Sex-related differences in cardiovascular pharmacotherapy: fiction or fact? Why can't we see the evidence?

There are sex-related differences (SRDs) in body composition, physiology, pharmacokinetics, efficacy, safety, and in dosage of some cardiovascular drugs. Thus, men and women may respond differently to certain drugs. However, information on SRDs in efficacy, safety, and dosage of cardiovascular drugs is scarce and their clinical relevance remains uncertain for two main reasons the traditional under-representation of women and drug efficacy and safety is not reported in a sex-disaggregated manner in randomized clinical trials (RCT). Thus, many RCTs were underpowered to analyse and detect SRDs, even if they do exist, and clinical practice guidelines (CPG) based on these RCTs recommend (with few exceptions) to treat women like men. Furthermore, women are less likely to receive CPG-recommended cardiovascular drugs (CPGRDs), present more adverse drug reactions, and may require lower doses of some drugs than men. In the era of 'precision medicine', this limited information should stimulate basic and clinical research to better understand the mechanisms underlying these SRDs in the efficacy and safety of CPGRDs because this represents the first step to develop a personalized pharmacotherapy. The aim of this narrative review is to analyse the reasons and consequences of the limited information on SRDs in efficacy, safety, and dosage of CPGRDs, to analyse whether the recommended doses are appropriate for women, to analyse the differences in the use of CPGRDs, and finally, to formulate recommendations to close our gaps in knowledge about SRDs and reverse the current situation to improve CVD prevention and treatment from a sex-specific perspective.