Among those with type 2 diabetes, women receive some cardioprotective treatments less often than men, according to a post-hoc analysis of data from the REWIND trial, conducted in nearly 10,000 adults from 24 countries.
At study entry, significantly fewer women received a statin, at 73%, or daily aspirin, at 44%, compared with men, who had treatment rates of 81% and 58%, respectively, Giulia Ferrannini, MD, reported today at the European Association for the Study of Diabetes (EASD) 2021 Annual Meeting.
The data also show that significantly fewer women received treatment with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin-receptor blocker (ARB), at 80%, than men, at 83%, although the absolute between-group difference was modest. Rates of a fourth metric of appropriate treatment, receipt of antihypertensive medications if systolic blood pressure ≥ 130 mm Hg, were nearly identical among women and men.
Cardiovascular Risk in Women “Less Well Managed”
“This is confirmation that women are less well managed than men when it comes to cardiovascular risk, especially if they have [type 2] diabetes,” Ferrannini said in an interview.
Similar observations have been documented before, including in a report in 2019.
The treatment disparity by sex among the 9901 women and men with type 2 diabetes enrolled in REWIND is particularly striking because in clinical trials “patients are generally better managed than in the real world,” Ferrannini noted. “Despite this, the pattern of disadvantage to women was still evident,” she added.
“In cardiovascular protection the gender issue is preponderant. Women are less well treated,” she said.
REWIND is the cardiovascular outcomes trial for the once-weekly injectable glucagon-like peptide-1 (GLP-1) receptor agonist dulaglutide (Trulicity, Lilly) in patients with type 2 diabetes.
The primary results, reported at the American Diabetes Association (ADA) 2019 Scientific Sessions and simultaneously published in The Lancet, showed dulaglutide significantly reduced major adverse cardiovascular events (MACE) by 12% compared with placebo. The study ran at about 300 centers worldwide, including many US and Canadian sites, and 46% of enrolled patients were women.
But despite undertreatment, women had significantly better outcomes in terms of MACe, the primary endpoint, during a median 5.4 years of follow-up compared with men. After adjustment for sex, other baseline characteristics, and study-treatment assignment, women had a significant 27% lower composite rate of nonfatal myocardial infarction, nonfatal stroke, or death from either cardiovascular or unknown causes compared with men, said Ferrannini, a researcher at the Karolinska Institute in Stockholm, Sweden.
The analysis by sex also showed that women had a significant outcome advantage compared with men for three of the four components of the combined MACE outcome: nonfatal myocardial infarction, cardiovascular death, and all-cause death, as well as for the outcome of hospitalization for heart failure, which was not part of the composite MACE outcome. The only MACE outcome component that showed no significant between-group difference was nonfatal stroke, which had roughly equal incidence rates among women and men.
Women Had Half the Prevalence of CVD at Baseline
The results also showed that the women with type 2 diabetes enrolled in REWIND had a prevalence of existing cardiovascular disease of 20%, which was half the rate of men at study entry, at 41%. However, the between-sex differences in the primary outcome, as well as each of the individual cardiovascular disease outcomes, didn’t change based on whether or not patients had a history of cardiovascular disease at baseline.
Only one outcome showed a between-sex difference linked to prevalent cardiovascular disease at study entry, the rate of all-cause mortality, which was not significantly different between men and women with a history of cardiovascular disease, but was 39% lower in women compared with men without such a history.
“The good news is that, at baseline and after 2 years, the majority of participants were meeting the relevant treatment targets regardless of sex,” commented Peter Novodvorsky, MUDr, a diabetes researcher at the University of Sheffield, UK, who chaired the session during which Ferrannini presented her findings.
A Role for Geography, or Selection Bias?
The new analyses did not examine whether the overall pattern of undertreatment of women differed among each of the 24 participating countries, or by region of the world.
“We have to assume that these results reflect current [routine] practice” in the 24 countries that contributed patients to the trial, noted Novodvorsky.
There is also “the well-known issue of selection bias” in randomized trials. The current findings raise the question of whether the women willing to take part in the trial somehow differed from the men, he suggested.
Ferrannini added: “Even if we do observe a gender difference in management, if the majority of women with type 2 diabetes are appropriately treated, this ‘restores’ their cardiovascular risk advantage compared with men, with the exception of stroke.”
The main hypothesis generated by the post-hoc analysis of REWIND is that “women with diabetes have better outcomes than men if they are treated properly,” she stressed, noting that this “would have to be tested in a trial designed to ascertain gender differences.”
REWIND was sponsored by Eli Lilly. Ferrannini has reported no relevant financial relationships.
EASD Annual Meeting. Abstract OP 01-5. Presented September 28, 2021.
Mitchel L. Zoler is a reporter for Medscape and MDedge based in the Philadelphia area. @mitchelzoler
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