Sex-specific effects of antiobesity and antidiabetic drugs
| 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) |