Diabetes has been recognized as a strong risk factor for cardiovascular complications, more so among females than males. Compared with only a twofold increase in males, diabetes increases the risk of cardiovascular disease by nearly fourfold in females. Evidence points to less favorable cardiovascular risk profiles and more adverse CVD risk factors and a faster development of these complications after initial diagnosis of type 2 diabetes in females compared with males. In addition, females are reported to have poorer outcomes after experiencing a cardiovascular event such as a MI, suggesting that disparities in the diagnosis and treatment of cardiovascular disease may lead to worsened outcomes for females. A recent meta-analysis of prospective cohort studies to assess the association between diabetes mellitus and the risk for major cardiovascular outcomes and all-cause mortality in females compared with men concluded that females with diabetes have a high risk for coronary heart disease, stroke, cardiac death, and all-cause mortality compared with males with diabetes. Females with diabetes were found to have a 58% and 13% greater risk of coronary heart disease and all-cause mortality, respectively, compared with males with diabetes. Despite extensive research in this area, the evidence explaining the etiologies and mechanisms underlying this disparity remain unclear. It has been postulated that females experience a greater increase in cardiovascular risk as they transition from a state of normoglycemia to one of hyperglycemia in diabetes due to sex differences in body anthropometrics, body hormones, fat storage, and body fat distribution. CVD also often presents later in life for females, and unfortunately, this occurs during a time when they are more likely to be diagnosed with multiple comorbid conditions that include type 2 diabetes. Cardiovascular conditions that include coronary artery disease, peripheral vascular disease, and strokes occur in higher rates among females with diabetes compared with females without diabetes. Evidence shows that the longitudinal burden and cumulative exposure of cardiovascular disease risk factors from childhood to adulthood may contribute to the greater burden of CVD among females in adulthood who develop type 2 diabetes ; however, additional research in this area is needed. This is especially important given females with diabetes develop strokes at a younger age compared with males with diabetes and are more likely to have coronary artery disease compared with females without diabetes.

Sex differences in cardiovascular consequences of diabetes such as complications, ischemic heart disease, and stroke have been demonstrated in the literature. In the general population, being a female is cardioprotective, lending to a lower cardiovascular risk profile in females compared with males. However, in the presence of type 2 diabetes, this cardioprotection for females is attenuated. A growing body of evidence has demonstrated that females with diabetes have a higher relative risk of cardiovascular disease (i.e., incident and fatal coronary heart diseases, stroke, etc.) compared with males with diabetes and also compared with men and females without diabetes. Differences in prescribing practices and the use of medications for cardiovascular disease management and treatment, the clustering of cardiovascular risk factors, and the disproportionate burden of other novel and emergent risk markers have been identified as causes for a higher relative risk of cardiovascular disease in females with diabetes. In addition, some studies have shown that the relative risk of ischemic heart disease due to diabetes can be nearly 50% higher among females with diabetes compared with males with diabetes, and the relative risk of stroke has been reported as 27% higher for females with diabetes than males with diabetes. While one systematic review reports limited evidence on the effects of diabetes on microvascular complications, one meta-analysis reports a 19% higher relative risk of vascular dementia among females with diabetes compared with males with diabetes. The reasons for these disparities in vascular complications between males and females remain unclear; however, evidence suggests the uptake and provision of healthcare is a plausible explanation and that aggressive risk factor management is needed for females with diabetes. Finally, some evidence points to females being less likely to be assessed for cardiovascular risk factors such as smoking ; therefore additional screening for diabetes-related complications in both men and females with diabetes is warranted. de Jong and colleagues suggest the higher relative risk of cardiovascular consequences conferred to females cannot be attributed solely to disparities in risk factor assessment and screening, since other factors including treatment and adherence centered around the uptake and provision of healthcare should also be considered. Therefore there is an urgent need for developing risk assessment strategies and therapeutic interventions that are sex and gender specific to prevent further cardiovascular consequences.

Obesity has been identified as the most prominent risk factor for type 2 diabetes. Compared with males with diabetes, significantly more females with type 2 diabetes have obesity, which often manifests as a higher body mass index and an increased central adiposity. Compared with males, females gain more weight to develop insulin resistance, which is associated with a greater reduction in protection from cardiovascular risk, increased endothelial dysfunction, more low-grade inflammation, and elevated factors resulting in hypercoagulability. Sex differences have also been observed in the relative risk of CVD related to measures of obesity such as waist circumference and waist-to-hip ratio between adults with and without diabetes; however, females with diabetes have the worst outcomes in these areas even in comparison to males.

Finally, females diagnosed with gestational diabetes comprise a unique population group that may be at increased risk for cardiovascular complications. A Canadian systematic review of more than 5,390,000 females who experienced approximately 101,000 cardiovascular events showed an increased risk for CVD (RR, 1.98; 95% CI, 1.57–2.50) for up to 10 years postpartum among females with gestational diabetes, who subsequently developed type 2 diabetes. Similar to the short-term diabetes exposure of gestational diabetes, hypertensive disorders of pregnancy and polycystic ovarian syndrome are both associated with a higher increase for type 2 diabetes and CVD risk factors due to females reportedly having higher rates of overweight/obesity, including central adiposity and dyslipidemia.

Racial/ethnic disparities are consistently reported in the age of diagnosis with diabetes, HbA _1c levels, body composition, and smoking, all which have been noted to influence development of CVD in adults with diabetes. For example, African Americans were more likely to be diagnosed with diabetes in younger age groups (18–39 and 40–49 years, compared with < 50), suggesting that early-onset type 2 diabetes may play a role in differences in risk of CVD events in African Americans. Among those with diabetes, MI rates were similar across most racial/ethnic groups, except Asians who had a lower rate of MI. In addition, all racial ethnic groups saw declines in overall rate of MI over time. Stroke rates, however, differed by racial/ethnic group, with non-Hispanic Blacks with diabetes having the highest rate of stroke and seeing no decline over time. In comparison, stroke rates fell in non-Hispanic Whites, Asian, and Hispanic adults with diabetes. Heart failure rates also declined across all racial/ethnic groups except Asians; however, the rate of heart failure remained twice as high for non-Hispanic Black adults with diabetes. Finally, non-Hispanic Blacks are at higher risk of end-stage renal disease (ESRD) compared with non-Hispanic Whites, despite similar access to care and control for demographic differences, clinical conditions, medications, and quality-of-care measures. Some differences in systolic blood pressure existed during follow-up in this group; however, these differences did not explain disparities in ESRD, suggesting work is needed to identify how to decrease disparity gaps noted in cardiovascular consequences of diabetes.

A large body of recent research has focused on understanding disparities in cardiovascular outcomes for Asian adults with type 2 diabetes. Studies in the United Kingdom highlight the importance of considering different ethnicities within the larger Asian population, with South Asian ethnicities noted for a higher risk of CVD compared with Whites and other Asian ethnicities. While diabetes was associated with a 5% increase in fatal and nonfatal CVD events in White Europeans, it was associated with a 28% increased risk in adults of South Asian ethnicity. This increased risk was primarily driven by increased risk of MI. Malay and Asian Indians with diabetes had a higher CVD risk compared with Chinese adults with diabetes in a study conducted in Singapore. Significant differences were also noted in risk profiles including a higher HbA _1c and increased risk of cardiovascular events at a younger age for South Asian adults compared with White Europeans in the United Kingdom. In a study conducted in Ontario, Canada, Chinese adults with diabetes developed fewer cardiovascular complications than Whites; however, the risk for South Asian adults with diabetes was similar to Whites. Differences also existed for complications and mortality, with South Asians showing a lower risk for mortality despite a similar risk for cardiovascular complications. A different pattern existed for a stroke, with Chinese adults showing a similar risk as white patients and South Asians with diabetes having a lower risk than Whites with diabetes. Interethnic differences within Asian populations are likely to exist based on differences in risk profiles (Buljubasic 2020). When using ethnic-specific BMI cutoffs, South Asian adults were more likely to have excess visceral fat associated with increased metabolic risk. Using a matched cohort of Dutch White and Chinese adults with diabetes, Bulijubasic found lower levels of cholesterol (LDL and total cholesterol), cardiac Troponin T, and C-reactive protein in Chinese adults 1-year postacute coronary syndrome diagnosis (Buljubasic 2020). However, in a study conducted in Kuala Lumpur, Malaysia, Chinese ethnicity was associated with a higher risk of asymptomatic left ventricular diastolic dysfunction among adults with diabetes and no known heart disease, compared with other Southeast Asian ethnicities. Differences also exist for macro- and microvascular complications of diabetes by Asian ethnicity, with higher risk for South Asians compared with whites. South Asians with diabetes had a higher prevalence of ischemic heart disease and nephropathy, despite having lower lipid levels. In addition, Pacific Islanders showed a higher prevalence of retinopathy and reduced renal function compared with whites. In a study conducted in Scotland, adults of Pakistani ethnicity developed diabetes earlier, had a higher HbA _1c , and had a higher risk of developing CVD (ischemic heart or cerebrovascular disease) compared with whites, while Chinese had a lower risk. The same incidence of CVD in Pakistanis occurred 10 years earlier than for whites or Chinese. More work is needed to understand if the differences are the result of access to healthcare, medication use patterns, medication adherence, management of cardiovascular risk factors over time, or other health behaviors.

To tailor interventions, some researchers have sought to test the utility of phenomapping groups with a higher risk. In one study using baseline data from the Action to control cardiovascular risk in diabetes (ACCORD) and Look Action for health in diabetes (AHEAD) trial cohorts, variables were clustered into those with the highest burden of comorbidities and complications, those with intermediate burden and complications, and those with the fewest comorbidities and complications. Those in the group with the fewest comorbidities and complications responded most favorably to a reduction in risk through the interventions. Racial/ethnic differences in unique subgroups have been observed, which may result in a differential risk of CVD over time. In a separate study using data from the National Health and Nutrition Examination Survey, the authors identified four primary phenotypes: diabetes related to aging, severe obesity, severe hyperglycemia, and young adulthood onset. Across all racial/ethnic groups, over half of individuals fit into a subgroup related to aging. One-third of Hispanic individuals were best fit into the severe hyperglycemia subgroup, whereas non-Hispanic Whites and non-Hispanic Blacks fit more often into the severe obesity subgroup. The subgroup related to young adulthood-onset diabetes had worse profiles for complications and worse lipid profiles, compared with the older age-related subgroup, but had similar prevalence across racial/ethnic groups. Further research is needed to understand how diabetes phenotypes can be used to optimize treatment strategies and minimize cardiovascular complications.

Obesity and body composition are a common area of focus to explain racial/ethnic differences in CVD risk. In a longitudinal study conducted in the United Kingdom of adults with diabetes and no CVD at baseline, whites with normal weight developed CVD a half year earlier compared with obese whites, but the risk was similar for normal weight and obese African Caribbean or South Asian adults with diabetes. Further, obese African Caribbean adults were more likely to develop CVD compared with overweight African Caribbean adults by 1.2 years, but there were no differences between obese and overweight whites. An important confounder in this study was smoking, another CVD risk factor, which was more prevalent in the normal weight groups. Many studies highlight the importance of considering metabolic markers beyond BMI in determining risk. For example, abdominal obesity, a known risk factor for CVD independent of BMI differs by race/ethnicity. In one study of US adults, non-Hispanic Black females and Mexican American females had the highest prevalence of abdominal obesity compared with other race/ethnicities. In a second study conducted in the United Kingdom, South Asians were noted to have a higher risk of CVD events at a similar BMI and higher levels of abdominal fat at the same BMI compared with white individuals. As accumulation of visceral fat is associated with higher CVD risk, this may explain some of the disparities in CVD outcomes for South Asian adults with diabetes. Recent research also suggests that metabolically healthy obese individuals may be at a decreased risk of developing CVD, while metabolically unhealthy normal weight individuals may have increased risk for CVD and total mortality. Non-Hispanic Blacks have a higher prevalence of having metabolically healthy obesity compared with non-Hispanic Whites. As a result, metabolic abnormalities and obesity may need to be considered on a continuum, with metabolically healthy individuals at the lower-risk end and likely to progress to an unhealthy phenotype over time.

Though the risk for diabetes increases with age, there is far less research investigating age-related disparities compared with disparities by sex or race/ethnicity. In a study conducted across a large, integrated primary care system in Spain, the prevalence of cardiovascular complications increased with age, while the relative importance of traditional risk factors such as hypertension or dyslipidemia stayed the same or decreased with advancing age. In addition, the only significant differences in CVD mortality were age over 80, higher Charlson score, presence of cognitive impairment, and no statin treatment. Based on these results, treatment for older adults with diabetes should be adapted to consider not only lowering of cardiovascular risk but also remaining life expectancy, functional and cognitive impairments, and availability of caregiver support. Finally, among older adult populations, females tend to demonstrate more adverse cardiovascular risk factor profiles compared with males, which suggests investigation of interactions between age and other sociodemographic factors may be of interest for future work.

Sex differences in risk factor control have been well studied and documented; however, the results remain inconclusive in terms of hemoglobin A1c (HbA _1c ), SBP, diastolic blood pressure (DBP), and low-density lipoprotein cholesterol (LDL-C) control by sex. For differences in hypertension (SBP and DBP) and dyslipidemia, mainly LDL-C, differences between males and females may be due to declines in estrogen levels and signaling after menopause. In addition, it has been shown that females are less likely to be prescribed medications such as aspirin, statins, and angiotensin-converting enzyme inhibitors in comparison to males and more likely to be prescribed diuretics. Other evidence suggests that biological differences and differences in treatment adherence between females and males could contribute to sex differences in diabetes-conferred cardiovascular complications. The duration of diabetes has been studied in some populations as a plausible cause for sex differences in cardiovascular consequences; however, it has not been shown to account for the observed differences between females and males and has not been as useful in understanding higher cardiovascular risk profiles among females with diabetes. Despite these theories, additional research is needed to understand the sex differences in CVD risk factors and the underlying mechanisms.

When considering biological differences and differences in treatment adherence between females and males, dyslipidemia is a cardiovascular risk factor worth exploring more. Dyslipidemia in type 2 diabetes often manifests as a cluster of abnormalities that include elevated triglycerides, decreased high-density lipoprotein cholesterol, and increased LDL-C. Typically occurring after 60 years of age, females with diabetes experience these abnormalities more frequently than their male counterparts. In addition, females with type 2 diabetes have higher LDL-C levels that are more likely to be poorly controlled ; however, they are less likely to receive statin therapy or any other lipid-lowering medications compared with males with diabetes. Some evidence suggests that these disparities may be partially attributed to females with diabetes conferring higher LDL-C levels compared with males with diabetes or that factors such as side effects that are less tolerable by females or the associated costs of statin medications could lead to suboptimal adherence among females compared with males.

Females with type 2 diabetes have been underrepresented in clinical trials focused on understanding the effect of therapies such as statins and newer diabetes medications on the development of cardiovascular disease, where adherence tends to be poorer among females. To address this gap, initiatives dedicated to increasing the participation by females with type 2 diabetes in clinical trials should be explored and implemented. In addition, research should focus on understanding the differential impact of medication therapies and interventions by sex on cardiovascular disease development in diabetes. Additional evidence is warranted to understand the biological and physiological mechanisms associated with differences, and work investigating the impact of more aggressive management of cardiovascular risk factors in females or sex-specific therapeutic guidelines would help inform clinical care.

Significant differences exist by race/ethnicity in cardiovascular risk factor control in adults with diabetes. Based on a study comparing national US data from 1988 to 1994 and 1999 to 2008, control of CVD risk factors in adults with diabetes improved over time; however, racial/ethnic disparities increased over the same period. African Americans and Mexican Americans with diabetes were over 50% more likely to have poor glycemic control compared with non-Hispanic White adults. There were no significant differences in blood pressure or total cholesterol between the racial/ethnic groups, and Mexican Americans with diabetes were less likely to smoke compared with non-Hispanic Whites. Similarly, in a study of low-income adults with diabetes in the United States, African Americans were less likely to meet individual or combined treatment goals. In a cohort of US veterans with diabetes, it was also found that non-Hispanic Blacks had a 2-fold-higher odds and Hispanics 1.5-fold higher odds of having at least one risk factor out of control compared with non-Hispanic Whites. When considering having multiple risk factors, non-Hispanic blacks were 1.4, 3.6, and 7.7 times more likely to have one, two, or three risk factors out of control. Hispanics similarly were 1.2, 2.3, and 4.1 times more likely to have one, two, or three risk factors out of control compared with non-Hispanic Whites. In the US Diabetes Collaborative Registry, only 14.7% of African Americans met HbA _1c , blood pressure, LDL, and smoking targets, compared with 22.5% of non-Hispanic Whites. These differences were not explained by access to care, as in an insured sample, racial/ethnic differences were more apparent in HbA _1c . Asian Indians, Filipinos, Hispanic, and African American adults all showed worse control of HbA _1c compared with non-Hispanic Whites. While many studies group individuals of Hispanic/Latino descent into one group, an analysis of data from the ACCORD trial noted differences among Hispanic groups in glucose control. In this sample, all Hispanic groups were less likely to achieve glucose control compared with non-Hispanic Whites.

Racial disparities are also consistently noted in Indigenous populations, with Native American, First Nations, and Australian Aboriginal adults with diabetes experiencing higher rates of cardiovascular disease and poorer risk factor control compared with their non-Indigenous counterparts. Using data from the California Health Interview Survey, Harjo et al. found that Native Americans with diabetes had a higher prevalence of high cholesterol, compared with non-Hispanic Whites, similar prevalence of hypertension, and a higher likelihood of being a current smoker. Using linked administrative datasets from 1996 to 2015, Chu et al. found declines in incidence of cardiac events among First Nations people with diabetes over time. However, these rates remained higher than other racial groups. Declines in incidence were hypothesized to result from increases in coronary artery revascularization procedures and prescriptions for cardioprotective medications within First Nations people over the same period. In a study of Australian Aboriginal and Anglo-Celt adults with diabetes, both groups showed improvement in HbA _1c over time; however, the gap between groups persisted with 70.6% of Aboriginal adults compared with 37.7% of Anglo-Celt adults having an HbA _1c over 7%. In addition, fewer Aboriginal patients received antihypertensive treatment or lipid-modifying treatment and were more likely to have retinopathy, microalbuminuria, and PAD compared with Anglo-Celt patients. The higher rates of retinopathy and microalbuminuria are likely a result of worse glycemic control in this group, but the younger age of diabetes diagnosis in Aboriginal adults could also play a role. Additionally, Aboriginal adults had significantly higher smoking rates, which may be a driver of disparities in macrovascular complications such as PAD. As PAD is independently associated with risk of cardiac mortality, this may explain the higher rate of death in Aboriginal adults with diabetes. Access to healthcare is an important consideration for indigenous populations as they are often located in more remote locations with fewer healthcare services. In a study of First Nations people in Ontario, Chu et al. found that while rates of admissions to the hospital for MI and heart failure decreased, the disparity between First Nations people and other adults remained. They noted that current approaches to services are insufficient to close the disparity gap, and poor postdischarge management resulting from poor primary care access may contribute to the ongoing gap. First Nations people face structural barriers such as limited access to facilities, higher levels of food insecurity, and more frequent negative interactions with healthcare providers, which must be addressed to make a meaningful change in outcomes.

Though potential overtreatment in adults aged 65 and older has received significant attention, studies continue to indicate HbA _1c between 6% and 6.9% results in optimal outcomes regardless of age. Individuals aged 65 and older have a higher incidence of all-cause and CVD mortality compared with younger age groups. Additionally, adjusted risk differences associated with increasing HbA _1c were larger in older individuals compared with younger, with each 1% increment of HbA _1c above 7% associated with higher short- and long-term all-cause and CVD mortality, regardless of age. It will be important for future research to investigate the risks and benefits of more aggressive treatment in older adults, including a collection of the impacts of different treatment regimens on quality of life for older adults and caregivers.

Based on the difficulty in preventing comorbidities once diabetes is clinically manifest, the focus is shifting to identifying individuals at high risk for diabetes. While a large body of evidence exists regarding the relationship between diabetes and CVD risk, less work has been conducted in individuals with prediabetes. The Centers for Disease Control and Prevention (CDC) estimates that over one-third of US adults have prediabetes, based on their fasting glucose or HbA _1c levels. Of this number, only 19% have been told by a health professional they have prediabetes and therefore may be unaware of their increased risk of developing type 2 diabetes. A higher proportion of males have prediabetes, compared with females (41.9% in males compared with 34.3% in females), and females are estimated to be more often aware of the diagnosis (20.9% in females compared with 17.4% in males). It is worth noting that research has been conducted to assess cardiovascular risk profiles in females with prediabetes compared with males with prediabetes. Similar data have been observed as for diabetes with females with prediabetes having worse cardiovascular risk profiles; however, more extensive research in this area is warranted. As with diabetes, the prevalence of prediabetes increases with age; however, disparities by race/ethnicity are less pronounced than in diabetes.

Due to the similar pathophysiology, the leading cause of morbidity and mortality in both diabetes and prediabetes is CVD. Lifestyle modification is a critical aspect of cardiovascular risk reduction in adults with prediabetes, including physical activity and nutrition. In a pilot study investigating the use of the Diabetes Prevention Program to lower Atherosclerotic cardiovascular disease (ASCVD) risk in adults with prediabetes, Kucera et al. found preliminary evidence for a decrease in cardiovascular risks using the nonpharmacological strategy. In addition, psychosocial factors may influence prediabetes outcomes similar to diabetes. Elevated depressive symptoms were associated with a higher risk of all-cause and CVD mortality, with the strongest magnitude of effect in individuals with prediabetes, compared with those with diabetes. This aligns with recommendations from the American Diabetes Association to provide depression screening for those at high risk of developing diabetes. More work is needed in this area to understand how best to identify and engage individuals with prediabetes to reduce their risk of both diabetes and CVD complications.

A growing body of work highlights the importance of considering the role of structural racism, structural inequalities, and social determinants of health when developing strategies to reduce CVD risk in individuals with diabetes. Social determinants of health are defined as the conditions in which people are born, grow, live, work, and age, which shape their health. These include factors like socioeconomic status, neighborhood and physical environment, social support networks, and access to healthcare. Social determinants also encompass more upstream factors that occur antecedent to social risks, including structural racism and structural inequalities. Racism is increasingly recognized as an upstream social determinant of CVD health that must be addressed. However, while a broad literature base highlights the influence of social determinants of health on outcomes in adults with diabetes, work is needed to understand the mechanisms of this relationship, interventions to improve the outcomes and minimize complications, and policies to target structural inequalities.

Socioeconomic status (SES) is commonly investigated, with conflicting results depending on where studies were conducted. For example, in a study conducted in South Africa, CVD comorbidity in adults with diabetes was more likely in those with higher education levels. This differs from studies conducted in North American and European countries, which found higher CVD risk in those with lower SES. Higher levels of material deprivation in a Canadian sample of adolescents with type 1 diabetes were associated with poorer glycemic control, less physical activity, and higher rates of smoking. Similarly, individuals in the two lowest-income quintiles in a study conducted in Sweden had two to three times higher risk of CV events compared with those in the highest-income quartile. The study conducted in South Africa did find a lower likelihood of reporting CVD comorbidities in adults with diabetes who had a high income, which is similar to other countries, and may reflect access to healthcare services and resources for diabetes management. The accumulation of cardiovascular risk over time is hypothesized to result in faster vascular changes, including arterial stiffness. More material deprivation has been associated with increased vascular stiffness, suggesting more vascular dysfunction. While most work to date focuses on objective measures of SES, such as education, employment, and income, one study found differential associations between objective and subjective measures of SES and CVD risk, highlighting the importance of an individual’s perspective of their social status. In this study, higher income was associated with lower LDL, and employment was associated with lower HbA _1c and higher LDL. Meanwhile, both the lowest and highest levels of subjective social status were significantly associated with higher diastolic blood pressure.

Material deprivation and SES have also been found to influence adherence to medications, a major consideration in ensuring effective care for individuals with diabetes. In a study of 72 primary care clinics in medically underserved neighborhoods of Philadelphia, United States, McClintock and colleagues found that participants with diabetes and CVD were significantly less likely to meet 80% adherence to antidepressant, oral hypoglycemic, or antihypertensive medications. Participants indicated multiple social determinants (social, emotional, and financial) impacted adherence to medications, and paying for medications was difficult given their other basic needs. Forgetting to take medications and a lack of knowledge or insight into the impact of poor adherence were also noted as reasons for nonadherence.