)

4

Hormone Therapy & Metabolic Measures

Salpeter SR, Diabetes Obes Metab, 2006;8:538-554. Hodis et al. NEJM 2003;349(6):535-45. Karim R, et al. JCEM 2008;93(1):131-8

HT HT

Effect of Estradiol Dose and Serum Estradiol Levels on Metabolic Measures in Early and Late Postmenopausal Women in the REPLENISH trial Sriprasert I. NAMS 2019 presentation on Sept 27, 2019 3

• 1. To identify the association of E2 dose and serum E2

level with change of metabolic measures

• 2. To compare these associations in early and late

postmenopausal women vs.

Objectives

5 Change of metabolic measures

Total cholesterol (CHOL) Low-density lipoprotein cholesterol (LDL) High-density lipoprotein cholesterol (HDL) Triglyceride (TRIG) Fasting blood glucose (GLUC)

E2 dose Serum E2 levels EARL Y postmenopause (< 6 years-since-menopause) LATE postmenopause (≥ 10 years-since-menopause)

Randomized, double-blinded, placebo-controlled trial

• Tested HT efficacy and safety
• 1 year intervention and follow-up
• Healthy postmenopausal women 40-65 years with a uterus
• Combined oral estradiol (E2) and progesterone (P4) or placebo

0.25 mg + 50 mg 0.5 mg + 50 mg 0.5 mg + 100 mg 1 mg + 100 mg

REPLENISH Trial

6

Mirkin S, et al. Maturitas 2015 May;81(1):28-35. Lobo RA, et al. Obstet and gynecol 2018 Jul;132(1):161-70.

Effect of Estradiol Dose and Serum Estradiol Levels on Metabolic Measures in Early and Late Postmenopausal Women in the REPLENISH trial Sriprasert I. NAMS 2019 presentation on Sept 27, 2019 4

• REPLENISH participants
• Available data at baseline and at least one follow-up visit
• Randomized E2 dose
• Serum E2 level
• Metabolic measures
• Early postmenopause ( < 6 years-since-menopause )
• Late postmenopause ( ≥ 10 years-since-menopause )
• The cut points were derived from differential effect of HT on CVD

demonstrated in primate and human studies.

Analysis Population

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Mikkola TS, et al. Ann Med 2004;36(6):402-13. Hodis HN, et al. NEJM 2016;374(13):1221-31.

Randomized E2 dose

• 0 mg, 0.25 mg, 0.5 mg and 1 mg

Serum E2 levels

• A single GC-MS/MS method

Serum P4 levels

• A single LC-MS/MS method

Metabolic measures

• At least 8-hour fasting blood sample
• CHOL, LDL, HDL, TRIG and GLUC

Measurements At baseline, 3, 6, 9 and 12 months

8

Mirkin S, et al. Maturitas 2015 May;81(1):28-35.

Effect of Estradiol Dose and Serum Estradiol Levels on Metabolic Measures in Early and Late Postmenopausal Women in the REPLENISH trial Sriprasert I. NAMS 2019 presentation on Sept 27, 2019 5 Baseline characteristics

• Two-sample t-test or chi-square test

Associations of E2 dose and serum E2 level with change

• f metabolic measures
• Mixed-effects linear models

Associations were expressed per

• 0.25 mg increase of E2 dose
• 1 pg/ml increase in serum E2 level

Statistical Analysis

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Table Baseline characteristics of women by postmenopausal strata

10 Early postmenopause Late postmenopause p

N=1216 N=297

Age (years) 53.2 (3.7) 58.4 (4.1) <0.0001 Years-since-menopause 2.4 (1.7) 14.1 (3.9) <0.0001 Body mass index(kg/m2) 26.8 (4.0) 26.7 (4.2) 0.90 Race White 806 (66.45) 185 (62.71) 0.19 African American 377 (31.08) 107 (36.27) Other 30 (2.47) 3 (2.02) Serum E2 level (pg/ml) 6.64 (7.24) 5.28 (3.34) 0.002 Serum P4 level (pg/ml) 59.94 (94.45) 54.13 (15.45) 0.29

Continuous variables reported as mean(standard deviation), t-test Categorical variables reported as frequency (percent), χ2 test

> <

Effect of Estradiol Dose and Serum Estradiol Levels on Metabolic Measures in Early and Late Postmenopausal Women in the REPLENISH trial Sriprasert I. NAMS 2019 presentation on Sept 27, 2019 6

Figure 1 Estimated change from baseline of metabolic measures per 0.25 mg increase in E2 dose by postmenopausal strata

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• 1.34

0.39

• 1.49

0.78

• 0.48
• 0.26

0.04

• 0.37

3.67

• 0.84

CHOL HDL LDL TRIG GLUC Change from baseline (mg/dl) Early postmenopause Late postmenopause

Estimates are from mixed effects models adjusted for baseline metabolic measure, serum P4 level and use of lipid-lowering medication

* significant

association with E2 dose

** significant

different association between early and late postmenopause

** ** ** ** ** * * *

• 0.05

0.001

• 0.05

0.09

• 0.02
• 0.05

0.02

• 0.09

0.08

• 0.02

CHOL HDL LDL TRIG GLUC Change from baseline (mg/dl) Early postmenopause Late postmenopause 12

Figure 2 Estimated change from baseline of metabolic measures per 1 pg/ml increase in serum E2 level by postmenopausal strata

* * *

Estimates are from mixed effects models adjusted for baseline metabolic measure, serum P4 level and use of lipid-lowering medication

* significant

association with serum E2 level

Effect of Estradiol Dose and Serum Estradiol Levels on Metabolic Measures in Early and Late Postmenopausal Women in the REPLENISH trial Sriprasert I. NAMS 2019 presentation on Sept 27, 2019 7

• E2 dose
• With higher E2 dose, CHOL and LDL was decreased and HDL

was increased in EARLY postmenopausal women.

• Meta-analysis: Dose-dependent E2 effects on lipids levels
• Significant lower CHOL and LDL with conventional-dose

estrogen compared to low-dose estrogen.

Discussion

13

Casanova G, et al. JCEM 2015 Mar;100(3):1028-37.

Mean difference (conventional-dose estrogen minus low-dose estrogen) CHOL (mg/dl)

• 5.50 (-0.88, -9.21)

LDL (mg/dl)

• 4.49 (-0.59, -8.39)
• E2 dose
• More favorable effect of E2 dose on CHOL, LDL and HDL among

early compared with late postmenopausal women.

• Estrogen in the Prevention of Atherosclerosis (EPAT) Trial:

Higher HDL and lower LDL explained 30% of E2 therapy benefit on atherosclerosis progression.

• Early versus Late Intervention Trial with Estradiol (ELITE):

Beneficial E2 effect on atherosclerosis progressionin early but not late postmenopausal women.

Discussion

14

Hodis et al. NEJM 2003;349(6):535-45. Karim R, et al. JCEM 2008;93(1):131-8. Hodis HN, et al. NEJM 2016;374(13):1221-31.

Effect of Estradiol Dose and Serum Estradiol Levels on Metabolic Measures in Early and Late Postmenopausal Women in the REPLENISH trial Sriprasert I. NAMS 2019 presentation on Sept 27, 2019 8

• Why did we observe differential effects on metabolic

measures between early and late postmenopausal women with E2 dose but not serum E2 level ?

Discussion

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E2 dose Serum E2 level

• Further exploration of determinants of attained serum E2 level in

response to E2 dose is needed.

• Strengths
• Randomized clinical trial data
• Different E2 doses (0 mg, 0.25 mg, 0.5 mg, 1 mg)
• Longitudinal follow-up
• Limitations
• Smaller sample size of late postmenopausal women

Discussion

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Effect of Estradiol Dose and Serum Estradiol Levels on Metabolic Measures in Early and Late Postmenopausal Women in the REPLENISH trial Sriprasert I. NAMS 2019 presentation on Sept 27, 2019 9

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Conclusion

• Among EARLY postmenopausal women
• Women who initiated HT at < 6 years-since-menopause.
• There were significant associations of both E2 dose

and serum E2 levels with metabolic measures.

• The differential effect of E2 dose on metabolic

measures among early compared with late postmenopausal women supports the timing hypothesis

• f E2 therapy on cardiovascular benefit.

Thank you very much for your attention

Contact information: sriprase@usc.edu