Different genders should be considered for the extraglycemic benefits of oral antidiabetic drugs - Letter to the editor

Sep 29, 2026

Letter to the editor discussing extraglycemic benefits of oral antidiabetic drugs, focusing on dipeptidyl peptidase-4 inhibitors (DPP-4i) in type 2 diabetes mellitus. The authors note that reduced osteoporosis risk reported in DPP-4i users may differ by sex, with hazard ratios favoring a stronger apparent benefit in males. They also highlight evidence linking DPP-4i to increased gallbladder or biliary disease risk, including cholecystitis, and emphasize gender-related differences in prevalence, incidence, and mortality when considering treatment choices.

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Letter to the editor

Extraglycemic benefits and sex differences

Evidence of gallbladder or biliary risks

Comment and acknowledgments

J Chin MedAssoc Letter to the editor Different genders should be considered for the extraglycemic benefits of oral antidiabetic drugs Wen-Hsun Changa,b, Chia-Hao Liub,c,d,* aDepartment of Nursing, Taipei Veterans General Hospital, Taipei, Taiwan, ROC; bDepartment of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC; cDepartment of Obstetrics and Gynecology, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC; dInstitute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC DEAR EDITOR, Many patients with type 2 diabetes mellitus (T2DM) need oral antidiabetic drug treatment for blood sugar control and to avoid or delay the T2DM-related complications that could damage the microvascular and macrovascular circulatory systems and subsequently develop various kinds of morbidities and eventually mortality.1 We read Dr. Chang’s study,2 editorial comments by Dr. Lee et al,3 and a letter to Editors by Dr. Lee et al4 to discuss the extraglycemic benefits of oral antidiabetic drugs, including dipeptidyl peptidase-4 inhibitors (DPP-4i) in patients with T2DM. We found with interest that all patients with T2DM treated with DPP-4i took advantage of the lowering risk of the development of osteoporosis, as shown by the authors, but it is important to note that the advantages of decreasing the risk of osteoporosis are different between the male and female populations. Males had an adjusted hazard ratio (HR) of 0.562 (95% confidence interval [CI]: 0.322–0. 878), and the females had an adjusted HR of 0.638 (95% CI: 0.364–0.980),2 suggesting that the extraglycemic benefits of DPP-4i may be more apparent in the male population. A recent meta-analysis enrolling 82 randomized controlled trials with 104,833 participants showed DPP-4i was significantly associated with an increased risk of the composite of gallbladder or biliary diseases with an odds ratio (OR) of 1.22 (95% CI: 1.04–1.43) compared with placebo or nonincretin drugs.5 Additionally, compared with sodium-glucose cotransporter-2 inhibitors, DPP-4i also increased the risk of the composite of gallbladder and biliary diseases, as well as cholecystitis.5 The prevalence and incidence of gallbladder or biliary tract diseases differ between male and female populations. The male population may have a higher risk of developing gallbladder or biliary tract diseases than the female population.6 Moreover, the male population is also strongly associated with a higher mortality rate compared with the female population,6 contributing to the concern about using DPP-4i as an antidiabetic agent in the T2DM male population. Since the extraglycemic benefits, such as the prevention of osteoporosis, are claimed by the authors, we comment that different genders may have a different impact on using DPP-4i as a choice in the management of patients with T2DM. We wonder about the authors’ opinions. ACKNOWLEDGMENTS This study was supported by grants from Taipei Veterans General Hospital (V111A-009) . REFERENCES 1. Wu TH, Lee IT, HoLT, SheuWH, Hwu CM. Combined lipid goal attainment in patients with type 2 diabetes and dyslipidemia: a head-to-head comparative trial of statins. J Chin MedAssoc 2022;85:832–9. 2. Chang CH, Lu CH, Chung CH, Su SC, Kuo FC, Liu JS, et al. Dipeptidylpeptidase-4 inhibitors attenuates osteoporosis in patients with diabetes: A nationwide, retrospective, matched-cohort study in Taiwan. J Chin Med Assoc 2022;85:747–53 . 3. Lee WL, Lee FK, Wang PH. Dipeptidyl peptidase-4 (DPP-4) inhibitors and osteoporosis. J Chin Med Assoc 2022;85:889–90 . 4. Li YT, Yang ST, Wang PH. Is it real of lower incidence of vitamin D deficiency inT2DM patients? J Chin MedAssoc 2022;85:958. 5. He L, Wang J, Ping F, Yang N, Huang J, Li W, et al. Dipeptidyl peptidase-4 inhibitors and gallbladder or biliary disease in type 2 diabetes: systematic review and pairwise and network meta-analysis of randomised controlled trials. BMJ 20

FAQs

What extraglycemic benefit of DPP-4 inhibitors is discussed in relation to sex differences?

The letter focuses on reduced risk of osteoporosis and argues that the advantage may differ between male and female populations.

What additional safety concerns does the letter raise about DPP-4 inhibitors?

It cites evidence that DPP-4 inhibitors are associated with an increased risk of gallbladder or biliary diseases and notes higher related risk compared with placebo or nonincretin drugs, including cholecystitis versus SGLT2 inhibitors.

What overall recommendation or concern do the authors express for clinical decision-making?

They suggest that different genders may have different impacts when choosing DPP-4i for managing patients with type 2 diabetes mellitus.

Sep 29, 2026

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