Gender Differences Seen With CV Prevention in Diabetes

While slightly fewer women than men were hitting the mark when it came to cardiovascular prevention in diabetes, they still managed to see positive outcomes, a researcher reported.

In a post-hoc analysis of the REWIND trial, fewer women with type 2 diabetes at high risk for cardiovascular disease (CVD) or already established heart disease were prescribed preventive medications to hit treatment targets compared with men, said Giulia Ferrannini, MD, of the Karolinska Institutet in Stockholm.

As she reported during the virtual European Association for the Study of Diabetes (EASD) meeting, at baseline fewer women were on angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) compared with men (80% vs 83%). Fewer women were also on an aspirin regimen (44% vs 58%), on statins, or had a low-density lipoprotein (LDL) cholesterol level below 100 mg/dL (73% vs 81%).

However, women were up to par with men in the proportion on any antihypertensive medication or having a systolic blood pressure at target, below 130 mm Hg (97% vs 96%).

"Overall, it seems like women were less well-treated at baseline, but we can see that this is a very high proportion of patients who were at target, and this is surely because we are in the context of a large cardiovascular outcomes trial," Ferrannini pointed out during her presentation of the findings.

This pattern only seemed to continue, as by year 2 of the study significantly more men were still being treated with ACE inhibitors or ARBs, statins, and aspirin compared with women.

However, when breaking down gender differences for the primary outcome of the REWIND trial -- a composite major adverse cardiac events (MACE) outcome, all-cause mortality, or heart failure (HF) requiring hospitalization -- women still maintained a significantly lower risk for all outcomes besides stroke compared with men, despite having slightly less treatment:

• Fatal or nonfatal stroke: HR 0.93 (95% CI 0.75-1.17)

• Fatal or nonfatal myocardial infarction: HR 0.77 (95% CI 0.62-0.96)

• CV death: HR 0.75 (95% CI 0.63-0.90)

• All-cause mortality: HR 0.77 (95% CI 0.67-0.88)

• HF requiring hospitalization: HR 0.71 (95% CI 0.57-0.88)

"The gender difference in the risk of outcomes seems not to be influenced by baseline cardiovascular disease status," as these patterns were similar for women with and without established CVD at baseline, Ferrannini said.

While women are thought to generally have greater protection than men against CVD due to estrogen, the running idea was that this protective advantage disappeared in type 2 diabetes, she explained.

"In diabetes, the common belief is that somehow women lose their advantage when it comes to cardiovascular outcomes. But if we manage to treat women well -- as they are in REWIND, with a high proportion of women reaching treatment targets -- we might still see the advantage that women have, even though patients have type 2 diabetes and are thought to be no longer protected," she continued. "We want to be positive here. If we treat women as they should be treated, they should keep their advantage even though they have diabetes."

The REWIND (Researching Cardiovascular Events With a Weekly Incretin in Diabetes) trial, first published in 2019, included a total of 9,901 patients with type 2 diabetes, randomly assigned to receive either the GLP-1 receptor agonist dulaglutide (Trulicity), 1.5 mg subcutaneously once weekly, or placebo. Of these participants, 31% had prior established cardiovascular disease, and 69% had risk factors putting them at high risk for developing heart disease.

Participants age 50 or older had to have concomitant vascular disease, defined as a previous myocardial infarction, ischemic stroke, revascularization, hospital admission for unstable angina, or imaging evidence of myocardial ischemia. Those 55 and older had to have concomitant myocardial ischemia, coronary, carotid, or lower extremity artery stenosis exceeding 50%, left ventricular hypertrophy, an estimated glomerular filtration rate under 60 mL/min/1.73 m², or albuminuria. Those 60 and older had to have at least two of the following risk factors: tobacco use, dyslipidemia, hypertension, or abdominal obesity.

The average age of the entire cohort was about 66, and mean HbA1c was 7.3.

About 46% of the cohort was comprised of women. At baseline, significantly fewer women than men had established cardiovascular disease (20.0% vs 41.4%). Underpinning this, far fewer women had a history of myocardial infarction (8.5% vs 22.9%), ischemic stroke (4.4% vs 6.1%), and coronary, carotid, or peripheral artery revascularization at baseline (8.8% vs 26.1%), Ferrannini said.

But women had a significantly higher baseline body mass index (33 vs 32) and higher LDL cholesterol (106 vs 93 mg/dL) and high-density lipoprotein cholesterol (49 vs 42 mg/dL).

Ferrannini noted that the findings should be viewed through the lens of clinical rather than statistical significance -- i.e., because of the large data set, it was easier to find statistically significant baseline differences between the sexes. A clinically significant finding, however, she added, was that the difference in baseline established cardiovascular disease in women was more than double the rate in men.

A limitation of the study, Ferrannini said, was a lack of data on the proportion of women on hormone-replacement therapy.

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