Sex- and Gender-Based Pharmacological Response to Drugs

Abstract

In humans, the combination of all sex-specific genetic, epigenetic, and hormonal influences of biologic sex produces different in vivo environments for male and female cells. We dissect how these influences of sex modify the pharmacokinetics and pharmacodynamics of multiple drugs and provide examples for common drugs acting on specific organ systems. We also discuss how gender of physicians and patients may influence the therapeutic response to drugs. We aim to highlight sex as a genetic modifier of the pharmacological response to drugs, which should be considered as a necessary step toward precision medicine that will benefit men and women. SIGNIFICANCE STATEMENT: This study discusses the influences of biologic sex on the pharmacokinetics and pharmacodynamics of drugs and provides examples for common drugs acting on specific organ systems. This study also discusses how gender of physicians and patients influence the therapeutic response to drugs.

Fig. 1.

Subgroup analyses (Borenstein et al., 2010) for the primary cardiovascular outcome* of GLP-1 receptor agonists (RAs). (A) Men. (B) Women. *Primary cardiovascular outcome: REWIND (Gerstein et al., 2019): first occurrence of any component of the composite outcome, which comprised nonfatal myocardial infarction, nonfatal stroke, and death from cardiovascular causes or unknown causes; HARMONY (Hernandez et al., 2018): first occurrence of any component of the composite outcome, which comprised death from cardiovascular causes, myocardial infarction, and stroke; ELIXA (Pfeffer et al., 2015): death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina; LEADER (Marso et al., 2016b): first occurrence of death from cardiovascular causes, nonfatal (including silent) myocardial infarction, or nonfatal stroke; SUSTAIN-6 (Marso et al., 2016a): first occurrence of death from cardiovascular causes, nonfatal myocardial infarction (including silent), or nonfatal stroke; and EXSCEL (Holman et al., 2017): first occurrence of any component of the composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (three-component MACE outcome). CI, confidence interval; seTE, standard error of treatment estimate; TE, treatment estimate.

Fig. 2.

Subgroup analyses (Borenstein et al., 2010) for the primary cardiovascular outcome* of SGLT2 inhibitors. (A) Men. (B) Women. *Primary cardiovascular outcome: EMPA-REG OUTCOME (Zinman et al., 2015): composite of death from cardiovascular causes, nonfatal myocardial infarction (excluding silent myocardial infarction), or nonfatal stroke; CANVAS (Neal et al., 2017): composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke; DECLARE-TIMI 58 (Wiviott et al., 2019): MACE defined as cardiovascular death, myocardial infarction, or ischemic stroke; DAPA-HF (McMurray et al., 2019b): composite of worsening heart failure or death from cardiovascular causes. CI, confidence interval; HR, hazard ratio; seTE, TE.

Fig. 3.

Summary of sex and gender influences on the pharmacological response to drugs. Biologic sex via sex-specific genetic and hormonal influences on cellular systems alters the transcriptome, proteome, and metabolome of all cells and organs as well as the gut microbiome and influences pharmacokinetics (e.g., absorption, distribution, metabolism, and elimination of drugs) and pharmacodynamics (e.g., the effect of drugs on receptors, ion channels, enzymes, and signaling pathways). Aging, race, and genetic polymorphism also influence pharmacokinetics and pharmacodynamics parameters in a sex-specific manner. In women, the hormonal influences of pregnancy, menopause, and the use of OCs also produce sex differences in the pharmacokinetics and pharmacodynamics of drugs. Finally, physician gender could add an additional level of difference in response to treatment.