Reminder of important clinical lesson

CASE REPORT

Hypoglycaemia begets hypoglycaemia

Alok Arora

Acute Medicine, Frenchay SUMMARY urinary incontinence. Glycaemic targets should be

Hospital, Bristol, UK Drug-induced (insulin/insulin secretagogue) individualised, taking into consideration the
Correspondence to hypoglycaemia is the most common cause of patient’s overall health and life expectancy. Older
Dr Alok Arora, hypoglycaemia particularly in the elderly. It is estimated people may tolerate higher levels of blood glucose
alokjarora@hotmail.com that hypoglycaemia of any severity occurs annually in before they develop osmotic symptoms because of
5–20% of patients taking antihyperglycaemic agents. a higher renal threshold for glucose with increasing
Although these hypoglycaemic episodes are rarely fatal, age. On the other hand, they may appear to toler-
they can be associated with serious clinical sequelae. ate lower levels of blood glucose because of dimin-
The half-life for most sulfonylurea medications is ished autonomic symptoms of hypoglycaemia
14–16 h; they can cause severe, prolonged leading to ‘dampened down’ hypoglycaemia warn-
hypoglycaemia. It is important to recognise, prevent and ings or none at all.
treat hypoglycaemic episodes secondary to the use of For older people, there are added risk factors
antihyperglycaemic agents. Patient education has which can lead to hypoglycaemia (box 1). Normal
become focused on minimising hyperglycaemia but fasting blood glucose does not exclude the diagnosis
emphasis must be placed on minimising even minor of diabetes in a frail elderly person. Stress-induced
subclinical hypoglycaemia because it will contribute to a hyperglycaemia (eg, acute infection) is common and
vicious cycle of hypoglycaemia begetting hypoglycaemia. needs to be considered for treatment.
Ten per cent dextrose is recommended for the reversal of Complexity of the care for this group often
all hypoglycaemic episodes rather than the conventional requires increased support in the community from
50% dextrose. Octreotide can be an option for recurrent experienced health professionals such as specialist
and relapsing hypoglycaemia in an acute setting. diabetes nurses and dieticians.
It is not uncommon to see elderly diabetic
patients from a nursing home background admitted
with acute-kidney injury due to multiple causes and
BACKGROUND
still taking oral hypoglycaemic agents; such patients
The results of the Diabetes Control and
do not need the much advocated 50 mL of 50%
Complications Trial (DCCT) and the UK Prospective
glucose repeatedly for their hypoglycaemic epi-
Diabetes Study (UKPDS) prove that near normogly-
sodes, but early enteral feeding is the key to an
caemia is clearly in the patient’s best interest.
early stabilisation and eventual discharge. The half-
The Action to Control Cardiovascular Risk in
life for most sulfonylurea medications is 14–16 h,
Diabetes (ACCORD) and Action in Diabetes and
which can cause severe, prolonged hypoglycaemia.
Vascular Disease (ADVANCE) trials showed that
Hypoglycaemia is a common finding in acute
strict control of blood sugar inpatients with type 2
care settings. The causes of recurrent hypogly-
diabetes doubled the risk of severe hypoglycaemia
caemia are multifactorial. With the advent of an
from 1.5% (standard care) to 3% (strict care).
aggressive lowering of HbA1c values to achieve
DCCT (insulin) and UKPDS (insulin or oral agents)
optimal glycaemic control, patients are at increased
also showed that intensive glucose control therapy
risk of hypoglycaemic episodes. Iatrogenic hypogly-
increased the risk of hypoglycaemia by twofold to
caemia can cause recurrent morbidity, sometimes
threefold, particularly in the elderly.
irreversible neurological complications and even
Population-based data indicate that the overall
death, and further preclude maintenance of eugly-
event rate for severe hypoglycaemia (requiring the
caemia over a lifetime of diabetes.
assistance of another individual) in insulin-treated
The case described highlights the problems
type 2 diabetes is approximately 30% of that in
encountered by the medical staff in treating hypo-
type 1 diabetes. However, because there are a
glycaemia in such situations.
greater number of individuals with type 2 than
type 1 diabetes, and because most people with type
2 diabetes ultimately require treatment with
insulin, most episodes of iatrogenic hypoglycaemia Box 1 Hypoglycaemia risk in the elderly
occur in people with type 2 diabetes, more so in
the elderly with cognitive impairment.
▸ Advanced age
Around 50% of older people with diabetes are
▸ Other illnesses or conditions as well as
asymptomatic. In addition to traditional micro-
diabetes
vascular and macrovascular complications seen in
To cite: Arora A. BMJ Case ▸ Being prescribed five or more medications
younger people, older people with diabetes are at
Rep Published online: ▸ Chronic renal problems
[please include Day Month risk of developing atypical complications or geriat-
Year] doi:10.1136/bcr-2013-
▸ Poor nutrition
ric syndromes such as cognitive dysfunction,
010156 ▸ Acute illness
depression, disability, falls, persistent pain and

Arora A. BMJ Case Rep 2013. doi:10.1136/bcr-2013-010156 1

 Reminder of important clinical lesson

CASE PRESENTATION count, microcytic anaemia with haemoglobin of 11 g/dL and a

A 78-year-old man was admitted from a residential home with mean corpuscular volume of 76 fL. His last recorded HbA1c
drowsiness and ‘off legs’. He was found to be hypoglycaemic was 54 (mmol/mol) indicating tight glycaemic controls.
with a glucose of 2.8 mmol by the ambulance crew and received A random serum cortisol was noted to be normal and the ques-
oral glucogel prehospital. tion of oral hypoglycaemic drug overdose did not arise as the
He had a background of cognitive impairment, type 2 dia- patient’s medications were supervised in the residential home,
betes mellitus, hypertension, gout and chronic kidney disease. but measurement of specific drug levels (or insulin/C-peptide if
His diabetic medications consisted of metformin (1 g twice a relevant) is recommended to rule out accidental, surreptitious
day) and gliclazide (160 mg in total). The rest of his medications or even malicious hypoglycaemia (box 2).
were paracetamol, amlodipine, doxazocin and allopurinol.
Initial observations included a blood pressure of 144/ DIFFERENTIAL DIAGNOSIS
84 mm Hg; his pulse rate was 86/min and regular; saturations A low-plasma glucose concentration in the absence of symptoms
were 94% on air; respiratory rate was 16/min and temperature of hypoglycaemia suggests the possibility of shifted glycaemic
was 37.4°C. thresholds, as may occur in patients with repeated episodes of
His urine dipstick was found to be nitrite positive in A&E hypoglycaemia or artefactual hypoglycaemia.
department and the initial laboratory bloods showed a moderate For patients with diabetes who may have asymptomatic hypo-
rise in inflammatory markers and an acute worsening of his glycaemia due to repeated episodes of hypoglycaemia and/or
chronic kidney disease with creatinine increasing from 130 to hypoglycaemia unawareness, intermittent use of continuous
190 mmols and a capillary glucose of 2.2 despite glucogel glucose monitoring may be valuable for the detection of noctur-
administration. nal hypoglycaemia or patterns of hypoglycaemia.
He was started on empirical trimethoprim for urinary
tract infection and received 50 mL of 50% glucose to treat his
OUTCOME AND FOLLOW-UP
hypoglycaemia. He was then seen by the medical team in the A&E
The patient’s discharge back to his residential home was delayed
department and transferred to the acute medical unit (AMU).
due to episodes of recurrent hypoglycaemia and the glicalazide
His blood glucose on AMU 4 h later was noted to be
was switched to saxagliptin as his estimated glomerular filtration
3.3 mmol and he was given a further 25 mL of 50% dextrose
rate (eGFR) was 29 m/min/1.73 m2.
that increased his capillary glucose to 14.2 mmol. During the
first 48 h of admission, he received 50% dextrose four times
due to rebound hypoglycaemia (glucose monitoring revealed DISCUSSION
glucose increments up to 14.2 mmol post 50% dextrose and In patients with diabetes, hypoglycaemia is defined as all epi-
falling to as low as 3.1 mmol in a couple of hours post 50% sodes of an abnormally low-plasma glucose concentration (with
dextrose) and was eventually started on a 10% dextrose intra- or without symptoms) that expose the individual to harm.
venous drip to prevent this rebound. People with diabetes become concerned about the possibility of
This pattern of fluctuating blood glucose and rebound hypo- hypoglycaemia at a self-monitored blood glucose level
glycaemia continued for another day until he started taking suf- ≤3.9 mmol/L. While that value is higher than the value used to
ficient food orally and his kidney function improved with diagnose hypoglycaemia in people without diabetes, it
treatment. He was in the hospital for a total of 5 days and recur-
rent hypoglycaemia was found to be one of the factors that
delayed the discharge.
It is interesting to note that the patient did not manifest any Box 3 Factors predisposing an individual to
symptoms of low blood glucose during this entire period. antihyperglycaemic drug-induced hypoglycaemia12

INVESTIGATIONS ▸ Age
Laboratory results showed a creatine of 190 mmols (baseline of ▸ Elderly in the presence of coexisting comorbid conditions
130 mmol), a C reactive protein of 42 with normal white cell ▸ Impaired kidney or liver function
▸ Adrenal insufficiency
▸ Gastrointestinal disease
▸ Lack of education on hypoglycaemia
Box 2 Important differentials for hypoglycemia ▸ Lifestyle
▸ Alcohol consumption in the absence of sufficient energy/
▸ Drugs (see box 3) carbohydrate intake
▸ Alcohol ▸ Exercise
▸ Critical illness ▸ Missed or delayed meals
▸ Malnourishment ▸ Salicylates (>4 g/day)
▸ Non-islet cell tumors secreting insulin-like growth factors ▸ Sulfonamide and macrolide antibiotics
▸ Cortisol deficiency ▸ Tricyclic antidepressants
▸ Endogenous hyperinsulinism (a β cell secretagogue or ▸ Phenylbutazone
tumour). ▸ Warfarin
▸ A functional β cell disorder, often termed nesidioblastosis, ▸ Fibrates
that can occur as a feature of the non-insulinoma ▸ Monoamine oxidase inhibitors
pancreatogenous hypoglycaemia syndrome or of postgastric ▸ Acetaminophen
bypass hypoglycaemia ▸ ACE inhibitors
▸ Accidental, surreptitious or even malicious hypoglycaemia. ▸ β-Blockers

2 Arora A. BMJ Case Rep 2013. doi:10.1136/bcr-2013-010156

 Reminder of important clinical lesson

approximates the lower limit of the physiological fasting non- The frequency of hypoglycaemia with thiazolidinediones is
diabetic range, the normal glycaemic threshold for glucose not significantly different from that of a placebo. No cases of
counter-regulatory hormone secretion and the highest ante- severe hypoglycaemia have been reported with monotherapy
cedent low glucose level reported to reduce sympathoadrenal with these agents.
responses to subsequent hypoglycaemia.1 2 Sulfonylurea-related hypoglycaemia is very different from the
The American Diabetes Association and the Endocrine insulin induced.4 5 A typical patient would be an ill elderly
Society Workgroup on Hypoglycemia recommends the follow- patient from a care home for whom too much intravenous dex-
ing classification of hypoglycaemia in diabetes.1 trose may be harmful as it promotes excess insulin release
1. Severe hypoglycaemia: An event requiring the assistance of (usually after 60–120 min due to the presence of oral agents
another person to actively administer carbohydrate. that potentiate insulin release) and the blood sugar drops,
2. Documented symptomatic hypoglycaemia: An event during prompting further treatment with more dextrose and the cycle
which typical symptoms of hypoglycaemia are accompanied continues. Such a situation might require half normal saline
by a measured plasma glucose concentration ≤3.9 mmol/L. +5% or 10% dextrose as a slow infusion to stabilise the
3. Asymptomatic hypoglycaemia: Asymptomatic hypoglycaemia glucose.5 6
is classified as an event not accompanied by typical symp- Blood sugar needs to be monitored every 2 h and the litera-
toms of hypoglycaemia but with a measured plasma glucose ture recommends observation for more than 24 h, and therefore
concentration of ≤3.9 mmol/L. it is best to keep it in between 5 and 7 mmol/L as higher levels
4. Probable symptomatic hypoglycaemia: Probable symptomatic would cause hyperinsulinaemia.
hypoglycaemia is classified as an event during which typical Use of glucagon is a potential problem for sulfonylurea7 8
symptoms of hypoglycaemia are not accompanied by a associated hypoglycaemia as it takes 20 min to work and the
plasma glucose determination. patients may develop nausea and vomiting and be unable to eat.
5. Relative hypoglycaemia: Relative hypoglycaemia is classified Glucagon 1 mg IM/SC usually increases blood sugar by 3–
as an event during which the person with diabetes reports 12 mmol in <60 min (intravenous dextrose is faster)7 8 and may
typical symptoms of hypoglycaemia, and interprets those as not increase it enough in malnourished people due to poor
indicative of hypoglycaemia, but with a measured plasma glycogen reserves in the liver.
glucose concentration >3.9 mmol/L. This category reflects Glucagon may increase the blood sugar too much, prompting
the fact that patients with chronically poor glycaemic a reactive hypoglycaemia due to excessive insulin release.
control can experience symptoms of hypoglycaemia at Paradoxically, glucagon can stimulate insulin release directly and
plasma glucose levels >3.9 mmol/L as glucose levels decline may cause a delayed drop in blood glucose.
into the physiological range.
The incidence of hypoglycaemia with use of antihyperglycae-
mic agents is most likely underestimated due to the altered Octreotide may be considered as a relatively new option
patient awareness of symptoms and under-reporting of episodes. The first prospective placebo-controlled study published in
Few large and randomised clinical trials have compared the rates 2008 concluded that the addition of octreotide to standard
of hypoglycaemia between antihyperglycaemic agents. In add- therapy in hypoglycaemic patients receiving treatment with sul-
ition, the frequency of hypoglycaemias is not mentioned in fonylurea increased the serum glucose values for the first 8 h
several publications. after administration in patients.9–11 Recurrent hypoglycaemic
A decrease in blood sugar due to oral agents may be due to episodes occurred less frequently in patients who received
skipped meals or exercise. However, concurrent illness (dehydra- octreotide compared with those who received placebo.
tion, etc), new onset of renal dysfunction and drug interactions Octreotide inhibits the release of insulin, glucagon and
(box 3) are major factors that cause oral agents induced hypogly- growth hormone. If given subcutaneously (SC), it peaks around
caemia; such events prolong the half-life of sulfonylureas. 30 min and has a half-life of 1.5–2 h. Uncommonly, it has been
These hypoglycaemic patients require a long period of obser- used in non-overdose sulfonylurea-related hypoglycaemia (used
vation (>24 h) in the emergency department due to the pro- frequently in a true overdose of sulfonylureas).
longed action of these agents and a search for the cause of A single 75 μg subcutaneous dose might be considered for a
hypoglycaemia is necessary and may require a significant change patient having recurrent hypoglycaemia after 50 mL of 50%
of medications before discharge. dextrose, but the patient still needs to stay for at least 24 h.
Insulin-related hypoglycaemia is relatively simple to treat; it is The newer dipeptidyl peptidase 4 inhibitors (Saxagliptin,
often due to a skipped meal/snack/exercises and is treated with Vildagliptin) control the glucose parameters with comparable
50 mL of 50% dextrose and food. efficacy to other antihyperglycaemic agents, without the asso-
The patient may be discharged early (6 h). Giving too much ciated weight gain or hypoglycaemia. As incretin hormones are
dextrose will not cause an increase in insulin release or cause more active in response to higher blood sugar levels (and are
paradoxical hypoglycaemia (these patients do not have their less active in response to low blood sugar), the risk of danger-
own insulin to release). ously low blood sugar (hypoglycaemia) is low with Saxagliptin.
Oral agents are not easy to treat and sulfonylureas are a The glucagon-like peptide (GLP1) receptor agonists
major problem; all these agents peak up to 8 h and may last (Exanetide, Liraglutide) offer the advantage of weight loss; they
>24 h and hypoglycaemia is seen many hours after the dose. also delay gastric emptying, which is a desirable effect for con-
Glyburide is more long acting than gliclazide and trolling postmeal glycaemia but one that can be associated with
glimeperide.3 4 nausea in some patients. No hypoglycaemia is seen with use of
Sulfonylurea and meglitinides (such as repaglinide) can cause a GLP-1 agonist as it works only in the presence of hypergly-
hypoglycaemia when used in monotherapy, as both classes of caemia, but hypoglycaemia can occur if its glucose-lowering
agents are insulin secretagogues. The frequency of hypoglycaemic effects are combined with an excess dose of sulfonylurea or
episodes with sulfonylureas tends to decrease after a few years of insulin (Exenatide has not been approved for use by those who
treatment. take insulin).

Arora A. BMJ Case Rep 2013. doi:10.1136/bcr-2013-010156 3

 Reminder of important clinical lesson

CONCLUSION Given the increased susceptibility of the elderly-to-severe

The major potential adverse effect of use of sulfonylurea agents hypoglycaemia and its consequences, antidiabetic therapies that
is a hyperinsulinaemic state that causes hypoglycaemia. It may minimise the risk of hypoglycaemic events should be selected.15
be observed during chronic therapeutic dosing, even with very
low doses of sulfonylurea, and especially in older patients.
Given the heterogeneity of the elderly population, which Learning points
includes patients with very different functional and cognitive
capacities, comorbidities and life expectancy, it is critical to
make a comprehensive assessment from a biopsychosocial per- ▸ Treating hypoglycaemia in an acute setting due to insulin
spective to address the vascular risk factors integrally and to and oral agents creates very different challenges. Some
establish individually tailored targets for glycaemia control.13 hypoglycaemic patients require a long period of observation
Hypoglycaemia may also result from accidental or intentional (>24 h) in the A&E department due to the prolonged action
poisoning in both diabetic and non-diabetic patients. The trad- of these oral agents.
itional approach to sulfonylurea-induced hypoglycaemia ▸ The goals of treatment for hypoglycaemia are to detect and
includes the administration of glucose and glucagon or diazox- treat a low blood glucose level promptly by using an
ide in those who remain hypoglycaemic despite repeated or con- intervention that provides the fastest rise in blood glucose to
tinuous glucose supplementation. a safe level, to eliminate the risk of injury and to relieve the
However, these antidotal approaches are associated with symptoms quickly and avoid rebound.
several shortcomings, including the further exacerbation of ▸ It is important to avoid overtreatment, since this can result
insulin release by glucose and glucagon, leading only to a tem- in rebound hyperglycaemia and weight gain.
porary beneficial effect and later relapse into hypoglycaemia, as ▸ Drug-induced hypoglycaemia is a major obstacle for
well as the adverse effects of both glucagon and diazoxide. individuals (especially in the elderly) trying to achieve
In 1999, a revised UK paramedic training syllabus and glycaemic targets and a timely discharge.
manual were introduced and in 2000, the Joint Royal Colleges ▸ Ten per cent dextrose is recommended for the reversal of all
Ambulance Liaison Committee ( JRCALC) published its prehos- hypoglycaemic episodes rather than the conventional 50%
pital treatment guidelines and recommended the use of 10% dextrose. Octreotide can be an option for recurrent and
dextrose for reversal of all hypoglycaemic episodes.14 relapsing hypoglycaemia in an acute setting.
Octreotide inhibits the secretion of several neuropeptides, ▸ Use of glucagon in an acute/prehospital setting is declining
including insulin, and has successfully been used to control life- as it can paradoxically stimulate insulin release directly and
threatening hypoglycaemia caused by insulinoma, sulfonylurea may cause a delayed drop in blood glucose.
overdose or persistent hyperinsulinaemic hypoglycaemia of ▸ Dipeptidyl peptidase 4 inhibitors (gliptins) should be used
infancy. more often if the patient’s eGFR (estimated glomerular
In patients with hypoglycaemia without diabetes mellitus, it is filtration rate) is <30 mL/min/1.73 m².
important to exclude potential hypoglycaemic aetiologies like ▸ The therapeutic strategy for frail elderly patients with type 2
drugs, critical illnesses, hormone deficiencies and non-islet cell diabetes should be individualised and focused on improving
tumours first. In the absence of these causes, the differential the quality of life, assuring patient safety and avoiding the
diagnosis narrows down to accidental, surreptitious or even adverse effects of anti-diabetic treatment.
malicious hypoglycaemia or endogenous hyperinsulinism.
In patients suspected of having endogenous hyperinsulinism,
as in the case above, it is useful to measure the parameters men-
Competing interests None.
tioned in box 4.
Patient consent Obtained.
Insulin or insulin secretagogue treatment of diabetes mellitus
is the most common cause of hypoglycaemia. The practice of Provenance and peer review Not commissioned; externally peer reviewed.
hypoglycaemia risk factor reduction is paramount and can be
performed by addressing the issue of hypoglycaemia, applying REFERENCES
the principles of intensive glycaemic therapy, and considering 1 Seaquist ER, Anderson J, Childs B, et al. Hypoglycemia and diabetes: a report of a
both the conventional risk factors and those indicative of com- workgroup of the American diabetes association and the endocrine society.
Diabetes Care 2013;36:1384–95.
promised defences against falling plasma glucose concentrations
2 Cryer PE, Axelrod L, Grossman AB, et al. Evaluation and management of adult
in persons with diabetes. hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline. J Clin
Endocrinol Metab 2009;94:709.
3 http://www.diabetes.ca/Files/CDAHypoglycemiaGuidelines.pdf (accessed 26 Apr
2013).
Box 4 Special tests in case of hyperinsulinaemic 4 Szoke E, Gosmanov NR, Sinkin JC, et al. Effects of glimepiride and glyburide
onglucose counterregulation and recovery from hypoglycemia. Metabolism
hypoglycaemia 2006;55:78.
5 Herbal G, Boyle PJ. Hypoglycemia: pathophysiology and treatment. Endocrinol
Metab Clin North Am 2000;29:725–43.
▸ Plasma glucose
6 Moore C, Woollard M. Dextrose 10% or 50% in the treatment of hypoglycaemia
▸ Insulin out of hospital? A randomised controlled trial. Emerg Med J 2005;22:512–15.
▸ C-peptide 7 Vukmir RB, Paris PM, Yealy DM. Glucagon: prehospital therapy for hypoglycemia.
▸ Proinsulin Ann Emerg Med 1991;20:375–9.
▸ β-hydroxybutyrate 8 Yale J. Hypoglycemia. Can J Diabetes 2008;32:S62–4.
9 O’Malley G, Dominici P, Aguilera E, et al. Comparison of octreotide and standard
▸ Circulating oral hypoglycaemic agents during an episode of therapy versus standard therapy alone for the treatment of sulfonylurea-induced
hypoglycaemia hypoglycaemia. Ann Emerg Med 2008;51:400–6.
▸ Insulin antibodies 10 Mclaughlin SA, Crandall CS, McKinney PE. Octreotide: an antidote for
sulfonylurea-induced hypoglycaemia. Ann Emerg Med 2000;36:133–8.

4 Arora A. BMJ Case Rep 2013. doi:10.1136/bcr-2013-010156

 Reminder of important clinical lesson

11 Carr R, Zed PJ. Octreotide for sulfonylurea-induced hypoglycaemia following 14 Joint Royal Colleges Ambulance Liaison Committee. Medical emergencies. In: Joint
overdose. Ann Pharmacother 2002;36:1727–32. Royal Colleges Ambulance Liaison Committee. Prehospital clinical guidelines.
12 Jennings AM, Wilson RM, Ward JD. Symptomatic hypoglycemia in London: Joint Royal Colleges Ambulance Liaison Committee, 2000.
NIDDM patients treated with oral hypoglycaemic agents. Diabetes Care http://www.warwick.ac.uk/fac/med/research/hsri/emergencycare/prehospitalcare/
1989;12:203–8. jrcalcstakeholderwebsite/guidelines/glucose_10_glx.pdf (accessed 15 June 2013).
13 Gómez Huelgas R, Díez-Espino J, Formiga F, et al. Treatment of type 2 diabetes in 15 Abdelhafiz AH, Sinclair AJ. Tailor treatment in the older patient with type 2
the elderly. Med Clin (Barc) 2013;140:134.e1–12. diabetes. Practitioner 2013;257:21–5.

Copyright 2013 BMJ Publishing Group. All rights reserved. For permission to reuse any of this content visit
http://group.bmj.com/group/rights-licensing/permissions.
BMJ Case Report Fellows may re-use this article for personal use and teaching without any further permission.
Become a Fellow of BMJ Case Reports today and you can:
▸ Submit as many cases as you like
▸ Enjoy fast sympathetic peer review and rapid publication of accepted articles
▸ Access all the published articles
▸ Re-use any of the published material for personal use and teaching without further permission
For information on Institutional Fellowships contact consortiasales@bmjgroup.com
Visit casereports.bmj.com for more articles like this and to become a Fellow

Arora A. BMJ Case Rep 2013. doi:10.1136/bcr-2013-010156 5