Do Women With Diabetes Need More CVD Risk Reduction Than Men?

BUSAN, SOUTH KOREA — Whether cardiovascular disease risk reduction efforts should be more aggressive in women than men with the diabetes depends on how you interpret the data.

Two experts came to different conclusions on this question during a heated, but jovial, debate last week here at the International Diabetes Federation 2019 Congress.

Endocrinologist David Simmons, MB BChir, Western Sydney University, Campbelltown, Australia, argued that diabetes erases the well-described life expectancy advantage of 4-7 years that women experience over men in the general population.

He also highlighted the fact that the heightened risk is of particular concern in both younger women and those with prior gestational diabetes.

But Timothy Davis, BMedSc MB BS, DPhil, an endocrinologist and general physician at Fremantle Hospital, Western Australia, countered that the data only show the diabetes-attributable excess cardiovascular risk is higher among women than men, but that the absolute risk is actually greater in men.

Moreover, he argued, at least in type 1 diabetes, there's no evidence that more aggressive cardiovascular risk factor management improves outcomes.

Yes: Diabetes Eliminates Female CVD Protection

Simmons began by pointing out that although, on average, women die at an older age than men, it has been known for over 40 years that this "female protection" is lost among insulin-treated women, particularly as a result of their increased risk for cardiovascular disease.

In a 2015 meta-analysis of 26 studies, women with type 1 diabetes were found to have about a 37% greater risk of all-cause mortality compared to men with the condition when mortality is contrasted with that of the general population, and twice the risk of both fatal and nonfatal vascular events.

The risk appeared to be greater among women who were younger at the time of diabetes diagnosis. "This is a really important point — the time we would want to intervene," Simmons said.

In another meta-analysis of 30 studies including 2,307,694 individuals with type 2 diabetes and 252,491 deaths, the pooled women-to-men ratio of the standardized mortality ratio for all-cause mortality was 1.14.

In those with versus without type 2 diabetes, the pooled standardized mortality ratio in women was 2.30 and in men was 1.94, both significant compared to those without diabetes.

And in a 2006 meta-analysis of 22 studies involving individuals with type 2 diabetes, the pooled data showed a 46% excess relative risk using standardized mortality ratios in women versus men for fatal coronary artery disease.

Meanwhile, in a 2018 meta-analysis of 68 studies involving nearly 1 million adults examining differences in occlusive vascular disease, after controlling for major vascular risk factors, diabetes roughly doubled the risk for occlusive vascular mortality among men (relative risk, 2.10), but tripled it among women (3.00).

Women with diabetes aged 35-59 years had the highest relative risk for death over follow-up across all age and sex groups: they had 5.5 times the excess risk compared to those without diabetes, while the excess risk for men of that age was 2.3-fold.

"So very clearly, it's these young women who are most at risk, "emphasized Simmons, who is an investigator for Novo Nordisk and a speaker for Medtronic, Novo Nordisk, and Sanofi.

Are Disparities Because of Differences in CVD Risk Factor Management?

The question has arisen whether the female/male differences might be because of differences in cardiovascular risk factor management, Simmons noted.

A 2015 American Heart Association (AHA) statement laid out the evidence for lower prescribing of statins, aspirin, beta-blockers, and angiotensin-converting enzyme (ACE) inhibitors among women compared with men, Simmons said.

And some studies suggest medication adherence is lower in women than men.

In terms of medications, fenofibrate appears to produce better outcomes in women than men, but there is no evidence of gender differences in the effects of statins, ACE inhibitors, or aspirin, Simmons said.

He also outlined the results of a 2008 study of 78,254 patients with acute myocardial infarction from 420 US hospitals in 2001-2006.

Women were older, had more comorbidities, less often presented with ST-elevation myocardial infarction (STEMI), and had a higher rate of unadjusted in-hospital death (8.2% vs 5.7%; P < .0001) than men. Of the partcipants, 33% of women had diabetes compared with 28% of men.

The in-hospital mortality difference disappeared after multivariable adjustment, but women with STEMI still had higher adjusted mortality rates than men.

"The underuse of evidence-based treatments and delayed reperfusion among women represent potential opportunities for reducing sex disparities in care and outcome after acute myocardial infarction," the authors concluded.

"It's very clear amongst our cardiology colleagues that something needs to be done and that we need more aggressive cardiological risk reduction in women," Simmons said.

"The AHA has already decided this. It's already a policy. So why are we having this debate?" he wondered.

He also pointed out that women with prior gestational diabetes are an exceptionally high-risk group, with a two-fold excess risk for cardiovascular disease within the first 10 years postpartum.

"We need to do something about this particularly high-risk group, independent of debates about gender," Simmons emphasized. "Clearly, women with diabetes warrant more aggressive cardiovascular risk reduction than men with diabetes, especially at those younger ages," he concluded.

No: Confusion About Relative Risk Within Each Sex and Absolute Risk

Davis began his counter argument by stating that estimation of absolute vascular risk is an established part of strategies to prevent cardiovascular disease, including in diabetes.

And that risk, he stressed, is actually higher in men.

"Male sex is a consistent adverse risk factor in cardiovascular disease event prediction equations in type 2 diabetes. Identifying absolute risk is important," he said, noting risk calculators include male sex, such as the risk engine derived from the United Kingdom Prospective Diabetes Trial.

And in the Australian population-based Fremantle study, of which Davis is an author, the absolute 5-year incidence rates for all outcomes — including myocardial infarction, stroke, heart failure, lower extremity amputation, cardiovascular mortality, and all-cause mortality — were consistently higher in men versus women in the first phase, which began in the 1990s and included 1426 individuals with diabetes (91% had type 2 diabetes).

In the ongoing second phase, which began in 2008 with 1732 participants, overall rates of those outcomes are lower and the discrepancy between men and women has narrowed, Davis noted.

Overall, the Fremantle study data "suggest that women with type 2 diabetes do not need more aggressive cardiovascular reduction than men with type 2 diabetes because they are not at increased absolute vascular risk," he stressed.

And in a "sensitivity analysis" of two areas in Finland, the authors concluded that the stronger effect of type 2 diabetes on the risk of CHD in women compared with men was in part explained by a heavier risk factor burden and a greater effect of blood pressure and atherogenic dyslipidemia in women with diabetes, he explained.

The Finnish authors wrote, "In terms of absolute risk of CHD death or a major CHD event, diabetes almost completely abolished the female protection from CHD."

But, Davis emphasized, rates were not higher in females.

So then, "Why is there the view that women with type 2 diabetes need more aggressive cardiovascular risk reduction than men with diabetes?"

"It probably comes back to confusion based on absolute risk versus a comparison of relative risk within each sex," he asserted.

ADA Standards of Medical Care 2019 Don't Mention Gender

Lastly, in a meta-analysis published just in July this year involving more than 5 million participants, compared to men with diabetes, women with diabetes had a 58% and 13% greater risk of CHD and all-cause mortality, respectively.

"This points to an urgent need to develop sex- and gender-specific risk assessment strategies and therapeutic interventions that target diabetes management in the context of CHD prevention," the authors concluded.

But, Davis noted, "It is not absolute vascular risk. It's a relative risk compared across the two genders. In the paper, there is no mention of absolute vascular risk."

"Greater CVD mortality in women with and without diabetes, versus men, doesn't mean there's also an absolute vascular increase in women versus men with diabetes," he said.

Moreover, Davis pointed out that in an editorial accompanying the 2015 meta-analysis in type 1 diabetes, Simmons had actually stated that absolute mortality rates are highest in men.

"I don't know what happened to his epidemiology knowledge in the last 4 years but it seems to have gone backwards," he joked to his debate opponent.

And, Davis asserted, even if there were a higher risk in women with type 1 diabetes, there is no evidence that cardiovascular risk reduction measures affect endpoints in that patient population. Only about 8% of people with diabetes in statin trials had type 1 diabetes.

Indeed, he noted, in the American Diabetes Association (ADA) Standards of Medical Care in Diabetes – 2019, the treatment goals for individual cardiovascular risk factors do not mention gender.

What's more, David said, there is evidence that women are significantly less likely than men to take prescribed statins and are more likely to have an eating disorder and underdose insulin, "suggesting significant issues with compliance...So, trying to get more intensive risk reduction in women may be a challenge."

"Women with diabetes do not need more aggressive cardiovascular risk reduction than men with diabetes, irrespective of type," he concluded.

International Diabetes Federation 2019 Congress. December 5, 2019.

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