Recommendations to avoid use of glibenclamide in the elderly and renal-impaired

Glibenclamide associated with higher risk of hypoglycaemia compared with other sulfonylureas

HSA had conducted a benefit-risk assessment of glibenclamide in consultation with endocrinologists and its Product Vigilance Advisory Committee (PVAC), prompted by reports of a disproportionately higher number of hospitalisation cases due to hypoglycaemia associated with glibenclamide as compared to other sulfonylureas (SUs). Based on the review, HSA would like to advise healthcare professionals that the use of glibenclamide should be avoided in elderly patients and those with renal impairment, as these patients are more susceptible to severe and recurrent hypoglycaemia.

Background

Glibenclamide has been registered in Singapore since 1990 as Daonil® (sanofi-aventis Singapore Pte Ltd) and there are nine generic products. It is also available as a combination product with metformin, known as Glucovance® (Merck Pte Ltd).

Studies have suggested that the risk of hypoglycaemia is higher in glibenclamide compared to other SUs due to its longer half-life and the presence of active metabolites which could accumulate in patients with poor renal function.^1,2

Furthermore, glibenclamide has greater penetration of pancreatic tissue, higher affinity for pancreatic beta-cell SU receptors,^3-6 and increased insulin sensitivity compared to some SUs.⁷ It is also known to attenuate counter-regulatory actions during hypoglycaemic episodes.⁸ Taken together, glibenclamide can result in sustained insulin release for protracted periods even after the drug is discontinued.^3-5 Patients with renal impairment, as well as the elderly with age-related decline in renal function, would be at a greater risk of developing severe, long-lasting hypoglycaemia.

The findings from literature are consistent with observations by local doctors, who reported that prolonged and recurrent hypoglycaemia were more common in glibenclamide users. The sustained effect of glibenclamide after drug discontinuation was also seen in some renal-impaired patients, who experienced recurrent hypoglycaemia while being treated with glucose infusion.

Evidence for comparative safety

Several studies which evaluated the safety of SUs consistently showed that glibenclamide is associated with a higher risk of hypoglycaemia when compared to other SUs, including glipizide, gliclazide and glimepiride.

• In a meta-analysis of 21 studies, glibenclamide was associated with a 83% greater risk of experiencing at least one episode of hypoglycaemia compared to other SUs.³ In addition, two of these studies reported major hypoglycaemic episodes, and the risk was over four times higher for glibenclamide compared with other SUs, although this was not statistically significant.

• In a retrospective cohort study (n=13,963), glibenclamide had the highest rate of hypoglycaemia at 16.6 per 1000 person-years compared to other SUs.⁴

• In a retrospective cohort study (n=33,243), the relative risks for hypoglycaemia with gliclazide and glipizide compared with glibenclamide were 0.74 (95% CI 0.59, 0.92) and 0.60 (95% CI 0.40, 0.92), respectively.⁹

• In a retrospective chart review of 57 cases of glibenclamide-associated hypoglycaemia reported to the Swedish Adverse Drug Reactions Advisory Committee, 24 patients had protracted hypoglycaemia lasting 12 to 72 hours, and 10 died.¹⁰ Death was seen even in patients who were on small doses of glibenclamide (2.5–5mg/day). Contributing factors included renal impairment, low food intake, diarrhoea, alcohol intake and interaction with other drugs.

Recommendations from WHO and other guidelines

In 2012, the World Health Organisation (WHO) reviewed the comparative safety and efficacy of glibenclamide in the elderly. The authors found that there was an increased relative risk of hypoglycaemia and resulting harm from the use of glibenclamide versus any of the other second-generation SUs, particularly gliclazide and glipizide.¹¹ They concluded that the evidence “unequivocally recommends against the use of glibenclamide in elderly patients”, and recommended that it should not be used for those older than 60 years of age.

In 2013, the Canadian Diabetes Association's guidelines on Pharmacologic Management of Type 2 Diabetes recommended that classes of antihyperglycaemic agents other than SUs should first be considered in patients at high risk of hypoglycaemia, such as the elderly and those with renal failure.¹² If a SU had to be used in such individuals, gliclazide and glimepiride were associated with less hypoglycaemia than glibenclamide.

The Kidney Disease Outcomes Quality Initiative (KDOQI) 2012 Diabetes Guidelines also stated that glibenclamide should be avoided in patients with chronic kidney disease (CKD) stages 3, 4 and 5 (i.e. glomerular filtration rate (GFR) <60ml/min/1.73m²).¹³ The KDOQI Guidelines recommended glipizide as the preferred second-generation SU, as it did not have active metabolites and did not increase the risk of hypoglycaemia.

HSA's advisory

After in-depth review and consultation with endocrinologists and its PVAC, HSA's assessment and recommendations are as follows: Glibenclamide should be avoided

• In patients older than 60 years old, or

• In patients with estimated glomerular filtration rate (eGFR) less than 60ml/min/1.73m², or

• In patients with serum creatinine above the upper limit of normal

The local package inserts of glibenclamide-containing medicines will be strengthened to reflect these recommendations. A Dear Healthcare Professional Letter was issued on 4 December 2013 to healthcare professionals to advise them on these new recommendations.

Healthcare professionals are advised to take into consideration the above recommendations when prescribing glibenclamide or Glucovance®. They are also encouraged to report adverse reactions associated with the use of glibenclamide or other SUs to the Vigilance Branch of HSA.

References

1. Drug Saf 1994; 11: 223-41

2. Micromedex® 2.0. Clinical Pharmacy Database. 2012

3. Diabetes Care 2007; 30: 389-94

4. J Am Geriatr Soc1996; 44: 751-5

5. Metabolism 2006; 55: 78-83

6. Acta Endocrinol (Copenh)1984; 105: 385-90

7. Diabet Med1994; 11: 974-80

8. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 12th edn

9. J Clin Epidemiol 1997; 50: 735-41

10. Diabetologia 1983; 24: 412-7

11. http://www.who.int/selection_medicines/committees/expert/19/applications/Sulfonylurea_18_5_A_R.pdf

12. Can J Diabetes 2013; 37: S61-8

13. Am J Kidney Dis 2012; 60: 850-86