Generally speaking, when it comes to medications, there are differences in both efficacy and safety, which are the two major issues in drug use. Both of these factors, which determine the success or failure of a treatment, fundamentally stem from the still incomplete implementation of gender equality principles in clinical trials. Let me explain: it's clear that cardiovascular diseases, at least up to a certain age, are more prevalent in men than in women. If the sample of women when testing new drugs is underrepresented, it's possible to fail to statistically recognize and fully document both the benefit and any potential risks to which women may be exposed. For example, overdoses of certain medications compared to standard doses can occur simply because of differences in body mass.

There are characteristics specific to the female sex—and we're not even talking about gender here, we're talking about biological sex—such as hormonal profiles or the presence of different drug elimination systems. At the cardiovascular level, this translates, for example, into a different effect, linked to the electrophysiological profile, that some drugs can have. Women typically have a different profile than men for a particular parameter called the QT interval, which makes them more exposed to drugs that further increase this parameter. The consequence can be an increased risk of arrhythmic events, even serious ones, in women, which, if not properly diagnosed and prevented early, can lead to very serious complications.

Some phases of a woman's life are very particular. There is an important study published in 2021 by The Lancet, The Lancet Women and Cardiovascular Disease Commission: reduce the global burden by 2030, on cardiovascular diseases in women, which shows how a woman's life, from childhood to old age, goes through many more phases than that of men: the entry into the reproductive phase, pregnancy, breastfeeding and then menopause with profound hormonal changes.
During each of these phases, the response to medications can vary significantly. The challenge isn't just understanding that the patient is female, but also understanding their life stage, as this can profoundly impact the type of therapy to be implemented. If we consider an 80-year-old woman, we realize that she has decreased muscle mass, often weighs less than she did when she was younger, and has impaired kidney function—this also occurs in men. Therefore, the dosage of some medications that are eliminated by the kidneys must be drastically reduced to avoid toxicity.

Equal representation is still lacking. It's clear that the situation has improved over the years, and there's a trend toward a gradual increase in the percentage of women in trials of drugs for cardiovascular diseases. However, it's also true that in many cases, the percentage certainly falls short of 50%.

It's also a problem related to the fact that when some studies include the 18-50 age group, for example, women pose a greater problem for those conducting the clinical trial. This is also understandable because for certain drugs, it is necessary to ensure that the woman is taking adequate contraceptive therapy: it is impossible to run the risk of a woman becoming pregnant during the clinical trial, as this could pose risks, particularly to the fetus, especially if it is unknown whether the drug has teratogenic effects.

There is therefore a phase of life—pre-menopause—that represents a potential risk and therefore an underrepresentation of women. During this phase, women typically have a lower cardiovascular risk than men, but it's important to understand whether this lower risk is real or not, as it depends on individual characteristics: is the woman a smoker? Is she obese? Is she hypertensive? Does she have family history of risk? This doesn't mean she isn't equally at risk. The problem is that underrepresentation, if we consider the entire lifespan of women in clinical studies, still exists. It's probably difficult to reach 50-50%, but that's undoubtedly the goal, because women's cardiovascular risk is catching up with men's. The reason is that exposure to environmental factors or similar lifestyles is increasing.

Much more so than before. Now there are both ad hoc courses—they can also be elective, supplementary, or elective courses—and in any case, they are also taught in the lectures of the course offered to all students. Gender-specific pharmacology topics are always addressed: when referring to a certain class of drugs, it is always noted whether the different risks for women versus men are relevant.

Issues such as women's different perceptions of risk are also addressed. A study was recently published in Switzerland showing that if a woman and a man go to the emergency room with symptoms that suggest a heart attack, the man is much more likely to be hospitalized than the woman. We know that symptoms can be different; women have a different set of symptoms than men and are also less psychologically ready to recognize them. Consequently, they may not be treated as effectively.

The risks associated with, for example, anticoagulants, being underweight or overweight, the different distribution of body fat, the risk of certain medications causing arrhythmias, and the risk of drug interactions with estrogen or progestins are reported. When these topics arise, we always address them.

In August of this year, the new guidelines on "cardiovascular diseases and therapies" during pregnancy and breastfeeding were published by the European Society of Cardiology. I collaborated with this multidisciplinary group on the medication section, on the complete list of all medications: which ones can be used, which ones are completely contraindicated, and so on.
This is a complex undertaking that will undoubtedly continue for years, because the problem is that for many drugs, we lack data on pregnancy. For many drugs, excluding those known to cause fetal malformations or a risk of miscarriage, there simply isn't enough data. Data exists for women exposed to the drugs by chance, or because they have been used empirically and therefore epidemiologically collected.

Studying a drug during pregnancy is not only extremely difficult, but in some cases it can also be ethically questionable. Based on data available from the scientific literature, especially observational studies, tables have been compiled for pregnancy and breastfeeding. These tables identify the so-called first-choice drugs—those that have demonstrated efficacy and safety for both mother and fetus—and the same applies to breastfeeding.

This is an increasingly important topic because when women had children between the ages of 18 and 30, cardiovascular risk was close to zero. Now that many women are living beyond 35-40, the risk of having a woman who already has prediabetes, hypertension, dyslipidemia, or obesity, has an increased cardiovascular risk, is frankly elevated.

Then, of course, there are women at high risk—those already known to be at high risk during pregnancy for certain conditions, such as cardiomyopathy—who are treated by a multidisciplinary team that addresses all the various issues, including medication. Some medications cannot be used during pregnancy due to the risk they pose to the fetus.

There are now few extreme cases. For example, women with transplants can become pregnant a year after the transplant; it is no longer contraindicated. However, there is a specific condition called pulmonary hypertension, in which the mortality risk is truly very high, and therefore a woman's decision to embark on a pregnancy is objectively courageous.

Regarding breastfeeding, some medications that are not recommended during pregnancy can be used while breastfeeding, while some medications that can be used during pregnancy are not recommended while breastfeeding. The medication is substituted for another, but the recommendation is always to never discourage a woman from breastfeeding her baby. Therefore, whenever possible, unless there is an absolutely life-saving therapy for the woman that is contraindicated during breastfeeding, breastfeeding is always recommended.

I'd like to add that we're talking about clinical research here, which is undoubtedly very important, but which is achieved after years of preclinical research, that is, research conducted in the laboratory on cells or animals (e.g., mice). Even in preclinical research, it's important to have studies that focus on different sexes, because cells can have a male or female genetic makeup, and so can the animals on which initial studies are conducted before reaching clinical trials. This aspect is very important, often overlooked, but it yields excellent results.

I was looking at a work just published by a very good colleague from the University of Florence, Paola Romagnani, who published a very important work in Science, intercepting a new mechanism in a potentially serious complication of pregnancy, pre-eclampsia.

Studies of this kind, which identify new therapeutic targets specifically linked to a woman's life stage—in this case, a pregnancy-related condition like preeclampsia or eclampsia—are of fundamental importance. This is a study conducted on animals, on experimental models, and this, in my opinion, is a message we need to convey: encourage gender-specific studies, even preclinical ones.