Skip to main content
SpringerLink
Log in

Higher Risk of Sulfonylurea-associated Hypoglycemic Symptoms in Women with Type 2 Diabetes Mellitus

  • Short Communication
  • Published:
Clinical Drug Investigation Aims and scope Submit manuscript

Abstract

Background

Although some evidence suggests that women may be at greater risk for hypoglycemia, no conclusion has been reached, and female sex has not been taken into account in antidiabetic drug-induced hypoglycemia. This study aimed to determine whether females are at a higher risk of sulfonylurea (SU)-associated hypoglycemia in daily clinical practice.

Methods

The incidence of adverse reactions of SU was investigated in 2119 Japanese patients who participated in the Drug Event Monitoring project of the Japan Pharmaceutical Association, which was conducted in Kumamoto prefecture. A multiple logistic regression analysis was used to determine the association between the incidence of hypoglycemic symptoms and female sex, with adjusted odds ratios (ORs) and 95 % confidence intervals (95 % CIs).

Results

Female sex was found to be significantly associated with hypoglycemic symptoms (female vs. male; OR 2.04; 95 % CI 1.22–3.41; p = 0.007). The concomitant use of other antihyperglycemic agents (≥2 vs. 0 concomitant drug; OR 2.80; 95 % CI 1.17–6.67; p = 0.021), a shorter duration of diabetes medication (<3 vs. ≥24 months; OR 4.14; 95 % CI 1.06–16.14; p = 0.041) and a longer follow-up period (OR 1.02; 95 % CI 1.00–1.04; p = 0.041) were identified as risk factors for hypoglycemia that were specific to females.

Conclusion

To the best of our knowledge, this is the first report to focus on female sex as a potential risk factor for SU-associated hypoglycemia. Our results support the importance of individualized therapy, which may be effective not only for reducing the risk of hypoglycemia in females but also the risk of its consequences, such as cardiovascular disease, dementia and increased mortality.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

References

  1. Hsu PF, Sung SH, Cheng HM, et al. Association of clinical symptomatic hypoglycemia with cardiovascular events and total mortality in type 2 diabetes: a nationwide population-based study. Diabetes Care. 2013;36(4):894–900.

    Article  PubMed Central  PubMed  Google Scholar 

  2. Miller ME, Bonds DE, Gerstein HC, et al. The effects of baseline characteristics, glycaemia treatment approach, and glycated haemoglobin concentration on the risk of severe hypoglycaemia: post hoc epidemiological analysis of the ACCORD study. BMJ. 2010;340:b5444.

    Article  PubMed Central  PubMed  Google Scholar 

  3. Simeone JC, Quilliam BJ. Predictors of emergency department and outpatient visits for hypoglycemia in type 2 diabetes: an analysis of a large US administrative claims database. Ann Pharmacother. 2012;46(2):157–68.

    Article  PubMed  Google Scholar 

  4. Vexiau P, Mavros P, Krishnarajah G, et al. Hypoglycaemia in patients with type 2 diabetes treated with a combination of metformin and sulphonylurea therapy in France. Diabetes Obes Metab. 2008;10(Suppl 1):16–24.

    Article  PubMed  Google Scholar 

  5. Sheu WH, Ji LN, Nitiyanant W, et al. Hypoglycemia is associated with increased worry and lower quality of life among patients with type 2 diabetes treated with oral antihyperglycemic agents in the Asia-Pacific region. Diabetes Res Clin Pract. 2012;96(2):141–8.

    Article  CAS  PubMed  Google Scholar 

  6. Aung PP, Strachan MW, Frier BM, et al. Severe hypoglycaemia and late-life cognitive ability in older people with type 2 diabetes: the Edinburgh Type 2 Diabetes Study. Diabet Med. 2012;29(3):328–36.

    Article  CAS  PubMed  Google Scholar 

  7. Lin CH, Sheu WH. Hypoglycaemic episodes and risk of dementia in diabetes mellitus: 7-year follow-up study. J Intern Med. 2013;273(1):102–10.

    Article  PubMed  Google Scholar 

  8. Mogensen UM, Andersson C, Fosbol EL, et al. Sulfonylurea in combination with insulin is associated with increased mortality compared with a combination of insulin and metformin in a retrospective Danish nationwide study. Diabetologia. 2015;58(1):50–8.

    Article  CAS  PubMed  Google Scholar 

  9. Hirst JA, Farmer AJ, Dyar A, et al. Estimating the effect of sulfonylurea on HbA1c in diabetes: a systematic review and meta-analysis. Diabetologia. 2013;56(5):973–84.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Genuth S. Should sulfonylureas remain an acceptable first-line add-on to metformin therapy in patients with type 2 diabetes? No, it’s time to move on! Diabetes Care. 2015;38(1):170–5.

    Article  CAS  PubMed  Google Scholar 

  11. Abrahamson MJ. Should sulfonylureas remain an acceptable first-line add-on to metformin therapy in patients with type 2 diabetes? Yes, they continue to serve us well! Diabetes Care. 2015;38(1):166–9.

    Article  CAS  PubMed  Google Scholar 

  12. Erhardt W, Bergenheim K, Duprat-Lomon I, et al. Cost effectiveness of saxagliptin and metformin versus sulfonylurea and metformin in the treatment of type 2 diabetes mellitus in Germany: a Cardiff diabetes model analysis. Clin Drug Invest. 2012;32(3):189–202.

    Article  CAS  Google Scholar 

  13. Deusenberry CM, Coley KC, Korytkowski MT, et al. Hypoglycemia in hospitalized patients treated with sulfonylureas. Pharmacotherapy. 2012;32(7):613–7.

    Article  CAS  PubMed  Google Scholar 

  14. Asplund K, Wiholm BE, Lithner F. Glibenclamide-associated hypoglycaemia: a report on 57 cases. Diabetologia. 1983;24(6):412–7.

    Article  CAS  PubMed  Google Scholar 

  15. Schejter YD, Turvall E, Ackerman Z. Characteristics of patients with sulphonurea-induced hypoglycemia. J Am Med Dir Assoc. 2012;13(3):234–8.

    Article  PubMed  Google Scholar 

  16. Li Y, Hu Y, Ley SH, et al. Sulfonylurea use and incident cardiovascular disease among patients with type 2 diabetes: prospective cohort study among women. Diabetes Care. 2014;37(11):3106–13.

    Article  CAS  PubMed  Google Scholar 

  17. Association The Japan Pharmaceutical. Summary report of the Drug Event Monitoring project in the 2010/11 financial year. J Jpn Pharm Assoc. 2011;63(11):1259–72.

    Google Scholar 

  18. Kajiwara A, Saruwatari J, Sakata M, et al. Risk factors for adverse symptoms during dipeptidyl peptidase-IV inhibitor therapy: a questionnaire-based study carried out by the Japan Pharmaceutical Association Drug Event Monitoring Project in Kumamoto Prefecture. Drug Saf. 2013;36(10):981–7.

    Article  CAS  PubMed  Google Scholar 

  19. Szalat A, Raz I. Gender-specific care of diabetes mellitus: particular considerations in the management of diabetic women. Diabetes Obes Metab. 2008;10(12):1135–56.

    PubMed  Google Scholar 

  20. Barnett AH, Cradock S, Fisher M, et al. Key considerations around the risks and consequences of hypoglycaemia in people with type 2 diabetes. Int J Clin Pract. 2010;64(8):1121–9.

    Article  CAS  PubMed  Google Scholar 

  21. Cryer PE. Glycemic goals in diabetes: trade-off between glycemic control and iatrogenic hypoglycemia. Diabetes. 2014;63(7):2188–95.

    Article  PubMed  Google Scholar 

  22. Seufert J, Brath H, Pscherer S, et al. Composite efficacy parameters and predictors of hypoglycaemia in basal-plus insulin therapy—a combined analysis of 713 type 2 diabetic patients. Diabetes Obes Metab. 2014;16(3):248–54.

    Article  CAS  PubMed  Google Scholar 

  23. Vlckova V, Cornelius V, Kasliwal R, et al. Hypoglycaemia with oral antidiabetic drugs: results from prescription-event monitoring cohorts of rosiglitazone, pioglitazone, nateglinide and repaglinide. Drug Saf. 2009;32(5):409–18.

    Article  CAS  PubMed  Google Scholar 

  24. Horton TJ, Grunwald GK, Lavely J, et al. Glucose kinetics differ between women and men, during and after exercise. J Appl Physiol (1985). 2006;100(6):1883–94.

    Article  CAS  Google Scholar 

  25. Faerch K, Borch-Johnsen K, Vaag A, et al. Sex differences in glucose levels: a consequence of physiology or methodological convenience? The Inter99 study. Diabetologia. 2010;53(5):858–65.

    Article  CAS  PubMed  Google Scholar 

  26. Franconi F, Campesi I, Occhioni S, et al. Sex-gender differences in diabetes vascular complications and treatment. Endocr Metab Immune Disord Drug Targets. 2012;12(2):179–96.

    Article  CAS  PubMed  Google Scholar 

  27. Cavalot F, Petrelli A, Traversa M, et al. Postprandial blood glucose is a stronger predictor of cardiovascular events than fasting blood glucose in type 2 diabetes mellitus, particularly in women: lessons from the San Luigi Gonzaga Diabetes Study. J Clin Endocrinol Metab. 2006;91(3):813–9.

    Article  CAS  PubMed  Google Scholar 

  28. Chiu CJ, Wray LA. Gender differences in functional limitations in adults living with type 2 diabetes: biobehavioral and psychosocial mediators. Ann Behav Med. 2011;41(1):71–82.

    Article  PubMed  Google Scholar 

  29. Hara Y, Hisatomi M, Ito H, et al. Effects of gender, age, family support, and treatment on perceived stress and coping of patients with type 2 diabetes mellitus. Biopsychosoc Med. 2014;8:16.

    Article  PubMed Central  PubMed  Google Scholar 

  30. Pietraszek A, Gregersen S, Hermansen K. Alcohol and type 2 diabetes. A review. Nutr Metab Cardiovasc Dis. 2010;20(5):366–75.

    Article  CAS  PubMed  Google Scholar 

  31. Sumida KD, Hill JM, Matveyenko AV. Sex differences in hepatic gluconeogenic capacity after chronic alcohol consumption. Clin Med Res. 2007;5(3):193–202.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Basch E. The missing voice of patients in drug-safety reporting. N Engl J Med. 2010;362(10):865–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Hakobyan L, Haaijer-Ruskamp FM, de Zeeuw D, et al. Comparing adverse event rates of oral blood glucose-lowering drugs reported by patients and healthcare providers: a post hoc analysis of observational studies published between 1999 and 2011. Drug Saf. 2011;34(12):1191–202.

    Article  CAS  PubMed  Google Scholar 

  34. Isacson D, Johansson L, Bingefors K. Nationwide survey of subjectively reported adverse drug reactions in Sweden. Ann Pharmacother. 2008;42(3):347–53.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We would like to thank the Japan Pharmaceutical Association and the Kumamoto Pharmaceutical Association, for providing the clinical data from a cross-sectional nation-wide survey of the JPA DEM project.

Author information

Authors and Affiliations

  1. Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan

    Ayami Kajiwara, Ayana Kita, Junji Saruwatari, Kentaro Oniki, Kazunori Morita & Kazuko Nakagawa

  2. Kumamoto Pharmaceutical Association, Kumamoto, Japan

    Masato Yamamura, Motoji Murase, Haruo Koda & Seisuke Hirota

  3. Division of Pharmaceutical Molecular Design, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan

    Tadao Ishizuka

  4. Center for Clinical Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan

    Tadao Ishizuka & Kazuko Nakagawa

Authors
  1. Ayami Kajiwara
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ayana Kita
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Junji Saruwatari
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kentaro Oniki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kazunori Morita
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Masato Yamamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Motoji Murase
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Haruo Koda
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Seisuke Hirota
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Tadao Ishizuka
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kazuko Nakagawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kazuko Nakagawa.

Ethics declarations

Funding

This work was supported by a grant-in-aid for scientific research: KAKENHI(C) No. 23510348 and 26360049 from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

Conflict of interest

Kajiwara A, Kita A, Saruwatari J, Oniki K, Morita K, Yamamura M, Murase M, Koda H, Hirota S, Ishizuka T, and Nakagawa K declare that they have no conflict of interest.

Ethical approval

All procedures in this study were in accordance with the 1964 Helsinki declaration and its amendments, and the institutional ethics committee of the Faculty of Life Sciences, Kumamoto University which approved the study.

Informed consent

Informed consent was obtained from all individual participants included in this study.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 33 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kajiwara, A., Kita, A., Saruwatari, J. et al. Higher Risk of Sulfonylurea-associated Hypoglycemic Symptoms in Women with Type 2 Diabetes Mellitus. Clin Drug Investig 35, 593–600 (2015). https://doi.org/10.1007/s40261-015-0314-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40261-015-0314-6

Keywords

Search

Navigation