Diabete e genere Alberto Maran

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Diabete e genere Alberto Maran
Diabete e genere

   Alberto Maran
Diabete e genere Alberto Maran
Prevalenza globale del diabete e proiezioni 2025

                                        33.0
             19.2                              47.8
                    36.2
                                               13.8       27.6
                                                   42.8      79.5   26.4
                                            3.4                       55.9
                           11.5                   9.8
                              27.3

                Mondo             135.286                 299.974     +120%
       Paesi sviluppati            50.974                  72.244          +40%
Paesi in via di sviluppo           84.313                 227.725     +170%
Diabete e genere Alberto Maran
P I D E M I O LO G I A D E L D I A B E T E

                    Andamento della prevalenza del diabete in Italia nel
Figura 1            corso
               Andamento     degli
                         della       anni
                               prevalenza del(2001-2014)
                                             diabete in Italia nelsecondo       i da<
                                                                  corso degli anni       ISTAT
                                                                                   (2001-2014) secondo i dati ISTAT (2).
Diabete e genere Alberto Maran
0,2 0,3       0,5
                   0
                            0-19             20-34          35-49           50-64              65-79               >=80                           Totale

                                                                                Classi di età
                 Prevalenza del diabete in funzione del sesso e dell’età

                                              La prevalenza complessiva di diabete è del 6,2%

                  25

                  20
Prevalenza (%)

                  15
                                                                                                                                                                   Maschi
                                                                                                                                                                   Femmine
                  10

                   5

                   0
                       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

                                                                                                                                                             108
                                                                                                                                                       104
                                                                                                                    Osservatorio Arno Diabete 2018
Diabete e genere Alberto Maran
La sindrome Metabolica come «Cluster»
                      di Fattori di rischio

                               Obesità Addominale
                                Intolleranza
                        Glucosio/Resistenza Insulina
       Diabete                      Ipertensione                             CVD
                             Dislipidemia Aterogena

                            Stato Proinfiammatorio/
                                 Protrombotico

National Cholesterol Educational Program (NCEP), Adult Treatment Panel (ATP) III; 2001
Diabete e genere Alberto Maran
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
                                                                                                                                               Page 21

                      Summary
  Author Manuscript

                         Background—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
  Author Manuscript

                         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
                                                                                                       HHS Public Access
                         deaths from these diseases were attributable to the combined effect of these four metabolic risk
                                                                                                      Authorburden
                         factors, compared with 67% (7.1 million deaths; 6.6–7.6) in 1980. The mortality          manuscript
                                                                                                                         of high
                                                                                                      Lancet   Diabetes
                         BMI and glucose nearly doubled between 1980 and 2010. At the country level, age-standardised     Endocrinol. Author manuscript; ava
                                                                             Author Ma

                                                                                            Published
                         death rates attributable to these four risk factors surpassed 925 deaths per in100,000
                                                                                                         final edited form men
                                                                                                                  among    as: in
                                                                                             Lancet Diabetes Endocrinol. 2014 August ; 2(8): 634–647. doi:10.1
Figure 3.                Belarus, Mongolia, and Kazakhstan, but were below 130 deaths per 100,000 for women and below
Diabete e genere Alberto Maran
Le evidenze crescenti hanno contribuito a rimuovere           fattori di rischio delle donne.
la falsa credenza che le donne fossero più protette dal       Tra i dati prodotti e disponibili menzioniamo la pubbli-
rischio CV.                                                   cazione delle prime raccomandazioni cliniche specifi-
                                         CAUSE DI MORTE
Questo ha assunto particolare rilievo sul piano epide-        che per le donne riguardo alla prevenzione delle malat-
                                                              tie CV (American Heart Association 1999).
miologico, diagnostico e di programmazione sanitaria,
per un’aumentata consapevolezza dell’importanza di            Un decennio più tardi (2011) fu sempre l’AHA a pubbli-
                                                              care lecardiovascolare
                                                             Rischio    linee guida pereladifferenze
                                                                                           prevenzione    delle malattie CV
                                                                                                     di genere
una valutazione di genere del rischio CV. In effetti negli
                                                              nelle donne che ebbero il merito di porre l’attenzione
                                                                              2

                      UOMO
anni passati c’è stata dispersione di risorse e danni in
                                                                                      DONNA
                                                              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
                            Altre   Malattia                  e metabolico che rappresentaAltre      un’opportunità
                     cause, 20%     coronarica, 20%
                                                                                                            Malattia unica
                                                              per valutare il rischio CV      nel corso
                                                                                          cause,   20% di coronarica,
                                                                                                            tutta la vita.22%
                                                                                                                            È
                                                              importante sapere che la preeclampsia o il diabete ge-
                                                                                Traumi
                Traumi                                        stazionale durante la gravidanza, e/o la nascita di un
  e avvelenamenti, 13%
                                           Ictus, 10%          e avvelenamenti, 4%
                                                              neonato pretermine o di un bambino che è piccolo per
                                                                             Malattie
                                                              la sua età gestazionale,     o un sanguinamento nel      terzo
                                                                                                                    Ictus, 15%
                                                                    respiratorie,  6%
                                                              trimestre sono tutti fattori associati a un aumentato ri-
          Malattie                         Altre malattie     schio CV. Per questi motivi nelle linee guida troviamo
  respiratorie, 7%                         CV, 12%                  Altre neoplasie,
                                                              raccomandata            10% accurata dell’anamnesi in
                                                                                 la raccolta
           Altre neoplasie, 13%                               relazione alla presenza di complicanzeAltre       malattie 3.
                                                                                                           in gravidanza
                                                              Con la menopausa vengono meno alcuni         CV,effetti
                                                                                                               15% protet-
                                             Cancro                  Cancro al seno, 3%
        Cancro al polmone, 4%                                 tivi esercitati dagli estrogeni, caratterizzati da:
                                             allo stomaco,
                                             2%                   Cancro al polmone, 2%
                                                                                                          Cancro
                              Cancro                                Cancro colo-rettale, 2%
                     colo-rettale, 2%
                                                                                                          allo stomaco, 1%
                                                                                                                         -
                                                                  tensina aldosterone (sistema RAA);
FIGURA 1.                                                  FIGURA 2.
Mortalità per cause in uomini di tutte le età (da European Mortalità
                                                               colesterolo-LDL, riduzione
                                                                     per cause in         deitutte
                                                                                   donne di   livelliledietà
                                                                                                          LP(a),
                                                                                                             (da APO
                                                                                                                 European
Cardiovascular Disease Statistics, 2012, mod.) .   1
                                                               A1 - APO.
Diabete e genere Alberto Maran
The natural history of non insulin-dependent
                          diabetes mellitus

                                        Onset of
                                        diabetes
 Environmental                                                    Complications
 factors
         nutrition
         obesity                                                                      Disability
         physical inactivity

                                                                                          DEATH
Genetic                            IGT                     e.g.
susceptibility

           Insulin resistence               Hyperglycaemia Retinopathy            Blindness
           Hyperinsulinaemia                HDL¯           Nephropathy            Renal failure
           HDL                                             Atherosclerosis        Coronary heart
                                                           Neuropathy             disease
                                                                                  Amputation

 WHO 94390
 HDL,high-density lipoprotein; IGT, impaired glucose tolerance
Diabete e genere Alberto Maran
INTERHEART: Risk of Acute Myocardial Infarction
associated with self-reported diabetes

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

                             Colhoun HM et al. Lancet 2004;364:685-696.
Diabete e genere Alberto Maran
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
Mortalità cardiovascolare in uomini e donne con diabete

                                   Uomini                                                              Donne
                     60                                                                 60

                     50        Diabete                                                  50
Mortalità per 1000

                                                                   Mortalità Per 1000
                               No Diabete                  2x
                     40                                                                 40

                     30                                                                 30                                 4-5x
                     20                                                                 20

                     10                                                                 10

                      0                                                                  0
                           0-3 4-7 8-11 12-1516-1920-23                                       0-3 4-7 8-11 12-1516-1920-23
                          Anni di Durata del follow-up (anni)                                Anni di durata del follow-up (anni)

               Modificata da Krolewski AS, et al. Am J Med 1991 (ref. 19 )
Rela
Rela
Sex differences in the effects of
33 Page 4 of 8          diabetes on vascular outcome                                                                       Curr Diab Rep (2018) 18: 33

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-
                                                                              Peters,
men adjusted relative risks (and 95% confidence intervals) pooled across cohort         Current Diabetes Reports (2018) 18: 33
                                                                                   studies
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.
Long-term survival aMer AMI in men and women with diabetes

                                            Crowley et al. Am Heart J 2003
PERCHE’ ???
Rispetto all’uomo:

  1. La donna è “più complicata”
  2. Menopausa ed assetto ormonale
  3. La donna vive più a lungo
  4. Poco considerata (scientificamente)
La donna è “più complicata”
Possible causes of high CVD in women with diabetes

                                           Rivellese et al. NMCD 2010
La donna è “più complicata”

                                              Differenze strutturali e/o funzionali dell’albero
                                                 cardiovascolare
                                               1.   Sintomi anginosi piu’ sfumati, dolore toracico atipico, sintomi
  Shortness of        Breaking out in
                                                    aspecifici, si reca dal medico più tardi -> Spesso cardiopatia
    breath             a cold sweat                 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.
Light-headedness or    Nausea (feeling sick         sanguinamenti) e vengono trattate meno intensamente
 sudden dizziness        to the stomach)

  Unusual or
  unexplained
                                                                 Trattamento TARDIVO
     fatigue
   (tiredness)                                                      PROGNOSI PEGGIORE
Adjusted women-to-men ratios of hazard ratios for association between risk factors and incident
                                       myocardial infarction.

©2018 by British Medical Journal Publishing Group
                                                              Elizabeth R C Millett et al. BMJ 2018;363:bmj.k4247
Smoking and Mortality among Women
                                                           with Type 2 Diabetes
Nurses’ Health Study - 20 Years of follow-up - 121.046 women

                                                                             Nondiabetic women
                                                                             Diabetic Women
Mortality rates (per 100.000 person-years)

                                             2500

                                             2000

                                             1500

                                             1000

                                              500

                                                0
                                                      Never     Past       1-14          15-34         >35
                                                                          cig/day       cig/day      cig/day

                                                              Al-Delaimy WK et al., Diabetes Care 24: 2043-2048, 2001.
Effetti favorevoli degli estrogeni nella donna

                                           FAVOREVOLE

                                       ↓ Colesterolo LDL
             Lipidi
                                       ↑ Colesterolo HDL

         Coagulazione                     ↓ Fibrinogeno

                                   ↓ Molecole di adesione
        Infiammazione

                                    ↓ Attività dell’enzima
                                             ACE
                                   ↑ Sintesi Ossido Nitrico
Funzione endoteliale e pressione        ↓ Endotelina-1
           arteriosa                ↓ Proliferazione delle
                                    cellule muscolari lisce

                                             Rivellese et al. NMCD 2010
Tissue-specific actions of oestrogens on energy balance and
metabolic regulation in rodent models

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/)
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
Fattori di rischio cardiovascolare: differenze di genere
                                   Diabete

 • 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
EPC e gradiente intersesso di rischio cardiovascolare

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.

                        Women             Age-matched men
                  120                                 30                                 12                                    0,9
                        *                                  *
.

                                                               †
                  100
                            †
                                                      25                                 10   *   †                            0,8
                                                                                                      †
                                                                                                                                     *†

                                                                                  .
                                                                                                                               0,7
CD34+KDR+ cells

                                               .

                                                                                                                       .
                   80                                 20                                  8                                    0,6

                                                                                  %FMD

                                                                                                                       c-IMT
                                               %KDR

                                                                                          6                                    0,5
                   60                                 15
                                                                                                                               0,4
                   40                                 10                                  4                                    0,3
                   20                                  5                                                                       0,2
                                                                                          2
                                                                                                                               0,1
                    0                                  0                                  0                                      0
                        Fertile     Post-                  Fertile     Post-
                            1         2

                                                                                              Fertile       Post-
                                                               1          2

                                                                                                                                     Fertile     Post-
                                                                                                  1            2
                                                                                                                                          1        2

                                  menopausal                         menopausal                           menopausal                           menopausal

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

                                                        F        M
                                            120
                                                  *
                          .
                                            100
                          CD34+KDR+ cells    80

                                             60

                                             40

                                             20

                                              0
                                                  0-1       2+

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

                                                                     Fadini et al. ATVB 2008
Sex differences in insulin resistance across the life span

Huebschmann et al (2019) Diabetologia DOI 10.1007/s00125-019-4939-5
© Elsevier. Adapted with permission from Sattar
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
Fattori di rischio cardiovascolare:
                 differenze di genere
                         Ipertensione Arteriosa

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

                                   The Strong Heart Study, Diabetes Care 1998
Differences in LDL size and fibrinogen by diabetic status in women and men

                                        The Strong Heart Study, Diabetes Care 1998
CONTROLLO dei
FDR CARDIOVASCOLARE (donne)

          NHANES III study
  (Third National Health and Nutrition Examination Survey)

                     < 7.5%
      of the Female population
     met six of the seven key CVD
            health metrics:
                      Not smoking
                 Eating a healthy diet
                Being physically active
                    Normal weight
                Normal blood pressure
                Normale glucose level
               Normal cholesterol levels
Cardiovascular Disease in Type 2 Diabetes: A
    Cardiovascular  Disease in Type 2 Diabetes: A
         Review of Sex-Related Differences in
    Review  of Sex-Related
         Predisposition      Differences in
                        and Prevention
    Predisposition         and
         Abdallah Al-Salameh,      Prevention
                              MD; Philippe Chanson, MD; Sophie Bucher, MD, PhD;
                    Virginie Ringa, MD, PhD; and Laurent Becquemont, MD, PhD
    Abdallah Al-Salameh, MD; Philippe Chanson, MD; Sophie Bucher, MD, PhD;
    Virginie Ringa,  MD, PhD; and Laurent Becquemont, MD, PhD
               Abstract
•   Women with type 2 diabetes had higher levels of low-density lipoprotein
               Type 2 diabetes mellitus is a major risk factor for cardiovascular disease. However, compiled data
    cholesterol,
    Abstract suggestandthatthey
                            type 2 are  less
                                   diabetes     likely
                                            affects      to ofreceive
                                                    the risk            statin
                                                               cardiovascular     therapy
                                                                              disease          when
                                                                                      differentially     compared
                                                                                                     according to sex. In with
    their
    Type 2male    counterparts.
               recent
            diabetes
                      years, large meta-analyses have confirmed that women with type 2 diabetes have a higher
                      mellitus is a major risk factor for cardiovascular disease. However, compiled data
                    relative risk of incident coronary heart disease, fatal coronary heart disease, and stroke compared with
    suggest thattheir
                   typemale
                         2 diabetes     affectsThe
                               counterparts.    thereasons
                                                      risk of for
                                                                cardiovascular
                                                                    these disparities  disease
                                                                                            are notdifferentially
                                                                                                        completely according
                                                                                                                       elucidated. to       sex. In
                                                                                                                                        A greater
•   Women       with
    recent years,        type
                     large
                 burden            2 diabetes
                           ofmeta-analyses
                               cardiometabolic    riskhad
                                                have          to putwas
                                                         confirmed
                                                         in women          onproposed
                                                                        that     moreaswith
                                                                                 women       weight   typeto
                                                                                                a partial          develop
                                                                                                              2 diabetes
                                                                                                             explanation.       havediabetes.
                                                                                                                                Indeed,     higher This
                                                                                                                                         a several
    relative riskstudies
                  of incident
                          suggestcoronary
                                    that womenheart   disease,afatal
                                                  experience       largercoronary       heartindisease,
                                                                            deterioration                     and stroke compared
                                                                                                  major cardiovascular         risk factors withand
    excess    weight
    their male put        is
                 counterparts. associated
                      on more weight Thethan     with
                                               do men
                                           reasons          a
                                                      forduringgreater
                                                            thesetheir        deterioration
                                                                         transitionare
                                                                    disparities        fromnotnormoglycemiain
                                                                                                   completely tocardiovascular
                                                                                                                       overt type 2Adiabetes.
                                                                                                                     elucidated.               risk
                                                                                                                                            greater
    factors’
    burden oflevels,
                 This      endothelial
                        excess
                 cardiometabolic weight risk indysfunction,
                                           is associated     with
                                                  women was proposed     low-grade
                                                                    higher     levels   of     inflammation,
                                                                                            biomarkers
                                                                                     as a partial         explanation. and
                                                                                                              of   endothelial      dysfunction,
                                                                                                                              Indeed, several
                 inflammation,      and  procoagulant     state. Moreover,     sex  differences      in cardiovascular risk use
                                                                                                       the   prescription     and         of some
    hypercoagulability
    studies suggest that women     state     in women
                                        experience      a largeras   compared
                                                                   deterioration        inwith
                                                                                            majormen.
                 cardiovascular drugs may compound an “existing” disparity. We searched PubMed for articles
                                                                                                                                     factors     and
    put on more weight than do men during their transition from normoglycemia to overt type 2 diabetes.
                 published in English and French, by using the following terms: (“cardiovascular diseases”) AND
    This excess(“diabetes
                    weight mellitus”)
                               is associated      with disparity”
                                            AND (“sex      higher levels
                                                                       OR “sex   of differences”
                                                                                      biomarkersORof“sex       endothelial         dysfunction,
                                                                                                                    related differences”         OR
•   Women
    inflammation,with  andtype      2  diabetes
                            procoagulant      state.  have
                                                      Moreover, been  sex  underrepresented
                                                                            differences       in  the             in
                                                                                                         prescription most
                 “sex-related differences” OR “sex disparities”). In this article, we review the available literature on theand   clinical
                                                                                                                                   use    of     trials
                                                                                                                                               some
    that   focused
    cardiovascular      on the
                       drugs
                 sex aspects    may
                                of   impact
                                    primary   andof
                                        compound       drug
                                                   secondary     interventions
                                                        an “existing”
                                                                  prevention  disparity.     (statin
                                                                                               We searched
                                                                                 of cardiovascular          therapy,
                                                                                                           disease   PubMed
                                                                                                                     in      newer
                                                                                                                         people     for articles
                                                                                                                                    with    type 2
    published in     English
                 diabetes,      andpredisposition
                            in the     French, bytousing        the following
                                                         cardiovascular     disease in terms:     (“cardiovascular
                                                                                          those people,                      diseases”)
                                                                                                             and in the control                AND
                                                                                                                                      of diabetes
    antidiabetic       drugs)
                 and associated
    (“diabetes mellitus”)       AND
                                    on   the    occurrence
                                    cardiovascular   risk factors.
                                        (“sex disparity”
                                                                      of    cardiovascular                disease.
                                                                OR “sex differences” OR “sex related differences” OR
                                                                                                                           This      precludes         firm
    conclusions        about the
    “sex-related differences”            effects
                                    OR “sex         ª of
                                                       2018 many
                                               disparities”).          drug
                                                            Mayo Foundation
                                                                  In this   for  treatments
                                                                                Medical
                                                                             article,   Education
                                                                                        we review         in women
                                                                                                  and Research
                                                                                                         the                   with
                                                                                                                 n Mayo Clin Proc.
                                                                                                               available                 type       2
                                                                                                                                   2019;94(2):287-308
                                                                                                                             literature     on the
    diabetes.
    sex aspects of primary and secondary prevention of cardiovascular disease in people with type 2

                    D
                             iabetes mellitus is a major risk diabetes. Modern studies show that CVD
    diabetes, in the predisposition to cardiovascular disease in those people, and in the control of diabetes
                             factor for cardiovascular disease is responsible for 24% to 30% of hospitaliza-
    and associated cardiovascular
                             (CVD).
                                           risk factors.
                                          Its    prevalence          is tions2 and around one-third of deaths3,4 in From Centre de
                                                                                                                                        recherche en Epidémiolo-
                    increasing worldwide,ª and
                                           2018 this
                                                Mayotrend
                                                     Foundation for Medical
                                                          is pro-           Education
                                                                       people    withanddiabetes.
                                                                                        Research n Despite
                                                                                                   Mayo Clin Proc. 2019;94(2):287-308
                                                                                                              improve-        gie et Santé des
Percentuale di donne arruolate in trial randomizzati
   controllati sullo scompenso cardiaco sul totale

                 Heiat, A. et al. Arch Intern Med2002;162:1682-688.
performed separately in individuals below and over 75                                  groups (Figure 2). However, the most striking finding
years of age, gender disparities were still documented in                              of this study was that, unlike men, T2DM women were
younger people,
            Gender   but they
                           diffwere
                                  erencesmore markedin type      in elderly
                                                                      2 diabetes       not (Italy)
                                                                                             able to reach the recommended LDL-C targets, in
patients , in spite of diabetic treatment.
         17
                                                                                       spite of a similar rate in the use of medications and the
            Valeria Manicardi , Maria Chiara Rossi , Elisabetta L same
                                  1                               2
                                                                                        Romeo  use3
                                                                                                   , Annalisa
                                                                                                      of statinsGiandalia
                                                                                                                     (41.2% 3of  , Mariella
                                                                                                                                    women Calabrese
                                                                                                                                                 and of men).  4
                                                                                                                                                                 , Fur-
            Elena Cimino , Daniela Antenucci , Paola Bollati , Patrizia
                            5                             6                  7
                                                                                           Li Volsi  8
                                                                                                      ,  Ada    Maff ettone  9
                                                                                                                              , Guglielmina
                                                                                       thermore, it was demonstrated that women with type 2       Speroni     10
                                                                                                                                                                 ,
            Concetta Suraci11, Elisabetta Torlone12, Giuseppina Russo3 (on behalf of Gruppo Donna AMD)
    Gender differences in lipid profile                                                diabetes have an HDL-C subpopulations profile shifted
            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 Clinicaltoward         small Medicine,
                                                                                        and Experimental       dense –University
                                                                                                                           and hence       less
                                                                                                                                   of Messina,     atheroprotective
                                                                                                                                               Messina,   Italy;
    The lipid profile is worse in women: total cholester-
            4. Diabetology Department,  Prato, Italy; 5. Diabetology,   Hospital of    – particles, similar to the finding in diabetic men who
                                                                                    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;
ol levels are   higher,Unit,
            9. Metabolic  andHospital
                                moreof women          (+7.2%)
                                         Monaldi, Naples,            do
                                                             Italy; 10.   not ofhave
                                                                        Department            suffered
                                                                                        Internal Medicine and myocardial
                                                                                                                  Diabetology,infarction
                                                                                                                                            22
                                                                                                                                               .
                                                                                                                               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.

            Summary. The impact of diabetes on cardiovascular risk                          ci sono differenze di genere nell’utilizzo di questi farmaci.
            is particularly evident in women who are most affected by                       Molti fattori biologici, e non solo, non ancora del tutto cono-
            major cardiovascular events, especially myocardial infarc-                      sciuti, sottendono queste differenze e vanno esplorati.
            tion, and have a higher mortality, confirming the loss of                       Parole chiave: genere, diabete di tipo 2, rischio cardiova-
            protection by estrogens in childbearing age. Italian data                       scolare.
            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-                           Gender differences in cardiovascular disease
            ly a worse lipid profile, and a higher frequency of reduction                        morbidity and mortality in type 2 diabetic
            in glomerular filtration rate. Other studies, such as Riace                          subjects
Figure 1. Favorable outcomes in diabetic men and women and age (AMD Annals). The intermediate outcomes (target of HbA1c, PA,
            andsystematically
C-LDL, BMI) are  Mind It, confirminthis.
                                     favorIn of
                                             themen,
                                                   world,    women with diabe-
                                                          independently        of age.
            tes are systematically under-treated with drugs for CV risk                          The widely recognized association between type 2
            factors, such as ASA, ACE-I, β-blockers, statins, and hypo-                     diabetes and cardiovascular disease (CVD) has a dif-
            glycemic agents, and this may explain the failure to achieve                    ferent significance according to sex, being stronger in
 Table 1. Clinical characteristics
            the targets.             and
                          On the contrary, treatment,        bydata
                                                the- IlItalian
                                       - Copyright      Pensierosex  and
                                                                      are age.
                                                                 Scientifico       Modifi
                                                                             bucking
                                                                             Editore       ed  from
                                                                                            diabetic
                                                                                     downloaded       Rossi
                                                                                                        women MC compared
                                                                                                                   et Mon,
                                                                                                by IP 147.162.241.198 al, 2013   .
                                                                                                                               17 .2020, 13:31:37
                                                                                                                                with
                                                                                                                           11 May       men. Diabetic women
            the trend by showing that there are gender differences in                       seem to lose their female advantage toward CVD, be-
            the use of these medications.
                                60        Review
                                               Further studies are needed to                ing more exposed to this Ital      complication          irrespective
                                                                                                                                   J Gender-Specific Med                 of
                                                                                                                                                         2016; 2(2): 60-68
            investigate biological and non-biological   Overallfactors, underly-                Age
Tabella 4 bis
Costi assistenziali (basati sulle tariffe: DRG, nomenclatore,
ecc.)                    Confronto femmine e maschi

                                             N         N

                                                 Osservatorio Arno Diabete 2018
Singole prestazioni specialistiche
                          Tabella 15bis più utilizzate nei soggetti
con e senza diabete
                                 Confronto femmine-maschi

           Emocromocitometrico

           Creatinina

 90.09.2

                                                            Osservatorio Arno Diabete 2018
Gender differences 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 Maffettone9, 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.

Gender-differences have been reported in diabetic patients: in Italy they are less pronounced
than in other countries, but it exists despite equal access to specialist care.
   Summary. The impact of diabetes on cardiovascular risk                             ci sono differenze di genere nell’utilizzo di questi farmaci.
■ The likelihood to reach metabolic targets (HbA1c,Molti
   is particularly evident    in   women      who     are most    affected    by        LDL-C,
                                                                                             fattoriBMI,    PA)eisnon
                                                                                                     biologici,       systematically
                                                                                                                        solo, non ancora del   unfavorable
                                                                                                                                                   tutto cono-
   major cardiovascular events, especially myocardial infarc-                         sciuti, sottendono queste differenze e vanno esplorati.
in diabetic    women as compared with men.
   tion, and have a higher mortality, confirming the loss of                          Parole chiave: genere, diabete di tipo 2, rischio cardiova-
   protection   by  estrogens       in  childbearing
■ Diabetic women have a worse lipid profile than men,      age.  Italian   data       scolare.and have a 2-fold higher CHD risk
   from the AMD Annals have documented that the achieve-
compared       with for
   ment of targets      men.      Myocardial
                            the major                   infarction
                                           CV risk factors                occurs earlier and has higher mortality in women with
                                                                is systemati-
DMcally
      compared
         unfavorable  with     men.with diabetes T2: women are
                         to women
   more obese, have a worse control of diabetes and especial-                             Gender differences in cardiovascular disease
■ Diabetic     women
   ly a worse lipid  profile,are
                               andsystematically
                                      a higher frequencyundertreated
                                                                of reduction           with    CV therapy,
                                                                                          morbidity                such asinASA,
                                                                                                          and mortality          type 2ACE        – I, β-
                                                                                                                                            diabetic
blockers, hypoglycemic agents, but not in Italy.
   in  glomerular   filtration    rate.  Other      studies,  such    as  Riace           subjects
   and Mind It, confirm this. In the world, women with diabe-
■ Pathophysiological              factors are
   tes are systematically under-treated                involved
                                                     with drugs for in  CVthe
                                                                            risk greater  Thedifficulty       to reachassociation
                                                                                                 widely recognized          LDL-C targets   between  in type 2
   factors, such as ASA, ACE-I, β-blockers, statins, and hypo-                        diabetes and cardiovascular disease (CVD) has a dif-
diabetic    women,        despite        the      same      drug
   glycemic agents, and this may explain the failure to achieve
                                                                     treatment        in Italy.
                                                                                      ferent significance according to sex, being stronger in
   the targets. On the contrary,          the- IlItalian
                                - Copyright       Pensierodata   are bucking
                                                           Scientifico                diabetic
                                                                       Editore downloaded         women compared
                                                                                          by IP 147.162.241.198           with
                                                                                                                Mon, 11 May 2020, men.
                                                                                                                                  13:31:37Diabetic women
   the trend by showing that there are gender differences in                          seem to lose their female advantage toward CVD, be-
   the use of these medications.
                         60         Review
                                         Further studies are needed to                ing more exposed to this Ital      complication         irrespective
                                                                                                                            J Gender-Specific Med                 of
                                                                                                                                                  2016; 2(2): 60-68
   investigate biological and non-biological factors, underly-                        menopausal status .      1,2

   ing these differences.                                                                 Accordingly, in newly diagnosed diabetic subjects
Cardiovascular   Disease
          Cardiovascular DiseaseininType
                                     Type22 Diabetes:
                                            Diabetes: AA
      Review  of Sex-Related
          Review  of Sex-RelatedDifferences
                                   Differences in
      Predisposition  andand
          Predisposition   Prevention
                             Prevention
      AbdallahAbdallah   Al-Salameh,
                Al-Salameh,          MD; Philippe
                                MD; Philippe      Chanson,
                                              Chanson,  MD;MD;Sophie
                                                               SophieBucher,
                                                                      Bucher, MD,
                                                                              MD, PhD;
                                                                                   PhD;
               Virginie Ringa, MD, PhD; and Laurent Becquemont, MD, PhD
      Virginie Ringa, MD, PhD; and Laurent Becquemont, MD, PhD
                  Abstract
      Abstract
                Type 2 diabetes mellitus is a major risk factor for cardiovascular disease. However, compiled data
      Type 2 diabetes
                suggest thatmellitus   is a major
                               type 2 diabetes        risk
                                                 affects thefactor
                                                              risk of for   cardiovascular
                                                                       cardiovascular    diseasedisease.  However,
                                                                                                 differentially         compiled
                                                                                                                according  to sex. Indata
                recent
      suggest that   typeyears,  large meta-analyses
                            2 diabetes   affects the riskhaveofconfirmed
                                                                 cardiovascularthat women
                                                                                       diseasewith type 2 diabetes
                                                                                                differentially        have a to
                                                                                                                 according      higher
                                                                                                                                   sex. In
• More research is needed to understand biological mechanisms
                relative  risk of incident  coronary   heart  disease,   fatal coronary   heart disease,
      recent years, large meta-analyses have confirmed that women with type 2 diabetes have a higher      and  stroke compared     with
                theirofmale   counterparts.
                                    coronaryThe     reasons   for these    disparities heart
                                                                                        are notdisease,
                                                                                                 completely
                                                                                                         and elucidated.   A greater
  underlying the sex differences in the risk of cardiovascular dis-
      relative risk     incident                heart   disease,   fatal coronary
                burden of cardiometabolic risk in women was proposed as a partial explanation. Indeed, several
      their male counterparts. The reasons for these disparities are not completely elucidated. A greater
                                                                                                               stroke compared        with
                studies suggest that women experience a larger deterioration in major cardiovascular risk factors and
  ease in people with type 2 diabetes.
      burden ofputcardiometabolic
      studies suggest
                     on more weight than
                         that women
                                          riskdoinmen
                                          experience
                                                     women
                                                       during was      proposedfrom
                                                                their transition      as anormoglycemia
                                                                                            partial explanation.       Indeed,
                                                                                                           to overt type           several
                                                                                                                          2 diabetes.
                This excess     weight is    associated awith
                                                            largerhigher
                                                                    deterioration
                                                                            levels of in   major cardiovascular
                                                                                         biomarkers   of endothelialrisk    factors and
                                                                                                                        dysfunction,
      put on more     weight than
                inflammation,      and do  men during
                                      procoagulant        their
                                                       state.     transition
                                                              Moreover,     sex from    normoglycemia
                                                                                 differences                to overt
                                                                                              in the prescription  andtype
                                                                                                                         use 2ofdiabetes.
                                                                                                                                 some
      This excess     weight isdrugs
                cardiovascular       associated      with higher
                                           may compound                 levels of
                                                                an “existing”         biomarkers
                                                                                   disparity.         of endothelial
                                                                                               We searched     PubMed for dysfunction,
                                                                                                                               articles
• More effort is needed to reduce the gap between the sexes in
                published
      inflammation,      and inprocoagulant
                                 English and state.
                                                French,Moreover,
                                                          by using the  sex following
                                                                              differencesterms:  (“cardiovascular
                                                                                             in the  prescriptiondiseases”)
                                                                                                                     and use of  AND some
  terms of the use of evidence-based treatment and
                (“diabetes
      published“sex-related
                  in English
                              mellitus”)  AND
                               differences”
                                                 (“sex
                                             OR “sex
                                   and French,
                                                         disparity”
                                                    by disparities”).
                                                                     OR     “sex  differences”
      cardiovascular drugs may compound an “existing” disparity. We searched PubMed for articles
                                                                        In this article,
                                                         using the following
                                                                                                 OR
                                                                                          we review
                                                                                       terms:
                                                                                                     “sex  related  differences”
                                                                                                     the available literature
                                                                                                (“cardiovascular     diseases”)
                                                                                                                                    OR
                                                                                                                                on the
                                                                                                                                     AND
  participation in clinical trials.
                sex aspects of primary and secondary prevention of cardiovascular disease in people with type 2
      (“diabetes mellitus”) AND (“sex disparity” OR “sex differences” OR “sex related differences” OR
                diabetes, in the predisposition to cardiovascular disease in those people, and in the control of diabetes
      “sex-related   differences” OR “sex disparities”). In this article, we review the available literature on the
                and associated cardiovascular risk factors.
      sex aspects of primary and secondary            prevention of cardiovascular disease in people with type 2
                                               ª 2018 Mayo Foundation for Medical Education and Research n Mayo Clin Proc. 2019;94(2):287-308
      diabetes, in the predisposition to cardiovascular disease in those people, and in the control of diabetes

                  D
      and associated cardiovascular    riskis factors.
                         iabetes mellitus       a major risk diabetes. Modern studies show that CVD
                             factor for cardiovascular
                                            ª 2018 Mayo Foundation    is responsible
                                                          disease for Medical Education for
                                                                                         and 24% to 30%
                                                                                             Research    of hospitaliza-
                                                                                                      n Mayo Clin Proc. 2019;94(2):287-308
                             (CVD).     Its     prevalence       is tions2 and around one-third of deaths3,4 in From Centre de
                                                                                                                                  recherche en Epidémiolo-
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
•   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
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
ve data and prospective controlled     progestin-only contraception for women with a history of

           Summary of important sex and gender differences
 fy the best method. Metabolic and
ording to combinations, specific
                                       gestational diabetes or diabetes, while other forms of contra-
                                       ception, especially intrauterine and subcutaneous types
           and challenges in T2DM management.
s, underlining complexity of the       should be preferred choices in insufficiently controlled

                                        Vomen vs men
portant sex and gender differences and challenges in T2DM management.
       !   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

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