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Sex- and gender-differences in chronic long-term complications of type 1 and type 2 diabetes mellitus in Italy

      Highlights

      • In Italy, complications of diabetes show different prevalence and clinical characteristics according to sex.
      • Such sex disparities are robust social determinants of health.
      • Updated epidemiologic and prognostic information coming from sex-specific studies are needed.

      Abstract

      Aims

      This review summarizes the contribution of Italian diabetologists devoted to a better understanding of the complex relationship linking sex/gender and long-term complications of type 1 (T1DM) and type 2 diabetes (T2DM) over the last fifteen years.

      Data synthesis

      Microvascular and macrovascular complications of diabetes show sex- and gender-related differences, involving pathophysiological mechanisms, epidemiological features and clinical presentation, due to the interaction between biological and psychosocial factors. These differences greatly impact on the progression of diabetes and its long-term complications, especially in the cardiovascular, renal and liver districts.

      Conclusion

      A better knowledge of such sex- and gender-related characteristics is required for a more precise patient phenotypization, and for the choice of a personalized antihyperglycemic treatment. Despite such mounting evidence, current diabetes clinical guidelines do not as yet adequately consider sex/gender differences.

      Keywords

      1. Introduction

      Sex and gender are important health determinants [
      • Mauvais-Jarvis F.
      • Bairey Merz N.
      • Barnes P.J.
      • Brinton R.D.
      • Carrero J.J.
      • DeMeo D.L.
      • et al.
      Sex and gender: modifiers of health, disease, and medicine.
      ] and, as such, they should be taken into account in the planning of personalized medicine approaches [
      • Lonardo A.
      • Byrne C.D.
      • Targher G.
      Precision medicine approaches in metabolic disorders and target organ damage: where are we now, and where are we going?.
      ].
      The term sex should properly refer to individual biological characteristics mainly linked to genetic background and sexual hormones, while gender implies a multidimensional concept, influenced by social, religious, and cultural determinants, as well as by individual behavior. However, such aspects usually interact and their specific contribution to the incidence and prevalence of several non-transmissible chronic diseases, like cardiovascular diseases (CVD), neurodegenerative diseases, cancer, obesity, and diabetes, remains undefined [
      • Ostan R.
      • Monti D.
      • Gueresi P.
      • Bussolotto M.
      • Franceschi C.
      • Baggio G.
      Gender, aging and longevity in humans: an update of an intriguing/neglected scenario paving the way to a gender-specific medicine.
      ]. As a consequence, in scientific literature, the terms sex and gender are often used as synonyms, and this may generate confusion.
      Sex and gender largely influence epidemiology, clinical presentation and outcomes of both type 1 (T1DM) and type 2 diabetes mellitus (T2DM) (Fig. 1). Worldwide, the prevalence of T2DM is increasing, especially in young subjects and in the female sex [
      International Diabetes Federation
      IDF diabetes atlas.
      ], likely due to the increased prevalence of obesity in females from low-income countries [
      • Franconi F.
      • Campesi I.
      • Occhioni S.
      • Tonolo G.
      Sex-gender differences in diabetes vascular complications and treatment.
      ,
      • Manicardi V.
      • Rossi M.C.
      • Romeo E.L.
      • Giandalia A.
      • Calabrese M.
      • Cimino E.
      • et al.
      On behalf of Gruppo Donna AMD. Gender differences in type 2 diabetes (Italy).
      ,
      • Harris M.I.
      • Flegal K.M.
      • Cowie C.C.
      • Eberhardt M.S.
      • Goldstein D.E.
      • Little R.R.
      • et al.
      Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in U.S. adults. The Third National Health and Nutrition Examination Survey, 1988-1994.
      ,
      • Kautzky-Willer A.
      • Harreiter J.
      • Pacini G.
      Sex and gender differences in risk, pathophysiology and complications of type 2 diabetes.
      ], although these differences are strongly influenced by age [
      • Huebschmann A.G.
      • Huxley R.R.
      • Kohrt W.M.
      • Zeitler P.
      • Regensteiner J.G.
      • Reusch J.E.B.
      Sex differences in the burden of type 2 diabetes and cardiovascular risk across the life course.
      ].
      Figure 1
      Figure 1Risk of micro and macrovascular complications in men and women with T2DM. The figure represents major factors contributing to the burden of risk factors, for microvascular and macrovascular disease in T2DM men and women across the continuum of the clinical history of the disease.
      The diabetes burden affects CVD risk more in females than in males, especially among T2DM individuals. However, evidence is accumulating on sex- and gender-differences also with regards to microvascular complications, and in T1DM subjects [
      • Lucà F.
      • Abrignani M.G.
      • Parrini I.
      • Di Fusco S.A.
      • Giubilato S.
      • Rao C.M.
      • et al.
      Update on management of cardiovascular diseases in women.
      ,
      • Mattioli A.V.
      • Sciomer S.
      • Moscucci F.
      • Maiello M.
      • Cugusi L.
      • Gallina S.
      • et al.
      Cardiovascular prevention in women: a narrative review from the Italian Society of Cardiology working groups on 'Cardiovascular Prevention, Hypertension and peripheral circulation' and on 'Women Disease.
      ,
      • Cosentino F.
      • Grant P.J.
      • Aboyans V.
      • Bailey C.J.
      • Ceriello A.
      • Delgado V.
      • et al.
      ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD.
      ].
      A relevant evidence on this field comes from Italian studies on large cohorts of T1DM and T2DM subjects, with some peculiar differences with respect to international literature.
      This review reports on studies investigating sex- and gender-differences in long-term complications associated with T1DM and T2DM in Italy in the last decades.

      1.1 Sex- and gender-differences in macrovascular complications of T2DM and T1DM

      Type 2 diabetes is the sixth leading cause of death for men and the seventh for women [
      • Heron M.
      Deaths: leading causes for 2017.
      ], with CVD accounting for about 50–70% of mortality in this population [
      • Cosentino F.
      • Grant P.J.
      • Aboyans V.
      • Bailey C.J.
      • Ceriello A.
      • Delgado V.
      • et al.
      ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD.
      ].
      Over the past decades, increased attention has been paid to the analysis of differences between men and women in the pathophysiology, diagnosis and prognosis of CVD, both in the general population and in T2DM subjects [
      • Mattioli A.V.
      • Sciomer S.
      • Moscucci F.
      • Maiello M.
      • Cugusi L.
      • Gallina S.
      • et al.
      Cardiovascular prevention in women: a narrative review from the Italian Society of Cardiology working groups on 'Cardiovascular Prevention, Hypertension and peripheral circulation' and on 'Women Disease.
      ,
      • Cosentino F.
      • Grant P.J.
      • Aboyans V.
      • Bailey C.J.
      • Ceriello A.
      • Delgado V.
      • et al.
      ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD.
      ].
      In T2DM, sex/gender differences have been largely unknowledged in CVD occurrence, outcomes and risk factors, and several data point to a higher burden of T2DM on CVD risk in women than in men [
      • Regensteiner J.G.
      • Golden S.
      • Huebschmann A.G.
      • Barrett-Connor E.
      • Chang A.Y.
      • Chyun D.
      • et al.
      Sex differences in the cardiovascular consequences of diabetes mellitus: a scientific statement from the American HeartAssociation.
      ,
      • Huxley R.
      • Barzi F.
      • Woodward
      Excess risk of fatal coronary heart disease associated with diabetes in men and women: meta-analysis of 37 prospective cohort studies.
      ,
      • Yusuf S.
      • Hawken S.
      • Ounpuu S.
      • Dans T.
      • Avezum A.
      • Lanas F.
      • et al.
      Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study.
      ,
      • Dinesh Shah A.
      • Langenberg C.
      • Rapsomaniki E.
      • Denaxas S.
      • Pujades-Rodriguez M.
      • Gale C.P.
      • et al.
      Type 2 diabetes and incidence of cardiovascular diseases: a cohort study in 1·9 million people.
      ,
      • Bragg F.
      • Holmes M.V.
      • Iona A.
      • Guo Y.
      • Du H.
      • Chen Y.
      • et al.
      China Kadoorie Biobank Collaborative Group. Association between diabetes and cause-specific mortality in rural and urban areas of China.
      ,
      • Peters S.A.
      • Huxley R.R.
      • Woodward M.
      Diabetes as a risk factor for stroke in women compared with men: a systematic review and meta-analysis of 64 cohorts, including 775,385 individuals and 12,539 strokes.
      ,
      • Peters S.A.
      • Huxley R.R.
      • Woodward M.
      Diabetes as risk factor for incident coronary heart disease in women compared with men: a systematic review and meta-analysis of 64 cohorts including 858,507 individuals and 28,203 coronary events.
      ,
      Prospective Studies Collaboration and Asia Pacific Cohort Studies Collaboration
      Sex-specific relevance of diabetes to occlusive vascular and other mortality: a collaborative meta-analysis of individual data from 980 793 adults from 68 prospective studies.
      ].
      Thus, while in the general population, women have a reduced CVD risk showing a 10-year delay in the occurrence of clinical manifestations of CVD compared with men, largely because of the estrogenic protection before menopause, these differences are not observed in T2DM women, who lose the beneficial effects of estrogens and display a higher CVD risk at a younger age, even before menopause.
      Accordingly, in absolute terms, CVD risk is higher overall in T2DM men than in women; however when comparing T2DM subjects vs non diabetic counterparts, the relative risk of developing CVD events is much higher in women than in men [
      • Kautzky-Willer A.
      • Harreiter J.
      • Pacini G.
      Sex and gender differences in risk, pathophysiology and complications of type 2 diabetes.
      ]. A meta-analysis on 37 prospective studies [
      • Lucà F.
      • Abrignani M.G.
      • Parrini I.
      • Di Fusco S.A.
      • Giubilato S.
      • Rao C.M.
      • et al.
      Update on management of cardiovascular diseases in women.
      ], including 447,064 T2DM subjects, demonstrated that the relative risk of fatal coronary heart disease (CHD) was 50% higher in women than in men (RR 3.50, 95% CI 2.70–4.53 vs 2.06, 1.81–2.34; P < 0.0001). Similar results were obtained in the INTERHEART, a case–control study involving more than 15,000 cases and controls from 52 countries [
      • Yusuf S.
      • Hawken S.
      • Ounpuu S.
      • Dans T.
      • Avezum A.
      • Lanas F.
      • et al.
      Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study.
      ]. International studies and meta-analyses have reported a 44% higher RR for CHD, 27% for stroke and 43% for CVD in women than in men with T2DM [
      • Dinesh Shah A.
      • Langenberg C.
      • Rapsomaniki E.
      • Denaxas S.
      • Pujades-Rodriguez M.
      • Gale C.P.
      • et al.
      Type 2 diabetes and incidence of cardiovascular diseases: a cohort study in 1·9 million people.
      ,
      • Bragg F.
      • Holmes M.V.
      • Iona A.
      • Guo Y.
      • Du H.
      • Chen Y.
      • et al.
      China Kadoorie Biobank Collaborative Group. Association between diabetes and cause-specific mortality in rural and urban areas of China.
      ,
      • Peters S.A.
      • Huxley R.R.
      • Woodward M.
      Diabetes as a risk factor for stroke in women compared with men: a systematic review and meta-analysis of 64 cohorts, including 775,385 individuals and 12,539 strokes.
      ,
      • Peters S.A.
      • Huxley R.R.
      • Woodward M.
      Diabetes as risk factor for incident coronary heart disease in women compared with men: a systematic review and meta-analysis of 64 cohorts including 858,507 individuals and 28,203 coronary events.
      ,
      Prospective Studies Collaboration and Asia Pacific Cohort Studies Collaboration
      Sex-specific relevance of diabetes to occlusive vascular and other mortality: a collaborative meta-analysis of individual data from 980 793 adults from 68 prospective studies.
      ], although this is not confirmed by other studies [
      • Woodward M.
      • Zhang X.
      • Barzi F.
      • Pan W.
      • Ueshima H.
      • Rodgers A.
      • et al.
      Asia Pacific Cohort Studies Collaboration. The effects of diabetes on the risks of major cardiovascular diseases and death in the Asia-Pacific region.
      ,
      • Alegre-Díaz J.
      • Herrington W.
      • López-Cervantes M.
      • Gnatiuc L.
      • Ramirez R.
      • Hill M.
      • et al.
      Diabetes and cause-specific mortality in Mexico City.
      ].
      In Italy, several studies have investigated potential sex/gender-differences in macrovascular disease, although gender-specific variables have seldom been investigated. The DAI study [
      • Avogaro A.
      • Giorda C.
      • Maggini M.
      • Mannucci E.
      • Raschetti R.
      • Lombardo F.
      • et al.
      Diabetes and Informatics Study Group, Association of Clinical Diabetologists, Istituto Superiore di Sanità. Incidence of coronary heart disease in type 2 diabetic men and women: impact of microvascular complications, treatment, and geographic location.
      ], a longitudinal prospective study patronized by the Associazione Medici Diabetologi (AMD) and by the Italian Ministry of Health (Istituto Superiore di Sanità) with the aim of evaluating the prevalence and incidence of CHD and its determinants in T2DM patients, used data extracted from electronic chart records from 201 diabetes clinics in the time periods from September–December 1998 and March–June 1999 (basal data) and followed every year from 2000 to 2003 (follow-up data). This analysis, conducted on 11,644 patients (6032 women and 5612 men) without evidence of CVD at baseline, provided information on CHD incidence and predictors in the two genders [
      • Avogaro A.
      • Giorda C.
      • Maggini M.
      • Mannucci E.
      • Raschetti R.
      • Lombardo F.
      • et al.
      Diabetes and Informatics Study Group, Association of Clinical Diabetologists, Istituto Superiore di Sanità. Incidence of coronary heart disease in type 2 diabetic men and women: impact of microvascular complications, treatment, and geographic location.
      ]. Major CHD events were overall more frequent in men than in women (28.8% vs 23.3%), but the relative gradient vs the general population was 50% higher in women than in men, thus confirming the stronger impact of diabetes on CVD risk in females [
      • Avogaro A.
      • Giorda C.
      • Maggini M.
      • Mannucci E.
      • Raschetti R.
      • Lombardo F.
      • et al.
      Diabetes and Informatics Study Group, Association of Clinical Diabetologists, Istituto Superiore di Sanità. Incidence of coronary heart disease in type 2 diabetic men and women: impact of microvascular complications, treatment, and geographic location.
      ].
      Subsequently, other studies explored these aspects in Italy, including the Multifactorial Intervention in type 2 Diabetes in Italy (MIND-IT) Study [
      • Franzini L.
      • Ardigò D.
      • Cavalot F.
      • Miccoli R.
      • Rivellese A.A.
      • Trovati M.
      • et al.
      Women show worse control of type 2 diabetes and cardiovascular disease risk factors than men: results from the MIND.IT Study group of the Italian Society of Diabetology.
      ], the Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter Study [
      • Penno G.
      • Solini A.
      • Bonora E.
      • Fondelli C.
      • Orsi E.
      • Zerbini G.
      • et al.
      Gender differences in cardiovascular disease risk factors, treatments and complications in patients with type 2 diabetes: the RIACE Italian multicentre study.
      ], and the AMD Annals Initiative [
      • Rossi M.C.
      • Cristofaro M.R.
      • Gentile S.
      • Lucisano G.
      • Manicardi V.
      • Mulas M.F.
      • et al.
      Sex disparities in the quality of diabetes care: biological and cultural factors may play a different role for different outcomes: a cross sectional observational study from AMD annal initiative.
      ]. The MIND IT [
      • Franzini L.
      • Ardigò D.
      • Cavalot F.
      • Miccoli R.
      • Rivellese A.A.
      • Trovati M.
      • et al.
      Women show worse control of type 2 diabetes and cardiovascular disease risk factors than men: results from the MIND.IT Study group of the Italian Society of Diabetology.
      ] study, promoted by the Italian Society of Diabetes (SID, Società Italiana di Diabetologia) evaluated the management and treatment of diabetes and the degree of application of the guidelines for CVD prevention in clinical practice in Italy (cross-sectional study), as well as the effect in glyco-metabolic control and CVD events of an intensive, multifactorial intervention (longitudinal study), in patients with T2DM and no history of previous CVD events, followed up at 10 hospital diabetes centers. A data analysis from 2465 individuals (1168 women and 1297 men) collected at the enrolment visit in the years 2004–2006 assessed the degree of glycemic control and CVD risk factors, as well as the impact of central obesity, age and drug use. The prospective observational study RIACE [
      • Penno G.
      • Solini A.
      • Bonora E.
      • Fondelli C.
      • Orsi E.
      • Zerbini G.
      • et al.
      Gender differences in cardiovascular disease risk factors, treatments and complications in patients with type 2 diabetes: the RIACE Italian multicentre study.
      ], also sustained by SID, had the primary objective of evaluating the impact of the estimated glomerular filtration rate (eGFR) and albuminuria on morbidity and mortality. Among the pre-specified secondary endpoints of this study there was the comparison of the baseline data collected at the enrolment visit, carried out in the years 2007–2008, between the two sexes (Fig. 2). The AMD Annals Initiative [
      • Rossi M.C.
      • Cristofaro M.R.
      • Gentile S.
      • Lucisano G.
      • Manicardi V.
      • Mulas M.F.
      • et al.
      Sex disparities in the quality of diabetes care: biological and cultural factors may play a different role for different outcomes: a cross sectional observational study from AMD annal initiative.
      ] was aimed at analyzing data entered in the electronic medical record of patients with T2DM followed in Italian hospitals and local diabetes centers, in order to assess the quality of care in Italy. One study, in particular, analyzed data of 415,294 subjects from 236 centers, extracted from the data-file for the year 2009, with the aim of highlighting any difference in the quality of care in T2DM between men and women.
      Figure 2
      Figure 2Prevalence of micro and macrovascular complications by gender in T2DM subjects. The columns represent the baseline prevalence of micro and macrovascular complications in men and women with type 2 diabetes (T2DM) participating in the RIACE study (J Intern Med 2013; 274:176–91). Any CVD, any type of cardiovascular disease; AMI, acute myocardial infarction; stroke; any ulcer/gangrene in lower limbs; any form of retinopathy; eGFR, estimated glomerular filtration rate <60 ml/min/1.73m2; detection of micro/macroalbuminuria.
      In the Verona Study [
      • Muggeo M.
      • Verlato G.
      • Bonora E.
      • Bressan F.
      • Girotto S.
      • Corbellini M.
      • et al.
      The Verona diabetes study: a population-based survey on known diabetes mellitus prevalence and 5-year all-cause mortality.
      ], a population-based survey on diabetes mellitus prevalence and all-cause mortality, mortality rates were higher in the diabetic than in the non-diabetic cohort at all ages, but women aged 65–74 years showed higher observed/expected ratio than men, while this difference was not observed in other age-groups. More recently, a registry study from Reggio Emilia analyzing data on major CVD events from 2012 to 2014 found that the eccess of risk in T2DM subjects vs the general population was similar in men and women for stroke (1.8 times) and heart failure (HF; 2.7 times), while that for myocardial infarction was higher in women (IRR 2.58, 95% CI 2.22–3.00 and IRR 1.78, 95% CI 1.60–2.00, in T2DM women and in men, respectively; P for interaction<0.0001) [
      • Ballotari P.
      • Venturelli F.
      • Greci M.
      • Giorgi Rossi P.
      • Manicardi V.
      Sex differences in the effect of type 2 diabetes on major cardiovascular diseases: results from a population-based study in Italy.
      ]. Similar results were reported in a registry study from Biobank in UK with over 500,000 participants, demonstrating that the risk for myocardial infarction was 1.29 times higher in T2DM women than in men [
      • de Jong M.
      • Woodward M.
      • Peters S.A.E.
      Diabetes, glycated hemoglobin, and the risk of myocardial infarction in women and men: a prospective cohort study of the UK Biobank.
      ].
      Regarding HF, significant sex- and gender-differences in etiology, epidemiology and clinical presentation, prognosis, comorbidities, and response to treatment have been reported in the general population [
      • Aimo A.
      • Vergaro G.
      • Barison A.
      • Maffei S.
      • Borrelli C.
      • Morrone D.
      • et al.
      Sex-related differences in chronic heart failure.
      ]. In T2DM, a meta-analysis of data from 47 cohorts, involving 12, 142, 998 individuals, showed a pooled multiple-adjusted RR for HF of 1.95 (1.70-2.22) in women and 1.74 (1.55-1.95) in men, with a pooled RRR of 1.09 (1.05-1.13) [
      • Ohkuma T.
      • Komorita Y.
      • Peters S.A.E.
      • Woodward M.
      Diabetes as a risk factor for heart failure in women and men: a systematic review and meta-analysis of 47 cohorts including 12 million individuals.
      ]. Furthermore, a meta-analysis by Bouthoorn et al. showed that the prevalence of left ventricular systolic dysfunction (LVSD) and HF with reduced ejection fraction (HFrEF) was higher among T2DM patients from a hospital setting compared with studies from the general population, prevailing in men than in women in both settings [
      • Bouthoorn S.
      • Gohar A.
      • Valstar G.
      • den Ruijter H.M.
      • Reitsma J.B.
      • Hoes A.W.
      • et al.
      Queen of Hearts Consortium. Prevalence of left ventricular systolic dysfunction and heart failure with reduced ejection fraction in men and women with type 2 diabetes mellitus: a systematic review and meta-analysis.
      ]. The same Authors also evaluated the sex-specific estimates for HF with preserved ejection fraction (HFpEF): the prevalence of LV diastolic dysfunction was similar in T2DM men and women, while HFpEF was more common in women [
      • Bouthoorn S.
      • Valstar G.B.
      • Gohar A.
      • den Ruijter H.M.
      • Reitsma H.B.
      • Hoes A.W.
      • et al.
      The prevalence of left ventricular diastolic dysfunction and heart failure with preserved ejection fraction in men and women with type 2 diabetes: a systematic review and meta-analysis.
      ]. As for risk factors and biomarkers of incident HF, no major sex differences were reported [
      • Suthahar N.
      • Lau E.S.
      • Blaha M.J.
      • Paniagua S.M.
      • Larson M.G.
      • Psaty B.M.
      • et al.
      Sex-specific associations of cardiovascular risk factors and biomarkers with incident heart failure.
      ].
      In Italy, the DYDA trial collected baseline clinical, ECG, routinalysis and echocardiographic data from 751 asymptomatic and adequately controlled T2DM patients recruited in 37 Italian diabetes clinics. This study found a high prevalence of early LV dysfunction, with age, worse HbA1c, traits of insulin resistance, treatment with metformin or doxazosin that were associated with a greater risk [
      • Giorda C.B.
      • Cioffi G.
      • de Simone G.
      • Di Lenarda A.
      • Faggiano P.
      • Latini R.
      • et al.
      DYDA Investigators. Predictors of early-stage left ventricular dysfunction in type 2 diabetes: results of DYDA study.
      ]. At the two-year follow-up of the same study, any LV dysfunction was very frequent in T2DM patients without overt CVD, and all-cause death or hospitalization occurred in 15% of these subjects [
      • Cioffi G.
      • Faggiano P.
      • Lucci D.
      • Maggioni A.P.
      • Manicardi V.
      • Travaglini A.
      • et al.
      Left ventricular dysfunction and outcome at two-year follow-up in patients with type 2 diabetes: the DYDA study.
      ]. Notably, in the DYDA trial, no sex differences were reported for ventricular dysfunction or HF. A high prevalence of LV diastolic dysfunction was also reported in 456 consecutive Italian postmenopausal T2DM women with normal blood pressure values. In this group, LV diastolic dysfunction was associated with HbA1c levels and obesity status, but not with ECG abnormalities [
      • Maiello M.
      • Zito A.
      • Cecere A.
      • Ciccone M.M.
      • Palmiero P.
      Left ventricular diastolic dysfunction in normotensive postmenopausal women with type 2 diabetes mellitus.
      ].
      Sex- and gender-differences in stroke prevalence and outcomes have also been largely reported in the general population [
      • Rexrode K.M.
      • Madsen T.E.
      • Yu A.Y.X.
      • Carcel C.
      • Lichtman J.H.
      • Miller E.C.
      The impact of sex and gender on stroke.
      ]. In T2DM subjects, the risk of stroke was up to eight-fold higher in women, especially at a younger age [
      • Mulnier H.E.
      • Seaman H.E.
      • Raleigh V.S.
      • Soedamah-Muthu S.S.
      • Colhoun H.M.
      • Lawrenson R.A.
      • et al.
      Risk of stroke in people with type 2 diabetes in the UK: a study using the General Practice Research Database.
      ]. An Italian study, evaluating all the discharge records for stroke for residents in the Tuscany region in the years 2004–2011 [
      • Policardo L.
      • Seghieri G.
      • Anichini R.
      • De Bellis A.
      • Franconi F.
      • Francesconi P.
      • et al.
      Effect of diabetes on hospitalization for ischemic stroke and related in-hospital mortality: a study in Tuscany, Italy, over years 2004-2011.
      ], demonstrated that T2DM was associated with a higher risk of stroke in both sexes, with an odds ratio (OR) of 1.31 (95% CI 1.28–1.34) in men and 1.24 (95% CI 1.21–1.37) in women. However, T2DM women showed a higher intrahospital mortality risk after ischemic stroke (OR 1.32; 1.06–1.64), whereas no sex/gender-difference was noted in the non-diabetic cohort. In the same clinical setting [
      • Policardo L.
      • Seghieri G.
      • Francesconi P.
      • Anichini R.
      • Franconi F.
      • Seghieri C.
      • et al.
      Gender difference in diabetes-associated risk of first-ever and recurrent ischemic stroke.
      ], the sex gap in the risk for the first ischemic stroke vs the non-diabetic population decreased progressively with ageing, but it was particularly higher in T2DM women aged 55–74 years vs T2DM men of the same age. T2DM was also associated with the risk of recurrence of stroke, irrespective of age [
      • Policardo L.
      • Seghieri G.
      • Francesconi P.
      • Anichini R.
      • Franconi F.
      • Seghieri C.
      • et al.
      Gender difference in diabetes-associated risk of first-ever and recurrent ischemic stroke.
      ]. Notably, a recent cross-sectional study showed that women with a prior stroke/TIA and multiple risk factors including diabetes, had an increased risk of all-cause hospitalization compared with men [
      • Chang T.E.
      • Goldstein L.B.
      • Leifheit E.C.
      • Howard V.J.
      • Lichtman J.H.
      Cardiovascular risk factor profiles, emergency department visits, and hospitalizations for women and men with a history of stroke or transient ischemic attack: a cross-sectional study.
      ].
      As for peripheral artery disease (PAD), up to date, available evidence on potential sex-related differences is still limited. In the Framingham study, the relative risk of claudicatio was significantly higher in T2DM women [
      • Brand F.N.
      • Abbott R.D.
      • Kannel W.B.
      Diabetes, intermittent claudication, and risk of cardiovascular events. The Framingham Study.
      ]. Conversely, recent data from Italy show that age, male sex and diabetes duration were independent predictors for PAD [
      • Papa G.
      • Degano C.
      • Iurato M.P.
      • Licciardello C.
      • Maiorana R.
      • Finocchiaro C.
      Macrovascular complication phenotypes in type 2 diabetic patients.
      ]. Moreover, an Italian study examining the risk of amputation in T2DM patients with PAD [
      • Lombardo F.L.
      • Maggini M.
      • De Bellis A.
      • Seghieri G.
      • Anichini R.
      Lower extremity amputations in persons with and without diabetes in Italy: 2001-2010.
      ], showed a higher risk of lower limb amputations in men than in women, with a RR of 2.6 (95% CI 2.5–2.8) for minor and of 2.0 (95% CI 1.9–2.2) for major amputations. Furthermore, from 2001 to 2010, male-female RR increased from 2.3 to 3.1 for minor amputations and from 1.8 to 2.6 for major ones, which is in line with the international literature [
      • Moxey P.W.
      • Hofman D.
      • Hinchliffe R.J.
      • Jones K.
      • Thompson M.M.
      • Holt P.J.
      Epidemiological study of lower limb amputation in England between 2003 and 2008.
      ,
      • Vamos E.P.
      • Bottle A.
      • Edmonds M.E.
      • Valabhji J.
      • Majeed A.
      • Millett C.
      Changes in the incidence of lower extremity amputations in individuals with and without diabetes in England between 2004 and 2008.
      ].
      Potential sex/gender differences in major CVD events have also been investigated in newly diagnosed T2DM and in pre-diabetic subjects. Biological sex influences prediabetes status, and impaired fasting glucose (IFG) is prevalent in men, while impaired glucose tolerance (IGT) prevails in women [
      • Kautzky-Willer A.
      • Harreiter J.
      • Pacini G.
      Sex and gender differences in risk, pathophysiology and complications of type 2 diabetes.
      ,
      • Mauvais-Jarvis F.
      Gender differences in glucose homeostasis and diabetes.
      ], with important clinical implications for the screening of the disease.
      Notably, among subjects with new T2DM diagnosis, about 50% already have long-term complications, with some differences between men and women [
      • Bonora E.
      • Trombetta M.
      • Dauriz M.
      • Travia D.
      • Cacciatori V.
      • Brangani C.
      • et al.
      Chronic complications in patients with newly diagnosed type 2 diabetes: prevalence and related metabolic and clinical features: the Verona Newly Diagnosed Type 2 Diabetes Study (VNDS) 9.
      ]. A monocentric Italian study conducted in subjects with a recent T2DM diagnosis, and followed up for 51.2 months, showed that male sex was among the predictors of early CVD occurrence [
      • Biancalana E.
      • Parolini F.
      • Mengozzi A.
      • Solini A.
      Phenotyping individuals with newly-diagnosed type 2 diabetes at risk for all-cause mortality: a single centre observational, prospective study.
      ]. Furthermore, another recent study, including a large cohort of adults with normal glucose tolerance (NGT), pre-diabetes and T2DM, found that only T2DM women showed a higher risk of events compared to men, whereas no sex/genderdifference was observed among pre-diabetic subjects after 5.6 years of follow-up [
      • Succurro E.
      • Fiorentino T.V.
      • Miceli S.
      • Perticone M.
      • Sciacqua A.
      • Andreozzi F.
      • et al.
      Relative risk of cardiovascular disease is higher in women with type 2 diabetes, but not in those with prediabetes, as compared with men.
      ]. The same Authors also demonstrated that LV maladaptations were worst in women with glucose intolerance [
      • Succurro E.
      • Miceli S.
      • Fiorentino T.V.
      • Sciacqua A.
      • Perticone M.
      • Andreozzi F.
      • et al.
      Sex-specific differences in left ventricular mass and myocardial energetic efficiency in non-diabetic, pre-diabetic and newly diagnosed type 2 diabetic subjects.
      ].
      Althoug many of these observations are largely attributable to biological (sex) differences in the impact of CVD risk factors, in the pathophysiology of vascular bed, and in clinical manifestations of CVD, gender-related variables may also play an important role in influencing prognosis, by causing delay in the diagnosis, undertreament of major CVD risk factors, modifying adherence to therapy and underuse of revascularization procedures in T2DM women, still misperceived as being at lower CVD risk than T2DM men [
      • Lonardo A.
      • Byrne C.D.
      • Targher G.
      Precision medicine approaches in metabolic disorders and target organ damage: where are we now, and where are we going?.
      ,
      • Kautzky-Willer A.
      • Harreiter J.
      • Pacini G.
      Sex and gender differences in risk, pathophysiology and complications of type 2 diabetes.
      ,
      • Huebschmann A.G.
      • Huxley R.R.
      • Kohrt W.M.
      • Zeitler P.
      • Regensteiner J.G.
      • Reusch J.E.B.
      Sex differences in the burden of type 2 diabetes and cardiovascular risk across the life course.
      ,
      • Regensteiner J.G.
      • Golden S.
      • Huebschmann A.G.
      • Barrett-Connor E.
      • Chang A.Y.
      • Chyun D.
      • et al.
      Sex differences in the cardiovascular consequences of diabetes mellitus: a scientific statement from the American HeartAssociation.
      ].
      Thus, the mechanisms behind the observed differences in CVD risk between T2DM men and women are likely to be attributable to a complex interaction between sex- and gender-related variables, which is still unsolved (Fig. 3).
      Figure 3
      Figure 3Factors contributing to Sex and Gender differences in T2DM. Sex (biological)- and gender (socio-cultural)- related factors contributing to the onset and progression of T2DM and its complications include a large set of variables, mechanisms and their potential interactions, although many of them still need to be elucidated.
      Among sex-related factors, it has been observed that women have an earlier and more pronounced deterioration in CVD risk factors than men. Furthemore, sex-specific risk factors such as gestational diabetes, pregnancy and menopause may contribute. Notably, T2DM women do not reach target values for major CVD risk factors, including glucose and lipid control, weight loss and reduction of inflammation and endothelial dysfunction markers as compared to men, as largely documented by international and Italian studies [
      • Peters S.A.
      • Huxley R.R.
      • Sattar N.
      • Woodward M.
      Sex differences in the excess risk of cardiovascular diseases associated with type 2 diabetes: potential explanations and clinical implications.
      ,
      • Wannamethee S.G.
      • Papacosta O.
      • Lawlor D.A.
      • Whincup P.H.
      • Lowe G.D.
      • Ebrahim S.
      • et al.
      Do women exhibit greater differences in established and novel risk factors between diabetes and non-diabetes than men? The British Regional Heart Study and British Women's Heart Health Study.
      ,
      • Du T.
      • Fernandez C.
      • Barshop R.
      • Guo Y.
      • Krousel-Wood M.
      • Chen W.
      • et al.
      Sex differences in cardiovascular risk profile from childhood to midlife between individuals who did and did not develop diabetes at follow-up: the Bogalusa Heart Study.
      ,
      • Giandalia A.
      • Alibrandi A.
      • Giorgianni L.
      • Lo Piano F.
      • Consolo F.
      • Longo Elia G.
      • et al.
      Resistin levels and inflammatory and endothelial dysfunction markers in obese postmenopausal women with type 2 diabetes mellitus.
      ,
      • Gouni-Berthold I.
      • Berthold H.K.
      • Mantzoros C.S.
      • Bohm M.
      • Krone W.
      Sex disparities in the treatment and control of cardiovascular risk factors in type 2 diabetes.
      ,
      • Franzini L.
      • Ardigò D.
      • Cavalot F.
      • Miccoli R.
      • Rivellese A.A.
      • Trovati M.
      • et al.
      Women show worse control of type 2 diabetes and cardiovascular disease risk factors than men: results from the MIND.IT Study group of the Italian Society of Diabetology.
      ,
      • Penno G.
      • Solini A.
      • Bonora E.
      • Fondelli C.
      • Orsi E.
      • Zerbini G.
      • et al.
      Gender differences in cardiovascular disease risk factors, treatments and complications in patients with type 2 diabetes: the RIACE Italian multicentre study.
      ,
      • Rossi M.C.
      • Cristofaro M.R.
      • Gentile S.
      • Lucisano G.
      • Manicardi V.
      • Mulas M.F.
      • et al.
      Sex disparities in the quality of diabetes care: biological and cultural factors may play a different role for different outcomes: a cross sectional observational study from AMD annal initiative.
      ].
      However, at variance with the international literature [
      • Gouni-Berthold I.
      • Berthold H.K.
      • Mantzoros C.S.
      • Bohm M.
      • Krone W.
      Sex disparities in the treatment and control of cardiovascular risk factors in type 2 diabetes.
      ], a gender bias in the management of T2DM suggesting undertreatment of women compared with men was not observed in Italian cohorts [
      • Franzini L.
      • Ardigò D.
      • Cavalot F.
      • Miccoli R.
      • Rivellese A.A.
      • Trovati M.
      • et al.
      Women show worse control of type 2 diabetes and cardiovascular disease risk factors than men: results from the MIND.IT Study group of the Italian Society of Diabetology.
      ,
      • Penno G.
      • Solini A.
      • Bonora E.
      • Fondelli C.
      • Orsi E.
      • Zerbini G.
      • et al.
      Gender differences in cardiovascular disease risk factors, treatments and complications in patients with type 2 diabetes: the RIACE Italian multicentre study.
      ,
      • Rossi M.C.
      • Cristofaro M.R.
      • Gentile S.
      • Lucisano G.
      • Manicardi V.
      • Mulas M.F.
      • et al.
      Sex disparities in the quality of diabetes care: biological and cultural factors may play a different role for different outcomes: a cross sectional observational study from AMD annal initiative.
      ], suggesting that other sex- (genetic, hormones) or gender-related variables (adherence, access to diabetes centers, care-givers, education, lifestyle) may be implicated.
      Accordingly, potential sex differences in the response to antidiabetic drugs have recently been uncovered [
      • Dennis J.M.
      • Henley W.E.
      • Weedon M.N.
      • Lonergan M.
      • Rodgers L.R.
      • Jones A.G.
      • et al.
      Sex and BMI alter the benefits and risks of sulfonylureas and thiazolidinediones in type 2 diabetes: a framework for evaluating stratification using routine clinical and individual trial data.
      ,
      • Raparelli V.
      • Elharram M.
      • Moura C.S.
      • Abrahamowicz M.
      • Bernatsky S.
      • Behlouli H.
      • et al.
      Sex differences in cardiovascular effectiveness of newer glucose-lowering drugs added to metformin in type 2 diabetes mellitus.
      ], an issue that should be further explored, since women are typically under-represented in clinical trials. Moreover, the relevant role of sex-genes interactions and sex hormones in influencing risk factors, their impact on vascular bed and the response to treatments should be fully elucidated [
      • Mauvais-Jarvis F.
      Estrogen and androgen receptors: regulators of fuel homeostasis and emerging targets for diabetes and obesity.
      ,
      • Mauvais-Jarvis F.
      • Manson J.E.
      • Stevenson J.C.
      • Fonseca V.A.
      Menopausal hormone therapy and type 2 diabetes prevention: evidence, mechanisms and clinical implications.
      ,
      • Yassin A.
      • Haider A.
      • Haider K.S.
      • Caliber M.
      • Doros G.
      • Saad F.
      • et al.
      Testosterone therapy in men with hypogonadism prevents progression from prediabetes to type 2 diabetes: eight-year data from a registry Study.
      ,
      • Russo G.T.
      • Giandalia A.
      • Romeo E.L.
      • Muscianisi M.
      • Ruffo M.C.
      • Alibrandi A.
      • et al.
      HDL subclasses and the common CETP TaqIB variant predict the incidence of microangiopatic complications in type 2 diabetic women: a 9 years follow-up study.
      ].
      Literature data show sex and gender differences also for T1DM and its long-term complications, including macrovascular disease. The perception of CVD risk in T1DM has evolved in the past decades, and T1DM patients with long-standing disease have been included in the very high-risk category in the recent ESC guidelines [
      • Cosentino F.
      • Grant P.J.
      • Aboyans V.
      • Bailey C.J.
      • Ceriello A.
      • Delgado V.
      • et al.
      ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD.
      ]. When applying ESC CVD risk stratification to the 34,705 T1DM subjects participating in the Italian AMD Annals Initiative, 64.7% of them have a very high CVD risk, 28.5% a high-risk category, while only 6.8% were in the moderate risk category [
      • Pintaudi B.
      • Corrao S.
      • Di Bartolo P.
      • Frison V.
      • Gallo M.
      • Manicardi V.
      • et al.
      Profili assistenziali nei pazienti con DM1 e DM2 in relazione alla stratificazione del rischio cardiovascolare.
      ]. Sex and gender differences have been also reported for macrovascular disease in T1DM patients, although not consistently [
      Diabetes control and complications trial/epidemiology of diabetes interventions and complications (DCCT/EDIC) research group. Risk factors for cardiovascular disease in type 1 diabetes.
      ], and these data are particularly evident for stroke [
      • Sundquist K.
      • Li X.
      Type 1 diabetes as a risk factor for stroke in men and women aged 15-49: a nationwide study from Sweden.
      ]. In 2015, Huxley published the first meta-analisys of 26 studies reporting on sex differences on standardized mortality risk (SMR) in T1DM: women showed 40% for all-cause mortality, 37% for stroke, 44% for CKD, 86% higher risk for fatal CVD events, and a more than 2 times higher risk for CHD compared to men [
      • Huxley R.R.
      • Peters S.A.
      • Mishra G.D.
      • Woodward M.
      Risk of all-cause mortality and vascular events in women versus men with type 1 diabetes: a systematic review and meta-analysis.
      ]. Sex differences have been also reported in the impact of T1DM on HF. Thus, a recent meta-analysis reported a risk for HF associated with T1DM of 5.15 (95% CI 3.43-7.74) in women and 3.47 (2.57-4.69) in men [
      • Ohkuma T.
      • Komorita Y.
      • Peters S.A.E.
      • Woodward M.
      Diabetes as a risk factor for heart failure in women and men: a systematic review and meta-analysis of 47 cohorts including 12 million individuals.
      ].
      Age of onset is an important risk stratifier for mortality and CVD risk in people with T1DM, showing a stronger impact in women: thus, the development of T1DM before 10 years of age resulted in a loss of 17.7 life-years (95% CI 14.5–20.4) for women and 14.2 life-years (12.1–18.2) for men [
      • Rawshani A.
      • Sattar N.
      • Franzén S.
      • Rawshani A.
      • Hattersley A.T.
      • Svensson A.M.
      • et al.
      Excess mortality and cardiovascular disease in young adults with type 1 diabetes in relation to age at onset: a nationwide, register-based cohort study.
      ].
      As for T2DM, the mechanism behind the higher impact of diabetes on CVD risk in women with T1DM is still unsolved, and data on sex/gender differences in CVD risk factors in this population are scarce. Gender-related variables may have influenced the results of a small study in Austria, documenting under-treatment with aspirin and statins in T1DM women [
      • Kautzky-Willer A.
      • Stich K.
      • Hintersteiner J.
      • Kautzky A.
      • Kamyar M.R.
      • Saukel J.
      • et al.
      Sex-specific-differences in cardiometabolic risk in type 1 diabetes: a cross-sectional study.
      ]. In 2011, the Italian AMD Annals Initiative reported on differences in 15,708 adult T1DM men (54.5%) and 13,094 women (45.5%) [
      • Manicardi V.
      • Russo G.
      • Napoli A.
      • Torlone E.
      • Li Volsi P.
      • Giorda C.B.
      • et al.
      AMD annals study group. Gender-disparities in adults with type 1 diabetes: more than a quality of care issue. A cross-sectional observational study from the AMD annals initiative.
      ]. Overall, no differences were noted in mean HbA1c levels, although more men than women were at target for HbA1c, while the opposite trend was observed for blood pressure control; smoking habit was worst in males and the prevalence of obesity in females, whereas no differences were noted in lipid profile [
      • Manicardi V.
      • Russo G.
      • Napoli A.
      • Torlone E.
      • Li Volsi P.
      • Giorda C.B.
      • et al.
      AMD annals study group. Gender-disparities in adults with type 1 diabetes: more than a quality of care issue. A cross-sectional observational study from the AMD annals initiative.
      ] (Fig. 4). T1DM women were also more often treated with continuous subcutaneous insulin infusion (CSII; 19.6% vs 13.9%), but less frequently treated with anti-hypertensive and hypolipidemic drugs. Notably, the sex/gender gap in reaching glucose targets should be seen in the light of the overall unsatisfactory glucose control reached by T1DM patients: less than 1/3 in T1DM reach HbA1c target, with better results among CSII users. The subsequent evaluation of the same cohort, in 2018, confirmed these trends (Fig. 4), with a preoccupying increase in the prevalence of obesity (from 0.4% in 2004 to 13.4% in 2018) [
      • Aglialoro A.
      • Bertuzzi F.
      • Celleno R.
      • Clemente G.
      • De Cosmo S.
      • Giorda C.B.
      • et al.
      Profili assistenziali nei pazienti adulti con Diabete Tipo 1.
      ]. These data were consistent with those from other populations (Australia, USA, Europe, Scotland [
      • McKnight J.A.
      • Wild S.H.
      • Lamb M.J.
      • Cooper M.N.
      • Jones T.W.
      • Davis E.A.
      • et al.
      Glycaemic control of Type 1 diabetes in clinical practice early in the 21st century: an international comparison.
      ,
      • Collier A.
      • Ghosh S.
      • Hair M.
      • Waugh N.
      Gender differences and patterns of cardiovascular risk factors in Type 1 and Type 2 diabetes: a population-based analysis from a Scottish region.
      ]. However, as reported for T2DM subjects from Italian cohorts, the peculiarity of Italian data, when compared to other countries, is that, in Italy, these differences are not attributable to the quality of care, which was comparable between T1DM men and women. Sex-related variables such as hormonal fluctuation through lifespan may contribute to glucose variability, especially in T1DM women, but also gender differences in psycological factors, difficulty in adaptation and acceptation of the disease and/or depression may be more frequent in T1DM women, although these same variables did not influence glucose control in a small cohort study [
      • Enzlin P.
      • Mathieu C.
      • Demyttenaere K.
      Gender differences in the psychological adjustment to type 1 diabetes mellitus: an explorative study.
      ], at odds with that reported in T2DM subjects by the Italian BENCH-D study [
      • Rossi M.C.
      • Lucisano G.
      • Pintaudi B.
      • Bulotta A.
      • Gentile S.
      • Scardapane M.
      • et al.
      The complex interplay between clinical and person-centered diabetes outcomes in the two genders.
      ].
      Figure 4
      Figure 4Unfavourable intermediate outcome indicators by gender and by year in T1DM subjects. The columns represent the percentage of subjects with unfavourable outcomes in the control of major risk factors at two different time points (year 2011 and year 2018) among type 1 diabetes (T1DM) adult men and women participating in the AMD Annals Initiative. HbA1c, glycated aemoglobin; LDL-C, low density lipoprotein cholesterol; BP, blood pressure; BMI, body max index; eGFR, estimated glomerular filtration rate.

      1.2 Sex and gender differences in microvascular complications and NAFLD inT2DM and T1DM

      Nephropathy Male sex is associated with an increased risk to progress toward acute kidney insufficiency (AKI) [
      • Neugarten J.
      • Golestaneh L.
      • Kolhe N.V.
      Sex differences in acute kidney injury requiring dialysis.
      ,
      • Carrero J.J.
      • Hecking M.
      • Chesnaye N.C.
      • Jager K.J.
      Sex and gender disparities in the epidemiology and outcomes of chronic kidney disease.
      ]; on the contrary recent data from USA show that chronic kidney disease (CKD) prevails in women (13 vs 10%) [
      • Tuttle K.R.
      • Alicic R.Z.
      • Duru O.K.
      • Jones C.R.
      • Daratha K.B.
      • Nicholas S.B.
      • et al.
      Clinical characteristics of and risk factors for chronic kidney disease among adults and children: an analysis of the CURE-CKD registry.
      ], with an increase of 28.2% in women and 25.3% in men registered in the 2007–2017 decade [
      • Fraser S.D.S.
      • Roderick P.J.
      Kidney disease in the global burden of disease study 2017.
      ]. A quite recent metanalysis identified male sex (HR 1.37) as a determinant of CKD progression to end stage renal disease (ESRD) [
      • Tsai W.C.
      • Wu H.Y.
      • Peng Y.S.
      • Ko M.J.
      • Wu M.S.
      • Hung K.Y.
      • et al.
      Risk factors for development and progression of chronic kidney disease: a systematic review and exploratory meta-analysis.
      ]. A sex effect on the risk to develop renal disease during the course of diabetes (diabetic kidney disease, DKD) has been inconstantly reported in the scientific literature. Such inconsistency is likely due to several factors: sex-linked differences in markers of eGFR (serum creatinine and cystatin C), different performance of equations to estimate eGFR, scarce use of already validated sex-specific cut-off of eGFR and albuminuria [
      • Neugarten J.
      • Golestaneh L.
      Influence of sex on the progression of chronic kidney disease.
      ], residual confounding factors, including the impact of CVD complications on renal function, differences in the study populations (percent of post-menopausal women, age of onset and disease duration). Certainly, sex hormones play an important role, although not fully elucidated yet: estrogens seem to exert protection [
      • Giandalia A.
      • Giuffrida A.E.
      • Gembillo G.
      • Cucinotta D.
      • Squadrito G.
      • Santoro D.
      • et al.
      Gender differences in diabetic kidney disease: focus on hormonal, genetic and clinical factors.
      ], and Yu et al. have shown that women ≥60 years have an increased prevalence of advanced DKD vs men [
      • Yu M.K.
      • Rees Lyles C.
      • Bent-Shaw L.A.
      • Young B.A.
      Pathways Authors
      Risk factor, age and sex differences in chronic kidney disease prevalence in a diabetic cohort: the pathways study.
      ]. In T1DM, age of onset and disease duration are important sex-related determinants. An early onset is protective toward the subsequent development of DKD in both sexes, while the prevalence of DKD increases in males with disease duration >25 years [
      • Möllsten A.
      • Svensson M.
      • Waernbaum I.
      • Berhan Y.
      • Schön S.
      • Nyström L.
      • et al.
      Cumulative risk, age at onset, and sex-specific differences for developing end-stage renal disease in young patients with type 1 diabetes: a nationwide population-based cohort study.
      ,
      • Orchard T.J.
      • Dorman J.S.
      • Maser R.E.
      • Becker D.J.
      • Drash A.L.
      • Ellis D.
      • et al.
      Prevalence of complications in IDDM by sex and duration. Pittsburgh epidemiology of diabetes complications study II.
      ].
      Another aspect of the sexual dimorphism in DKD resides in the renal haemodynamic. It has been shown that female adolescents with T1DM or T2DM are prone to develop glomerular hyperfiltration [
      • Lovshin J.A.
      • Škrtić M.
      • Bjornstad P.
      • Moineddin R.
      • Daneman D.
      • Dunger D.
      • et al.
      Hyperfiltration, urinary albumin excretion, and ambulatory blood pressure in adolescents with Type 1 diabetes mellitus.
      ,
      • Bjornstad P.
      • Nehus E.
      • El Ghormli L.
      • Bacha F.
      • Libman I.M.
      • McKay S.
      • et al.
      Insulin sensitivity and diabetic kidney disease in children and adolescents with type 2 diabetes: an observational analysis of data from the TODAY Clinical Trial.
      ], likely due to increased resistance at the level of glomerular efferent arteriola, with reduced renal plasma flow and increased intraglomerular hydrostatic pressure; other potentially involved mechanisms include an increased nitric oxide (NO) bioavailability (an enhanced NO synthase activity has been documented in female animal models, with increased vasodilation of afferent arteriola) [
      • Slyvka Y.
      • Malgor R.
      • Inman S.R.
      • Ding J.
      • Heh V.
      • Nowak F.V.
      Antioxidant diet and sex interact to regulate NOS isoform expression and glomerular mesangium proliferation in Zucker diabetic rat kidney.
      ].
      In 2004 MacIsaac documented for the first time the presence of a non albuminuric CKD phenotype in T2DM: normoalbuminuric subjects with eGFR <60 ml/min/1.73 m2 (measured with 99 mTc-DTPA) were mainly aging women [
      • MacIsaac R.J.
      • Tsalamandris C.
      • Panagiotopoulos S.
      • Smith T.J.
      • McNeil K.J.
      • Jerums G.
      Nonalbuminuric renal insufficiency in type 2 diabetes.
      ]. These observations have been replicated in ample cohorts [
      • Thomas M.C.
      • MacIsaac R.J.
      • Jerums G.
      • Weekes A.
      • Moran J.
      • Shaw J.E.
      • et al.
      Nonalbuminuric renal impairment in type 2 diabetic patients and in the general population (national evaluation of the frequency of renal impairment cO-existing with NIDDM [NEFRON] 11).
      ,
      • Retnakaran R.
      • Cull C.A.
      • Thorne K.I.
      • Adler A.I.
      • Holman R.R.
      UKPDS Study Group
      Risk factors for renal dysfunction in type 2 diabetes: U.K. Prospective Diabetes Study 74.
      ], and the Italian diabetologists have largely contributed to the increased knowledge in the field. The RIACE study, a prospective observational survey performed in 15,773 T2DM individuals, described differences in CKD related to T2DM, with a prevalence of the non albuminuric phenotype in the female sex [
      • Penno G.
      • Solini A.
      • Bonora E.
      • Fondelli C.
      • Orsi E.
      • Zerbini G.
      • et al.
      Renal Insufficiency and Cardiovascular Events (RIACE) Study Group. Clinical significance of nonalbuminuric renal impairment in type 2 diabetes.
      ], and a reduced prevalence of such phenotype before 55 years of age, suggesting that sex, rather than age, might influence a misclassification of a certain subject subset also determining a potential overestimation of CKD prevalence in T2DM. Data from Annali AMD have confirmed in both T1DM and T2DM a higher prevalence of the normoalbuminuric CKD, also showing that, in patients with T2DM and hypertension, together with age, diabetes duration, BMI, low GFR at baseline and other clinical characteristics, female sex can predict the risk of eGFR reduction over time [
      • De Cosmo S.
      • Viazzi F.
      • Pacilli A.
      • Giorda C.
      • Ceriello A.
      • Gentile S.
      • et al.
      the AMD-Annals Study Group
      Predictors of chronic kidney disease in type 2 diabetes: a longitudinal study from the AMD Annals initiative.
      ,
      • Piscitelli P.
      • Viazzi F.
      • Fioretto P.
      • Giorda C.
      • Ceriello A.
      • Genovese S.
      • et al.
      Predictors of chronic kidney disease in type 1 diabetes: a longitudinal study from the AMD Annals initiative.
      ,
      • Viazzi F.
      • Russo G.T.
      • Ceriello A.
      • Fioretto P.
      • Giorda C.
      • De Cosmo S.
      • et al.
      Natural history and risk factors for diabetic kidney disease in patients with T2D: lessons from the AMD-annals.
      ]. Such observation has been somehow confirmed in T1DM, where male sex, retinopathy and smoking were related to the presence of albuminuria, while female sex was related with low eGFR [
      • Pacilli A.
      • Viazzi F.
      • Fioretto P.
      • Giorda C.
      • Ceriello A.
      • Genovese S.
      • et al.
      AMD-Annals Study Group
      Epidemiology of diabetic kidney disease in adult patients with type 1 diabetes in Italy: the AMD-Annals initiative.
      ].

      1.2.1 Retinopathy

      In 2020, diabetic retinopathy (DR) has been confirmed to be a relevant cause of global blindness in subjects aged >50 years (0.86 million cases [0.59–1.23]) [
      GBD 2019 blindness and vision impairment collaborators; vision loss expert group of the global burden of disease study. Causes of blindness and vision impairment in 2020 and trends over 30 years, and prevalence of avoidable blindness in relation to VISION 2020: the right to sight: an analysis for the global burden of disease study.
      ], and an independent predictor of CVD mortality [
      • Xu X.H.
      • Sun B.
      • Zhong S.
      • Wei D.D.
      • Hong Z.
      • Dong A.Q.
      Diabetic retinopathy predicts cardiovascular mortality in diabetes: a meta-analysis.
      ]. In Europe, the prevalence of DR is 25.7%, higher in T1DM (mean annual incidence: 4.6%) [
      • Li J.Q.
      • Welchowski T.
      • Schmid M.
      • Letow J.
      • Wolpers C.
      • Pascual-Camps I.
      • et al.
      Prevalence, incidence and future projection of diabetic eye disease in Europe: a systematic review and meta-analysis.
      ] and reduced visual acuity due to DR has been confirmed to be more common among women than men (OR 2.52 [1.48–3.73]) [
      • Flaxman S.R.
      • Bourne R.R.A.
      • Resnikoff S.
      • Ackland P.
      • Braithwaite T.
      • Cicinelli M.V.
      • et al.
      Vision Loss Expert Group of the Global Burden of Disease Study. Global causes of blindness and distance vision impairment 1990-2020: a systematic review and meta-analysis.
      ]; pregnancy could accelerate disease progression [
      • Morrison J.L.
      • Hodgson L.A.
      • Lim L.L.
      • Al-Qureshi S.
      Diabetic retinopathy in pregnancy: a review.
      ]. Data on the relationship between sex and risk to develop DR appear contradictory: its prevalence, either in T1DM and T2DM, is higher in men [
      • Hammes H.P.
      • Kerner W.
      • Hofer S.
      • Kordonouri O.
      • Raile K.
      • Holl R.W.
      DPV-Wiss Study Group
      Diabetic retinopathy in type 1 diabetes-a contemporary analysis of 8,784 patients.
      ,
      • Kostev K.
      • Rathmann W.
      Diabetic retinopathy at diagnosis of type 2 diabetes in the UK: a database analysis.
      ], but studies of some years ago showed an opposite trend, although the clinical course of the disease was more severe in males [
      • Klein R.
      • Klein B.E.
      • Moss S.E.
      • Cruickshanks K.J.
      The Wisconsin Epidemiologic Study of diabetic retinopathy. XIV. Ten-year incidence and progression of diabetic retinopathy.
      ]. Besides the obvious role of sexual hormones, other potential sex-specific determinants of DR have been suggested: low albuminemia in men, high HbA1c, reduced eGFR and low uric acid in women. In T2DM, Italian data show a prevalence of DR below 10% [
      • Pugliese G.
      • Solini A.
      • Zoppini G.
      • Fondelli C.
      • Zerbini G.
      • Vedovato M.
      • et al.
      Renal insufficiency and cardiovascular events (RIACE) study group. High prevalence of advanced retinopathy in patients with type 2 diabetes from the renal insufficiency and cardiovascular events (RIACE) Italian multicenter study.
      ], markedly lower to that reported in Germany (20.12%) [
      • Hammes H.P.
      • Welp R.
      • Kempe H.P.
      • Wagner C.
      • Siegel E.
      • Holl R.W.
      • et al.
      Risk factors for retinopathy and DME in type 2 diabetes-results from the German/Austrian DPV database.
      ]. In the RIACE Study, no difference in sex-related prevalence of proliferative or non-proliferative DR was observed (Fig. 2), while maculopathy, although uncommon, was strongly linked to female sex, but not to HbA1c, hypertension, age, smoking habits, triglycerides [
      • Pugliese G.
      • Solini A.
      • Zoppini G.
      • Fondelli C.
      • Zerbini G.
      • Vedovato M.
      • et al.
      Renal insufficiency and cardiovascular events (RIACE) study group. High prevalence of advanced retinopathy in patients with type 2 diabetes from the renal insufficiency and cardiovascular events (RIACE) Italian multicenter study.
      ]; some years ago, the DAI study showed a prevalence of DR of about 18%, significantly higher in the female sex [
      • Avogaro A.
      • Giorda C.
      • Maggini M.
      • Mannucci E.
      • Raschetti R.
      • Lombardo F.
      • et al.
      Diabetes and Informatics Study Group, Association of Clinical Diabetologists, Istituto Superiore di Sanità. Incidence of coronary heart disease in type 2 diabetic men and women: impact of microvascular complications, treatment, and geographic location.
      ].

      1.2.2 Neuropathy

      Diabetic neuropathy (DN), a hard to diagnose microvascular complication shows a high prevalence, with about 50% of T1DM and T2DM individuals developing signs of the involvement of peripheral or nervous system after 10–15 years of disease [
      • Hussain N.
      • Adrian T.E.
      Diabetic neuropathy: update on pathophysiological mechanism and the possible involvement of glutamate pathways.
      ]. Only a few studies have evaluated the prevalence of DN according to sex. In the BARI 2D study, performed in Caucasians, prevalence of peripheral DN was 46.2% in women and 52.6% in men [
      • Pop-Busui R.
      • Lu J.
      • Lopes N.
      • Jones T.L.
      BARI 2D Investigators. Prevalence of diabetic peripheral neuropathy and relation to glycemic control therapies at baseline in the BARI 2D cohort.
      ]. Conversely, in Asia, DN prevails in women [
      • Liu Z.
      • Fu C.
      • Wang W.
      • Xu B.
      Prevalence of chronic complications of type 2 diabetes mellitus in outpatients – a cross-sectional hospital-based survey in urban China.
      ], confirming the relevant influence exerted by genetic and environmental factors. Regarding the relationship between sex and autonomic neuropathy, a metanalysis including mainly T1DM individuals pointed to a predictive value of QTc elongation of 3.8-fold higher in men [
      • Whitsel E.A.
      • Boyko E.J.
      • Siscovick D.S.
      Reassessing the role of QTc in the diagnosis of autonomic failure among patients with diabetes: a meta-analysis.
      ]. Sexual dysfunction, a common manifestation of autonomic neuropathy, is more common in males, although the presence of autonomic dysfunction is a good predictor of sexual dysfunction in T1DM women [
      • Hotaling J.M.
      • Sarma A.V.
      • Patel D.P.
      • Braffett B.H.
      • Cleary P.A.
      • Feldman E.
      • et al.
      Cardiovascular autonomic neuropathy, sexual dysfunction, and urinary incontinence in women with Type 1 diabetes.
      ]. In Italy, the more recent available epidemiological data refer to the 1990–2010 decades, coming from population studies, cohorts from general practitioners and diabetes outpatient clinics. The mean prevalence of polyneuropathy ranges between 20% and 28%; when stratifying by degree of certainty of the diagnosis (possible, probable or confirmed by instrumental procedure), the prevalence of the latter is about 36% [
      • Spallone V.
      Neuropatia diabetica in italia.
      ]. In such cohorts, prevalence was two-fold higher in females. Recently, a multicentre study has defined frequency and characteristics of painful DN diagnosed with instrumental methods, identifying the female sex as the only independent determinant of such clinical condition [
      • Truini A.
      • Spallone V.
      • Morganti R.
      • Tamburin S.
      • Zanette G.
      • Schenone A.
      • et al.
      Neuropathic Pain Special Interest Group of the Italian Society of Neurology. A cross-sectional study investigating frequency and features of definitely diagnosed diabetic painful polyneuropathy.
      ]. The specific role of sex- or gender-related variables on this disabling complication should be better addressed by future studies.

      1.2.3 Diabetic foot

      The clinical condition usually identified as “diabetic foot” is a complication with a multifactorial pathogenesis, determining a high degree of disability, associated with a high risk of hospitalization for CVD events and renal insufficiency, and encumbered by a high mortality rate [
      • Saluja S.
      • Anderson S.G.
      • Hambleton I.
      • Shoo H.
      • Livingston M.
      • Jude E.B.
      • et al.
      Foot ulceration and its association with mortality in diabetes mellitus: a meta-analysis.
      ]. Moreover, it determines a high direct and indirect economic burden to the national health systems. Its prevalence is higher in the male sex, although a higher mortality in women carrying DN is reported [
      • Aragón-Sánchez J.
      • Víquez-Molina G.
      • López-Valverde M.E.
      • Aragón-Hernández J.
      • Rojas-Bonilla J.M.
      • Murillo-Vargas C.
      Long-term mortality of a cohort of patients undergoing surgical treatment for diabetic foot infections. An 8-year follow-up study.
      ]. The occurrence of osteomyelitis does not seem to be sex-related [
      • Zhang L.X.
      • Wang Y.T.
      • Zhao J.
      • Li Y.
      • Chen H.L.
      Sex differences in osteomyelitis of the foot in persons with diabetes mellitus: a meta-analysis.
      ]. Several Italian centres have provided a relevant contribution to the knowledge in this field. A large observation performed on a Tuscany administrative database (165,650 subjects with diabetes, equally distributed for sex, followed up to 6 years) has also considered the pathogenesis of foot lesions. In patients carrying vascular diabetic foot, risk of atherosclerotic disease, chronic renal disease or death was significantly higher in males, except for stroke; in the presence of predominantly neuropathic foot lesions, risk was higher in women [
      • Seghieri G.
      • Policardo L.
      • Gualdani E.
      • Anichini R.
      • Francesconi P.
      Gender difference in the risk for cardiovascular events or mortality of patients with diabetic foot syndrome.
      ]. Another recent study retrospectively examined the hospitalization outcomes in the 2011–2015 years in a regional reference centre, identifying the male sex as the one characterized by a worse prognosis: recovering time and mortality rate (24.5% vs 16.1%, p = 0.02) were higher in males [
      • Iacopi E.
      • Pieruzzi L.
      • Riitano N.
      • Abbruzzese L.
      • Goretti C.
      • Piaggesi A.
      The weakness of the strong sex: differences between men and women affected by diabetic foot disease.
      ].

      1.2.4 NAFLD

      Non-alcoholic fatty liver disease (NAFLD) is the most frequent form of chronic liver disease in Western countries. It encompasses a broad spectrum of conditions ranging from hepatic steatosis to nonalcoholic steatohepatitis (NASH), cirrhosis and hepatocarcinoma especially when it occurs in diabetic subjects [
      • Targher G.
      • Byrne C.D.
      Nonalcoholic fatty liver disease: a novel cardiometabolic risk factor for type 2 diabetes and its complications.
      ,
      • Targher G.
      • Lonardo A.
      • Byrne C.D.
      Nonalcoholic fatty liver disease and chronic vascular complications of diabetes mellitus.
      ].
      The relationship between NAFLD and T2DM is so tight and complex that several Authors have suggested that this condition should be added to the list of T2DM long-term complications, recently naming it “MAFLD, metabolic dyscfunction-associated fatty liver disease”.
      Thus, NAFLD exacerbates hepatic insulin resistance and increases the risk of developing T2DM, worsens glycemic control and contributes to the pathogenesis of long-term T2DM complications, including CVD and CKD [
      • Targher G.
      • Byrne C.D.
      Nonalcoholic fatty liver disease: a novel cardiometabolic risk factor for type 2 diabetes and its complications.
      ,
      • Targher G.
      • Lonardo A.
      • Byrne C.D.
      Nonalcoholic fatty liver disease and chronic vascular complications of diabetes mellitus.
      ].
      A growing body of data indicate sex/gender differences in the occurrence of NAFLD and its progression, and several Italian studies have contributed to this field [
      • Targher G.
      • Byrne C.D.
      Nonalcoholic fatty liver disease: a novel cardiometabolic risk factor for type 2 diabetes and its complications.
      ,
      • Targher G.
      • Lonardo A.
      • Byrne C.D.
      Nonalcoholic fatty liver disease and chronic vascular complications of diabetes mellitus.
      ,
      • Balakrishnan M.
      • Patel P.
      • Dunn-Valadez S.
      • Dao C.
      • Khan V.
      • Ali H.
      • et al.
      Women have a lower risk of nonalcoholic fatty liver disease but a higher risk of progression vs men: a systematic review and meta-analysis.
      ].
      A recent meta-analysis [
      • Balakrishnan M.
      • Patel P.
      • Dunn-Valadez S.
      • Dao C.
      • Khan V.
      • Ali H.
      • et al.
      Women have a lower risk of nonalcoholic fatty liver disease but a higher risk of progression vs men: a systematic review and meta-analysis.
      ] showed that, in the general population, women had a 19% lower risk of NAFLD, a similar risk of NASH and 37% higher risk of advanced fibrosis than men, with age being a modifier of the effect, since NASH and advanced fibrosis were more severe in older women. Sex-related differences in obesity prevalence and its phenotypic distribution, and the role of sex-hormones and their decline after menopause, may have played a relevant role in determining these differences [
      • Lonardo A.
      • Suzuki A.
      Sexual dimorphism of NAFLD in adults. Focus on clinical aspects and implications for practice and translational research.
      ,
      • Lonardo A.
      • Nascimbeni F.
      • Ballestri S.
      • Fairweather D.
      • Win S.
      • Than T.A.
      • et al.
      Sex differences in NAFLD: state of the art and identification of research gaps.
      ,
      • Ballestri S.
      • Nascimbeni F.
      • Baldelli E.
      • Marrazzo A.
      • Romagnoli D.
      • Lonardo A.
      NAFLD as a sexual dimorphic disease: role of gender and reproductive status in the development and progression of nonalcoholic fatty liver disease and inherent cardiovascular risk.
      ]. Estrogens seem to exert direct anti-fibrotic effects in the liver, thus protecting against NASH, as suggested by studies in patients with chronic viral hepatitis [
      • Shimizu I.
      • Kohno N.
      • Tamaki K.
      • Shono M.
      • Huang H.W.
      • He J.H.
      • et al.
      Female hepatology: favorable role of estrogen in chronic liver disease with hepatitis B virus infection.
      ,
      • Baden R.
      • Rockstroh J.K.
      • Buti M.
      Natural history and management of hepatitis C: does sex play a role?.
      ]. However, literature data suggest that in metabolic liver disease the risk of advanced fibrosis is comparable in men and women, who show an accelerate progression after menopause.
      Italian studies also contributed to the knowledge in this field. A monocentric Italian study found that T2DM subjects with no-virus nor alcohol-related persistently elevated liver enzymes overtime (a surrogate marker of metabolic hepatocellular damage) were more likely to be men, younger and to have a shorter diabetes duration [
      • Giandalia A.
      • Romeo E.L.
      • Ruffo M.C.
      • Muscianisi M.
      • Giorgianni L.
      • Forte F.
      • et al.
      Clinical correlates of persistently elevated liver enzymes in type 2 diabetic outpatients.
      ].
      In the AMD Annals data from 94,577 T2DM patients, the prevalence of NAFLD by using the Fatty Liver Index (FLI) was 59.6%, and FLI-NAFLD was associated with impairment in renal function, higher albumin excretion, HbA1c and blood pressure, lower HDL cholesterol, and poorer quality of care [
      • Forlani G.
      • Giorda C.
      • Manti R.
      • Mazzella N.
      • De Cosmo S.
      • Rossi M.C.
      • et al.
      AMD-Annals Study Group
      The burden of NAFLD and its characteristics in a nationwide population with type 2 diabetes.
      ].
      The AMD Annals data also showed that this condition is partly dynamic, with about 5% of diabetic patients potentially recovering from NAFLD every year. Analysis of predictive factors for NAFLD showed that younger male patients with insulin resistance or organ damage are at higher risk of presenting NAFLD at baseline, developing the disease within three years, and having a lower probability of disease regression. In the same cohort, the male sex was associated with a greater risk of more advanced fibrosis, as determined by Fibrosis 4 [FIB-4] score at baseline, while the FIB-4 score at three years was associated with lower values of baseline renal function, LDL, and BMI and FIB-4 score [
      • Giorda C.B.
      • Forlani G.
      • Manti R.
      • Mazzotti A.
      • De Cosmo S.
      • Rossi M.C.
      • et al.
      AMD-Annals Study Group
      Trend over time in hepatic fibrosis score in a cohort of type 2 diabetes patients.
      ].
      Italian data from the DARWIN-T2D network of the Italian Diabetes Society (SID) [
      • Morieri M.L.
      • Vitturi N.
      • Avogaro A.
      • Targher G.
      • Fadini G.P.
      DARWIN-T2D Network of the Italian Diabetes Society
      Prevalence of hepatic steatosis in patients with type 2 diabetes and response to glucose-lowering treatments. A multicenter prospective study in Italian specialistic care.
      ] found that MAFLD, diagnosed using the HSI, hepatic steatosis index, and validated against ultrasound in a subgroup of patients, affected about 75% of T2DM patients and was associated with macroangiopathy and nephropathy.
      Several studies reported on the association between NAFLD and CKD and a recent meta-analysis on 13 studies (1,222,032 individuals) reported that NAFLD is significantly associated with about 1.45-fold increase of long-term incidence of clinically meaningful renal impairment (CKD stage ≥3) [
      • Mantovani A.
      • Petracca G.
      • Beatrice G.
      • Csermely A.
      • Lonardo A.
      • Schattenberg J.M.
      • et al.
      Non-alcoholic fatty liver disease and risk of incident chronic kidney disease: an updated meta-analysis.
      ].
      Also mortality from chronic liver disease is higher in T2DM subjects, and a study on a large set of T2DM patients (54.6% men) from the Veneto Region, in Northern Italy, showed a standardized mortality ratio of 2.47 (95% CI = 2.19–2.78) in men and 2.70 (2.24–3.23) in women, largely attributable to NAFLD [
      • Zoppini G.
      • Fedeli U.
      • Gennaro N.
      • Saugo M.
      • Targher G.
      • Bonora E.
      Mortality from chronic liver diseases in diabetes.
      ].

      2. Conclusions

      Italian data obtained on large populations of T1DM and T2DM subjects show sex/gender difference in the epidemiology of diabetes and its complications. For macrovascular disease, data appear consistent with the international literature: also in Italy, T2DM women showed a higher diabetes-related CVD risk, when compared to men. Such a landascape is destined to get worse when considering the actual more stringent targets recommended for T2DM patients [
      • Pintaudi B.
      • Scatena A.
      • Piscitelli G.
      • Frison V.
      • Corrao S.
      • Manicardi V.
      • et al.
      Clinical profiles and quality of care of subjects with type 2 diabetes according to their cardiovascular risk: an observational, retrospective study.
      ]. For the other chronic complications, the observations of a prevailing non-albuminuric phenotype of CKD, as well as of painful polyneuropathy in women and the differences in the severity of NAFLD, have received robust support from Italian contributions.

      2.1 Implications for clinical practice and future perspectives

      Available data on sex and gender differences in diabetes from international and Italian studies may have important implications for clinical practice, starting from the diagnosis of the disease. Thus, prediabetes forms are differently prevalent in men and women, and women at early diabetes stages, including prediabetes, already carry a higher CVD risk factors burden than men.
      Moreover, progress in reducing T2DM mortality has been more effective in men than in women [
      • Gregg E.W.
      • Gu Q.
      • Cheng Y.J.
      • Narayan K.M.
      • Cowie C.C.
      Mortality trends in men and women with diabetes, 1971 to 2000.
      ], although this picture has improved in recent years, suggesting that clinicians should be aware of the greater risk of severe consequences of CVD in women. The high risk of stroke and heart failure occurrence should also be acknowledged in women with both T2DM and T1DM. Moreover, greater attention should be paid to the management of major CVD risk factors and to the recognition of unconventional clinical presentation of CVD symptoms, to tempestively initiate appropriate medical or surgical therapies.
      With regards to microvascular complications, the acknowledgment of differences in the prevalence of specific renal phenotypes is important for the diagnosis and management of DKD, and the enormous burden of painful neuropathy should also be recognized in women with diabetes. The higher burden of diabetic foot and amputations among T2DM men is another fundamental aspect that merits consideration.
      Also, the different adverse impact of sex on NAFLD deserves particular attention, with women being more prone to advanced liver disease, and this should ideally be addressed by appropriate specialistic liver counselling.
      Unfortunately, research on sex and gender differences in diabetes and its complications is still limited and this implies that current guidelines do not have sufficient evidence to release sex-specific recommendations (Table 1). Notably, women are still largely under-represented in clinical trials, which renders the field of efficacy and safety of current CVD treatments still unsufficiently explored in females.
      Table 1Future agenda in sex- and gender-specific diabetes research.
      Causality association studies
      Use of appropriate animal models and translational research
      Studies on sex-differences in the pathophysiology, including the complex interplay of genes, epigenetic, hormones and lifestyle
      Appropriate methodology for sex- and gender-specific analysis in clinical studies
      RCTs proving evidence of sex-specific differences by adequate intervention and study design
      Adequate inclusion of women in clinical studies
      Addition of gender-related variables in clinical studies
      Efficacy and tolerability of drugs in men and women
      Intervention studies to overcome hormones default
      Inclusion of pre- and post-menopausal women in clinical trials
      Moreover, while the role of sex differences in diabetes has been increasingly recognized and several Authors, including many Italian researchers, have contributed to this field, the large gap in the research area of gender–related differences should be still filled up. We should consider that gender is an equally important variable as biological sex in human health and diseases, since it may influence the attitudes and behaviours of societies, clinicians, and patients [
      • Pelletier R.
      • Choi J.
      • Winters N.
      • Eisenberg M.J.
      • Bacon S.L.
      • Cox J.
      • et al.
      Sex differences in clinical outcomes after premature acute coronary syndrome.
      ,
      • Pelletier R.
      • Ditto B.
      • Pilote L.
      A composite measure of gender and its association with risk factors in patients with premature acute coronary syndrome.
      ] potentially influencing patient's risk exposure, adherence to treatments and, overall, the use of the health-care system, including access to health care and help-seeking behaviours. Gender may also differently trigger clinicians'attitudes and therapeutic approaches [
      • Mauvais-Jarvis F.
      • Bairey Merz N.
      • Barnes P.J.
      • Brinton R.D.
      • Carrero J.J.
      • DeMeo D.L.
      • et al.
      Sex and gender: modifiers of health, disease, and medicine.
      ,
      • Shannon G.
      • Jansen M.
      • Williams K.
      • Cáceres C.
      • Motta A.
      • Odhiambo A.
      • et al.
      Gender equality in science, medicine, and global health: where are we at and why does it matter?.
      ].
      The crucial role of gender-related variables in the field of CVD emerged from a small number of studies demonstrating that women with myocardial infarction often underestimate their risk and seek consultation later in comparison to men [
      • Regitz-Zagrosek V.
      • Oertelt-Prigione S.
      • Prescott E.
      • Franconi F.
      • Gerdts E.
      • Foryst-Ludwig A.
      • et al.
      EUGenMed Cardiovascular Clinical Study Group
      Gender in cardiovascular diseases: impact on clinical manifestations, management, and outcomes.
      ,
      • Mosca L.
      • Barrett-Connor E.
      • Wenger N.K.
      Sex/gender differences in cardiovascular disease prevention: what a difference a decade makes.
      ]; mortality one year after an acute coronary event was more strongly associated with gender than with biological sex, and gender better predicted CVD risk factors control [
      • Pelletier R.
      • Choi J.
      • Winters N.
      • Eisenberg M.J.
      • Bacon S.L.
      • Cox J.
      • et al.
      Sex differences in clinical outcomes after premature acute coronary syndrome.
      ,
      • Pelletier R.
      • Ditto B.
      • Pilote L.
      A composite measure of gender and its association with risk factors in patients with premature acute coronary syndrome.
      ].
      All these issues should be part of our research agenda in the next few years, since updated epidemiologic and prognostic information coming from sex- and gender-specific studies are still urgently needed.

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