Original Research
The Hypoglycemic Risk of Glyburide (Glibenclamide) Compared with Modified-Release Gliclazide

https://doi.org/10.1016/j.jcjd.2015.01.001Get rights and content

Abstract

Objectives

The risk for hypoglycemia when taking glyburide compared with modified-release gliclazide remains to be established in older adults in routine care. We investigated the risk of a hospital encounter with hypoglycemia following a new prescription for glyburide compared with modified-release gliclazide.

Methods

In 2 population-based matched retrospective cohort studies in Ontario, Canada, between 2002 and 2011, we examined older adults who were newly prescribed glyburide or gliclazide as monotherapy or in the presence of metformin. Our primary outcome was a hospital encounter with hypoglycemia assessed within 90 days.

Results

The baseline characteristics between matched groups were similar. Initiating glyburide vs. gliclazide as monotherapy was associated with a higher risk for a hospital encounter with hypoglycemia (69 patients of 4374 taking glyburide [1.58%] vs. 8 patients of 4374 taking gliclazide [0.18%], absolute risk increase 1.40% [95% CI 1.01% to 1.79%], number needed to harm 71 [55 to 99], odds ratio 8.63 [95% CI 4.15 to 17.93], p<0.0001). Similar findings were noted when glyburide vs. gliclazide was initiated in the presence of metformin (110 patients of 8038 taking glyburide [1.37%] vs. 19 patients of 8038 taking gliclazide [0.24%], absolute risk increase 1.13% [95% CI 0.86% to 1.40%], number needed to harm 77 [71 to 116], odds ratio 6.06 [95% CI 3.68 to 9.97], p<0.0001).

Conclusions

Glyburide was associated with a higher risk for hypoglycemia than modified-release gliclazide. The results of our studies may help to convince healthcare professionals who use glyburide to consider modified-release gliclazide as a safer alternative.

Résumé

Objectifs

Il reste à déterminer le risque d’hypoglycémie lors de la prise de glyburide comparativement à la prise de gliclazide à libération modifiée chez les aînés en soins courants. Nous avons étudié le risque d’une visite à l’hôpital liée à l’hypoglycémie à la suite d’une nouvelle ordonnance de glyburide par rapport au gliclazide à libération modifiée.

Méthodes

Dans 2 études rétrospectives, en population, de cohortes appariées en Ontario, au Canada, entre 2002 et 2011, nous avons examiné des aînés qui avaient nouvellement reçu une ordonnance de glyburide ou de gliclazide en monothérapie ou en présence de metformine. Notre critère d’évaluation principal était une visite à l’hôpital et l’hypoglycémie évaluées dans les 90 jours.

Résultats

Les caractéristiques initiales entre les groupes appariés étaient similaires. L’introduction du glyburide vs du gliclazide en monothérapie a été associée à un risque plus élevé d’une visite à l’hôpital liée à l’hypoglycémie (69 patients sur 4374 prenant du glyburide [1,58 %] vs 8 patients sur 4374 prenant du gliclazide [0,18 %], augmentation absolue du risque, 1,40 % [IC à 95 %, 1,01 % à 1,79 %], nombre de sujets à traiter pour observer un effet indésirable, 71 [55 à 99], ratio d’incidence approché, 8,63 [IC à 95 %, 4,15 à 17,93], p < 0,0001). Des résultats similaires ont été notés lors de l’introduction du glyburide vs au gliclazide en présence de metformine (110 patients sur 8038 prenant du glyburide [1,37 %] vs 19 patients sur 8038 prenant du gliclazide [0,24 %], augmentation du risque absolu, 1,13 % [IC à 95 %, 0,86 % à 1,40 %], nombre de sujets à traiter pour observer un effet indésirable, 77 [71 à 116], ratio d’incidence approché, 6,06 [IC à 95 %, 3,68 à 9,97], p < 0,0001).

Conclusions

Le glyburide a été associé à un risque plus élevé d’hypoglycémie que le gliclazide à libération modifiée. Les résultats de nos études peuvent aider à convaincre les professionnels de la santé qui utilisent le glyburide à envisager le gliclazide à libération modifiée comme une alternative qui démontre une plus grande innocuité.

Introduction

Sulfonylureas are easy to administer, low in cost and, through their insulin-secreting mechanism, are among the most potent of all oral hypoglycemic agents 1, 2 These drugs, however, must be used very carefully in older adults to avoid hypoglycemia because this population commonly has medical comorbidities, takes multiple medications and has altered drug metabolism.

In Canada, glyburide (glibenclamide) and gliclazide are 2 commonly prescribed sulfonylureas. Because of glyburide’s high affinity for the sulfonylurea receptor (3), its long duration of action and its glucose-lowering metabolites (4), the risk for hypoglycemia with glyburide is anticipated to be higher than that with other sulfonylureas 5, 6, 7. Accordingly, diabetes guidelines have cautioned against the use of glyburide when treating older persons in favour of other oral hypoglycemic agents (8). However, to our knowledge, the risk for hypoglycemia when using glyburide compared with a long-acting alternative, modified-release gliclazide (9), has not been examined in a large representative population of older adults in routine practice. For this reason, we conducted 2 population-based cohort studies to examine the risk of hospital encounters with hypoglycemia after the initiation of glyburide vs. once-daily modified-release gliclazide in the outpatient setting.

Section snippets

Study design and setting

We conducted 2 population-based matched retrospective cohort studies of older adults using linked healthcare databases in Ontario, Canada. Ontario has approximately 1.8 million adults aged 65 years or older who have comprehensive universal healthcare, including coverage for outpatient prescription medications, physician services, hospitalizations and diagnostic testing (10). The reporting of these studies follows guidelines for observational studies (Appendix Table A1) (11).

The studies were

Baseline characteristics

We identified 18 804 patients who had been prescribed glyburide (n=13 550) or gliclazide (n=5254). Baseline characteristics of the 2 groups before and after matching are presented in Table 1, and the characteristics of patients with and without laboratory values available in the year prior are illustrated in Appendix Table A4. After matching, we retained 4374 patients in each group, and baseline characteristics were similar in the groups. Over the course of the study, there were 4288 unique

Principal findings and main implications

Despite cautionary guidelines, glyburide continues to be initiated in older adults in routine care (8). Yet long-acting modified-release gliclazide is more convenient for patients (once a day) than the many glyburide dosing regimens. When prescribed as monotherapy or in the presence of metformin, modified-release gliclazide is a safer sulfonylurea than glyburide and is associated with less hypoglycemia. Although modified-release gliclazide has a long duration of action, its hypoglycemia risk

Conclusions

Although glyburide is effective in lowering blood glucose in patients with diabetes, its use in older adults is associated with a much higher risk for hypoglycemia than is modified-release gliclazide. The results of our studies may help to convince physicians, pharmacists and patients who still use glyburide to consider modified-release gliclazide a more convenient and safer alternative.

Acknowledgements

We thank Brogan Inc, Ottawa, for use of its drug product and therapeutic class database. We thank Gamma Dynacare for the use of their outpatient laboratory database and the team at London Health Sciences Centre, St Joseph’s Health Care and the Thames Valley Hospitals for providing access to the Cerner laboratory database. We thank Salimah Shariff, PhD (from ICES Western in London, Canada) for administrative support.

References (36)

  • A.J. Krentz et al.

    Comparative tolerability profiles of oral antidiabetic agents

    Drug Saf

    (1994)
  • D. Tessier et al.

    Glibenclamide vs gliclazide in type 2 diabetes of the elderly

    Diabet Med

    (1994)
  • Meneilly GS, Knip A, Tessier D. Canadian Diabetes Association Guidelines: Diabetes in the elderly, 2013....
  • AA Pharma Inc. Product Monograph: Gliclazide MR: Gliclazide modified-release tables 30 mg. 2010....
  • S. Bronskill et al.

    Aging in Ontario: An ICES chartbook of health service use by older adults

    (2010)
  • A.R. Levy et al.

    Coding accuracy of administrative drug claims in the Ontario drug benefit database

    Can J Clin Pharmacol

    (2003)
  • A.M. Patel et al.

    Statin toxicity from macrolide antibiotic coprescription: A population-based cohort study

    Ann Intern Med

    (2013)
  • N.F. Siddiqui et al.

    Secular trends in acute dialysis after elective major surgery: 1995 to 2009

    CMAJ

    (2012)
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