**Background:** Cardiovascular disease (CVD) is the leading cause of mortality among women, and type 2 diabetes mellitus (T2DM) confers a threefold higher relative risk of cardiovascular death in women compared with women without diabetes, versus only a twofold increased risk in men. Prior research has suggested that women with diabetes experience a greater burden of traditional cardiometabolic risk factors, less aggressive management of those risk factors, and more adverse socioeconomic factors than men. However, earlier studies were often limited by not accounting for diabetes duration, glycemic control, or specific glucose-lowering treatment. The Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) provides a unique opportunity to examine sex differences at a comparable early stage of T2DM with detailed clinical and metabolic phenotyping.
**Methods:** GRADE enrolled 5,047 participants (1,837 women, 3,210 men) across 36 clinical centers (including 10 Veterans Affairs sites) in the USA from July 2013 to August 2017. Eligible individuals had T2DM duration <10 years, were aged ≥30 years (≥20 for Native Americans), were on metformin monotherapy (≥1,000 mg daily), and had a centrally measured HbA1c of 6.8%–8.5% (51–69 mmol/mol) at randomization after metformin optimization. Exclusion criteria included type 1 diabetes, eGFR <30 mL/min/1.73 m², NYHA class ≥III heart failure, major cardiovascular event within the prior year, and recent cancer. This report is a cross-sectional analysis of baseline data. Demographic and clinical variables were collected by self-report. Physical measurements (height, weight, waist circumference, blood pressure) were taken in duplicate and averaged by trained clinical research staff. Laboratory data—including HbA1c, lipid panels, and fasting glucose—were analyzed at a central laboratory using standardized procedures. Hypertension was defined by self-report, antihypertensive use, or measured systolic BP ≥130 mmHg or diastolic BP ≥80 mmHg. Hyperlipidemia was defined by self-report, lipid-lowering medication use, or LDL-C ≥100 mg/dL. Sex-specific thresholds were applied for waist circumference (≥88 cm women, ≥102 cm men; lower for Asian Americans) and low HDL-C (<50 mg/dL women, <40 mg/dL men). Differences between sexes were tested using t-tests for continuous variables and Pearson's χ² tests for categorical variables. A Holm adjustment was applied for hypothesis testing of the main analyses on blood pressure and lipid management. Exploratory interaction analyses examined whether sex differences varied by age, race, ethnicity, income, and education using linear or logistic regression with interaction terms.
**Key Results:** Compared with men, women were younger (mean age 55.4 vs 58.2 years, p<0.001), had fewer years of formal education (10.3% vs 5.4% with some high school only), lower incomes (8.2% vs 4.5% earning <$10,000/year), and were more likely to be divorced, separated, or widowed (32.8% vs 19.7%). Women had higher mean BMI (35.4 vs 33.7 kg/m², p<0.001) and a substantially higher prevalence of class III obesity (BMI ≥40 kg/m²: 23.6% vs 14.5%). More women met the sex-specific threshold for increased waist circumference (92.9% vs 79%). Lipid profiles were significantly worse in women: mean LDL-C was 96.9 mg/dL versus 86.8 mg/dL in men (p<0.001), and 64% of women had low HDL-C by sex-specific criteria compared with 47% of men. Despite this greater burden, women with hyperlipidemia were significantly less likely to receive statin therapy (58.8% vs 70.7%, p<0.001) and less likely to achieve LDL-C <100 mg/dL (57.7% vs 69.2%, p<0.001). Among statin-treated participants, this sex gap in target achievement persisted across age groups and was most pronounced in younger women (<45 years). In contrast, there were no significant sex differences in the proportion of individuals receiving blood pressure medications among those with hypertension (women 71.2% vs men 73.1%, p=0.454) or in the achievement of BP targets at either <140/90 mmHg (76.2% vs 74.8%, p=0.58) or <130/80 mmHg (44.8% vs 42%, p=0.211). However, women with hypertension were significantly less likely to be prescribed ACE inhibitors or angiotensin receptor blockers (57.4% vs 62.7%, p=0.003). Women also had higher use of antidepressant or anxiolytic medications (22.5% vs 17.1%, p=0.001). Younger women (age <45 years) had the highest mean BMI, the highest prevalence of low HDL-C, and were least likely to achieve target LDL-C despite statin therapy. Sensitivity analyses excluding VA study sites did not alter the findings.
**Clinical Implications:** This contemporary, well-phenotyped cohort demonstrates that despite decades of awareness, women with early-stage T2DM continue to carry a disproportionate burden of cardiometabolic risk factors and receive less aggressive lipid-lowering therapy compared with men, especially at younger ages. The combination of higher obesity prevalence, worse lipid profiles, lower statin use, lower ACE inhibitor/ARB use, and greater socioeconomic disadvantage (lower income, less education, higher rates of being single/divorced/widowed, and more antidepressant use) creates a cumulative risk profile that likely contributes to the persistent excess relative risk of cardiovascular mortality in women with diabetes. Notably, BP management appears to have improved compared with earlier studies, but gaps in lipid management and ACE inhibitor/ARB prescribing persist. The findings underscore the need for sex-specific clinical awareness and targeted interventions—particularly for younger women—to close treatment gaps and address both traditional and socioeconomic risk factors that may otherwise propagate cardiovascular disparities in this population.