Glibenclamide-induced profound hypoglycaemic crisis: a case report

Abstract

The value of sulphonylureas in the long-term treatment of type II diabetes has been questioned. The potential benefits of an antidiabetic drug must be carefully weighed against the risk of developing hazardous adverse effects like hypoglycaemia. We present drug-induced hypoglycaemia in a 77-year-old Pakistani male who had hypertension, type II diabetes and renal parenchymal disease (grade I), presented to the emergency department complaining of a 1-day history of fever, loose motions and drowsiness. His fever was low grade, intermittent, and not associated with rigors and chills. He had four episodes of watery stools for 1 day, with no associated vomiting but with drowsiness. He was aphasic, unable to walk and did not recognize his family members. The patient was taken to his local doctor who found him to be hypoglycaemic, with a blood sugar of 45 mg/dl. He was managed with intravenous (IV) dextrose and referred to the hospital. Hypoglycaemia is perhaps the most widespread and underreported complication of oral hypoglycaemic agents and may lead to overwhelming morbidity and mortality. Patient evaluation and proper counselling may help in identifying patients at greatest risk and avoid complications associated with these commonly prescribed drugs.

Introduction

Sulfonylureas were among the first oral hypoglycaemic agents developed, in addition to progressing from being a building block in the treatments connected with type II diabetes mellitus. These agents are widely prescribed, partly due to their low cost and tolerability [Rogers et al. 2011]. Glibenclamide (glyburide), a second-generation sulfonylurea is the most well known. The American Diabetes Association (ADA) recommends the addition of a sulphonylurea, when target haemoglobin A1c (HbA1c) has not been achieved with first-line agents [Nathan et al. 2009]. According to the ADA algorithm, all patients should start with therapeutic lifestyle modifications and metformin if no contraindications are present. Next, depending on the HbA1c level, patients should receive either a sulfonylurea or insulin [Nathan et al. 2009]. These agents produce their hypoglycaemic effects by stimulating the pancreas to secrete insulin; thus hypoglycaemia is a major adverse effect [Burge et al. 1998]. Glibenclamide is associated with hypoglycaemia more frequently when compared with other sulfonylureas [Gangji et al. 2007], and it is a significant medical concern in the type II diabetic geriatric population. A variety of risk factors need to be examined when investigating sulfonylurea-induced hypoglycaemia. These include advanced age (>60 years), polypharmacy, undercurrent health issues like renal impairment, alcohol intake, sepsis, intentional overdose, as well as liver cirrhosis [Bussing and Gende, 2002]. Currently, glibenclamide is not recommended for patients with renal impairment (creatinine clearance of less than 50 ml/min) or severe hepatic impairment, owing to the risk of hypoglycaemia. Moreover, it should be used with caution in elderly patients [Rogers et al. 2011]. Ageing alters the pharmacokinetic and pharmacodynamic properties of glibenclamide, and a lower elimination rate with a higher volume of distribution and free fraction is observed [Schwinghammer et al. 1991]. We present a case report of glibenclamide-induced severe hypoglycaemia. Written informed consent was obtained from the patient for publication of this case report and any associated images. To our knowledge, this is the first case of glibenclamide-induced hypoglycaemia reported from Khyber Pakhtunkhwa, Pakistan.

Case presentation

A 77-year-old gentleman presented to the general practitioner (GP) with complaints of fever, loose motions and drowsiness of 1-day duration. His fever was low grade, intermittent and not associated with rigors and chills. He had experienced four episodes of watery stools during the previous 24 hours with no associated vomiting. The patient was drowsy, aphasic, did not recognize his family members and was unable to walk. The local GP found him to be hypoglycaemic with a blood sugar of 45 mg/dl. He was managed with dextrose and referred to the hospital.

There was no history of decreased food intake. The patient had been taking normal diet, appropriate for culture and locality, that is, naan (bread), a staple in the diet taken three times daily with beans, pulses or meat with vegetables. This patient had been increasingly hungry due to recurrent hypoglycaemia in the preceding weeks and was eating more than usual.

The patient was a diagnosed case of hypertension, renal parenchymal disease (grade I) and type II diabetes mellitus, and had been taking the tablet form of glibenclamide, 5 mg twice a day for the past 5 years, amlodipine besylate, 5 mg occasionally, and dutasteride and tamsulosin combination for his benign prostatic hyperplasia. His last dose of glibenclamide had been administered 24 hours prior to admission. The patient was brought immediately to the hospital. He was pale and dehydrated, while his examination was otherwise unremarkable. His blood glucose was 50 mg/dl and the other baseline investigations are listed in Table 1. He was placed on 3 hourly blood glucose monitoring record (Figure 1) and was started on IV 5% dextrose along with normal saline. An intake and output record was maintained. Over the next 24 hours the patient experienced repeated hypoglycaemic episodes that were treated with dextrose boluses. Once the patient became normoglycaemic and was able to maintain it for a period of 24 hours without any IV fluids, he was discharged with a plan to follow up in 1 week with blood glucose readings. All the hypoglycaemic agents were withheld. The patient was asked to maintain a record of blood glucose levels. He was advised to take repaglinide on an as-required basis. His renal profile remained unchanged after 1 week and his self-monitored blood glucose levels were within normal limits. He was well controlled on diet and exercise, hence no antidiabetic agent was re-started.

Table 1.

Laboratory results.

Urine examination		Urea	89 mg/dl
Albumin	+	Creatinine	2.64 mg/dl
Sugar	Nil	eGFR	25.11 ml/min/1.73 m2
Leukocytes	+	Chloride	110.9 mmol/l
Nitrate	Nil	Bicarbonate	19.4 mmol/l
Pus cells	02–03/HPF	Lactic acid	24.2 mg/dl
Complete blood count		ALT (SGPT)	23 U/l
Haemoglobin	12.5 g/dl	Uric Acid	5.7 mg/dl
Total leukocytes	10.8 × 109/l	Calcium	6.9 mg/ dl
Platelet count	175 × 109/l	Phosphorus	4.4 mg/ dl
Neutrophils	90%	Amylase	47 U/l
Lymphocytes	8%	C-reactive protein	0.61 mg/dl
Monocytes	2%	Ionized calcium	1.09 mmol/l
Biochemistry		Albumin	3.1 g/dl
Sodium	139.9 mmol/l	Mg	2.8 g/dl
Potassium	4.36 mmol /l	pH	7.34 mmHg
HbA1c	5.70%	trophi	0.01 ng/ml

IV, intravenous; BPH, benign prostatic hyperplasia; PRN, pro re nata (when necessary); eGFR, estimated glomerular filtration rate; HPF, high power field; HbA1c, glycated haemoglobin; ALT, alanine transaminase; SGPT, serum glutamate-pyruvate transaminase; trophi, Trophonin I.

Figure 1.

Blood glucose measurements.

Discussion

Hypoglycaemia is a well-known complication in diabetic patients and is mostly related to drugs. However, its occurrence in nondiabetic patients is less well described [Binder and Bendtson, 1992]. Mild, and even potentially asymptomatic hypoglycaemia has not routinely been documented in the literature, reinforcing the under-reporting of drug-induced hypoglycaemia. In the most recent systematic review conducted that focused on patients taking medications at recommended doses, severe, symptomatic hypoglycaemic episodes were still experienced [Murad et al. 2009]. Cases of hypoglycaemia without apparent cause should alert healthcare professionals to the possibility of unintentional oral hypoglycaemic agents’ ingestion. In our case, there was no hint of planned or accidental overdosing. The adverse reaction in the form of hypoglycaemia in this case had been confirmed by assessment through the Naranjo adverse drug reactions probability scale and the score was 6, which indicated probable adverse reaction. Adverse effects are further potentiated by concomitant administration of salicylates, coumarin derivatives, anticholinergics and sulphonamides. However, in our case the patient had no past medication history of such kind. The presentation of our patient is consistent with the results of a report on 57 cases by Asplund and colleagues in which a fatal outcome was observed even with small doses of glibenclamide (2.5–5 mg/day) [Asplund et al. 1983]. The contributing factors, including impaired renal function, poor intake and diarrhoea were present in the current case. Furthermore, Schwingwhamer and colleagues pointed out the impact of the ageing process on the pharmacokinetics and pharmacodynamics of glibenclamide [Schwingwhamer et al. 1991]. In our patient, there appeared to be a prolonged hypoglycaemic effect lasting 24–48 hours.

Conclusion

Glibenclamide should be used with caution especially in geriatic population. All patients taking glibenclamide must be educated on common signs and symptoms of hypoglycaemia. Specific characteristics, including renal insufficiency and advancing age may predispose patients to the development of drug-induced hypoglycaemia. Patient evaluation is critical in identifying patients at greatest risk and in preventing complications. Preventative strategies include drug avoidance, minimizing dose of offending agents, using controlled-release formulations where available, limiting use of the multiple medications that may cause hypoglycaemia, and frequent, proactive blood-glucose monitoring.