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MENOPAUSA E RISCHIO DIABETE

CARLA GIORDANO

INSEGNAMENTO ENDOCRINOLOGIA

DIRETTORE UOC DI MM ENDOCRINE, METABOLICHE E DELLA NUTRIZIONE

AOUP PAOLO GIACCONE

RESPONSABILE DEL LABORATORIO COLTURE CELLULARI, ATEN CENTER, VIALE DELLE SCIENZE, PALERMO

UNIVERSITÀ DEGLI STUDI DI PALERMO

Diapositiva preparata da CARLA GIORDANO e ceduta alla Società Italiana di Diabetologia.

Per ricevere la versione originale si prega di scrivere a [email protected]

DISCLOSUREINFORMATION

Research supportEli Lilly, Novo Nordisk, Novartis, Astra

Zeneca, MSD, Takeda, MSK, Sanofi,

Advisory BoardBoheringer Ingelheim, Eli Lilly, Novo

Nordisk, Janssen, Shire, Novartis, Abbott



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CV death All-causemortality

Haz

ard

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TYPE 2 DIABETES IS INCREASINGLY PREVALENT

• GLOBALLY, 387 MILLION PEOPLE ARE LIVING WITH DIABETES1

1. IDF Diabetes Atlas 6th Edition 2014 http://www.idf.org/diabetesatlas; 2. Centers for Disease Control and Prevention 2011; 3. Seshasai et al. N Engl J Med 2011;364:829-41

3

• At least 68% of people >65 years with diabetes die of heart disease2

This will rise to 592 million by 20351

Mortality risk associated with diabetes (n=820,900)3

From: https://s3-eu-west-1.amazonaws.com/mevents/easd/empa-reg-slide-kit.pptx



DIABETES IS ASSOCIATED WITH SIGNIFICANT

LOSS OF LIFE YEARS

Seshasai et al. N Engl J Med 2011;364:829-414

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040 50 60 70 80 90

Age (years)

Year

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lost

Men7

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2

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040 50 60 70 80 900

Age (years)

Women

Non-vascular deaths

Vascular deaths

On average, a 50-year-old individual with diabetes and no history of vascular disease will die 6 years earlier compared to someone without diabetes

From: https://s3-eu-west-1.amazonaws.com/mevents/easd/empa-reg-slide-kit.pptx



Fonti di rilevamento della popolazione con diabete

Farmaceutica: 80,5%

Esenzioni ticket: 73,4%

17%

58,5%

4,2%

0,8%

1.4%

0,3%

10,4%

Schede Dimissione: 6,7%

Popolazione totale: 640.846 = 6.34%

2017

Esenzioni: 73,4%



Trend di prevalenza e spesa negli anni

2017

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97

1998

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Prevalenza pop F Prevalenza pop M Spesa media trattato F Spesa media trattato M



Caratteristiche demografiche della popolazione con diabete

2017

Classi di età

Maschi Femmine Totale

N % N % N %

0-19 6.327 1,9 6.060 1,9 12.395 1,9

20-34 6.842 2,1 12.028 3,8 18.882 2,9

35-49 24.649 7,5 26.387 8,5 51.106 8,0

50-64 90.099 27,5 61.297 19,6 151.644 23,7

65-79 148.874 45,4 128.690 41,1 278.009 43,3

>=80 51.205 15,6 78.388 25,1 129.576 20,2

Totale 327.996 100,0 312.850 100,0 640.846 100,0



Prevalenza del diabete in funzione di età e sesso

2017

0,6 0,92,2

8,6

20,6 20,5

6,7

0,71,5 2,3

5,6

15,4

17,7

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0-19 20-34 35-49 50-64 65-79 >=80 TOTALE

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Maschi Femmine



Prevalenza del diabete in funzione di età e sesso

2017

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0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 75 78 81 84 87 90 93 96 99 102

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Voci di spesa del SSN per assisteregli uomini e le donne con diabete

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1500

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TOTALE Ricoveri Specialistica Farmaci

Eur

o

Dispositivi

Donne (età 67,6 anni )

Uomini (età 65,9 anni)

Osservatorio ARNO Diabete SID-CINECA - 2017 (anno 2016)



European Heart Journal (2015) 36, 2696–2705 Source: WHO Mortality Database

CAUSE di MORTE - epidemiologia

UOMINI

DONNE

In EUROPA(mal. cardiovascolari)

nelle F, 49% dellecause di morte (>4 milioni di morti/anno) (nelM, 40%)

CARDIOPATIA ISCHEMICA simile nell’ M e nella F (19% vs20%)

F piu’ MAL. CEREBROVASCOLARI degli M (14% vs 9%)



Source: American Heart Association

CARDIOVASCULAR MORTALITY



Cardiovascular disease is mainly a disease of

old WOMEN (> 65 anni)

SI DICE CHE … IN REALTA’



EVENTI CARDIACI (Uomo e Donna)

Il rischio di EVENTI CARDIACI avversi è da 2 a 4 volte superiore nei diabeticirispetto ai non-diabetici

La donna diabetica presenta un rischio > (circa il doppio) rispetto all’uomo di sviluppare EVENTI CARDIACI.



PERCHE’ ???

1. La donna è “più complicata”

2. La donna vive piu’ a lungo

3. Poco considerata (scientificamente)

4. Menopausa ed assetto ormonale

Rispetto all’uomo:




Shortness of breath

Breaking out in a cold sweat

Unusual or unexplained

fatigue (tiredness)

Light-headedness or sudden dizziness

Nausea (feeling sick to the stomach)

Differenze strutturali e/o funzionali dell’albero cardiovascolare

1. Sintomi anginosi piu’ sfumati, dolore toracico atipico, sintomi aspecifici, si reca dal medico più tardi -> Spesso cardiopatia ischemica silente

2. Minore sensibilità ai test diagnostici

3. Coronaropatia colpisce i vasi piu’ piccoli (meno rivascolarizzabili)

4. Le complicanze legate al trattamento sono maggiori (per es. sanguinamenti) e vengono trattate meno intensamente

Trattamento TARDIVO

PROGNOSI PEGGIORE



2. La donna vive più a lungo



3. La donna è poco considerata

donnepoco rappresentate

(20% di pz arruolati)



Discrepancies arise from physiologicaldifferences in methods used to assessglucose homeostasis, ranging fromclinical indices of insulin sensitivity tosteady state methods to assess insulinaction.

4. MENOPAUSA E DIABETE



Endocrine Reviews; Copyright 2017 DOI: 10.1210/er.2016-1146

INTRODUCTIONIt is now clear that diabetes has reached epidemic proportions, with almosthalf of the US population having either undiagnosed or diagnosed pre-diabetes or diabetes. In addition, the US population is aging which will furtherincrease the incidence of type 2 diabetes. In fact, in 2020 more than 50million women will be in a postmenopausal state, which may predispose totype 2 diabetes. Large randomized controlled trials have suggested thatmenopausal hormone therapy (MHT) reduces the incidence of type 2diabetes in women. Surprisingly, however, the mechanisms and clinicalimplications of these findings are still a matter of controversy. Since thepublication of the preliminary findings of the Women’s Health Initiative (WHI)in 2002, reporting an increased risk of cardiovascular events, the use of MHTin US women has decreased by 80% which may aggravate the burden oftype 2 diabetes. The WHI, however, was conducted in predominantly olderwomen in their 60s and 70s who were started on high doses of MHT (theconventional doses at that time). In contrast, in younger women, the net effectof MHT on all-cause mortality is neutral or even beneficial. In women withouta uterus, those in the 50-59 age group had a generally favorable balance ofbenefits and risk on conjugated estrogens (CE) alone and a trend towardreduced mortality.



EFFECTS OF MENOPAUSE ON BODY COMPOSITIONAND

ENERGY BALANCE

Ovarian agingDiapositiva preparata da CARLA GIORDANO e ceduta alla Società Italiana di Diabetologia.


Menopausa ed assetto ormonale



Menopausa ed assetto ormonale

FUMO: piu’ pericolo nelle donne(coronarie più piccole)

IPERTENSIONE: peso maggiorenell’infarto miocardico rispetto all’uomo(piu’ donne rispetto all’uomo sono ipertese>60 anni)

COLESTEROLEMIA: aumenta COL-TOT e COL-LDL, oltre ai TG

DIABETE: non solo annulla il “vantaggiofemminile” nel rischio CV, ma conferisceun rischio aumentato rispetto all’uomo

INSULINA RESISTENZA: aumenta con la menopausa

SINDROME METABOLICA (sia in diabetiche che non): aumenta progressivamente da sei anni prima a sei anni dopo la menopausa indipendentemente dall’età e da altri fattori di rischio

Maggior impatto dei FDR cardiovascolare Maggior numero di FDR cardiovascolare



ALTERAZIONI ENDOCRINE NELLA DONNA DIABETICA

Ruolo protettivodegli

estrogeni

Ruolo deleteriodegli

androgeni



Differenze nei livelli di estradiolo fra i diabetici ed i controlli(uomini e donne in post-menopausa).

Ding, E. L. et al. JAMA 2006;295:1288-1299

p = 0.007 Diapositiva preparata da CARLA GIORDANO e ceduta alla Società Italiana di Diabetologia.


Differenze nei livelli di Testosterone fra le donnecon diabete tipo 2 ed i controlli.

Ding, E. L. et al. JAMA 2006;295:1288-1299

p < 0.001

Premenopausal Women

Postmenopausal Women



TESTOSTERONE T, SHBG E SINDROME METABOLICA

Brand J S et al. Int. J. Epidemiol. 2010;ije.dyq158



MENOPAUSA E TESSUTO ADIPOSO

Massa grassa

Modificazioni nella composizione

corporea

Alterazioni nella sensibilità insulinica e nel metabolismo del glucosio

↓Massa magraAdiposità addominale

Toth MJ et al, Ann N Y Acad Sci, 904: 502-506, 2000 (modificato)

Carenza estrogenica Processo dell’invecchiamentoRidotta attività fisica

Aumentato rischio cardiovascolareDiapositiva preparata da CARLA GIORDANO e ceduta alla Società Italiana di Diabetologia.


• INCREASED WAIST-HIP RATIO (WHR), SUGGESTING THAT MENOPAUSE INCREASES ABDOMINAL

ADIPOSITY, INDEPENDENTLY FROM CHRONOLOGICAL AGING AND TOTAL BODY FAT.

• LONGITUDINAL STUDIES USING COMPUTED TOMOGRAPHY (CT) SCANS, HAVE CONFIRMED

THAT POSTMENOPAUSAL STATUS IS ASSOCIATED WITH A PREFERENTIAL INCREASE IN INTRA-

ABDOMINAL FAT THAT IS INDEPENDENT OF AGE AND TOTAL BODY FAT MASS.

• THE CAUSE OF THE INCREASED ABDOMINAL FAT HAS BEEN SUGGESTED TO BE SECONDARY TO

DECREASED BASAL METABOLIC RATE WITHOUT CHANGE IN FOOD INTAKE.

• ONLY WOMEN WHO BECAME POSTMENOPAUSAL HAD AN INCREASE IN VISCERAL FAT. IN

ADDITION, PHYSICAL ACTIVITY DECREASED 2 YEARS BEFORE MENOPAUSE AND ENERGY

INTAKE WAS HIGHER BEFORE THE ONSET OF MENOPAUSE. ALTHOUGH ENERGY EXPENDITURE

(FROM FAT OXIDATION) DECREASED WITH AGE, THE DECREASE IN ENERGY EXPENDITURE WAS

GREATER IN WOMEN WHO BECAME POSTMENOPAUSAL COMPARED WITH PREMENOPAUSAL

CONTROLS.

• THE ONSET OF MENOPAUSE IN WOMEN IS CHARACTERIZED BY A REDUCTION IN FAT

OXIDATION AND A DECREASE IN ENERGY EXPENDITURE, AND FAVORING AN INCREASE IN

TOTAL BODY AND VISCERAL FAT, WITHOUT CHANGES IN ENERGY INTAKE.

Endocrine Reviews Endocrine Society, 2017 in pressFranck Mauvais-Jarvis, JoAnn E. Manson, John C. Stevenson, Vivian A. Fonseca



• RECENT STUDIES DERIVED FROM GENETICALLY MODIFIED FEMALE MICESUGGEST THAT THE MENOPAUSAL DECREASE IN ENERGY EXPENDITURERESULTS FROM LOSS OF 17Β-ESTRADIOL (E2) ACTIVATION OF ITS MAINRECEPTOR, THE ESTROGEN RECEPTOR-Α (ERΑ, PRODUCT OF THE ESR1 GENE).

• DECREASED E2 ACTIVATION OF ERΑ IN NEURONS OF THE VENTROMEDIALNUCLEUS OF THE HYPOTHALAMUS (VMH) IMPAIRS THE ABILITY OF THESYMPATHETIC NERVOUS SYSTEM (SNS) TO REGULATE ADIPOSE TISSUEDISTRIBUTION WHICH FAVORS VISCERAL FAT ACCUMULATION. IN ADDITION,THE MENOPAUSAL DECREASE OF ERΑ ACTIVATION IN VMH NEURONS ALSODECREASES THE SNS ACTIVATION OF BROWN ADIPOSE TISSUETHERMOGENESIS, THUS LIMITING ENERGY EXPENDITURE.

Endocrine Reviews Endocrine Society, 2017 in pressFranck Mauvais-Jarvis, JoAnn E. Manson, John C. Stevenson, Vivian A. Fonseca



Man, 23 years old, BMI 25 kg/m2, visceral fat from area L2 to L5 216 cm2, subcutaneous fat 649 cm2, liverfat 1.9%

Woman, 19 years old, BMI 24 kg/m2, visceral fat from area L2 to L5 138 cm2, subcutaneous fat 807 cm2, liver fat 1.1%;

Man, 59 years old, BMI 33, visceral fat from area L2 to L5 901 cm2, subcutaneous 879 cm2, liver fat 9.6%

Woman, 57 years old, BMI 34, visceral fat from area L2 to L5 712 cm2, subcutaneous fat 2158 cm2, liver fat 5.1%



MENOPAUSA COME PREDITTORE DI SINDROME METABOLICAdi IFG E DI DIABETE DI TIPO 2

Incremento del 60% del rischio di Sindrome Metabolica,indipendente da età, BMI ed attività fisica,associato a:a) decremento della SHBG b) incremento del testosterone libero

Incremento del rischio di diabete di tipo 2: controversoDiapositiva preparata da CARLA GIORDANO e ceduta alla Società Italiana di Diabetologia.


ALTERAZIONI LIPIDICHE IN MENOPAUSA (2)

Si osservano in post-menopausa, soprattutto nelle donne più magre,

• Incremento del Colesterolo totale• Incremento del Colesterolo- LDL• Incremento delle LDL piccole e dense• Incremento dei Trigliceridi• Riduzione del Colesterolo HDL

Triade lipidica

dell’ Insulino-Resistenza



MENOPAUSA, SINDROME METABOLICA E SUE COMPONENTI



Odds Ratios per il rischio di sviluppare la Sindrome Metabolica nel corso della transizione menopausale e della menopausa,

corretti per una serie di fattori fra cui età e BMI.

Janssen I et al, Arch Intern Med, 168(14): 1568-1575, 2008



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Perimenopausa Postmenopausa

Odds Ratios (OR) per il rischio di sviluppare la sindrome metabolica nel periodo peri- e post-menopausale

per anno per anno

La differenza fra i due OR è

statisticamente significativa (p<0.001)

Janssen I et al, Arch Intern Med, 168(14): 1568-1575, 2008

I.C. 1.35-1.56 1.18-1.30



Meta-analysis of fasting glucose level (A) and fasting insulin level (B) in postmenopausal vs. premenopausal women

Pu et al, Climateric 2017



Meta-analysis of metabolic syndrome incidence between surgical menopause and natural menopause.

Pu et al, Climateric 2017



Effects of menopause on insulin resistance

Insulin resistance is readily detectable in ovariectomized mice

Decreased E2 action via Erα is the predominant mechanismproducing resistance after menopause

In liver, decreased Erα activation allows hyperinsulinemia (derivedfrom muscle insulin resistance) to promote liver triglyceride depositionand fails to suppress liver triglyceride (VLDL) export resulting inhepatic steatosis and insulin resistance

The decrease in Erα action in macrophages and adipose tissuecontributes to inflammation,insulin resistance and atherosclerosis.



Effects of menopause on insulin secretion

Menopause alters insulin secretion in ways that are notdetected by standard clinical measurement of glucoseand insulin levels and are revealed only duringdynamic testing

In postmenopausal women, decreased E2 action via Erα and Erβ impair islet β-cell survival and secretionrespectivelyDiapositiva preparata da CARLA GIORDANO e ceduta alla Società Italiana di Diabetologia.


SEX- AND GENDER-RELATED PREVALENCE, CARDIOVASCULAR RISK

AND THERAPEUTIC APPROACH IN METABOLIC SYNDROME



SEX- AND GENDER-RELATED FACTORS ASSOCIATED WITH PREVALENCE OF MS



EFFECT OF MENOPAUSE ON GLUCOSE HOMEOSTASIS AND DIABETES

STUDY OF WOMEN ‘S HEALTH ACROSS THE NATION (SWAN)

The alteration in glucose homeostasis observed around menopause was

related to chronological aging rather than ovarian menopause itself. However,

a follow up of the same study concludes that lower premenopausal E2 levels

during the early menopausal transition is associated with 47% higher risk of

developing diabetes, which is consistent with a role of ovarian aging.

Matthews KA et al., J Am Coll Cardiol 54: 2366-2373, 2009Matthews KA et al, J Am Coll Cardiol 62: 191-200, 2013Park SK et al., Diab Med 34(4):531-538, 2017




EPIC-INTERACT STUDY

A prospective case-cohort study with a follow up of 11 years, concluded

that early menopause before the age of 40- leading to more prolonged E2

deficiency- is associated with a 32% greater risk of type 2 diabetes

compared to menopause at age 50-54 years.

Brand JS, Diabetes Care 36: 1012-1019, 2013Diapositiva preparata da CARLA GIORDANO e ceduta alla Società Italiana di Diabetologia.



THE DONGFENG-TONGJI COHORT STUDY

This Chinese observational study in 16,299 Chinese women reported that

early menopausal age (≤45years) is associated with 20% increased risk

of diabetes compared to the average menopausal age of 49.5 years.

Shen L. et al., Diabetes & Metabolism, 43(4):345-350, 2017Diapositiva preparata da CARLA GIORDANO e ceduta alla Società Italiana di Diabetologia.



NATIONAL HEALTH AND NUTRITION EXAMINATION SURVEY (NHANES) I EPIDEMIOLOGIC FOLLOW-UP STUDY

Women with bilateral ovariectomy with a follow-up period of 9 years

exhibited a 57% increased risk of diabetes compared to women with

natural menopause Appiah D. et al., Diabetes Care 37: 725-733, 2014

Malacara JM et al., Maturitas 28: 35-45, 1997Diapositiva preparata da CARLA GIORDANO e ceduta alla Società Italiana di Diabetologia.



Le Blanc ES et al., Menopause, Vol. 24, No. 1, 2017



Diabetologia, 2017

Flow chart of study participants from the Rotterdam Study cohorts



Intracrinology of the menopause and glucose homeostasis

In post-menopausal women, the main female hormone E2 issynthetized in extragonadal sites such as breast, brain, muscle,muscle, bone and adipose tissue where E2 acts locally as aparacrine or intracrine factor.

In postmenopausal women, E2 peripheral action depends on itsbiosynthesis from a circulating source of adrenal androgens

The EPIC-InterAct study, concluded that early menopause– leading to more prolonged E2 deficiency- is associated with agreater risk of type 2 diabetes.



Lifelong impact and interaction between sex and gender on development and outcomes of T2DM:

Kautzky-Willer A. et al. Endocr Review 2016



Insulin secretion and sensitivity in men and women with normal glucose tolerance (NGT), impaired glucose metabolism [IGM IGT

and/or IFG], and overt type 2 diabetes (T2DM)



Effects of MHT on glucose homeostasis



MECHANISM OF MHT ANTIDIABETIC ACTIONS



Comparison of transdermal E2 and oral CE delivery



Essential points

• Large randomized controlled trials suggest that menopausal hormone therapy(MHT) using estrogens, delays the onset of type 2 diabetes in women.

• MHT is neither appropriate nor FDA-approved for the prevention of type 2 diabetes in women.

• Discrepancies in studies assessing the mechanism of MHT antidiabetic actionsarise from differences in methods used, ranging from clinical indices of insulinsensitivity (HOMA-IR) to steady state methods to assess insulin action(Euglycemic, hyperinsulinemic clamp).

• MHT improves β-cell insulin secretion, glucose effectiveness and insulinsensitivity as measured in clinical setting.

• New physiological studies designed to unravel the mechanism of action of MHT on glucose homeostasis are warranted.



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