Sex and Gender Differences in Cardiovascular Drug Therapy

Abstract

This chapter outlines sex differences in pharmacokinetics and pharmacodynamics of the most frequently used drugs in cardiovascular diseases, e.g., coronary artery disease, hypertension, heart failure. Retrospective analysis of previously published drug trials revealed marked sex differences in efficacy and adverse effects in a number of cardiovascular drugs. This includes a higher mortality among women taking digoxin for heart failure, more torsade de pointes arrhythmia in QT prolonging drugs and more cough with ACE inhibitors. Trends towards a greater benefit for women and/or female animals have been observed in some studies for endothelin receptor antagonists, the calcium channel blocker amlodipine, the ACE-inhibitor ramipril and the aldosterone antagonist eplerenone. However, reproduction of these results in independent studies and solid statistical evidence is still lacking. Some drugs require a particularly careful dose adaptation in women: the beta-blocker metoprolol, the calcium channel blocker verapamil, loop-, and thiazide diuretics. In conclusion, sex differences in pharmacokinetics and pharmacodynamics have to be taken into account for cardiovascular drug therapy in women.

Results of prospective multicenter study on heart failure on Campania Internal Medicine wards: the FASHION study

“…33 Unfortunately, sex-specific diagnostic and treatment modalities have yet to gain similar attention which, in part, reflects incomplete understanding of physiological and cellular mechanisms contributing to gender differences in etiology of some cardiovascular diseases and failure to consider sex differences in pharmacokinetics and pharmacodynamics of drugs used to treat most cardiovascular diseases. 34,35 Progress in understanding these mechanisms is slow due to the continued use of male animals in many types of experiments, lack of reporting of the sex and hormonal status of animals and cells used in mechanistic studies, and the absence of reporting of clinical trial results by gender. [36][37][38] Gender differences in HF have been reported in relationship with the underlying physiology related to the sexual differences in hormonal status, metabolism and so on.…”

Epigenome-Wide Association (DNA Methylation) Study of Sex Differences in Normal Human Kidney

“…In the United States (as of 2014), chronic kidney disease is known to affect approximately 30 million adults, where males exhibit a higher prevalence and progression of renal disease, and is associated with a higher incidence of End Stage Renal Disease (ESRD) [68]. There has also been a wealth of clinical data demonstrating sex differences in drug responses and efficacy [1][2][3][4][5][6]. In this study, 3 of the 4 genes selected for validation, ABCA3, LAMA5 and PLAT, exhibited lower mRNA expression levels in males (higher methylation in their corresponding differentially methylated sites).…”

“…There has been a wealth of clinical data demonstrating sex differences in drug responses and efficacy [1][2][3][4][5][6]. Around 6-7% of new drug applications that include a sex analysis component have shown statistically significant differences in pharmacokinetic profiles as well as toxicokinetic activities, adverse drug reactions, and drug efficacy and safety [7].…”

Primary and Secondary Prevention of Ischemic Heart Disease in Women

“…There are multiple choices for antihypertensive therapy in women, including angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), beta-blockers, calcium channel blockers, and diuretics. Blood pressure lowering with these agents is similar in men and women, although women are more likely to have side effects [53]. In a subgroup analysis from the Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial (ALLHAT), no differences between men and women were observed in CHD outcomes [54].…”