Erin Michos, MD: Sex Specific Differences in Risk Factor Profiles in Diabetes Care

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Strategic Alliance Partnership | <b>The Metabolic Institute of America</b>

Although men are known to have higher rates of diabetes and cardiovascular disease (CVD), women with diabetes often have a greater risk profile regarding adverse events.

A recent presentation given at the 6th Annual Heart in Diabetes meeting, accumulated the known data on these sex differences, from observations on less controlled LDL-C and blood pressure in women to the potential for achieve greater benefit from GLP-1 receptor agonist treatment in women.

In an interview with HCPLive, the presenting author, Erin Michos MD, Division of Cardiology, Johns Hopkins School of Medicine, discussed what these data may mean for women with diabetes and what can be done to address these sex-specific issues.

This transcription has been edited for clarity.

HCPLive: Can you provide a summary of your discussion on the sex differences in diabetes impact on atherosclerotic cardiovascular disease (ASCVD) and heart failure and note any key highlights?

At this meeting, I'm talking about sex differences in the risk that diabetes confers in heart failure and ASCVD. While there's a greater prevalence of diabetes in men, diabetes confers a greater relative risk of cardiovascular outcomes in women.

In the risk for myocardial infarction, diabetes confers a fourfold increased risk in women compared to a twofold increase in men. Women at the time of diabetes diagnosis have a higher body mass index (BMI) and they tend to have more cardio metabolic risk factors. They have dyslipidemia, and elevated blood pressure at the time of diabetes diagnosis, which may be why they are at greater risk for cardiovascular complications.

But, the good news is that these novel agents that we have, SGLT2 inhibitors and GLP-1 receptor agonists seem to have equal efficacy in both men and women. Similar glucose control, but also similar reduction in major adverse cardiovascular outcomes. Women benefit equally as men do for these important therapies, so we need to prescribe them for appropriate patients irregardless of sex.

Actually, there's even real world data, not from the trials, but real world data suggesting that GLP-1 receptor agonists may even benefit women even more than men. They can seem to confer greater weight loss in women than in men. With a similar glycemic control, women do tend to have a few more side effects, gastrointestinal side effects with GLP-1’s than men do. But again, most of the time, the side effects can be managed with appropriate counseling and with the GLP-1’s, starting slow and working your way up.

HCPLive: What is the larger importance of including more women in clinical trials?

It's really, really important because we've shown this and demonstrated this over and over again, that women are underrepresented in cardiovascular clinical trials relative to the disease burden in the population. We examine this for both lipid lowering studies and cardiometabolic studies. And it is true for certain conditions like acute coronary syndrome, the prevalence is less in women than in men.

But if you benchmark enrollment and trials to the burden of disease in the population, women are underrepresented. Historically, only like 25% of trial participants are female. So, you can look for interactions by sex, but if there's not enough women in the trial, you're not going to have enough statistical power to see if there's an effect modification, not only for efficacy, but for safety.

Clinical trials serve as the backbone of how we get FDA approvals and implement these into our guidelines. If we're going to disseminate this in our clinical population, we want to make sure that trial results are representative of the patients we see every day in clinic, so not only women, but we also need to make sure we have adequate enrollment of older adults and adults that come from underrepresented minority, racial ethnic groups.

HCPLive: How does gestational diabetes play into this conversation?

Unfortunately, gestational diabetes is on the rise both in the United States and globally. It’s kind of mirroring the trends and rise in obesity. Obviously, obesity pre pregnancy is a big risk factor for these adverse pregnancy outcomes, including gestational diabetes.

We have an oral presentation here at Heart in Diabetes being presented by one of my mentees, Dr. Sam Anza. He's a medicine resident at Rochester General. And what we showed in a national sample of over 15 years of delivery hospitalizations was that women with GDM compared to controls had increased risk of acute cardiovascular complications, so they were nearly twofold more likely to have preeclampsia. And they were also at increased risk for having stroke, peripartum cardiomyopathy, and acute kidney injury.

This is really, really important and why we need to try to prevent gestational diabetes in the first place, but also make sure that they're closely followed. But even if we get women through the pregnancy and delivery, that we know that gestational diabetes is associated with a tenfold increased risk of developing type 2 diabetes, and there's a lot of emerging area whether this some of these agents like GLP-1 receptor agonists may potentially be useful in this group.

But not only that, it's associated with a twofold increased risk of developing cardiovascular events and this could be even more 10 years out from their index pregnancy. Even if you look at women who had GDM, but didn't develop interim type 2 diabetes, they still have an elevated risk of developing coronary artery calcium that was shown in the CARDIA study and about a 60% increased risk of a clinical cardiovascular event, even if they're euglycemia after delivery, it'll still have long term complications.

HCPLive: As a multidisciplinary issue, how does a care team need to be shaped to be able to address these issues?

For women who have had adverse pregnancy outcomes like gestational diabetes, it's really important that they're taken care of by a multidisciplinary team, and postpartum in the fourth trimester, you know that there's this appropriate handoff between OB/GYN to primary care.

Outside of this, one of the conversations we've been having at this meeting is around obesity management. Obviously, obesity is one of the big drivers of diabetes and other comorbidities such as heart failure, particularly heart failure with preserved ejection fraction, atrial fibrillation.

One of the big messages, I think, is that cardiologists need to be in this space of managing diabetes. There’s just not enough obesity medicine specialists, and there's more than double cardiologists and endocrinologists. Because obesity can lead to so many downstream cardiovascular complications cardiologists need to get involved in this space.

We have new agents now, because many patients still struggle with their weight, even after counseling them about diet and lifestyle. You know, obesity is skyrocketing. 42% of US adults are obese and 70% are overweight and obese. Now we have agents like semaglutide, that can confer a 28 pound weight loss at the maximum dose.

Just released was the results from SURMOUNT-1, a trial of tirzepatide. I mean, it's unbelievable, they showed at the highest dose of 50 milligrams, there was a 22% relative weight loss, which translates to 52 pounds. 52 pounds of weight loss with a pharmacological agent is bariatric surgery levels of weight loss, and this should have substantial impact on our patients, preventing these long term comorbidities that we see from obesity.

I think cardiologists really need to get involved in obesity medicine management, or at least know how to appropriately refer and counsel their patients about these new therapeutic options.