Oestrogen replacement therapy and diabetes P. Gourdy (France)

1. Hormone replacement therapyand diabetes • Oestrogen replacement therapy and diabetes P. Gourdy (France)

2. Hormone replacement therapy in diabetic patients : what about estrogens ? 15th MGSD Meeting – Athens 2017 Prof. Pierre Gourdy Diabetology Department - Toulouse University Hospital Institute of Metabolic & Cardiovascular Diseases - INSERM UMR1048/I2MC University of TOULOUSE - FRANCE

3. Disclosures Professor Pierre Gourdy No conflict of interest to declare in relation with this presentation

4. Diabetes and menopause : a frequent condition but still little studied More than 10% of menopaused women are living with diabetes worldwide IDF Atlas 2015 In France, 5% to 8% of all menopaused women in the usual window of opportunity for HRT (50-60 yrs) are treated for diabetes Mandereau-Bruno L et al. BEH 2014

5. Diabetes and age at menopause : European Prospective Investigation into Cancer and Nutrition Brand JS et al. Human Reprod 2014

6. Management of estrogen deficiency in menopausal women with diabetes : main objectives and issues • To systematically consider climacteric disorders and traditional outcomes linked to menopause (not only osteoporosis), as in non-diabetic women ! • To control the specific risks of HRT in the context of diabetes : highly variable according to individual clinical profiles Stuenkel CA. Climacteric 2017

7. Diabetes and menopause : evaluation of the specific risks associated with diabetic status Influence of HRT on glucose control ? Clinical profile: to be systematically checked ! • Type of diabetes • Obesity / Metabolic syndrome • Diabetes duration • Antidiabetic treatments • Risk of hypoglycemia • Glycemic control (A1c) • CV risk factors • Diabetic complications

8. Glucose tolerance Endogenous estrogens and estradiol replacement therapy protect animal models from HFD-induced obesity and diabetes NCD HFD Gourdy P. Unpublished data

9. 10 450 *** *** 8 400 *** *** 350 adipose tissue weight 6 (% total weight) *** 300 glycemia (mg/dl) 250 4 * 200 Wild-type 2 150 a ER -/- 100 0 50 Subcutaneous Perigonadic Mesenteric -30 0 30 60 90 time after glucose injection ( min) The beneficial actions of estrogens on energy homeostasis and glucose metabolism are mediated by estrogen receptor α Wild-type ERα-/- Glucose tolerance Adipose tissues Handgraaf S et al. Diabetes 2013

10. Influence of estrogen deficiency on the different tissues involved in glucose homeostasis Direct or indirect consequences of estrogen deficiency on glucose metabolism  Insulin resistance  Insulin secretion Mauvais-Jarvis F et al. Endocrine Reviews 2013

11. HR (CI 95%) Diabetes incidence HRT Placebo HERS (CEE + MPA) 6.2% 9.5% 0.65 (0.48-0.89) WHI (CEE + MPA) 3.5% 4.2% 0.79 (0.67-0.93) WHI (CEE alone) 8.3% 9.3% 0.88 (0.77-1.01) Prevention of diabetes by hormonal menopause therapy : evidence from the main randomized trials Kanaya AM et al. Ann Intern Med 2003 Margolis KL et al. Diabetologia 2004 Bonds DE et al. Diabetologia 2006 CEE : conjugate equine estrogens MPA : medroxyprogesterone acetate

12. Menopause in women with diabetes : potential influence on glycemic control • Direct effect of hormonal changes (estrogen deficiency,  androgen / estrogen ratio) on glucose metabolism regulation : • Android distribution of fat mass •  Insulin resistance •  Insulin secretion • Indirect influence due to neuro-psycho-social modifications : • Sleep disorders • Depressive symptoms • Lifestyle modifications (alimentation / physical activity) • Influence of climacteric symptoms on diabetes management • Change in perception of hypoglycemia ... Beneficial action of Hormonal Replacement Therapy (HRT) ?

13. Menopause in women with type 1 diabetes : influence of HRT on glycemic control Type 1 Diabetes Very few data – No study supporting a deleterious effect The Cochrane Collaboration 2013

14. Cohort of 15 435 women with T2D, aged 50 yrs or more 25% receiving HRT (before WHI publications!) Lower A1c level in HRT users Ferrara A et al. Diabetes Care 2001

15. Cross-over : CEE 0,625 mg/jour vs Placebo (8 week treatment - 4 week wash-out) 25 women with T2D - 59 yrs - BMI 31.6 kg/m² - HbA1c 8.8% Hysterectomy 80% - Ovariectomy 40% Beneficial effect on : FPG : 7.2 vs 8.4 mmol/l (p<0.001) HbA1c : 8.7% vs 9.3% (p<0.05) Improved lipid profile Friday KE et al. J Clin Endocrinol Metab 2001

16. 107 studies published between April 1966 and October 2004 • In non diabetic menopaused women, HRT significantly decreased : • New cases of diabetes : RR= 0,7 (0,6 à 0,9) • HOMAIR : - 12,9% (- 17,1 à - 8,6) • In diabetic menopaused women, HRT significantly decreased : • Fasting Plasma Glucose : - 11,5% (- 18,0 à - 5,1) • HOMAIR : - 35,8% (- 51,7 à - 19,8) Salpeter SR et al. Diabetes Obesity & Metabolism 2006

17. Transdermal E2 50 µg/d vs CEE 0,625 mg/d for 6 months (+ micronized progesterone 300 mg/d) 21 women with T2D - 54 yrs - BMI 26.6 kg/m² - HbA1c < 7% Araujo DA et al. Climacteric 2002

18. Early menopause (< 6 yrs, EPM) : 22 non-diabetic women (56 yrs) vs long-standing menopause (> 10 yrs, LPM) : 24 non-diabetic women (63 yrs) Cross-over study : transdermal E2 (patch 0.05 mg x 3) vs placebo (1 week) Hyperinsulinemic euglycemic clamp Pereira RI et al. J Clin Endocrinol Metab 2015

19. Diabetes and menopause : evaluation of the specific risks associated with diabetic status Influence of HRT on glucose control ? Clinical profile: to be systematically checked ! Cardiovascular risk ? • Type of diabetes • Obesity / Metabolic syndrome • Diabetes duration • Antidiabetic treatments • Risk of hypoglycemia • Glycemic control (A1c) • CV risk factors • Diabetic complications Thrombo-embolic risk ? Osteoporosis and fracture risk ? Cancer risk ?

20. Cardiovascular events : diabetes impact is more pronounced in women Recent meta-analysis evaluating the influence of diabetes on acute coronary syndromes (858 507 subjects, 28 203 events) and strokes (775 385 subjects, 12 539 events) Peters SA et al. Diabetologia 2014 Peters SA et al. Lancet 2014

21. Diabetes and risk of thrombo-embolic events : meta-analysis 2008 Case/control : 1.22 (0.75-1.96) Cohorts : 1.56 (1.23-1.98) Total : 1.41 (1.12-1.77) Ageno W et al. Circulation 2008

22. Reduced resistance to mechanical stress + Increased risk of falling Napoli N et al. Nature Reviews Endocrinology 2016

23. Napoli N et al.. Nature Reviews Endocrinology 2016

24. Vrachnis N et al.. Arch Gynecol Obst 2016

25. OVARY : + 17% BREAST : + 20% ENDOMETRIUM : + 97% Tsilidis KK et al.. BMJ 2015

26. Diabetes and menopause : evaluation of the specific risks associated with diabetic status Influence of HRT on glucose control ? Clinical profile: to be systematically checked ! Cardiovascular risk ? • Type of diabetes • Obesity / Metabolic syndrome • Diabetes duration • Antidiabetic treatments • Risk of hypoglycemia • Glycemic control (A1c) • CV risk factors • Diabetic complications Thrombo-embolic risk ? Osteoporosis and fracture risk ? Cancer risk ? Sexual dysfonction & depression ?

27. Functional complaints related to menopause in women with type 2 diabetes (Veterans USA, 45 - 60 yrs, surgical MP 52%) Symptoms associated with menopause are more severe in diabetic women with HbA1c > 7% Rouen PA et al. J of Women’s Health 2015

28. 26 studies – 3168 diabetic women and 2823 non diabetic women Prevalence of sexual dysfunction (vs non diabetics) OR IC 95% Diabetes (all types) 2.02 1.49 – 2.72 Type 1 diabetes 2.27 1.23 – 4.16 Type 2 diabetes 2.49 1.55 – 3.99 Before menopause 2.91 1.25 – 6.75 Post-menopausal 3.15 0.83 – 11.93 Diabetes duration < 10 yrs 1.84 1.28 – 2.64 Diabetes duration > 10 yrs 2.31 1.32 – 4.04 Pontiroli AE et al. J Sex Med 2013

29. Management of menopause in women with diabetes : a multifactorial individualized approach • Evaluation of specific risks related to diabetic status (insulin resistance) •  Accentuation of visceral adiposity and insulin resistance •  Increased cardiovascular risk •  Increased risk of hormone-dependent cancers •  Increased risk of osteoporosis • Preventive and therapeutic interventions • Balanced diet – PHYSICAL ACTIVITY +++ • Treatment of insulin resistance : METFORMINE • Intensification of anti-diabetic treatment in case of worsened hyperglycemia • Optimized control of cardiovascular risk factors +++ • Psychological support – Management of depression /sleep disorders +++ • Gynecological and bone status follow-up (cancer screening) +++ Lorenzini-Grandmottet F et al. EMC 2016

30. HRT is not associated with an increased risk of T2D HRT is not associated with an adverse effect on blood glucose in diabetic women HRT is considered in case of menopausal symptoms in women with T2D after taking co-morbidities into account Bruce D. Post Reproductive Health 2016

31. Estrogen-based HRT in in menopausal women with diabetes : when and how? • Indication : climacteric symptoms (+/- bone status) • Respect the usual contraindications (history of thromboembolic or CV events) • + consider individual clinical profiles : long-standing diabetes with CV risk factors and/or severe microvascular complications • Favor the transdermal route and the lower effective dose of estradiol • Favor the use of natural progesterone • Only prescribe in early menopause (< 5 years) and for limited duration • Don’t forget local/topic treatment +++ Improved health perception / Quality of Life : usually positive influence on diabetes management Stuenkel CA. Climacteric 2017 Lorenzini-Grandmottet F et al. EMC 2016

32. Finnan B et al. Nature Med 2012 GLP-1-Estrogen conjugate