Download Oestrogen replacement therapy and diabetes

Hormone replacement therapy
and diabetes

Oestrogen replacement
therapy and diabetes
P. Gourdy (France)
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
Disclosures
Professor Pierre Gourdy
No conflict of interest to declare in relation with this presentation
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
Diabetes and age at menopause :
European Prospective Investigation into Cancer and Nutrition
Brand JS et al. Human Reprod 2014
Management of estrogen deficiency in menopausal
women with diabetes : main objectives and issues
1. To systematically consider climacteric disorders and traditional
outcomes linked to menopause (not only osteoporosis), as in
non-diabetic women !
2. To control the specific risks of HRT in the context of diabetes :
highly variable according to individual clinical profiles
Stuenkel CA. Climacteric 2017
Diabetes and menopause : evaluation of the
specific risks associated with diabetic status
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
Influence of HRT on glucose control ?
Endogenous estrogens and estradiol replacement therapy
protect animal models from HFD-induced obesity and diabetes
Subcutaneous fat
***
(mg)
ns
1500
1000
ns
ns
0
0
sham
ovx
sham
E2
400
***
***
Glycemia (mg/dl)
Glycemia (mg/dl)
***
100
0
0
30
ovx + E2
60
90
Time after glucose injection (min)
400
***
***
300
***
200
***
**
100
0
-30
E2
ovx
400
200
ovx
Glucose tolerance
sham
300
ns
500
Glycemia (mg/dl)
(mg)
2000
NCD
HFD
***
2000
3000
1000
Gonadal fat
2500
4000
300
200
100
0
-30
0
30
60
90
Time after glucose injection (min)
-30
0
30
60
90
Time after glucose injection (min)
Gourdy P. Unpublished data
The beneficial actions of estrogens on energy homeostasis and
glucose metabolism are mediated by estrogen receptor α
Wild-type
ERα-/-
adipose tissue weight
(% total weight)
glycemia (mg/dl)
Glucose tolerance
Adipose tissues
10
8
***
450
400
350
300
250
200
150
100
50
***
***
***
-30
***
0
30
60
time after glucose injection ( min)
90
6
4
*
2
Wild-type
ERa -/-
0
Subcutaneous Perigonadic
Mesenteric
Handgraaf S et al. Diabetes 2013
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
Prevention of diabetes by hormonal menopause therapy :
evidence from the main randomized trials
Diabetes incidence
HR (CI 95%)
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)
CEE : conjugate equine estrogens
Kanaya AM et al. Ann Intern Med 2003
Margolis KL et al. Diabetologia 2004
MPA : medroxyprogesterone acetate
Bonds DE et al. Diabetologia 2006
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) ?
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
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
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
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
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
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
Diabetes and menopause : evaluation of the
specific risks associated with diabetic status
Clinical profile: to be
systematically checked !
 Type of diabetes
 Obesity / Metabolic syndrome
Influence of HRT on glucose control ?
Cardiovascular risk ?
Thrombo-embolic risk ?
 Diabetes duration
 Antidiabetic treatments
Osteoporosis and fracture risk ?
 Risk of hypoglycemia
 Glycemic control (A1c)
 CV risk factors
 Diabetic complications
Cancer risk ?
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
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
Reduced resistance to
mechanical stress
+
Increased risk of
falling
Napoli N et al. Nature Reviews Endocrinology 2016
Napoli N et al.. Nature Reviews Endocrinology 2016
Vrachnis N et al.. Arch Gynecol Obst 2016
OVARY : + 17%
BREAST : + 20%
ENDOMETRIUM : + 97%
Tsilidis KK et al.. BMJ 2015
Diabetes and menopause : evaluation of the
specific risks associated with diabetic status
Clinical profile: to be
systematically checked !
 Type of diabetes
 Obesity / Metabolic syndrome
Influence of HRT on glucose control ?
Cardiovascular risk ?
Thrombo-embolic risk ?
 Diabetes duration
 Antidiabetic treatments
Osteoporosis and fracture risk ?
 Risk of hypoglycemia
 Glycemic control (A1c)
Cancer risk ?
 CV risk factors
 Diabetic complications
Sexual dysfonction & depression ?
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
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
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
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
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
Finnan B et al. Nature Med 2012
GLP-1-Estrogen conjugate