Article Figures & Data
Figures
- 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.
Tables
Drug/Substance Sex- and Gender-Related Aspects References Heart failure Digoxin Greater mortality in women with HFrEF than in men in post hoc analysis Diamanti-Kandarakis et al. (2007); Tchoukhine et al. (2011) ACEIs Effective in women in lower doses than in men Santema et al. (2019) ACEIs More frequently adverse effects in women (cough) Mackay et al. (1999) β Blockers Effective in women in lower doses than in men Santema et al. (2019) β Blockers More adverse effects in women, particular substances that are metabolized via Cyp2D6 interaction with oral contraceptives Kendall et al. (1982); Tanaka and Hisawa (1999); Labbé et al. (2000); Flock et al. (2013); Navarro et al. (2016); Overgaard et al. (2016); Wilding et al. (2016); Cataldi et al. (2019) Sacubitril-valsartan Led to a significant reduction in event rate vs. valsartan in women, which was not observed in men (0.73 in women and 1.03 in men; P interaction = 0.017) Flock et al. (2013); McMurray et al. (2019a); Navarro et al. (2016); Overgaard et al. (2016); Wilding et al. (2016); Cataldi et al. (2019) Aldosterone receptor antagonists. Strong trends for better mortality reduction in women than in men Merrill et al. (2019) Antiarrhythmic drugs Class III antiarrhythmic drugs (e.g., amiodarone, sotalol) Stronger QT prolongation and more torsade de pointes arrhythmia in women Kurokawa et al. (2012) Antihypertensive drugs Diuretics More often prescribed to women, more electrolyte disturbances in women Amlodipine Stronger blood pressure reduction in women, more edema in women Kloner et al. (1995) Drug/Substance Sex- and Gender-Related Aspects References Antiobesity drugs Orlistat Greater weight loss in men, better metabolic improvement in women, decrease in androgen levels and higher ovulation rates in women with polycystic ovary syndrome independent of weight changes Diamanti-Kandarakis et al. (2007); Tchoukhine et al. (2011) Lorcaserin Inactivation in the liver by CYP3A4, CYP2D6, and flavin-containing monooxygenase, which all show greater expression in women; estrogen-modulated anorectic effect Ostlund et al. (2003); Cataldi et al. (2019) Naltrexone/bupropion combination Buproprion: accumulates in fat (women have more fat mass); activation to CYP2B6 in the liver (greater expression in women); higher distribution volume, plasma levels, and half-life in women; sex effect on the ratio buprion clearance/bioavailability naltrexon: greater exposure in women testosterone: competitive inhibitor of naltrexone conversion to 6β-naltrexol US Food and Drug Administration; Center for Drug Evaluation and Research (2012a); Laib et al. (2014) Phentermine/topiramate combination Higher drug exposure in females for topiramate; higher (nor)epinephrine-induced lipolysis in women phentermine: estrogenic regulation of monoamine transporters US Food and Drug Administration; Center for Drug Evaluation and Research (2012b) Liraglutide 3 mg Estrogens modulate the effect of GLP-1 on the reward system control of GLP-1; secretion by progesterone sex impacts exposure of liraglutide 3 mg; 32% greater exposure of women than men at comparable body weight: Effect of sex was independent of body weight. Higher degradation and elimination in men than in women; slower gastric emptying in women than men; larger weight loss in women Flock et al. (2013); Navarro et al. (2016); Overgaard et al. (2016); Wilding et al. (2016); Cataldi et al. (2019) Antihyperglycemic drugs Metformin Lower risk of breast and colorectal cancer in women as well as hepatocellular cancer in men; greater reduction of incident diabetes in women with a history of gestational diabetes compared with women who are parous prediabetic without prior gestational diabetes in men only, coronary artery calcium severity was significantly lower under metformin Martin-Castillo et al. (2010); Lee et al. (2011); Diabetes Prevention Program Research Group (2019) Thiazolidinediones Lower malignancy risk in women who are diabetic, increased risk of bone fractures in women who are postmenopausal, higher mortality in women under rosiglitazone monotherapy Habib et al. (2010); Wheeler et al. (2013); Sun et al. (2014) DPP-4 inhibitors More often prescribed to males and older patients with comorbidities. Zhang et al. (2010) GLP-1A, including liraglutide 0.6–1.8 mg (Fig. 1) More often prescribed to young obese females. Exenatide: more adverse gastrointestinal events in women but also a tendency to greater weight loss and reductions of fasting glucose and blood pressure levels. Semaglutide: post hoc gender analysis: comparable but even slightly greater reduction of body weight and HbA1c in females, similar proportion of men and women in regard to adverse events across treatment groups, but women reported more gastrointestinal side effects in all groups Hirsch et al. (2011); Pencek et al. (2012); Marso et al. (2016a), (2016b); Leiter et al. (2019) SGLT2 inhibitors (Fig. 2) Higher risk of balanitis and vulvovaginitis; more urinary tract infections and genital mycosis in women; higher risk of ketoacidosis in women (female:male ratio: 1.21); higher risk of Fournier gangrene (male:female ratio: 2.4) canagliflozin: higher risk of fractures and for lower limb amputations; empagliflozin: post hoc subgroup analysis: lower rates of death from cardiovascular causes in males; no sex interaction Johnsson et al. (2013); Zinman et al. (2016); Fadini et al. (2017); Bersoff-Matcha et al. (2019); Kluger et al. (2019) Insulin Women have higher risk of severe (nocturnal) hypoglycemia maybe due to higher insulin doses compared with men in relation to their body weight despite reaching glycemic targets less often than men McGill et al. (2013)
Data Supplement
- Supplemental Table -
Supplemental Table - Sex Differences in PK in Adult Men and Women, and Effect of Pregnancy, Menstrual Cycle, OC and HRT.
Supplemental References
- Supplemental Table -
In this issue
Sex-Based Pharmacology
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- Article
- Abstract
- I. Introduction
- II. Genetic and Hormonal Basis
- III. Pharmacokinetics and Pharmacodynamics
- IV. Sex-Specific Pharmacology of Drugs Acting in Different Physiologic Systems
- V. Role of Physician and Patient Gender in Drug Response
- VI. Conclusions and Future Directions
- Acknowledgments
- Authorship Contributions
- Footnotes
- Abbreviations
- References
- Figures & Data
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