A case of severe relapsing sulphonylurea-induced hypoglycaemia

Abstract

The authors report a case of a 64-year-old woman who was diagnosed with severe relapsing sulphonylurea-induced hypoglycaemia. Sulphonylureas are frequently used in patients with type 2 diabetes mellitus. They promote insulin secretion independent of the prevailing glucose level and thus are associated with an increased risk of hypoglycaemia. In patients with adequate renal function, gliclazide’s effect lasts 10–24 hours and it is usually completely eliminated within 144 hours postdose. Since our patient suffered from chronic kidney disease, gliclazide’s effect was prolonged and she was experiencing spontaneous hypoglycaemic episodes up to 21 days postomission of gliclazide. This case highlights two important aspects. Primarily, the prolonged effect of sulphonylureas in patients with impaired renal function, hence highlighting the need to be cautious prior to prescribing sulphonylureas in such patients. Secondly, the importance of prolonged observation of patients on sulphonylureas even after the initial hypoglycaemic event is corrected, due to the extended effects of such drugs.

Background

Hypoglycaemia is a frequently encountered, potentially serious condition. The most common cause of hypoglycaemia in type 2 diabetes is antidiabetic agents; mainly exogenous insulin and sulphonylureas.¹ These agents reduce glucose levels invariably of the prevailing glucose level and hence provide a high risk for hypoglycaemia.² Treating and preventing hypoglycaemia is of paramount importance. Hypoglycaemia may lead to serious events, provoking major vascular events in the acute setting and possible cognitive impairment in the long term. The authors present a case of severe relapsing sulphonylurea-induced hypoglycaemia.^{3 4}

Case presentation

A 64-year-old woman presented to hospital in view of recurrent severe hypoglycaemic episodes. These hypoglycaemic episodes were occuring with increasing frequency over the last few months. She was a type 2 diabetic managed on immediate release gliclazide 80 mg two times/day for a number of years. She also suffered from chronic kidney disease and severe aortic stenosis and was waiting for an aortic valve replacement. On arrival to the emergency department, her capillary blood glucose level was 2.5 mmol/L and she was encouraged to drink a sugary drink and was administered 100 mL of 10% dextrose intravenously. After her capillary blood glucose level improved to 6 mmol/L, a detailed history was obtained. She denied any change in her medications but admitted to frequent omission of her gliclazide in view of the hypoglycaemic episodes. She experienced a 5 kg unintentional weight loss in spite of a good appetite; she denied any change in bowel habit, abdominal pain, recent febrile episodes, headaches and chest pain.

A physical examination was unremarkable except for a harsh ejection systolic murmur and a soft second heart sound consistent with her severe aortic stenosis.

In view of the above presentation, the patient was admitted for further observation and investigations. In the course of her in-patient stay, she experienced multiple further episodes of spontaneous hypoglycaemia. During one of her hypoglycaemic episodes (plasma glucose level of 2 mmol/L), a serum cortisol, proinsulin, insulin, C-peptide and β-hydroxybutyrate levels were taken. She was started on a continuous 5% dextrose intravenous infusion at 84 mL/hour to prevent further hypoglycaemic episodes and her gliclazide was omitted.

Initial laboratory data revealed a normal full blood count, C-reactive protein, serum electrolytes and liver function tests. Her serum creatinine level was chronically elevated at 165 μmol/L (estimated glomerular filtration rate (eGFR): 29 mL/min/1.73 m²). There was no deterioration in her renal function (previous serum creatinine level was 170 μmol/L with an eGFR: 28 mL/min/1.73 m²). Her cortisol level was 285 nmol/L and her serum-free T4, serum-free T3 and thyroid-stimulating hormone (TSH) were within normal limits. In view of the inappropriately low cortisol level, a short synacthen test was performed. This ruled out adrenal insufficiency. A non-contrast CT scan of her thorax, abdomen and pelvis ruled out any malignancy in view of her history of unintentional weight loss.

The proinsulin, insulin and C-peptide levels were elevated and β-hydroxybutyrate level was low consistent with endogenous insulin secretion secondary to gliclazide’s effect. After 5 days of stable glucose levels and no further hypoglycaemic episodes, the patient was discharged. She was advised to stay off gliclazide for now and was given a close out-patient follow-up appointment.

After 3 weeks, she was readmitted with another hypoglycaemic episode that required intravenous dextrose. The patient reported that she had had several recurrent fasting hypoglycaemic episodes at home despite being off gliclazide since her previous presentation.

Serum chromogranin A was elevated at 923 µg/L (normal value: <102 µg/L). However, both omeprazole administration and chronic kidney disease could have led to a false-positive result. MRI of her pancreas and liver did not detect any pancreatic and liver pathology. Furthermore, an octreotide scintigraphy scan did not demonstrate any abnormal focus of increased uptake. During her admission, she sustained other episodes of fasting hypoglycaemia. Proinsulin, insulin, C-peptide and β-hydroxybutyrate levels and a urine sulphonylurea screen were taken during one of her hypoglycaemic episodes (plasma glucose level of 2.6 mmol/L). The proinsulin, insulin and C-peptide levels were elevated (although not as much as before) and β-hydroxybutyrate level was low while the urine for sulphonylurea screen was still positive 3 weeks after stopping gliclazide. These results are summarised in table 1.

Table 1.

C-peptide, insulin, proinsulin and β-hydroxybutyrate levels on day 1 and day 21 post-gliclazide omission

	C-peptide (ng/mL)	Insulin (μU/mL)	Proinsulin (pmol/L)	β-hydroxybutyrate (μmol/L)
Day 1 post-gliclazide omission	18.9	43.8	36.3	<60
Day 21 post-gliclazide omission	3.3	9.9	4.1	<60

Throughout her admission, the frequency of her hypoglycaemic episodes decreased and eventually she started to have episodes of hyperglycaemia. In view of her chronic kidney disease and severe sulphonylurea-induced hypoglycaemia, she was started on a daily dose of insulatard 5 units/day. Her glycaemic control was satisfactory without further hypoglycaemic or hyperglycaemic episodes and she was eventually deemed fit for discharge with regular out-patients follow-up appointments.

Outcome and follow-up

Following discharge, the patient has remained well with satisfactory glycaemic control (HbA_1c of 44.3 mmol/mol) and is being followed up regularly by the diabetologists and diabetes education nurses.

Discussion

In patients with diabetes mellitus, hypoglycaemia is defined as a plasma glucose level of ≤3.9 mmol/L.⁵ The American Diabetes Association and the Endocrine Society Workgroup on hypoglycaemia recommends classifying hypoglycaemia in diabetics into five categories⁶:

1. Severe hypoglycaemia: an event requiring assistance of another person to actively administer carbohydrates, glucagon or other corrective actions. Plasma glucose levels are not necessary but the recovery in neurological state are considered sufficient evidence for a low plasma glucose level.

2. Documented symptomatic hypoglycaemia: an event with typical symptoms of hypoglycaemia associated with a plasma glucose level of ≤3.9 mmol/L.

3. Asymptomatic hypoglycaemia: a plasma glucose level of ≤3.9 mmol/L without any associated symptoms of hypoglycaemia.

4. Probable symptomatic hypoglycaemia: an event with typical symptoms of hypoglycaemia without plasma glucose level determination.

5. Pseudohypoglycaemia: an event where a diabetic patient reports typical symptoms of hypoglycaemia associated with a plasma glucose level of >3.9 mmol/L but approaching that level.

There are multiple risk factors that can precipitate hypoglycaemia. These include tight glycaemic control, blood glucose fluctuations, long duration of diabetes, impaired awareness of hypoglycaemia, severe hepatic dysfunction, impaired renal function and renal dialysis therapy, malignancy including neuroendocrine tumours and non-islet cell tumours, increased physical exercise, increasing age, alcohol, food malabsorption, adrenal insufficiency, growth hormone deficiency, hypothyroidism, hypopituitarism and autoimmune insulin syndromes. Furthermore, drug interactions with hypoglycaemic agents are also an important cause of hypoglycaemia.^{1 2} Figure 1 outlines the differential diagnosis and investigations of adult hypoglycaemia.⁷

Figure 1.

Flowchart outlining the differential diagnosis and investigations of hypoglycaemia. Adapted from Gama et al. EUS, endoscopic ultrasound; GH, growth hormone; IGF, insulin-like growth factor; TFT, thyroid function tests.

For patients with type 2 diabetes, sulphonylureas are the oral antidiabetic agents that pose the greatest risk for iatrogenic hypoglycaemia especially in the elderly and those with renal and liver dysfunction.⁸ Sulphonylureas bind to the sulphonylurea receptor in the pancreatic β-cells. The sulphonylurea receptor is a component of the ATP-sensitive potassium channel. This channel regulates the release of insulin from pancreatic β-cells. Sulphonylureas by binding and inhibiting these channels, lead to a calcium influx which stimulates insulin secretion.^{8 9} Gliclazide is a second-generation sulphonylurea.⁸ In patients with adequate renal function, gliclazide's effect lasts 10-24 hours and it is usually completely eliminated 144 hours postdose.¹⁰ Thus, since about 60%–70% of gliclazide is excreted in the urine, its half-life is prolonged in diabetic patients with chronic kidney disease.¹⁰

Hence, due to gliclazide's prolonged action, glucose needs to be monitored every 1–2 hours and ideally a slow infusion of 5% or 10% dextrose should be administered in cases of recurrent hypoglycaemic episodes.⁵ A slow infusion is preferred from a bolus infusion as a bolus represents an excessive dextrose load and this may result in excess insulin secretion from the sulphonylurea sensitised pancreatic β-cells resulting in rebound hypoglycaemia.^{5 9} For the same reason, glucagon should also be avoided as it may also cause a reactive hypoglycaemia due to excessive insulin release in response to the glucagon-induced hyperglycaemia.⁵ Furthermore, glucagon can stimulate insulin release directly causing a delayed drop in plasma glucose.⁹ In addition, conscious patients with recurrent episodes of hypoglycaemia should also be advised to eat small regular meals and snacks (containing long-acting carbohydrates), after the initial hypoglycaemic episode is corrected.²

Sulphonylurea-induced hypoglycaemia may require a long period of observation due to the prolonged action of sulphonylureas.⁹ In addition, a thorough search for the underlying cause behind the sulphonylurea-induced hypoglycaemia is necessary. This case was noteworthy due to the prolonged action of gliclazide in a patient with stable chronic kidney disease resulting in severe relapsing sulphonylurea-induced hypoglycaemia.

In cases of severe relapsing sulphonylurea-induced hypoglycaemia, treatment options include octreotide and diazoxide.⁹ Octreotide inhibits insulin, glucagon and growth hormone secretion. The dose and duration of octreotide administration is still a controversial issue. One might consider a single 75 µg subcutaneous dose of octreotide after 50 mL of 50% dextrose infusion if patients are still having recurrent hypoglycaemia.⁵ Other dose regimens include 50–100 µg of octreotide given every 6–12 hours.¹¹ Another option includes diazoxide. This inhibits insulin release but may cause hypotension and reactive tachycardia and is best avoided in patients with aortic stenosis.⁹ A three-arm crossover study revealed that hypoglycaemia occurred less frequently in subjects on octreotide when compared with those on diazoxide.¹¹

In conclusion, sulphonylureas should be used with caution especially in patients with renal and hepatic insufficiency and in the elderly. Patient education is crucial, especially early recognition of the symptoms and signs of hypoglycaemia with emphasis on frequent proactive capillary blood glucose monitoring. This allows patients to detect and correct hypoglycaemic episodes earlier. In addition, in view of the prolonged action of sulphonylureas, physicians should be made aware that it is unsafe to discharge patients with sulphonylurea-induced hypoglycaemia, after the initial hypoglycaemic event is corrected as these hypoglycaemic episodes may recur.⁵

Learning points.

• Hypoglycaemia is a potentially serious condition with the most common cause in type 2 diabetics being antidiabetic agents; mainly exogenous insulin and sulphonylureas.

• Sulphonylureas should be used with caution in patients with renal and hepatic insufficiency and in the elderly.

• Physicians and patients should be made aware of the importance of prolonged observation with frequent glucose monitoring for patients who develop hypoglycaemia while on sulphonylureas, even after the initial hypoglycaemic event is corrected.