Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa...

46
Diabete e genere Alberto Maran

Transcript of Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa...

Page 1: Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa fra i 50 e gli 80 anni, 1 caso su 4 ha un’età superiore a 80 anni, mentre solo

Diabete e genere

Alberto Maran

Page 2: Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa fra i 50 e gli 80 anni, 1 caso su 4 ha un’età superiore a 80 anni, mentre solo

19.2

11.5

3.4

33.0

27.6

26.4

Prevalenza globale del diabete e proiezioni 2025

13.8

Mondo

Paesi sviluppati

Paesi in via di sviluppo

36.2

27.39.8

47.8

79.555.9

42.8

+120%

+40%

+170%

135.286

50.974

84.313

299.974

72.244

227.725

Page 3: Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa fra i 50 e gli 80 anni, 1 caso su 4 ha un’età superiore a 80 anni, mentre solo

14

E P I D E M I O LO G I A D E L D I A B E T E

diabete sono collocati nella fascia di età compresa fra i 50 e gli 80 anni, 1 caso su 4 ha un’età superiore a 80 anni, mentre

solo 7 casi su 100 e 24 casi su 100 hanno un’età inferiore a 19 anni e 34 anni, rispettivamente (Figura 2). Nell’Italian Lon-

gitudinal Study on Aging (6), uno studio prospettico di coorte che ha coinvolto 5632 soggetti di età compresa fra 65 e 84

anni, la prevalenza del diabete risultava pari al 13,8%. La prevalenza del diabete appare ancora più elevata nei soggetti di

età superiore a 65 anni presenti in strutture per lungo-degenti, raggiungendo il 17% secondo quanto emerso da un’ana-

lisi condotta nel 2013 in 83 strutture della regione Piemonte che accoglievano 5076 residenti (7).

Per quanto riguarda la di!usione del diabete per area geografica, secondo i dati ISTAT, la prevalenza è mediamente più

Figura 1 X Andamento della prevalenza del diabete in Italia nel corso degli anni (2001-2014) secondo i dati ISTAT (2).

�'�+�"�$,����

�'�+�"�$,����

��������

Figura 2 X Prevalenze del diabete in funzione dell’età e del genere secondo i dati dell’Osservatorio ARNO 2015 (4).

Andamento della prevalenza del diabete in Italia nel corso degli anni (2001-2014) secondo i da< ISTAT

Page 4: Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa fra i 50 e gli 80 anni, 1 caso su 4 ha un’età superiore a 80 anni, mentre solo

Prevalenza del diabete in funzione del sesso e dell’età

Osservatorio Arno Diabete 2018

��Osservatorio Arno Diabete

Tabella 2&DUDWWHULVWLFKH�GHPRJUDÀFKH�GHOOH�SHUVRQH�FRQ�GLDEHWH

&ODVVL�GL�HWj0DVFKL )HPPLQH 7RWDOH

N � N � N �

0-19 ����� ��� ����� ��� ����� ���

����� ����� ��� ������ ��� ������ ���

����� ������ ��� ������ ��� ������ ���

����� ������ ���� ������ ���� ������� ����

����� ������� ���� ������� ���� ������� ����

! �� ������ ���� ������ ���� ������� ����

7RWDOH ������� ����� ������� ����� ������� �����

*UDÀFR��3UHYDOHQ]D�GHO�GLDEHWH�LQ�IXQ]LRQH�GHO�VHVVR�H�GHOO·HWj2

0,2 0,51,8

8,3

20,2

17,9

6,5

0,31,2

2,2

5,3

15,116,2

5,9

0

5

10

15

20

25

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

Classi di età

Prev

alen

za (%

)

Maschi

Femmine

*UDÀFR��D3UHYDOHQ]D�GHO�GLDEHWH�LQ�IXQ]LRQH�GHO�VHVVR�H�GHOO·HWj

0

5

10

15

20

25

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100

104

108

Prev

alen

za (%

)

Maschi

Femmine

2� /D�SUHYDOHQ]D�FRPSOHVVLYD�GL�GLDEHWH�q�GHO�����

La prevalenza complessiva di diabete e del 6,2%

Page 5: Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa fra i 50 e gli 80 anni, 1 caso su 4 ha un’età superiore a 80 anni, mentre solo

Obesità Addominale

IntolleranzaGlucosio/Resistenza Insulina

Ipertensione

Dislipidemia Aterogena

Stato Proinfiammatorio/Protrombotico

National Cholesterol Educational Program (NCEP), Adult Treatment Panel (ATP) III; 2001

Diabete CVD

La sindrome Metabolica come «Cluster» di Fattori di rischio

Page 6: Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa fra i 50 e gli 80 anni, 1 caso su 4 ha un’età superiore a 80 anni, mentre solo

Figure 3. Deaths attributable to the individual and combined effects of high body mass index, blood pressure, cholesterol, and glucose in 2010, by disease.

Page 21

Lancet Diabetes Endocrinol. Author manuscript; available in PMC 2015 September 16.

Author Manuscript

Author Manuscript

Author Manuscript

Author Manuscript

Cardiovascular disease, chronic kidney disease, and diabetes mortality burden of cardio-metabolic risk factors between 1980 and 2010: comparative risk assessment

The Global Burden of Metabolic Risk Factors for Chronic Diseases Collaboration

SummaryBackground—Elevated blood pressure and glucose, serum cholesterol, and body mass index (BMI) are risk factors for cardiovascular diseases (CVDs); some of these factors also increase the risk of chronic kidney disease (CKD) and diabetes. We estimated CVD, CKD, and diabetes mortality attributable to these four cardio-metabolic risk factors for all countries and regions between 1980 and 2010.

Methods—We used data on risk factor exposure by country, age group, and sex from pooled analysis of population-based health surveys. Relative risks for cause-specific mortality were obtained from pooling of large prospective studies. We calculated the population attributable fractions (PAF) for each risk factor alone, and for the combination of all risk factors, accounting for multi-causality and for mediation of the effects of BMI by the other three risks. We calculated attributable deaths by multiplying the cause-specific PAFs by the number of disease-specific deaths from the Global Burden of Diseases, Injuries, and Risk Factors 2010 Study. We propagated the uncertainties of all inputs to the final estimates.

Findings—In 2010, high blood pressure was the leading risk factor for dying from CVDs, CKD, and diabetes in every region, causing over 40% of worldwide deaths from these diseases; high BMI and glucose were each responsible for about 15% of deaths; and cholesterol for 10%. After accounting for multi-causality, 63% (10.8 million deaths; 95% confidence interval 10.1–11.5) of deaths from these diseases were attributable to the combined effect of these four metabolic risk factors, compared with 67% (7.1 million deaths; 6.6–7.6) in 1980. The mortality burden of high BMI and glucose nearly doubled between 1980 and 2010. At the country level, age-standardised death rates attributable to these four risk factors surpassed 925 deaths per 100,000 among men in Belarus, Mongolia, and Kazakhstan, but were below 130 deaths per 100,000 for women and below 200 for men in some high-income countries like Japan, Singapore, South Korea, France, Spain, The Netherlands, Australia, and Canada.

Conflict of interestNoneAuthor contributionGD and ME designed the study concept. YL, GMD, EC, GAS, MC, FF, JKL, MMF, and MR analysed exposure and effect size data. YL and EC analysed attributable fractions and deaths. Collaborating group members contributed exposure and effect size data. ME and GD wrote the first draft of the paper, with input from other writing group and collaborating group members. GD, SSL, and ME oversaw research.

HHS Public AccessAuthor manuscriptLancet Diabetes Endocrinol. Author manuscript; available in PMC 2015 September 16.

Published in final edited form as:Lancet Diabetes Endocrinol. 2014 August ; 2(8): 634–647. doi:10.1016/S2213-8587(14)70102-0.

Author Manuscript

Author Manuscript

Author Manuscript

Author Manuscript

Cardiovascular disease, chronic kidney disease, and diabetes mortality burden of cardio-metabolic risk factors between 1980 and 2010: comparative risk assessment

The Global Burden of Metabolic Risk Factors for Chronic Diseases Collaboration

SummaryBackground—Elevated blood pressure and glucose, serum cholesterol, and body mass index (BMI) are risk factors for cardiovascular diseases (CVDs); some of these factors also increase the risk of chronic kidney disease (CKD) and diabetes. We estimated CVD, CKD, and diabetes mortality attributable to these four cardio-metabolic risk factors for all countries and regions between 1980 and 2010.

Methods—We used data on risk factor exposure by country, age group, and sex from pooled analysis of population-based health surveys. Relative risks for cause-specific mortality were obtained from pooling of large prospective studies. We calculated the population attributable fractions (PAF) for each risk factor alone, and for the combination of all risk factors, accounting for multi-causality and for mediation of the effects of BMI by the other three risks. We calculated attributable deaths by multiplying the cause-specific PAFs by the number of disease-specific deaths from the Global Burden of Diseases, Injuries, and Risk Factors 2010 Study. We propagated the uncertainties of all inputs to the final estimates.

Findings—In 2010, high blood pressure was the leading risk factor for dying from CVDs, CKD, and diabetes in every region, causing over 40% of worldwide deaths from these diseases; high BMI and glucose were each responsible for about 15% of deaths; and cholesterol for 10%. After accounting for multi-causality, 63% (10.8 million deaths; 95% confidence interval 10.1–11.5) of deaths from these diseases were attributable to the combined effect of these four metabolic risk factors, compared with 67% (7.1 million deaths; 6.6–7.6) in 1980. The mortality burden of high BMI and glucose nearly doubled between 1980 and 2010. At the country level, age-standardised death rates attributable to these four risk factors surpassed 925 deaths per 100,000 among men in Belarus, Mongolia, and Kazakhstan, but were below 130 deaths per 100,000 for women and below 200 for men in some high-income countries like Japan, Singapore, South Korea, France, Spain, The Netherlands, Australia, and Canada.

Conflict of interestNoneAuthor contributionGD and ME designed the study concept. YL, GMD, EC, GAS, MC, FF, JKL, MMF, and MR analysed exposure and effect size data. YL and EC analysed attributable fractions and deaths. Collaborating group members contributed exposure and effect size data. ME and GD wrote the first draft of the paper, with input from other writing group and collaborating group members. GD, SSL, and ME oversaw research.

HHS Public AccessAuthor manuscriptLancet Diabetes Endocrinol. Author manuscript; available in PMC 2015 September 16.

Published in final edited form as:Lancet Diabetes Endocrinol. 2014 August ; 2(8): 634–647. doi:10.1016/S2213-8587(14)70102-0.

Author Manuscript

Author Manuscript

Author Manuscript

Author Manuscript

Page 7: Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa fra i 50 e gli 80 anni, 1 caso su 4 ha un’età superiore a 80 anni, mentre solo

15

È opinione diffusa che l’incidenza e la prevalenza delle malattie CV siano superiori nell’uomo rispetto alla don-na, ma sostanziosi dati epidemiologici evidenziano una realtà diversa.Tra i tanti riferimenti, riportiamo la fonte di European Cardiovascular Disease Statistics (2012), la quale ri-leva che in Europa ogni anno muoiono 4.000.000 di persone a causa delle malattie CV, comprendendo sia la cardiopatia ischemica sia lo stroke. Negli uomini la mortalità per cause CV si riscontra nel 42% dei casi, mentre nelle donne la percentuale è ad-dirittura superiore e si attesta al 52%!1.Riportiamo, dalla stessa fonte, tutte le cause di morte nelle Figure!1 e 2, riferite a tutte le età.Le evidenze crescenti hanno contribuito a rimuovere la falsa credenza che le donne fossero più protette dal rischio CV. Questo ha assunto particolare rilievo sul piano epide-miologico, diagnostico e di programmazione sanitaria, per un’aumentata consapevolezza dell’importanza di una valutazione di genere del rischio CV. In effetti negli anni passati c’è stata dispersione di risorse e danni in

outcome di salute nel tentativo di adattare alla donna quello che è efficace nell’uomo, dal punto di vista sia diagnostico sia terapeutico. Fino a poco tempo fa le donne sono state arruolate in modo insufficiente nel trial clinici, e quindi sotto-studiate, sottodiagnosticate e sottotrattate, anche se finalmente adesso le società scientifiche interna-zionali sembra stiano dimostrando nei confronti delle caratteristiche e delle diversità di genere un interesse sempre maggiore. Per poter migliorare il management clinico del rischio CV nelle donne, sappiamo infatti che sono necessari studi dedicati per comprendere meglio le specificità delle malattie CV femminili e trattamenti più mirati dei fattori di rischio delle donne.Tra i dati prodotti e disponibili menzioniamo la pubbli-cazione delle prime raccomandazioni cliniche specifi-che per le donne riguardo alla prevenzione delle malat-tie CV (American Heart Association 1999). Un decennio più tardi (2011) fu sempre l’AHA a pubbli-care le linee guida per la prevenzione delle malattie CV nelle donne!2 che ebbero il merito di porre l’attenzione su importanti criticità specifiche del sesso femminile. La donna infatti presenta alcune variabili ed eventi fi-siologici della vita riproduttiva, quali la gravidanza e la menopausa, che rappresentano importanti condizioni di vulnerabilità per il rischio CV. La gravidanza, in particolare, è un test di stress CV e metabolico che rappresenta un’opportunità unica per valutare il rischio CV nel corso di tutta la vita. È importante sapere che la preeclampsia o il diabete ge-stazionale durante la gravidanza, e/o la nascita di un neonato pretermine o di un bambino che è piccolo per la sua età gestazionale, o un sanguinamento nel terzo trimestre sono tutti fattori associati!a un aumentato ri-schio CV. Per questi motivi nelle linee guida troviamo raccomandata la raccolta accurata dell’anamnesi in relazione alla presenza di complicanze in gravidanza!3.Con la menopausa vengono meno alcuni effetti protet-tivi esercitati dagli estrogeni, caratterizzati da:t� B[JPOF�BOUJPTTJEBOUF�t� JOJCJ[JPOF�EFMMB�QSPMJGFSB[JPOF�DFMMVMBSF�t� NJHMJPSF�GVO[JPOF�FOEPUFMJBMF�F�FRVJMJCSJP�FNPTUBUJDP�t� NPEVMB[JPOF�GBWPSFWPMF�EFM�TJTUFNB�SFOJOB�BOHJP-

tensina aldosterone (sistema RAA);t� BVNFOUP� EFM� DPMFTUFSPMP�)%-� F� EJNJOV[JPOF� EFM�

colesterolo-LDL, riduzione dei livelli di LP(a), APO A1 - APO.

Epidemiologia e aspetti clinici delle malattie cardiovascolari e

cerebrovascolari

FIGURA 1.Mortalità per cause in uomini di tutte le età (da European Cardiovascular Disease Statistics, 2012, mod.) 1.

Altre cause, 20%

Malattia coronarica, 20%

Ictus, 10%

Altre malattie CV, 12%

Cancro allo stomaco, 2%

Cancro al polmone, 4%

Altre neoplasie, 13%

Malattie respiratorie, 7%

Traumi e avvelenamenti, 13%

Cancro colo-rettale, 2%

16

Rischio cardiovascolare e differenze di genere

Molte linee guida sono concordi nel ridurre il cut off di identificazione di rischio CV elevato per le donne: non più un valore !"20% di rischio assoluto a 10 anni, ma un valore !"10%.I motivi di questa revisione sono legati sia alla rilevazio-ne sia ai principali strumenti di valutazione del rischio che tendono a sottostimare il rischio nelle donne, sia alla maggior incidenza di stroke che le donne registra-no rispetto agli uomini, dato che presuppone una stra-tegia preventiva più efficace"4.

Altri interessanti dati utili alla comprensione del rischio CV di genere derivano dallo studio INTERHEART 2004" 5 e da una sua analisi di Anand del 2008" 6. Lo studio, che è stato condotto su 27.098 partecipanti, di 52 paesi, di cui 6.787 donne, ha permesso di stima-re in maniera differenziale l’effetto di 9 fattori di rischio nei due sessi. È stato dimostrato che l’ipertensione, il diabete, l’effetto protettivo dell’esercizio fisico e il con-sumo di alcool avrebbero un peso maggiore nel rischio CV del sesso femminile. Questo studio ha evidenziato che l’età mediana del pri-mo evento CV era negli uomini di nove anni più bassa rispetto alle donne"6.L’European Heart Network della Società Europea di Cardiologia ha riassunto in un documento evidenze e raccomandazioni sulla salute CV delle donne; riportia-NP�OFM�#PY���EJWFSTJ�QVOUJø7.Approfondiamo due patologie CV con diversità di ge-nere: cardiopatia ischemica e stroke.

Focus sulla cardiopatia ischemica e diversità di genereSecondo l’VIII Rapporto Health Search"8 la prevalenza delle malattie ischemiche di cuore aumenta con l’età e con l’età si riduce moderatamente la differenza di prevalenza tra i due sessi (Fig. 3).Esistono alcune importanti differenze nei due generi in peso relativo dei fattori di rischio, età di insorgenza, manifestazione clinica, diagnosi e prognosi. Nelle don-ne, la malattia CV si manifesta con un ritardo rispetto al genere maschile di circa 7-10 anni. La copertura estrogenica posticipa la comparsa delle placche, ma con l’avvento della menopausa aumenta anche la vul-

FIGURA 2.Mortalità per cause in donne di tutte le età (da European Cardiovascular Disease Statistics, 2012, mod.) 1.

Altre neoplasie, 10%

Malattie respiratorie, 6%

Traumi e avvelenamenti, 4%

Altre cause, 20%

Malattia coronarica, 22%

Ictus, 15%

Altre malattie CV, 15%

Cancro allo stomaco, 1%Cancro colo-rettale, 2%

Cancro al polmone, 2%

Cancro al seno, 3%

Box 1. Allerta per il cuore delle donne

Evidenze sulle donne e ricerca CV1) Le malattie CV rappresentano la principale causa di

morte nelle donne, stimabile nel 54% in Europa.2) Le donne usualmente manifestano patologie CV

10 anni dopo rispetto agli uomini; il rischio cresce dopo la menopausa, in parte a causa del deficit ormonale ovarico che favorisce l’instaurarsi di iper-tensione, diabete, dislipemia, obesità centrale e sindrome metabolica.

3) Le donne sono sottorappresentate nella ricerca CV: su 62 trial clinici randomizzati pubblicati dal 2006 al 2009 con 380.891 pazienti arruolati, solo il 33,5% era rappresentato da donne, e solo il 50% di questi trial hanno riportato analisi sui risultati legati alle dif-ferenze di genere.

4) Questa sottorappresentazione è particolarmente marcata negli ambiti della terapia ipolipemizzan-te, della cardiopatia ischemica e dello scompen-so cardiaco.

Donne e diabetet� -F�EPOOF�DPO�EJBCFUF�QSFTFOUBOP�VO�SJTDIJP�QJá�FMF-

vato di sviluppare malattia coronarica o stroke, una prognosi peggiore dopo infarto miocardico e una più elevata mortalità da malattie CV rispetto agli uomini.

Donne e cardiopatia ischemicat� /FMMF�NBOJGFTUB[JPOJ�DMJOJDIF�EFMMB�DPSPOBSPQBUJB�DJ�

sono differenze di genere: maggior prevalenza per ischemia silente nelle donne, prevalenza simile per l’angina.

t� 4J� TPOP� SJTDPOUSBUF� EJGGFSFO[F� TJHOJmDBUJWF� OFM� SJ-schio di eventi avversi da procedure di rivascola-rizzazione. Il rischio durante e dopo tali procedure, inclusi la dissezione coronarica e il sanguinamento locale, è maggiore nelle donne.

Donne e scompenso cardiacot� -a prevalenza di scompenso cardiaco è superiore

negli uomini fino a 75 anni, dai 75 anni in poi la situazione si rovescia e la prevalenza diventa mag-giore nelle donne.

CAUSE DI MORTE

UOMO DONNA

Page 8: Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa fra i 50 e gli 80 anni, 1 caso su 4 ha un’età superiore a 80 anni, mentre solo

e.g.

Onset of diabetes

Complications

Disability

IGT

Insulin resistenceHyperinsulinaemiaHDL

HyperglycaemiaHDL¯

RetinopathyNephropathyAtherosclerosisNeuropathy

BlindnessRenal failureCoronary heart diseaseAmputation

Environmental factors

nutritionobesityphysical inactivity

Genetic susceptibility D

EATH

The natural history of non insulin-dependent diabetes mellitus

WHO 94390HDL,high-density lipoprotein; IGT, impaired glucose tolerance

Page 9: Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa fra i 50 e gli 80 anni, 1 caso su 4 ha un’età superiore a 80 anni, mentre solo

INTERHEART: Risk of Acute Myocardial Infarctionassociated with self-reported diabetes

Colhoun HM et al. Lancet 2004;364:685-696.

Overall and Region-by-Region Odds ratio after adjusting for age, sex and smoking

Page 10: Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa fra i 50 e gli 80 anni, 1 caso su 4 ha un’età superiore a 80 anni, mentre solo

Associa'on of risk factors with acute myocardial infarc'on in men and women a6er adjustment for age, sex, and geographic region

INTERHEART. Lancet 2004

Page 11: Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa fra i 50 e gli 80 anni, 1 caso su 4 ha un’età superiore a 80 anni, mentre solo

Mortalità cardiovascolare in uomini e donne con diabete

Modificata da Krolewski AS, et al. Am J Med 1991 (ref. 19 )

DiabeteNo Diabete

60Uomini

0-3Anni di Durata del follow-up (anni)

50

40

30

20

10

0

Donne

4-7 8-11 12-1516-1920-23

60

0-3Anni di durata del follow-up (anni)

50

40

30

20

10

04-7 8-11 12-1516-1920-23

Mor

talit

àpe

r 100

0

Mor

talit

àPe

r 100

0

2x

4-5x

Page 12: Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa fra i 50 e gli 80 anni, 1 caso su 4 ha un’età superiore a 80 anni, mentre solo

Rela<ve risk of cardiovascular events in people with diabetes

Barret-Connor et al. Arch Int Med 2004

Page 13: Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa fra i 50 e gli 80 anni, 1 caso su 4 ha un’età superiore a 80 anni, mentre solo

Rela<ve risks of coronary heart disease (CHD) in women

Barret-Connor et al. Arch Int Med 2004

Page 14: Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa fra i 50 e gli 80 anni, 1 caso su 4 ha un’età superiore a 80 anni, mentre solo

than men [26]. Thus, sex differences in the healthcare provid-ed for the prevention, management, and treatment of diabetesand its complications could well contribute to women’s great-er excess relative risks of diabetes complications, particularlyin those parts of the world where access to care in women ismore limited than in men. However, this under-treatment forwomen is not restricted to those with diabetes, and there is noreason to suppose things should be worse in relation to diabe-tes than to other major risk factors or comorbidities. Thus,since some other risk factors for CVD, such as high bloodpressure or elevated total cholesterol [17, 18], do not exhibita female disadvantage, physician bias cannot be the only ex-planation for the sex differential in diabetes.

Another possible cause of women’s additional risk fromdiabetes is that they are less aware of their risk of CVD, orare less likely to adhere to treatment recommendations oncethey are at high risk of CVD. For instance, an American studyfound adherence to antidiabetic medication to be slightly low-er amongst women than men [27]. This leads one to considerthe differential social structures contrasting the sexes. It mightbe that women are more concerned about their families thanthemselves, or just are less aware of their CVD risks as muchas do men. However, this again is unlikely to be specific todiabetes.

Biological Factors

Most likely, natural biology has a large influence on the sexdifferential in vascular diseases associated with diabetes.Women generally have more favourable levels of cardiovas-cular risk factors than men, but this pattern is not seen withdeterioration in glycaemic control and progression towardsdiabetes [28••, 29••]. Several studies have shown that the dif-ferences in risk factor levels between diabetic and non-diabetic individuals are greater in women than in men—par-ticularly for anthropometric variables [30, 31]. Thus, differ-ences between women and men in the prevalence of over-weight and obesity and, potentially more importantly, thesex dimorphism in body composition and fat distributionmay be involved.

Overweight and obesity are key risk factors for the devel-opment of diabetes and progression to its complications. Aswith diabetes, halting the rise in the prevalence of obesity at its2010 levels has been included among the UN’s global NCDtargets for 2025 [2]. Global trends in adult body mass index(BMI), however, suggest that the probability of meeting theglobal obesity target is virtually zero [32]. Estimates fromNCD-RisC demonstrate that the global age-standardised prev-alence of obesity, defined as a BMI ! 30 kg/m2, has increasedfrom 3% in 1975 to 11% in 2014 in men and from 6 to 15% in

Fig. 2 Results from prior meta-analyses of sex differences in the effects of diabetes on vascular outcomes, summarised through the ratios of women-to-men adjusted relative risks (and 95% confidence intervals) pooled across cohort studies

33 Page 4 of 8 Curr Diab Rep (2018) 18: 33

Sex differences in the effects of diabetes on vascular outcome

Peters, Current Diabetes Reports (2018) 18: 33

Page 15: Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa fra i 50 e gli 80 anni, 1 caso su 4 ha un’età superiore a 80 anni, mentre solo

Le donne con T2DM hanno anche un aumentato rischio di Stroke

Age-adjusted HR for stroke in DM2 subjects vs non diabetic subjects was:- 2.08 (95%CI:1.94-2.24) in men- 2.32 (95%CI: 2.16-2.49) in women.

The increase in risk attributable to diabetes was highest- in young women (HR 8.18; 95%CI 4.31-15.51) and decreased with age.

Page 16: Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa fra i 50 e gli 80 anni, 1 caso su 4 ha un’età superiore a 80 anni, mentre solo

Long-term survival aMer AMI in men and women with diabetes

Crowley et al. Am Heart J 2003

Page 17: Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa fra i 50 e gli 80 anni, 1 caso su 4 ha un’età superiore a 80 anni, mentre solo

PERCHE’ ???

1. La donna è “più complicata”2. Menopausa ed assetto ormonale 3. La donna vive più a lungo4. Poco considerata (scientificamente)

Rispetto all’uomo:

Page 18: Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa fra i 50 e gli 80 anni, 1 caso su 4 ha un’età superiore a 80 anni, mentre solo

La donna è “più complicata”

Page 19: Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa fra i 50 e gli 80 anni, 1 caso su 4 ha un’età superiore a 80 anni, mentre solo

Possible causes of high CVD in women with diabetes

Rivellese et al. NMCD 2010

Page 20: Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa fra i 50 e gli 80 anni, 1 caso su 4 ha un’età superiore a 80 anni, mentre solo

La donna è “più complicata”

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 diagnostici3. 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 TARDIVOPROGNOSI PEGGIORE

Page 21: Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa fra i 50 e gli 80 anni, 1 caso su 4 ha un’età superiore a 80 anni, mentre solo

Adjusted women-to-men ratios of hazard ratios for association between risk factors and incident myocardial infarction.

Elizabeth R C Millett et al. BMJ 2018;363:bmj.k4247©2018 by British Medical Journal Publishing Group

Page 22: Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa fra i 50 e gli 80 anni, 1 caso su 4 ha un’età superiore a 80 anni, mentre solo

Al-Delaimy WK et al., Diabetes Care 24: 2043-2048, 2001.

Mor

talit

y ra

tes

(per

100

.000

per

son-

year

s)

Smoking and Mortality among Womenwith Type 2 Diabetes

Nurses’ Health Study - 20 Years of follow-up - 121.046 women

0

500

1000

1500

2000

2500

Never Past 1-14 15-34 >35cig/day cig/day cig/day

Nondiabetic women

Diabetic Women

Page 23: Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa fra i 50 e gli 80 anni, 1 caso su 4 ha un’età superiore a 80 anni, mentre solo

Effetti favorevoli degli estrogeni nella donna

Rivellese et al. NMCD 2010

FAVOREVOLE

Lipidi ↓ Colesterolo LDL↑ Colesterolo HDL

Coagulazione ↓ Fibrinogeno

Infiammazione ↓ Molecole di adesione

Funzione endoteliale e pressionearteriosa

↓ Attività dell’enzimaACE

↑ Sintesi Ossido Nitrico↓ Endotelina-1

↓ Proliferazione dellecellule muscolari lisce

Page 24: Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa fra i 50 e gli 80 anni, 1 caso su 4 ha un’età superiore a 80 anni, mentre solo

Tramunt et al (2020) Diabetologia DOI 10.1007/s00125-019-05040-3 ©The Authors 2019. Distributed under the terms of the CC BY 4.0 Attribution License (http://creativecommons.org/licenses/by/4.0/)

Tissue-specific actions of oestrogens on energy balance and metabolic regulation in rodent models

Page 25: Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa fra i 50 e gli 80 anni, 1 caso su 4 ha un’età superiore a 80 anni, mentre solo

Le cellule endoteliali e le cellule muscolari lisce esprimono i recettori per gli estrogeni ERs-alpha and ERs-beta.

Gli estrogeni hanno a breve termine un effetto

vasodilatante e a lungo termine una azione di

inibizione verso il danno vascolare e di prevenzione

dell’aterosclerosi

Page 26: Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa fra i 50 e gli 80 anni, 1 caso su 4 ha un’età superiore a 80 anni, mentre solo

• Gli estrogeni hanno un effetto protettivo in quanto promuovono la produzione di NO! vasodilatazione endotelio dipendente maggiore nelle donne rispetto agli uomini

• L’obesità è associata ad una riduzione della vasodilatazione endoteliale in entrambi i sessi

• Nel diabete, mentre gli uomini non subiscono un’ulteriore compromissione della funzione endoteliale, nelle donne vi è una notevole riduzione della funzione endoteliale che diventa simile agli uomini

Circulation 2000; 201:2040-2046

DiabeteFattori di rischio cardiovascolare: differenze di genere

Page 27: Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa fra i 50 e gli 80 anni, 1 caso su 4 ha un’età superiore a 80 anni, mentre solo

EPC e gradiente intersesso di rischio cardiovascolare

0

5

10

15

20

25

30

1 2

%KD

R

.

* †

0

20

40

60

80

100

120

1 2

CD34

+KDR

+ ce

lls

. * †

0

2

4

6

8

10

12

1 2

%FM

D

.

* ††

00,10,20,30,40,50,60,70,80,9

1 2

c-IM

T

. * †

Women Age-matched men

Il livello delle EPC circolanti (vasculoprotettive) è più alto nelle donne in età fertile rispetto agli uomini di pari età.Tale differenze viene abolita nelle donne post-menopausali rispetto agli uomini coevi.

I meccanismi di rigenerazione vascolare rispecchiano il gradiente intersesso della funzione endoteliale (FMD), del rimodellamento vascolare (IMT) e del di rischio cardiovascolare

Fadini et al. ATVB 2008

Fertile Post-menopausal

Fertile Post-menopausal

Fertile Post-menopausal

Fertile Post-menopausal

Page 28: Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa fra i 50 e gli 80 anni, 1 caso su 4 ha un’età superiore a 80 anni, mentre solo

0

20

40

60

80

100

120

0-1 2+

CD34

+KDR

+ ce

lls

.

F M*

EPC e gradiente intersesso di rischio cardiovascolare. Effetto dei fattori di rischio

Fadini et al. ATVB 2008

La compresenza di 2+ faJori di rischio CV abolisce il gradiente intersesso di EPCs

Page 29: Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa fra i 50 e gli 80 anni, 1 caso su 4 ha un’età superiore a 80 anni, mentre solo

Huebschmann et al (2019) Diabetologia DOI 10.1007/s00125-019-4939-5 © Elsevier. Adapted with permission from Sattar

Sex differences in insulin resistance across the life span

Page 30: Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa fra i 50 e gli 80 anni, 1 caso su 4 ha un’età superiore a 80 anni, mentre solo

Obesity levels are higher among women than men at the time of type 2 diabetes diagnosis

Huebschmann et al (2019) Diabetologia DOI 10.1007/s00125-019-4939-5

Page 31: Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa fra i 50 e gli 80 anni, 1 caso su 4 ha un’età superiore a 80 anni, mentre solo

Fattori di rischio cardiovascolare:differenze di genere

IpertensioneArteriosa

Forme specifiche di ipertensione nella donna, come l’ipertensione gravidica e l’eclampsia (10% delle gravidanze), sono associate ad un rischio di malattia

cardiovascolare futura nella donna tra 2 e 8 volte superiore, e richiedono pertanto attente misure di valutazione, terapia e prevenzione secondaria

Page 32: Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa fra i 50 e gli 80 anni, 1 caso su 4 ha un’età superiore a 80 anni, mentre solo

Differences in HDL and ApoAI by diabe'c status in women and men

The Strong Heart Study, Diabetes Care 1998

Page 33: Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa fra i 50 e gli 80 anni, 1 caso su 4 ha un’età superiore a 80 anni, mentre solo

Differences in LDL size and fibrinogen by diabetic status in women and men

The Strong Heart Study, Diabetes Care 1998

Page 34: Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa fra i 50 e gli 80 anni, 1 caso su 4 ha un’età superiore a 80 anni, mentre solo

CONTROLLO deiFDR CARDIOVASCOLARE (donne)

NHANES III study

of the Female population met six of the seven key CVD

health metrics:

Not smokingEating a healthy diet

Being physically activeNormal weight

Normal blood pressureNormale glucose level

Normal cholesterol levels

< 7.5%

(Third National Health and Nutrition Examination Survey)

Page 35: Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa fra i 50 e gli 80 anni, 1 caso su 4 ha un’età superiore a 80 anni, mentre solo

• Women with type 2 diabetes had higher levels of low-density lipoproteincholesterol, and they are less likely to receive statin therapy when compared with their male counterparts.

• Women with type 2 diabetes had to put on more weight to develop diabetes. Thisexcess weight is associated with a greater deterioration in cardiovascular riskfactors’ levels, endothelial dysfunction, low-grade inflammation, and hypercoagulability state in women as compared with men.

• Women with type 2 diabetes have been underrepresented in most clinical trials that focused on the impact of drug interventions (statin therapy, newerantidiabetic drugs) on the occurrence of cardiovascular disease. This precludes firmconclusions about the effects of many drug treatments in women with type 2 diabetes.

Cardiovascular Disease in Type 2 Diabetes: AReview of Sex-Related Differences inPredisposition and PreventionAbdallah Al-Salameh, MD; Philippe Chanson, MD; Sophie Bucher, MD, PhD;Virginie Ringa, MD, PhD; and Laurent Becquemont, MD, PhD

Abstract

Type 2 diabetes mellitus is a major risk factor for cardiovascular disease. However, compiled datasuggest that type 2 diabetes affects the risk of cardiovascular disease differentially according to sex. Inrecent years, large meta-analyses have con!rmed that women with type 2 diabetes have a higherrelative risk of incident coronary heart disease, fatal coronary heart disease, and stroke compared withtheir male counterparts. The reasons for these disparities are not completely elucidated. A greaterburden of cardiometabolic risk in women was proposed as a partial explanation. Indeed, severalstudies suggest that women experience a larger deterioration in major cardiovascular risk factors andput on more weight than do men during their transition from normoglycemia to overt type 2 diabetes.This excess weight is associated with higher levels of biomarkers of endothelial dysfunction,in"ammation, and procoagulant state. Moreover, sex differences in the prescription and use of somecardiovascular drugs may compound an “existing” disparity. We searched PubMed for articlespublished in English and French, by using the following terms: (“cardiovascular diseases”) AND(“diabetes mellitus”) AND (“sex disparity” OR “sex differences” OR “sex related differences” OR“sex-related differences” OR “sex disparities”). In this article, we review the available literature on thesex aspects of primary and secondary prevention of cardiovascular disease in people with type 2diabetes, in the predisposition to cardiovascular disease in those people, and in the control of diabetesand associated cardiovascular risk factors.

ª 2018 Mayo Foundation for Medical Education and Research n Mayo Clin Proc. 2019;94(2):287-308

D iabetes mellitus is a major riskfactor for cardiovascular disease(CVD). Its prevalence is

increasing worldwide, and this trend is pro-jected to persist because of the demographicshift and the obesity pandemic. The globalprevalence of diabetes was estimated at8.8% in 2017, with a slightly higher preva-lence among men (9.1%) than amongwomen (8.4%).1 However, despite large var-iations in the reported male-to-female ratiobetween studies in different countries andethnicities, there is little evidence to sup-port a sex difference in the prevalence ofdiabetes. Most people with diabetes havetype 2 diabetes mellitus (T2DM). On theother hand, CVD is the leading cause ofmorbidity and mortality in people with

diabetes. Modern studies show that CVDis responsible for 24% to 30% of hospitaliza-tions2 and around one-third of deaths3,4 inpeople with diabetes. Despite improve-ments in CVD morbidity and mortality dur-ing recent decades, the population-attributable risk for diabetes as a cardiovas-cular risk factor continues to increase5 andthe cardiovascular burden of diabetes re-mains important.

Although women without diabetes havea lower risk of developing CVD comparedwith men without diabetes of the same age,this “female advantage” seems to diminishor disappear in the setting of T2DM. Indeed,the relative risk of CVD in people withT2DM compared with people without dia-betes is greater in women than in men,

From Centre derecherche en Epidémiolo-gie et Santé desPopulations (CESP),Université Paris-Sud,Université Paris-Saclay,INSERM, Villejuif (A.A.-S.,S.B., V.R., L.B.), AssistancePublique-Hôpitaux deParis, Hôpitaux Universi-taires Paris-Sud, Hôpital deBicêtre, Service d’Endocri-nologie et des Maladies dela Reproduction, LeKremlin-Bicêtre (A.A.-S.,P.C.), Assistance Publique-Hôpitaux de Paris(AP-HP), HôpitauxUniversitaires Paris-Sud,Hôpital de Bicêtre, Centre

Af!liations continued atthe end of this article.

REVIEW

Mayo Clin Proc. n February 2019;94(2):287-308 n https://doi.org/10.1016/j.mayocp.2018.08.007www.mayoclinicproceedings.org n ª 2018 Mayo Foundation for Medical Education and Research

287

Cardiovascular Disease in Type 2 Diabetes: AReview of Sex-Related Differences inPredisposition and PreventionAbdallah Al-Salameh, MD; Philippe Chanson, MD; Sophie Bucher, MD, PhD;Virginie Ringa, MD, PhD; and Laurent Becquemont, MD, PhD

Abstract

Type 2 diabetes mellitus is a major risk factor for cardiovascular disease. However, compiled datasuggest that type 2 diabetes affects the risk of cardiovascular disease differentially according to sex. Inrecent years, large meta-analyses have con!rmed that women with type 2 diabetes have a higherrelative risk of incident coronary heart disease, fatal coronary heart disease, and stroke compared withtheir male counterparts. The reasons for these disparities are not completely elucidated. A greaterburden of cardiometabolic risk in women was proposed as a partial explanation. Indeed, severalstudies suggest that women experience a larger deterioration in major cardiovascular risk factors andput on more weight than do men during their transition from normoglycemia to overt type 2 diabetes.This excess weight is associated with higher levels of biomarkers of endothelial dysfunction,in"ammation, and procoagulant state. Moreover, sex differences in the prescription and use of somecardiovascular drugs may compound an “existing” disparity. We searched PubMed for articlespublished in English and French, by using the following terms: (“cardiovascular diseases”) AND(“diabetes mellitus”) AND (“sex disparity” OR “sex differences” OR “sex related differences” OR“sex-related differences” OR “sex disparities”). In this article, we review the available literature on thesex aspects of primary and secondary prevention of cardiovascular disease in people with type 2diabetes, in the predisposition to cardiovascular disease in those people, and in the control of diabetesand associated cardiovascular risk factors.

ª 2018 Mayo Foundation for Medical Education and Research n Mayo Clin Proc. 2019;94(2):287-308

D iabetes mellitus is a major riskfactor for cardiovascular disease(CVD). Its prevalence is

increasing worldwide, and this trend is pro-jected to persist because of the demographicshift and the obesity pandemic. The globalprevalence of diabetes was estimated at8.8% in 2017, with a slightly higher preva-lence among men (9.1%) than amongwomen (8.4%).1 However, despite large var-iations in the reported male-to-female ratiobetween studies in different countries andethnicities, there is little evidence to sup-port a sex difference in the prevalence ofdiabetes. Most people with diabetes havetype 2 diabetes mellitus (T2DM). On theother hand, CVD is the leading cause ofmorbidity and mortality in people with

diabetes. Modern studies show that CVDis responsible for 24% to 30% of hospitaliza-tions2 and around one-third of deaths3,4 inpeople with diabetes. Despite improve-ments in CVD morbidity and mortality dur-ing recent decades, the population-attributable risk for diabetes as a cardiovas-cular risk factor continues to increase5 andthe cardiovascular burden of diabetes re-mains important.

Although women without diabetes havea lower risk of developing CVD comparedwith men without diabetes of the same age,this “female advantage” seems to diminishor disappear in the setting of T2DM. Indeed,the relative risk of CVD in people withT2DM compared with people without dia-betes is greater in women than in men,

From Centre derecherche en Epidémiolo-gie et Santé desPopulations (CESP),Université Paris-Sud,Université Paris-Saclay,INSERM, Villejuif (A.A.-S.,S.B., V.R., L.B.), AssistancePublique-Hôpitaux deParis, Hôpitaux Universi-taires Paris-Sud, Hôpital deBicêtre, Service d’Endocri-nologie et des Maladies dela Reproduction, LeKremlin-Bicêtre (A.A.-S.,P.C.), Assistance Publique-Hôpitaux de Paris(AP-HP), HôpitauxUniversitaires Paris-Sud,Hôpital de Bicêtre, Centre

Af!liations continued atthe end of this article.

REVIEW

Mayo Clin Proc. n February 2019;94(2):287-308 n https://doi.org/10.1016/j.mayocp.2018.08.007www.mayoclinicproceedings.org n ª 2018 Mayo Foundation for Medical Education and Research

287

Page 36: Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa fra i 50 e gli 80 anni, 1 caso su 4 ha un’età superiore a 80 anni, mentre solo

Heiat, A. et al. Arch Intern Med2002;162:1682-688.

Percentuale di donne arruolate in trial randomizzati controllati sullo scompenso cardiaco sul totale

Page 37: Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa fra i 50 e gli 80 anni, 1 caso su 4 ha un’età superiore a 80 anni, mentre solo

62 Ital J Gender-Speci! c Med 2016; 2(2): 60-68

men to have micro/macroalbuminuria. No differences were found in blood pressure targets. The proportion of patients reaching the HbA1c target was in favor of men in the Italian study17, in line with other studies in Italy and Europe19,20.

Table 1 shows that sex disparities are more evident in older people (>75 years), particularly with reference to reaching HbA1c targets. In fact, when the analyses were performed separately in individuals below and over 75 years of age, gender disparities were still documented in younger people, but they were more marked in elderly patients17, in spite of diabetic treatment.

Gender di! erences in lipid pro" le

The lipid profi le is worse in women: total cholester-ol levels are higher, and more women (+7.2%) do not

reach the LDL-C target (<100 mg/dl) as compared with men, particularly in the subgroup treated with lipid-lowering medications21; in order to better explore age- and gender-related differences in LDL-C management, these data showed that more women did not reach the LDL-C target when compared with men, and this be-tween-gender gap in reaching LDL-C targets increased with age and diabetes duration, favoring men in all groups (Figure 2). However, the most striking fi nding of this study was that, unlike men, T2DM women were not able to reach the recommended LDL-C targets, in spite of a similar rate in the use of medications and the same use of statins (41.2% of women and of men). Fur-thermore, it was demonstrated that women with type 2 diabetes have an HDL-C subpopulations profi le shifted toward small dense – and hence less atheroprotective – particles, similar to the fi nding in diabetic men who have suffered myocardial infarction22.

Table 1. Clinical characteristics and treatment, by sex and age. Modi! ed from Rossi MC et al, 201317..

Overall Age <75 yrs Age !75 yrs

Diabetic characteristics M F M F M F

N° 227,169 188,125 179,807 130,518 47,210 57,230

Age (years) (X ± SD) 65.7 ± 11.1 68.4 ± 11.4 61.9 ± 9.2 63.1 ± 9.2 79.8 ± 3.7 80.6 ± 4.1

Diabetes treatment (%)

Diet 7.8 6.4 8.0 6.8 7.2 5.5

Oral agents 63.4 60.4 65.0 63.0 57.4 54.6

Oral agents + Insulin 13.3 16.7 13.5 17.0 12.6 16.1

Insulin 15.5 16.4 13.6 13.1 22.8 23.8

Lipid lowering agents 41.2 41.2 42.2 43.0 37.3 37.5

Antihypertensive treatment 56.6 61.0 54.6 58.3 64.3 67.3

"2 antihypertensive agents 33.0 36.1 36.4 41.1 46.7 53.1

Figure 1. Favorable outcomes in diabetic men and women and age (AMD Annals). The intermediate outcomes (target of HbA1c, PA, C-LDL, BMI) are systematically in favor of men, independently of age.

IJGSM_2.indd 62IJGSM_2.indd 62 13/10/2016 09:23:3213/10/2016 09:23:32

- Copyright - Il Pensiero Scientifico Editore downloaded by IP 147.162.241.198 Mon, 11 May 2020, 13:31:37

60

Summary. The impact of diabetes on cardiovascular risk is particularly evident in women who are most a! ected by major cardiovascular events, especially myocardial infarc-tion, and have a higher mortality, con" rming the loss of protection by estrogens in childbearing age. Italian data from the AMD Annals have documented that the achieve-ment of targets for the major CV risk factors is systemati-cally unfavorable to women with diabetes T2: women are more obese, have a worse control of diabetes and especial-ly a worse lipid pro" le, and a higher frequency of reduction in glomerular " ltration rate. Other studies, such as Riace and Mind It, con" rm this. In the world, women with diabe-tes are systematically under-treated with drugs for CV risk factors, such as ASA, ACE-I, #-blockers, statins, and hypo-glycemic agents, and this may explain the failure to achieve the targets. On the contrary, the Italian data are bucking the trend by showing that there are gender di! erences in the use of these medications. Further studies are needed to investigate biological and non-biological factors, underly-ing these di! erences.Key words: gender, type 2 diabetes, cardiovascular risk.

Di! erenze di genere nel diabete di tipo 2 (in Italia)Riassunto. L’impatto del diabete sul rischio cardiovasco-lare è particolarmente evidente nelle donne, che sono più colpite da eventi cardiovascolari maggiori, soprattutto da infarto, e hanno una mortalità maggiore, confermando la perdita della protezione degli estrogeni anche in età fertile. I dati italiani degli Annali AMD hanno documentato che il raggiungimento dei target per i principali fattori di rischio CV è sistematicamente sfavorevole alle donne con diabete T2: in particolare le donne sono più obese, hanno un peg-giore compenso del diabete, soprattutto un peggiore pro" -lo lipidico, e una maggior frequenza di riduzione del " ltrato glomerulare. Anche i dati dello Studio RIACE e Mind.It sono in accordo. Numerosi studi hanno messo in evidenza che le donne con diabete sono sistematicamente sotto-trattate con i farmaci per il controllo dei fattori di rischio CV, quali ASA, ACE-I, beta-bloccanti, statine, ipoglicemizzanti, e que-sto può spiegare il mancato raggiungimento dei target. Ma i dati italiani sono in controtendenza dimostrando che non

Review60

Gender di! erences in type 2 diabetes (Italy)Valeria Manicardi1, Maria Chiara Rossi2, Elisabetta L Romeo3, Annalisa Giandalia3, Mariella Calabrese4, Elena Cimino5, Daniela Antenucci6, Paola Bollati7, Patrizia Li Volsi8, Ada Ma! ettone9, Guglielmina Speroni10, Concetta Suraci11, Elisabetta Torlone12, Giuseppina Russo3 (on behalf of Gruppo Donna AMD)1. Department of Internal Medicine, Hospital of Montecchio, AUSL of Reggio Emilia, Italy; 2. CORESEARCH - Center for Outcomes Research and Epidemiology srl, Pescara, Italy; 3. Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy; 4. Diabetology Department, Prato, Italy; 5. Diabetology, Hospital of Niguarda, Milan, Italy; 6. Endocrinology, Lanciano (Chieti), Italy; 7. Department of Internal Medicine and Diabetology, San Carlo Hospital, Milan, Italy; 8. Diabetology Department, AAS5, Pordenone, Italy; 9. Metabolic Unit, Hospital of Monaldi, Naples, Italy; 10. Department of Internal Medicine and Diabetology, Hospital of Codogno (ASST Lodi), Italy; 11. Diabetology, San Paolo Hospital, Civitavecchia (Rome), Italy; 12. AO MISEM, Perugia, Italy. Received 2 March 2016; accepted 11 March 2016.

Ital J Gender-Speci" c Med 2016; 2(2): 60-68

ci sono di! erenze di genere nell’utilizzo di questi farmaci. Molti fattori biologici, e non solo, non ancora del tutto cono-sciuti, sottendono queste di! erenze e vanno esplorati.Parole chiave: genere, diabete di tipo 2, rischio cardiova-scolare.

Gender di! erences in cardiovascular disease morbidity and mortality in type 2 diabetic subjects

The widely recognized association between type 2 diabetes and cardiovascular disease (CVD) has a dif-ferent signifi cance according to sex, being stronger in diabetic women compared with men. Diabetic women seem to lose their female advantage toward CVD, be-ing more exposed to this complication irrespective of menopausal status1,2.

Accordingly, in newly diagnosed diabetic subjects without clinical CVD, carotid atherosclerosis was more prevalent in newly diagnosed diabetic women than in nondiabetic female controls3, thus confi rming the loss of the protective effects of estrogens on the vascular bed also at early stages of the disease.

A meta-analysis of 37 prospective cohort studies in-vestigated the risk of fatal coronary heart disease (CHD) in type 2 diabetes in a total of 447,064 patients4. The re-sults of this analysis indicated a higher rate of fatal CHD events in diabetic compared with non-diabetic subjects (5.4 vs 1.6%), but more interestingly a 50% higher relative risk for fatal events in diabetic women than in diabetic men (RR 3.50, 95% CI 2.70-4.53 vs 2.06, 1.81- 2.34; P <0.0001).

The higher mortality for CHD in diabetic women was found also in a recent population study5: an excess of cardiovascular mortality risk was observed in diabetic patients of both genders; however, this risk was greater in females than males (males: IRR 1.56; 95% CI 1.38-1.76; females: IRR 1.69; 95% CI 1.47-1.93; Wald test for interaction, p = 0.1266).

Also data on stroke emphasizes the greater risk in di-

IJGSM_2.indd 60IJGSM_2.indd 60 13/10/2016 09:23:3213/10/2016 09:23:32

- Copyright - Il Pensiero Scientifico Editore downloaded by IP 147.162.241.198 Mon, 11 May 2020, 13:31:37

60

Summary. The impact of diabetes on cardiovascular risk is particularly evident in women who are most a! ected by major cardiovascular events, especially myocardial infarc-tion, and have a higher mortality, con" rming the loss of protection by estrogens in childbearing age. Italian data from the AMD Annals have documented that the achieve-ment of targets for the major CV risk factors is systemati-cally unfavorable to women with diabetes T2: women are more obese, have a worse control of diabetes and especial-ly a worse lipid pro" le, and a higher frequency of reduction in glomerular " ltration rate. Other studies, such as Riace and Mind It, con" rm this. In the world, women with diabe-tes are systematically under-treated with drugs for CV risk factors, such as ASA, ACE-I, #-blockers, statins, and hypo-glycemic agents, and this may explain the failure to achieve the targets. On the contrary, the Italian data are bucking the trend by showing that there are gender di! erences in the use of these medications. Further studies are needed to investigate biological and non-biological factors, underly-ing these di! erences.Key words: gender, type 2 diabetes, cardiovascular risk.

Di! erenze di genere nel diabete di tipo 2 (in Italia)Riassunto. L’impatto del diabete sul rischio cardiovasco-lare è particolarmente evidente nelle donne, che sono più colpite da eventi cardiovascolari maggiori, soprattutto da infarto, e hanno una mortalità maggiore, confermando la perdita della protezione degli estrogeni anche in età fertile. I dati italiani degli Annali AMD hanno documentato che il raggiungimento dei target per i principali fattori di rischio CV è sistematicamente sfavorevole alle donne con diabete T2: in particolare le donne sono più obese, hanno un peg-giore compenso del diabete, soprattutto un peggiore pro" -lo lipidico, e una maggior frequenza di riduzione del " ltrato glomerulare. Anche i dati dello Studio RIACE e Mind.It sono in accordo. Numerosi studi hanno messo in evidenza che le donne con diabete sono sistematicamente sotto-trattate con i farmaci per il controllo dei fattori di rischio CV, quali ASA, ACE-I, beta-bloccanti, statine, ipoglicemizzanti, e que-sto può spiegare il mancato raggiungimento dei target. Ma i dati italiani sono in controtendenza dimostrando che non

Review60

Gender di! erences in type 2 diabetes (Italy)Valeria Manicardi1, Maria Chiara Rossi2, Elisabetta L Romeo3, Annalisa Giandalia3, Mariella Calabrese4, Elena Cimino5, Daniela Antenucci6, Paola Bollati7, Patrizia Li Volsi8, Ada Ma! ettone9, Guglielmina Speroni10, Concetta Suraci11, Elisabetta Torlone12, Giuseppina Russo3 (on behalf of Gruppo Donna AMD)1. Department of Internal Medicine, Hospital of Montecchio, AUSL of Reggio Emilia, Italy; 2. CORESEARCH - Center for Outcomes Research and Epidemiology srl, Pescara, Italy; 3. Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy; 4. Diabetology Department, Prato, Italy; 5. Diabetology, Hospital of Niguarda, Milan, Italy; 6. Endocrinology, Lanciano (Chieti), Italy; 7. Department of Internal Medicine and Diabetology, San Carlo Hospital, Milan, Italy; 8. Diabetology Department, AAS5, Pordenone, Italy; 9. Metabolic Unit, Hospital of Monaldi, Naples, Italy; 10. Department of Internal Medicine and Diabetology, Hospital of Codogno (ASST Lodi), Italy; 11. Diabetology, San Paolo Hospital, Civitavecchia (Rome), Italy; 12. AO MISEM, Perugia, Italy. Received 2 March 2016; accepted 11 March 2016.

Ital J Gender-Speci" c Med 2016; 2(2): 60-68

ci sono di! erenze di genere nell’utilizzo di questi farmaci. Molti fattori biologici, e non solo, non ancora del tutto cono-sciuti, sottendono queste di! erenze e vanno esplorati.Parole chiave: genere, diabete di tipo 2, rischio cardiova-scolare.

Gender di! erences in cardiovascular disease morbidity and mortality in type 2 diabetic subjects

The widely recognized association between type 2 diabetes and cardiovascular disease (CVD) has a dif-ferent signifi cance according to sex, being stronger in diabetic women compared with men. Diabetic women seem to lose their female advantage toward CVD, be-ing more exposed to this complication irrespective of menopausal status1,2.

Accordingly, in newly diagnosed diabetic subjects without clinical CVD, carotid atherosclerosis was more prevalent in newly diagnosed diabetic women than in nondiabetic female controls3, thus confi rming the loss of the protective effects of estrogens on the vascular bed also at early stages of the disease.

A meta-analysis of 37 prospective cohort studies in-vestigated the risk of fatal coronary heart disease (CHD) in type 2 diabetes in a total of 447,064 patients4. The re-sults of this analysis indicated a higher rate of fatal CHD events in diabetic compared with non-diabetic subjects (5.4 vs 1.6%), but more interestingly a 50% higher relative risk for fatal events in diabetic women than in diabetic men (RR 3.50, 95% CI 2.70-4.53 vs 2.06, 1.81- 2.34; P <0.0001).

The higher mortality for CHD in diabetic women was found also in a recent population study5: an excess of cardiovascular mortality risk was observed in diabetic patients of both genders; however, this risk was greater in females than males (males: IRR 1.56; 95% CI 1.38-1.76; females: IRR 1.69; 95% CI 1.47-1.93; Wald test for interaction, p = 0.1266).

Also data on stroke emphasizes the greater risk in di-

IJGSM_2.indd 60IJGSM_2.indd 60 13/10/2016 09:23:3213/10/2016 09:23:32

- Copyright - Il Pensiero Scientifico Editore downloaded by IP 147.162.241.198 Mon, 11 May 2020, 13:31:37

Page 38: Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa fra i 50 e gli 80 anni, 1 caso su 4 ha un’età superiore a 80 anni, mentre solo

Costi assistenziali (basati sulle tariffe: DRG, nomenclatore, ecc.)

Osservatorio Arno Diabete 2018

��Osservatorio Arno Diabete

Tabella 4 bis&RVWL�DVVLVWHQ]LDOL��EDVDWL�VXOOH�WDULIIH��'5*��QRPHQFODWRUH��HFF��

Confronto femmine e maschi

6SHVD�PHGLD���DQQR )HPPLQH��N ���������

0DVFKL��N ���������

¨Ȳ� )HPPLQH� YV�0DVFKL

&RVWR�SHU�SHUVRQD�FRQ�GLDEHWH ½������ ½������ ����

)DUPDFHXWLFD ½������ ½������ ���

�������GL�FXL�SHU�DQWLGLDEHWLFL�DQWL�LSHUJOLFHPLFL ½���������� ½���������� ����

'LVSRVLWLYL��VWULVFH��VLULQJKH��DJKL��ODQFHWWH� ½��� ½��� ��

5LFRYHUL�RVSHGDOLHUL ½������ ½������ ����

6SHFLDOLVWLFD ½���� ½���� ����

&RVWR�SHU�SHUVRQD�WUDWWDWD�FRQ�IDUPDFL�DQWL�LSHUJOLFHPLFL�

6SHVD�PHGLD�SHU�WUDWWDWR��WXWWL�L�IDUPDFL� ½������� ½������� ����

������GL�FXL�SHU�IDUPDFL�DQWL�LSHUJOLFHPLFL����� ½����������� ½����������� ����

'LVSRVLWLYL�GLDJQRVWLFR�WHUDSHXWLFL��$,5�� ½����� ½����� ���

&RVWR�SHU�SHUVRQD�FRQ�DOPHQR�XQ�ULFRYHUR�QHOO·DQQR

6SHVD�PHGLD�SHU�ULFRYHUDWR� ½������� ½������� �����

&RVWR�QHJOL�XWLOL]]DWRUL�GHOOD�VSHFLDOLVWLFD

6SHVD�PHGLD�SHU�XWLOL]]DWRUH�VSHFLDOLVWLFKH�H�GLDJQRVWLFKH� ½����� ½����� �����

Page 39: Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa fra i 50 e gli 80 anni, 1 caso su 4 ha un’età superiore a 80 anni, mentre solo

Singole prestazioni specialistiche piu utilizzate nei soggetti con e senza diabete

Osservatorio Arno Diabete 2018

��Osservatorio Arno Diabete

Tabella 15bis6LQJROH�SUHVWD]LRQL�VSHFLDOLVWLFKH�SL��XWLOL]]DWH�QHL�VRJJHWWL�FRQ�H�VHQ]D�GLDEHWH

Confronto femmine-maschi

&RGLFHSUHVWD]LRQH 'HVFUL]LRQH

��VX�SRSROD]LRQH�FRQ�GLDEHWH 6SHVD�PHGLD�SUR�FDSLWH��½�

)HPPLQH��1 ��������

0DVFKL��1 ��������

¨���)HPPLQH�YV�0DVFKL

)HPPLQH��1 ��������

0DVFKL��1 ��������

¨���)HPPLQH�YV�0DVFKL

������� 3UHOLHYR�GL�VDQJXH ���� ���� ����� ��� ��� �����

������� *OXFRVLR ���� ���� ����� ��� ��� �����

������� Emocromocitometrico ���� ���� ����� ��� ��� �����

������� Creatinina ���� ���� ����� ��� ��� �����

������� +%$�F��HPRJORELQD�JOLFDWD� ���� ���� ����� ���� ���� �����

������� &ROHVWHUROR�WRWDOH ���� ���� ����� ��� ��� �����

������� 7ULJOLFHULGL ���� ���� ����� ��� ��� ������

������� (VDPH�XULQH�VWDQGDUG ���� ���� ����� ��� ��� ����

������� &ROHVWHUROR�+'/ ���� ���� ����� ��� ��� ������

������� $/7��*37� ���� ���� ����� ��� ��� �����

90.09.2 $67��*27� ���� ���� ����� ��� ��� ������

������� **7� ���� ���� ����� ��� ��� ������

������� 8UDWR���XULFHPLD� ���� ���� ����� ��� ��� ������

����� 9LVLWD�VSHFLDOLVWLFD�GL�FRQWUROOR�GL�TXDOVLDVL�WLSR� ���� ���� ����� ���� ���� ������

������� 3RWDVVLR� ���� ���� ���� ��� ��� �����

������� 0LFURDOEXPLQXULD ���� ���� ������ ��� ��� ������

������� 76+ ���� ���� ������ ��� ��� ������

������� 6RGLR� ���� ���� ���� ��� ��� �����

������� 8UHD��D]RWR� ���� ���� ����� ��� ��� �����

���� 3ULPD�YLVLWD�VSHFLDOLVWLFD�GL�TXDOVLDVL�WLSR ���� ���� ���� ���� ���� �����

����� ECG ���� ���� ������ ��� ��� ������

������� Calcio totale ���� ���� ������ ��� ��� ������

������� 9LVLWD�HQGRFULQRORJLFD�GLDEHWRORJLFD�GL�FRQWUROOR ���� ���� ������ ��� ��� ������

������� 9LWDPLQD�' ���� ��� ������� ��� ��� �������

������� )7� ���� ��� ������� ��� ��� �������

������� 9(6 ���� ���� ������ ��� ��� ������

������� 3URWHLQH��HOHWWURIRUHVL� ���� ���� ������ ��� ��� �����

������� &ROHVWHUROR�/'/ ���� ���� ����� ��� ��� �����

������� )HUULWLQD� ���� ��� ������ ��� ��� ������

������� )RVIDWDVL�DOFDOLQD ��� ��� ������ ��� ��� �����

������� 36$ ��� ���� ������� ��� ��� �������

����$�� 3ULPD�YLVLWD�HQGRFULQRORJLFD�GLDEHWRORJLFD ��� ��� ����� ��� ��� �����

Page 40: Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa fra i 50 e gli 80 anni, 1 caso su 4 ha un’età superiore a 80 anni, mentre solo

60

Summary. The impact of diabetes on cardiovascular risk is particularly evident in women who are most a! ected by major cardiovascular events, especially myocardial infarc-tion, and have a higher mortality, con" rming the loss of protection by estrogens in childbearing age. Italian data from the AMD Annals have documented that the achieve-ment of targets for the major CV risk factors is systemati-cally unfavorable to women with diabetes T2: women are more obese, have a worse control of diabetes and especial-ly a worse lipid pro" le, and a higher frequency of reduction in glomerular " ltration rate. Other studies, such as Riace and Mind It, con" rm this. In the world, women with diabe-tes are systematically under-treated with drugs for CV risk factors, such as ASA, ACE-I, #-blockers, statins, and hypo-glycemic agents, and this may explain the failure to achieve the targets. On the contrary, the Italian data are bucking the trend by showing that there are gender di! erences in the use of these medications. Further studies are needed to investigate biological and non-biological factors, underly-ing these di! erences.Key words: gender, type 2 diabetes, cardiovascular risk.

Di! erenze di genere nel diabete di tipo 2 (in Italia)Riassunto. L’impatto del diabete sul rischio cardiovasco-lare è particolarmente evidente nelle donne, che sono più colpite da eventi cardiovascolari maggiori, soprattutto da infarto, e hanno una mortalità maggiore, confermando la perdita della protezione degli estrogeni anche in età fertile. I dati italiani degli Annali AMD hanno documentato che il raggiungimento dei target per i principali fattori di rischio CV è sistematicamente sfavorevole alle donne con diabete T2: in particolare le donne sono più obese, hanno un peg-giore compenso del diabete, soprattutto un peggiore pro" -lo lipidico, e una maggior frequenza di riduzione del " ltrato glomerulare. Anche i dati dello Studio RIACE e Mind.It sono in accordo. Numerosi studi hanno messo in evidenza che le donne con diabete sono sistematicamente sotto-trattate con i farmaci per il controllo dei fattori di rischio CV, quali ASA, ACE-I, beta-bloccanti, statine, ipoglicemizzanti, e que-sto può spiegare il mancato raggiungimento dei target. Ma i dati italiani sono in controtendenza dimostrando che non

Review60

Gender di! erences in type 2 diabetes (Italy)Valeria Manicardi1, Maria Chiara Rossi2, Elisabetta L Romeo3, Annalisa Giandalia3, Mariella Calabrese4, Elena Cimino5, Daniela Antenucci6, Paola Bollati7, Patrizia Li Volsi8, Ada Ma! ettone9, Guglielmina Speroni10, Concetta Suraci11, Elisabetta Torlone12, Giuseppina Russo3 (on behalf of Gruppo Donna AMD)1. Department of Internal Medicine, Hospital of Montecchio, AUSL of Reggio Emilia, Italy; 2. CORESEARCH - Center for Outcomes Research and Epidemiology srl, Pescara, Italy; 3. Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy; 4. Diabetology Department, Prato, Italy; 5. Diabetology, Hospital of Niguarda, Milan, Italy; 6. Endocrinology, Lanciano (Chieti), Italy; 7. Department of Internal Medicine and Diabetology, San Carlo Hospital, Milan, Italy; 8. Diabetology Department, AAS5, Pordenone, Italy; 9. Metabolic Unit, Hospital of Monaldi, Naples, Italy; 10. Department of Internal Medicine and Diabetology, Hospital of Codogno (ASST Lodi), Italy; 11. Diabetology, San Paolo Hospital, Civitavecchia (Rome), Italy; 12. AO MISEM, Perugia, Italy. Received 2 March 2016; accepted 11 March 2016.

Ital J Gender-Speci" c Med 2016; 2(2): 60-68

ci sono di! erenze di genere nell’utilizzo di questi farmaci. Molti fattori biologici, e non solo, non ancora del tutto cono-sciuti, sottendono queste di! erenze e vanno esplorati.Parole chiave: genere, diabete di tipo 2, rischio cardiova-scolare.

Gender di! erences in cardiovascular disease morbidity and mortality in type 2 diabetic subjects

The widely recognized association between type 2 diabetes and cardiovascular disease (CVD) has a dif-ferent signifi cance according to sex, being stronger in diabetic women compared with men. Diabetic women seem to lose their female advantage toward CVD, be-ing more exposed to this complication irrespective of menopausal status1,2.

Accordingly, in newly diagnosed diabetic subjects without clinical CVD, carotid atherosclerosis was more prevalent in newly diagnosed diabetic women than in nondiabetic female controls3, thus confi rming the loss of the protective effects of estrogens on the vascular bed also at early stages of the disease.

A meta-analysis of 37 prospective cohort studies in-vestigated the risk of fatal coronary heart disease (CHD) in type 2 diabetes in a total of 447,064 patients4. The re-sults of this analysis indicated a higher rate of fatal CHD events in diabetic compared with non-diabetic subjects (5.4 vs 1.6%), but more interestingly a 50% higher relative risk for fatal events in diabetic women than in diabetic men (RR 3.50, 95% CI 2.70-4.53 vs 2.06, 1.81- 2.34; P <0.0001).

The higher mortality for CHD in diabetic women was found also in a recent population study5: an excess of cardiovascular mortality risk was observed in diabetic patients of both genders; however, this risk was greater in females than males (males: IRR 1.56; 95% CI 1.38-1.76; females: IRR 1.69; 95% CI 1.47-1.93; Wald test for interaction, p = 0.1266).

Also data on stroke emphasizes the greater risk in di-

IJGSM_2.indd 60IJGSM_2.indd 60 13/10/2016 09:23:3213/10/2016 09:23:32

- Copyright - Il Pensiero Scientifico Editore downloaded by IP 147.162.241.198 Mon, 11 May 2020, 13:31:37

60

Summary. The impact of diabetes on cardiovascular risk is particularly evident in women who are most a! ected by major cardiovascular events, especially myocardial infarc-tion, and have a higher mortality, con" rming the loss of protection by estrogens in childbearing age. Italian data from the AMD Annals have documented that the achieve-ment of targets for the major CV risk factors is systemati-cally unfavorable to women with diabetes T2: women are more obese, have a worse control of diabetes and especial-ly a worse lipid pro" le, and a higher frequency of reduction in glomerular " ltration rate. Other studies, such as Riace and Mind It, con" rm this. In the world, women with diabe-tes are systematically under-treated with drugs for CV risk factors, such as ASA, ACE-I, #-blockers, statins, and hypo-glycemic agents, and this may explain the failure to achieve the targets. On the contrary, the Italian data are bucking the trend by showing that there are gender di! erences in the use of these medications. Further studies are needed to investigate biological and non-biological factors, underly-ing these di! erences.Key words: gender, type 2 diabetes, cardiovascular risk.

Di! erenze di genere nel diabete di tipo 2 (in Italia)Riassunto. L’impatto del diabete sul rischio cardiovasco-lare è particolarmente evidente nelle donne, che sono più colpite da eventi cardiovascolari maggiori, soprattutto da infarto, e hanno una mortalità maggiore, confermando la perdita della protezione degli estrogeni anche in età fertile. I dati italiani degli Annali AMD hanno documentato che il raggiungimento dei target per i principali fattori di rischio CV è sistematicamente sfavorevole alle donne con diabete T2: in particolare le donne sono più obese, hanno un peg-giore compenso del diabete, soprattutto un peggiore pro" -lo lipidico, e una maggior frequenza di riduzione del " ltrato glomerulare. Anche i dati dello Studio RIACE e Mind.It sono in accordo. Numerosi studi hanno messo in evidenza che le donne con diabete sono sistematicamente sotto-trattate con i farmaci per il controllo dei fattori di rischio CV, quali ASA, ACE-I, beta-bloccanti, statine, ipoglicemizzanti, e que-sto può spiegare il mancato raggiungimento dei target. Ma i dati italiani sono in controtendenza dimostrando che non

Review60

Gender di! erences in type 2 diabetes (Italy)Valeria Manicardi1, Maria Chiara Rossi2, Elisabetta L Romeo3, Annalisa Giandalia3, Mariella Calabrese4, Elena Cimino5, Daniela Antenucci6, Paola Bollati7, Patrizia Li Volsi8, Ada Ma! ettone9, Guglielmina Speroni10, Concetta Suraci11, Elisabetta Torlone12, Giuseppina Russo3 (on behalf of Gruppo Donna AMD)1. Department of Internal Medicine, Hospital of Montecchio, AUSL of Reggio Emilia, Italy; 2. CORESEARCH - Center for Outcomes Research and Epidemiology srl, Pescara, Italy; 3. Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy; 4. Diabetology Department, Prato, Italy; 5. Diabetology, Hospital of Niguarda, Milan, Italy; 6. Endocrinology, Lanciano (Chieti), Italy; 7. Department of Internal Medicine and Diabetology, San Carlo Hospital, Milan, Italy; 8. Diabetology Department, AAS5, Pordenone, Italy; 9. Metabolic Unit, Hospital of Monaldi, Naples, Italy; 10. Department of Internal Medicine and Diabetology, Hospital of Codogno (ASST Lodi), Italy; 11. Diabetology, San Paolo Hospital, Civitavecchia (Rome), Italy; 12. AO MISEM, Perugia, Italy. Received 2 March 2016; accepted 11 March 2016.

Ital J Gender-Speci" c Med 2016; 2(2): 60-68

ci sono di! erenze di genere nell’utilizzo di questi farmaci. Molti fattori biologici, e non solo, non ancora del tutto cono-sciuti, sottendono queste di! erenze e vanno esplorati.Parole chiave: genere, diabete di tipo 2, rischio cardiova-scolare.

Gender di! erences in cardiovascular disease morbidity and mortality in type 2 diabetic subjects

The widely recognized association between type 2 diabetes and cardiovascular disease (CVD) has a dif-ferent signifi cance according to sex, being stronger in diabetic women compared with men. Diabetic women seem to lose their female advantage toward CVD, be-ing more exposed to this complication irrespective of menopausal status1,2.

Accordingly, in newly diagnosed diabetic subjects without clinical CVD, carotid atherosclerosis was more prevalent in newly diagnosed diabetic women than in nondiabetic female controls3, thus confi rming the loss of the protective effects of estrogens on the vascular bed also at early stages of the disease.

A meta-analysis of 37 prospective cohort studies in-vestigated the risk of fatal coronary heart disease (CHD) in type 2 diabetes in a total of 447,064 patients4. The re-sults of this analysis indicated a higher rate of fatal CHD events in diabetic compared with non-diabetic subjects (5.4 vs 1.6%), but more interestingly a 50% higher relative risk for fatal events in diabetic women than in diabetic men (RR 3.50, 95% CI 2.70-4.53 vs 2.06, 1.81- 2.34; P <0.0001).

The higher mortality for CHD in diabetic women was found also in a recent population study5: an excess of cardiovascular mortality risk was observed in diabetic patients of both genders; however, this risk was greater in females than males (males: IRR 1.56; 95% CI 1.38-1.76; females: IRR 1.69; 95% CI 1.47-1.93; Wald test for interaction, p = 0.1266).

Also data on stroke emphasizes the greater risk in di-

IJGSM_2.indd 60IJGSM_2.indd 60 13/10/2016 09:23:3213/10/2016 09:23:32

- Copyright - Il Pensiero Scientifico Editore downloaded by IP 147.162.241.198 Mon, 11 May 2020, 13:31:37

Gender-differences have been reported in diabetic patients: in Italy they are less pronouncedthan in other countries, but it exists despite equal access to specialist care.

■ The likelihood to reach metabolic targets (HbA1c, LDL-C, BMI, PA) is systematically unfavorablein diabetic women as compared with men.

■ Diabetic women have a worse lipid profile than men, and have a 2-fold higher CHD riskcompared with men. Myocardial infarction occurs earlier and has higher mortality in women with DM compared with men.

■ Diabetic women are systematically undertreated with CV therapy, such as ASA, ACE – I, β-blockers, hypoglycemic agents, but not in Italy.

■ Pathophysiological factors are involved in the greater difficulty to reach LDL-C targets in diabetic women, despite the same drug treatment in Italy.

Page 41: Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa fra i 50 e gli 80 anni, 1 caso su 4 ha un’età superiore a 80 anni, mentre solo

• More research is needed to understand biological mechanismsunderlying the sex differences in the risk of cardiovascular dis-ease in people with type 2 diabetes.

• More effort is needed to reduce the gap between the sexes in terms of the use of evidence-based treatment and participation in clinical trials.

Cardiovascular Disease in Type 2 Diabetes: AReview of Sex-Related Differences inPredisposition and PreventionAbdallah Al-Salameh, MD; Philippe Chanson, MD; Sophie Bucher, MD, PhD;Virginie Ringa, MD, PhD; and Laurent Becquemont, MD, PhD

Abstract

Type 2 diabetes mellitus is a major risk factor for cardiovascular disease. However, compiled datasuggest that type 2 diabetes affects the risk of cardiovascular disease differentially according to sex. Inrecent years, large meta-analyses have con!rmed that women with type 2 diabetes have a higherrelative risk of incident coronary heart disease, fatal coronary heart disease, and stroke compared withtheir male counterparts. The reasons for these disparities are not completely elucidated. A greaterburden of cardiometabolic risk in women was proposed as a partial explanation. Indeed, severalstudies suggest that women experience a larger deterioration in major cardiovascular risk factors andput on more weight than do men during their transition from normoglycemia to overt type 2 diabetes.This excess weight is associated with higher levels of biomarkers of endothelial dysfunction,in"ammation, and procoagulant state. Moreover, sex differences in the prescription and use of somecardiovascular drugs may compound an “existing” disparity. We searched PubMed for articlespublished in English and French, by using the following terms: (“cardiovascular diseases”) AND(“diabetes mellitus”) AND (“sex disparity” OR “sex differences” OR “sex related differences” OR“sex-related differences” OR “sex disparities”). In this article, we review the available literature on thesex aspects of primary and secondary prevention of cardiovascular disease in people with type 2diabetes, in the predisposition to cardiovascular disease in those people, and in the control of diabetesand associated cardiovascular risk factors.

ª 2018 Mayo Foundation for Medical Education and Research n Mayo Clin Proc. 2019;94(2):287-308

D iabetes mellitus is a major riskfactor for cardiovascular disease(CVD). Its prevalence is

increasing worldwide, and this trend is pro-jected to persist because of the demographicshift and the obesity pandemic. The globalprevalence of diabetes was estimated at8.8% in 2017, with a slightly higher preva-lence among men (9.1%) than amongwomen (8.4%).1 However, despite large var-iations in the reported male-to-female ratiobetween studies in different countries andethnicities, there is little evidence to sup-port a sex difference in the prevalence ofdiabetes. Most people with diabetes havetype 2 diabetes mellitus (T2DM). On theother hand, CVD is the leading cause ofmorbidity and mortality in people with

diabetes. Modern studies show that CVDis responsible for 24% to 30% of hospitaliza-tions2 and around one-third of deaths3,4 inpeople with diabetes. Despite improve-ments in CVD morbidity and mortality dur-ing recent decades, the population-attributable risk for diabetes as a cardiovas-cular risk factor continues to increase5 andthe cardiovascular burden of diabetes re-mains important.

Although women without diabetes havea lower risk of developing CVD comparedwith men without diabetes of the same age,this “female advantage” seems to diminishor disappear in the setting of T2DM. Indeed,the relative risk of CVD in people withT2DM compared with people without dia-betes is greater in women than in men,

From Centre derecherche en Epidémiolo-gie et Santé desPopulations (CESP),Université Paris-Sud,Université Paris-Saclay,INSERM, Villejuif (A.A.-S.,S.B., V.R., L.B.), AssistancePublique-Hôpitaux deParis, Hôpitaux Universi-taires Paris-Sud, Hôpital deBicêtre, Service d’Endocri-nologie et des Maladies dela Reproduction, LeKremlin-Bicêtre (A.A.-S.,P.C.), Assistance Publique-Hôpitaux de Paris(AP-HP), HôpitauxUniversitaires Paris-Sud,Hôpital de Bicêtre, Centre

Af!liations continued atthe end of this article.

REVIEW

Mayo Clin Proc. n February 2019;94(2):287-308 n https://doi.org/10.1016/j.mayocp.2018.08.007www.mayoclinicproceedings.org n ª 2018 Mayo Foundation for Medical Education and Research

287

Cardiovascular Disease in Type 2 Diabetes: AReview of Sex-Related Differences inPredisposition and PreventionAbdallah Al-Salameh, MD; Philippe Chanson, MD; Sophie Bucher, MD, PhD;Virginie Ringa, MD, PhD; and Laurent Becquemont, MD, PhD

Abstract

Type 2 diabetes mellitus is a major risk factor for cardiovascular disease. However, compiled datasuggest that type 2 diabetes affects the risk of cardiovascular disease differentially according to sex. Inrecent years, large meta-analyses have con!rmed that women with type 2 diabetes have a higherrelative risk of incident coronary heart disease, fatal coronary heart disease, and stroke compared withtheir male counterparts. The reasons for these disparities are not completely elucidated. A greaterburden of cardiometabolic risk in women was proposed as a partial explanation. Indeed, severalstudies suggest that women experience a larger deterioration in major cardiovascular risk factors andput on more weight than do men during their transition from normoglycemia to overt type 2 diabetes.This excess weight is associated with higher levels of biomarkers of endothelial dysfunction,in"ammation, and procoagulant state. Moreover, sex differences in the prescription and use of somecardiovascular drugs may compound an “existing” disparity. We searched PubMed for articlespublished in English and French, by using the following terms: (“cardiovascular diseases”) AND(“diabetes mellitus”) AND (“sex disparity” OR “sex differences” OR “sex related differences” OR“sex-related differences” OR “sex disparities”). In this article, we review the available literature on thesex aspects of primary and secondary prevention of cardiovascular disease in people with type 2diabetes, in the predisposition to cardiovascular disease in those people, and in the control of diabetesand associated cardiovascular risk factors.

ª 2018 Mayo Foundation for Medical Education and Research n Mayo Clin Proc. 2019;94(2):287-308

D iabetes mellitus is a major riskfactor for cardiovascular disease(CVD). Its prevalence is

increasing worldwide, and this trend is pro-jected to persist because of the demographicshift and the obesity pandemic. The globalprevalence of diabetes was estimated at8.8% in 2017, with a slightly higher preva-lence among men (9.1%) than amongwomen (8.4%).1 However, despite large var-iations in the reported male-to-female ratiobetween studies in different countries andethnicities, there is little evidence to sup-port a sex difference in the prevalence ofdiabetes. Most people with diabetes havetype 2 diabetes mellitus (T2DM). On theother hand, CVD is the leading cause ofmorbidity and mortality in people with

diabetes. Modern studies show that CVDis responsible for 24% to 30% of hospitaliza-tions2 and around one-third of deaths3,4 inpeople with diabetes. Despite improve-ments in CVD morbidity and mortality dur-ing recent decades, the population-attributable risk for diabetes as a cardiovas-cular risk factor continues to increase5 andthe cardiovascular burden of diabetes re-mains important.

Although women without diabetes havea lower risk of developing CVD comparedwith men without diabetes of the same age,this “female advantage” seems to diminishor disappear in the setting of T2DM. Indeed,the relative risk of CVD in people withT2DM compared with people without dia-betes is greater in women than in men,

From Centre derecherche en Epidémiolo-gie et Santé desPopulations (CESP),Université Paris-Sud,Université Paris-Saclay,INSERM, Villejuif (A.A.-S.,S.B., V.R., L.B.), AssistancePublique-Hôpitaux deParis, Hôpitaux Universi-taires Paris-Sud, Hôpital deBicêtre, Service d’Endocri-nologie et des Maladies dela Reproduction, LeKremlin-Bicêtre (A.A.-S.,P.C.), Assistance Publique-Hôpitaux de Paris(AP-HP), HôpitauxUniversitaires Paris-Sud,Hôpital de Bicêtre, Centre

Af!liations continued atthe end of this article.

REVIEW

Mayo Clin Proc. n February 2019;94(2):287-308 n https://doi.org/10.1016/j.mayocp.2018.08.007www.mayoclinicproceedings.org n ª 2018 Mayo Foundation for Medical Education and Research

287

Page 42: Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa fra i 50 e gli 80 anni, 1 caso su 4 ha un’età superiore a 80 anni, mentre solo

I Fattori di rischio• Non modificabili

• Età• Sesso• Razza• Familiarità

• Modificabili– Maggiori

• Fumo• Ipertensione arteriosa• Iperdislipidemia• Diabete / iperinsulinemia / resistenza insulinica• Obesità / sindrome metabolica• Sedentarietà fisica

– Meno documentati• Dieta / abuso di bevande alcoliche• Iperomocisteinemia• Ipercoagulabilità / Infiammazione• Contraccettivi orali / terapie ormonali

Goldstein et al., Circulation 2001; 103:163

Page 43: Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa fra i 50 e gli 80 anni, 1 caso su 4 ha un’età superiore a 80 anni, mentre solo

• Prospective cohort of 2357 healthy men (mean age, 72 years)enrolled in the Physicians’ Health Study

• 970 men (41%) survived >90 years• The probability of surviving >90 years was 54% in the absence

of:– Smoking– Diabetes– Obesity– Hypertension– Sedentary life style

Page 44: Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa fra i 50 e gli 80 anni, 1 caso su 4 ha un’età superiore a 80 anni, mentre solo

Caratteristiche peculiari della macroangiopatia diabetica nella donna

Fisiopatologiche" maggior interessamento del microcircolo

" erosione di placca, vasospasmo, dissezione coronarica e cardiomiopatia stress-

correlata piuttosto che rottura di placca

Cliniche" ritardato accesso al pronto soccorso,

" sintomi di presentazione atipici, incerti valori di riferimento della troponina" maggior incidenza di complicazioni periprocedurali durante angioplastica" peggior outcome dopo by-pass aorto-coronarico" eccesso di mortalità durante fibrinolisi

Epidemiologiche" età di insorgenza della coronaropatia e dell’arteriopatia obliterante più tardiva

" minor trend alla riduzione della mortalità da malattie CVD negli ultimi 10 anni

Razziali" elevata prevalenza di infarto tra le donne afro-americane

Sociali" minor accesso delle donne delle minoranze a programmi riabilitativi" minor riduzione del fumo

Page 45: Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa fra i 50 e gli 80 anni, 1 caso su 4 ha un’età superiore a 80 anni, mentre solo

nancy outweighs the risk of any given contraception option[108]. Conceiving with diabetes can more than double the riskof birth defects in the offspring. Nevertheless, there is still agap of evidence regarding the important topic of safe andeffective contraception in diabetic women. Most studies aresmall or use administrative data and prospective controlledstudies are needed to clarify the best method. Metabolic and

vascular risks vary according to combinations, specificdosages and formulations, underlining complexity of the

problem. Exposure to progestin appears to deteriorate glucosemetabolism, potentially also interacting with triglycerides,especially when estrogen levels are low and progestin-onlycontraception related to increased risk of thromboembolism.Therefore, at present there should be caution prescribingprogestin-only contraception for women with a history ofgestational diabetes or diabetes, while other forms of contra-

ception, especially intrauterine and subcutaneous typesshould be preferred choices in insufficiently controlled

Table 3 – Recommendations.

For clinical practice: ! Consider reproductive history, sexual function and family planning in risk evaluationand treatment plan

! Careful attention to psychosocial problems and specific approaches to improve out-comes in particular in diabetic women.

! Diabetic men benefit from better knowledge-based structured education and instru-mental support.

! Treat to target (HbA1c, LDL cholesterol, blood pressure) and adhere to evidence basedguidelines similarly in both sexes

! Consider drug doses, specific side effects and potential drug interactions carefully par-ticularly in women taking into consideration body weight, age and hormonal status

For future research: ! To clarify the cause of the excess cardio- and cerebrovascular risk of diabetic women! To clarify differences in treatment modalities and drug metabolism! To study gender-differences in clinical inertia regarding glycaemic control, targets of

lipids, blood pressure and monitoring of complications! To study the cause of sex differences in drug adherence! To study in more detail sex-differences in risk of hypoglycaemia and metabolic control! To monitor more precisely development of cancers as well as fractures in relation to

sex, BMI, diabetes duration and drug therapy! Sex-specific reporting of baseline characteristics in trials! Sex-specific reporting of results of RCTs! Sex-analysis in study design including appropriate sample size calculations including

hormonal status of participants (pre- or postmenopausal, oral contraceptives, hor-mone replacement therapy etc.)

! A balanced sex-ratio in weight loss programs and RCTs with weight loss drugs! Balanced sex-ratio of patients in RCTs including early phases of clinical trials with car-

diovascular and antihyperglycemic drugs! Development and validation of new sex-specific concepts regarding diagnosis and

therapy of diabetes and its complications (in particular CVD) in order to improvelong-term outcome in both sexes

Table 2 – Summary of important sex and gender differences and challenges in T2DM management.

Women vs. Men: ! High risk of missing early diagnosis based on fasting glucose measurements only! Greater impact of reproductive factors and silent inflammation! Higher rates of obesity contributing to complications and influencing therapeutic choice! Greater risk of stigmatisation of obese young women channelling treatment options! Better attendance at structured diabetes education! Lower success of glucose-lowering therapy and greater risk of failure of dual therapy! Potentially higher degree of worriedness and uncertainty related to insulin therapy! Higher risk of hypoglycemia on insulin treatment! Dyslipidemia more closely related to CVD! Worse control of cardiovascular risk factors and monitoring of complications! Lower adherence of evidence based cardiovascular therapy! Greater relative risk of CHD, stroke as well as CV and total mortality! More side effects and lower drug adherence in women regarding use of statins! Higher rates of depression further aggravating therapeutic success! Depression and psychosocial stress show greater impact on CVD! More comorbidities and thus higher risk of polypharmacy! Missing data of sex differences of potential drug efficacy on complications! Missing information on sex-specific effects and adverse events for most available drugs! Studies in pregnancy missing, some common drugs (e.g. RAS blockers, statins) teratogenic

d i a b e t e s r e s e a r c h a n d c l i n i c a l p r a c t i c e 1 3 1 ( 2 0 1 7 ) 2 3 0 –2 4 1 237

Summary of important sex and gender differences and challenges in T2DM management.

Vomen vs men

diabetes research and clinical prac/ce 131 (2017) 230–241

Page 46: Diabete e genere · EPIDEMIOLOGIA DEL DIABETE diabete sono collocati nella fascia di età compresa fra i 50 e gli 80 anni, 1 caso su 4 ha un’età superiore a 80 anni, mentre solo

•Informarsi ma soprattutto educarsi alla salute

•Seguire strategie per uno stile di vita adeguato e corretto

•Partecipare alla gestione della propria salute insieme agli operatori sanitari competenti della salute