Hypoglycemia Requiring Emergency Services Intervention: Patient Characteristics, Outcome and Cardiovascular Risk Profile
Phase: NA
Conditions: Diabetes Mellitus, Hypoglycemia
Sponsor: University of Leeds

Protocol version 1: 10th January 2012 
 
 
 
 
Study protocol 
 
 
 
 
 
 
Hypoglycemia requiring emergency services 
intervention: patient characteristics, 
outcome and cardiovascular risk profile 
 
 
 
 
 
 
 
PI: R Ajjan 
Co-Investigators: S Heller, L Clapham 
Statistical analysis: P Baxter 

Protocol version 1: 10th January 2012 
 
Background 
Hypoglycemia is a common complication of diabetes treatment, particularly 
when glucose control is intensified (1-3). Until recently, hypoglycemia was 
regarded as an acceptable “side effect” of glucose lowering therapy, given the 
benefits of tight glycemic control at reducing microvascular, and to some extent 
macrovascular, complications of diabetes (2-7).  However, studies in the past 
few years have demonstrated that hypoglycemia is probably a more serious side 
effect that initially thought (8-11). A major warning as to the potential dangers 
of hypoglycemia was delivered in the ACCORD study (12), when excess mortality 
was demonstrated in the intensive glucose arm of the trial, necessitating study 
termination and fuelling speculation about the role of intensive glucose control in 
the management of diabetes. The fear of hypoglycemia-induced death in 
diabetes is not unfounded as there are clear mechanistic pathways to explain 
this link. Hypoglycemia is associated with repolarisation abnormalities in the 
heart and increased thrombosis potential as we and others have shown (13-15). 
Indeed, large scale studies and anecdotal reports have shown associations 
between acute cardiac events/mortality and hypoglycemic events (11,16-18). 
Moreover, 
our 
preliminary 
data 
in 
Leeds 
have 
revealed 
that 
severe 
hypoglycemia, requiring emergency services intervention in 856 patients, is 
associated with 17.1% mortality within 12 months of the event (unpublished 
data). This death rate is comparable to diabetes patients sustaining acute 
cardiac ischemic event in Leeds, which currently stands at 15.8% (19). Also, the 
mean age of the diabetes cohort was only 61 years, and therefore the high 
death rate following hypoglycemia is certainly a major cause for concern (for 
gender and diabetes type distribution, see Figure 1). Moreover, our data showed 
that in excess of 200 individuals had recurrent severe hypoglycemic events, 
despite local pathways designed to ensure higher levels of clinical support. 
Interestingly, of the type 2 diabetes subjects, 28% were not on insulin, being 
managed with oral hypoglycemic agents (95% treated with sulphonylureas). The 
degree of documented hypoglycemia in this group was comparable to individuals 
on insulin therapy with glucose levels at the arrival of ambulance crew of 
1.8±1.1 and 1.9±0.7 mmol/l, respectively (p>0.1, unpublished data). 
 
 
 
 
Figure 1. Type of diabetes and gender 
distribution 
of 
individuals 
with 
severe 
hypoglycemia 
requiring 
emergency 
services 
intervention 
in 
Leeds 
(1307 
events). 
 
 
It is unclear at this stage whether the observed increased mortality following 
severe hypoglycemia is directly related to low plasma glucose or whether severe 
hypoglycemia is more likely to occur in individuals with terminal clinical 
conditions (20), which may be due, for example, to weight loss and/or 
decreased appetite. Naturally, this needs to be clarified as it has important 
clinical implications for the treatment of these individuals. 
Studies on the occurrence of severe hypoglycaemia in the community have been 
both limited and incomplete. In particular, the predictors of severe hypoglycemia 

Protocol version 1: 10th January 2012 
 
in the community have not been fully evaluated, which is partly due to the 
inadequate methodologies used or the inappropriate statistical methods 
employed (21-23). A recent retrospective observational study, conducted in 
Australia, has shown that duration of insulin treatment, renal factors and 
diabetic neuropathy are some of the predictors of severe hypoglycemia (24). 
Furthermore, this study has demonstrated that high HbA1c levels are not 
necessarily associated with lower risk of severe hypoglycaemia. It remains 
unclear, however, whether infrequent blood glucose testing and inadequate 
clinical support has a role in increasing the risk of severe hypoglycemia, whereas 
the effect of co-morbidities requires further clarification. For example, any 
clinical condition that is associated with weight loss or reduced appetite may be 
contributing to hypoglycemia. Another example is excess alcohol intake, which 
may also result in frequent and severe hypoglycemia (more details are provided 
below). 
 
 
Hypothesis 
Inadequate education, infrequent glucose testing and clinical co-morbidities in 
subjects with diabetes are associated with severe hypoglycemic episodes. 
Therefore, structured diabetes specialist input with regular glucose testing is 
important to reduce the risk of severe hypoglycemia. 
 
Aims 
The proposed work is divided into two parts through an observational and an 
interventional study. 
1. Observational study: characterise individuals with severe hypoglycemia. 
2. Interventional preliminary study: investigate the effect of regular glucose 
monitoring and specialist nurse input into a) future hypoglycemic events,         
b) confidence with diabetes management/quality of life and c) clinical outcome. 
 
Plan of investigation 
We have already developed a pathway for ambulance services to report cases of 
severe hypoglycemia in Leeds requiring their intervention (Figure 2). 

Protocol version 1: 10th January 2012 
 
Figure 2.  A summary of the current severe hypoglycemia pathway in Leeds. 
YAS: Yorkshire Ambulance Services, DNS: Diabetes Nurse Specialist, GP: 
General Practioner. 
We will continue to follow this pathway but will have a dedicated nurse to deal 
with the patients and will extend the study to include Sheffield. Inclusion of 
Sheffield will help to boost the number of patients enrolled and will clarify any 
potential regional variability. The research nurse will be experienced in managing 
individuals with diabetes and will be conducting both parts of the study, under 
the supervision of the principal investigator.  The proposed study is summarised 
in Figure 3 and further detailed below. 
 
 
 
Ambulance crew informs YAS  
of hypoglycaemia treated at home   
YAS sends referral to local diabetes 
team (with consent of patient) 
DNS contacts patient within 5 days 
DNS involved with patient care 
as necessary 
Patient advised to contact GP  
(GP informed) 

Protocol version 1: 10th January 2012 
 
 
Figure 3. Summary of study design, including both observational and 
interventional parts. Intensive nursing support and standard clinical care are 
explained in more detail below. 
 
Observational study 
Various details will be collected to elucidate the characteristics of patients 
undergoing severe hypoglycemia requiring emergency services intervention. 
 
Demographic and general data. Address, age, sex, type of diabetes and 
duration, weight, body mass index, blood pressure, presence of macrovascular 
and microvascular complications, current treatment, status at home (living 
alone), driving status, alcohol consumption, smoking history, mobility, non-
diabetes related co-morbidities. We will also clarify who made the ambulance call 
(patient/carer/other). 
 
Patient questionnaire (see appendix 1). This will address whether a patient 
feels confident regarding managing his/her diabetes, how often glucose is 
monitored, can the patient adjust insulin, does the patient understand the 
dangers of hypoglycemia, presence of hypoglycemia awareness, frequency of 
low glucose levels, treatment options of hypoglycemia. 
 
Emergency services inform the research team of severe hypoglycaemia
(through a dedicated number)
Research nurse involved
Collects basic information
Gets in touch with patient
Patients invited to participate
(randomized to standard or intensive nursing support)
Quality of life, frequency of hypoglycaemia and clinical outcome
(assessed at 12 months)
Intensive nursing support
Structured glucose monitoring
Standard clinical care 
(as per local guidelines)

Protocol version 1: 10th January 2012 
 
Examination. Check injection sites for lipoatrophy or lipohypertrophy and 
examine for signs of peripheral neuropathy (monofilament test). 
 
Blood and urine tests. These will be arranged as part of routine clinical care in 
both groups, unless recent blood tests have been done. The following tests will 
be included: HbA1c, urea and electrolytes, liver function tests, full lipid profile, 
thyroid function tests (where appropriate), urinary albumin/creatinine ratio 
(ACR). HbA1c will be measured every 3 months, U&Es, LFTS and lipid profile 6 
monthly.  ACR will be checked at enrolment and at 12 months. All above tests 
will be requested more frequently if clinically indicated. 
 
Interventional study 
We will conduct a preliminary interventional study, where patients will be 
randomised to either intensive monitoring/treatment modification, where 
patients are closely followed up by the research nurse, or conventional therapy 
following local protocols. Individuals in the interventional part of the study will 
be:  
i) Regularly contacted by the research nurse as detailed below. 
ii) Encouraged to check their glucose levels as appropriate, at least twice a day 
or more frequently as necessary.  
iii) Special leaflets regarding different aspects of diabetes will be given to 
patients and will be discussed. These will include leaflets for alcohol, exercise, 
Carbohydrate counting and awareness as appropriate (please see below).  
iv)  Patients will have a dedicated phone number that they can ring for urgent 
advice.  
v) There will be a dedicated email line set up to answer less urgent queries and 
help with patient support. An email system is already set up in Leeds by the PI, 
and patients using this service experienced significant improvement in diabetes 
control (data not shown). 
 
The research nurse will make every attempt to establish the cause of severe 
hypoglycemia by taking a detailed medical history in order to clarify clinical co-
morbidities and assess social circumstances including alcohol intake, patient 
independence and help provided by carers. The nurse will also document current 
medications with special attention to dose and frequency of hypoglycemic 
agents, including insulin. Routine blood tests to assess overall glycemic control, 
renal and liver function will be performed, which may further help to shed light 
on the cause of low blood glucose. Hypoglycemic treatment may be changed in 
cases of concern but only after review by the PI, and the medical team in charge 
of the patient will be informed. For example, a sulphonylurea may be stopped or 
replaced if deemed inappropriate for the patient and insulin regimens/doses may 
also be altered. Follow up of patients after changes to medical therapy are 
detailed below but some may have more frequent contact with the nurse as per 
clinical need. The nurse employed will have extensive experience in the 
management of diabetes and will have the necessary knowledge to adjust 
doses/mixtures/intervals of insulin as appropriate, with adequate support 
provided by the PI in difficult clinical scenarios. Other diabetes disciplines, such 

Protocol version 1: 10th January 2012 
 
as dietician support may be sought if the research nurse and/or PI find this to be 
necessary. In cases of newly diagnosed (or suspected) clinical conditions, 
referrals to an appropriate specialty will be made after review by the PI. If social 
circumstances are found to be inappropriate, for example in the case of older 
individuals not managing on their own, the physician in charge of the patient will 
be informed and steps will be taken to provide support according the need of 
each individual. 
In summary, the research nurse will concentrate on establishing the cause of the 
severe hypoglycemic episode and together with the PI will alter treatment, 
involve other diabetes/non-diabetes disciplines as appropriate and introduce 
changes to social support as required. 
  
The research nurse will contact the patient weekly for the first month, every two 
weeks for the following month followed by contact at months 3, 6 and 12. Face 
to face contact with the patient will be arranged at enrolment, 1, 3 and 12 
months. Patient will be asked to fill in the questionnaire at enrolment and end of 
3rd month, with selected patients asked to complete the form again at 12 months 
(explained in Figure 4). Blood tests will be arranged as detailed above. In the 
standard arm, patient will be contacted only once as per current arrangement 
and subsequent treatment left to the discretion of the attending physician 
(summarised in Figure 4).  
 
Figure 4. Summary of the preliminary interventional part of the study. U&Es: 
urea 
and 
electrolytes, 
LFTs: 
liver 
function 
tests, 
UACR: 
urinary 
albumin/creatinine ratio, MACE: major adverse cardiovascular events, m: 
Individuals with severe hypoglycemia
requiring emergency services intervention
Standard arm
Contact once by research nurse
(further management at the discretion of the 
attending physician)
Tests: HbA1c (3 monthly), U&Es/LFTs/lipids (6 monthly), UACR at 0 & 12 months
Questionnaire: enrolment and third month
Clinical outcome at 12 months: Death, MACE, microvascular disease (combined or separately)
Regular glucose testing 
(at least twice/d for 3m)
Structured education
(appendix 2)
Intensive arm
Regular contact by research nurse
Weekly for the 1st month, fortnightly for the second 
month then at 3, 6 and 12 months
(face to face contact at enrolment, 1m, 3m and 12m)

Protocol version 1: 10th January 2012 
 
month, d: day. Questionnaire will be done at enrolment and 3 months in both 
groups. If a significant difference exists between the two time points in the same 
patient, the questionnaire will be repeated at 12 months. Clinical outcome at 12 
months will also include frequency of hypoglycemia, analysed separately.  
  
Pilot study to investigate hypoglycemia-induced thrombotic potential 
Funding for this part is not sought and therefore no details are given (can 
be provided if requested). 
 
Statistical analysis 
The observational part of the study will collect various data and will be the basis 
for future studies. Power calculations were based on the interventional study. 
Given our current data showing a death rate in excess of 17% within one year of 
hypoglycemia, we calculated that 200 individuals are needed in each of the 
study arms to detect a drop in mortality to 10% in intensively monitored 
patients (at p=0.05).  Between group analysis will be done using unpaired 
t-test for normally distributed data and the non-parametric Mann-Whitney 
test will be used for data that are not normally distributed. For categorical 
data, 2X2 contingency tables will be used and multiple regression analysis 
will be performed to determine potential causes of hypoglycemia.    

Protocol version 1: 10th January 2012 
 
Appendix 1 (patient questionnaire-will not be seen by the research nurse) 
 
How much do you feel you understand about diabetes? 
1. More than enough 
2. Just enough 
3. Could do with more knowledge 
4. I know very little 
5. I do not understand diabetes at all 
 
Do you think diabetes education in your area is adequate at present?  
1. Perfect 
2. Acceptable 
3. Could be better 
4. Poor 
5. Non-existent 
 
How often do you test your blood glucose (sugar) levels? 
1. At least twice a day with additional testing as needed. 
2. At least once a day. 
3. Less than once a day but at least twice a week. 
4. Less than once a week. 
5. Never. 
 
Do you get concerned about testing your blood glucose and what it may 
show? 
1. Never as I know what to do. 
2. I do get concerned sometimes but this is rare. 
3. I often get concerned. 
4. I am always concerned. 
5. I am terrified of checking my glucose levels as I have no idea how to manage 
the various numbers. 
 
Do you check your blood glucose when you feel hypoglycemic? 
1. Always. 
2. Almost always. 
3. Sometimes 
4. Rarely. 
5. Never. 
 
How often do you get hypoglycemic attacks (blood glucose less than 3.6 
mmol/l)? 
1. Less than once every 3 months. 
2. Monthly. 
3. Weekly 
4. Twice to 3 times per week. 
5. Daily. 
 
In the past 12 months, how many times have you had hypoglycemic 
attacks requiring the assistance of another person? 
1. None. 
2. Once. 
3. On 2-3 occasions. 
4. On 4-5 occasions 

Protocol version 1: 10th January 2012 
 
5. More than 5 times. 
 
Do you get hypoglycemic warning with low glucose levels? 
1. Always. 
2. Yes but they are getting less prominent. 
3. Sometimes I do not. 
4. Rarely and very little. 
5. Not at all. 
 
Do you know why diabetes control is important? 
1. Yes, I fully understand. 
2. I think I know. 
3. I have a rough idea. 
4. I may but not that sure. 
5. I have no idea. 
 
Do your hypoglycemic episodes have a major impact on your quality of 
life? 
1. Never. 
2. Rarely. 
3. Sometimes. 
4. They have a major impact on quality of life. 
5. Hypoglycemia is making me miserable. 
 
Is close support from a diabetes nurse helpful to control your blood 
glucose? 
1. Definitely, no question about it. 
2. Yes, but it depends on the person. 
3. To some extent. 
4. Only marginal benefit. 
5. Useless. 
 
For insulin users: Do you know how to adjust/modify your insulin doses 
according to your glucose readings? 
1. I am in full control. 
2. Yes, but I may need occasional advice. 
3. Yes, but prefer to have advice for reassurance. 
4. I have little knowledge. 
5. I have no idea. 
 
Do you know what to do when you get severe hypoglycemia? 
1. Yes. 
2. I have a good idea. 
3. I know some but not all aspects. 
4. My knowledge is weak. 
5. I have no idea. 
 
Does close diabetes nurse support make you more confident at 
managing your diabetes? 
1. Definitely. 
2. Certainly has an effect to some extent. 
3. Has a marginal effect. 
4. Very little effect. 

Protocol version 1: 10th January 2012 
 
5. No effect at all. 
 
Are you aware of the guidance regarding hypoglycemia and driving? 
1. Yes, I am fully aware of the guidelines. 
2. I probably know all the details 
3. I know some of the details but not all 
4. I know very little. 
5. I have no idea. 
 
Appendix 2. Structured education (intensive arm of the study) 
 
In all patients, diabetes and complications will be discussed with special 
emphasis on hypoglycemia. Attention will also be given to hypoglycemia and 
driving and appropriate leaflets will be distributed (please see below).  
 
1. Insulin users 
In all insulin users, hypoglycemia with insulin use will be discussed together 
with the effects of exercise and alcohol on blood glucose (see appendix 3a). 
Also, hypoglycaemia unawareness will be discussed in detail. More specific 
education will be given according to type of insulin regime   
a. Basal bolus and complex insulin regimes 
Teach CHO counting (structured education with dietitian 
already in place) 
b. BD or od insulin 
Discuss CHO awareness (see appendix 3a) 
 
2.  Non-insulin users 
a. Discuss various hypoglycaemic agents and explain dangers of 
hypoglycaemia with each (see appendix 3c) 
b. Discuss carbohydrate awareness (see appendix 3b) 
c. Effects of exercise and alcohol on blood glucose 
 
 
 
 

Protocol version 1: 10th January 2012 
 
Appendix 3. Educational leaflets 
 
 
The following leaflets will be distributed and discussed (as appropriate): 
 
Alcohol and hypoglycemia 
 
Exercise and hypoglycemia 
 
Carbohydrate counting 
 
Carbohydrate awareness 
 
Oral diabetes tablets and the risk of hypoglycemia 
 
Examples are given in appendix 3a, 3b and 3c 
 
 

Protocol version 1: 10th January 2012 
 
Appendix 3a 
 
 
ALCOHOL and DIABETES 
 
Try to keep to the safe limits 
• 
Women: less than 2 units/day (max 
14u / week) 
• 
Men: less than 3 units/day (max 
21u/week) 
• 
1 Unit=½ pint ordinary strength 
beer, lager or cider 
 
1 small glass wine or sherry 
     
1 pub single spirits 
 
REMEMBER 
 
 
not to drink on an empty stomach 
 
 
not to drink and drive 
 
 
alcohol is high in calories 
 
 
carbohydrate (CHO) in alcohol is not counted! 
 
 
EXERCISE and DIABETES 
 
 
If you are exercising you may need to: 
• 
Reduce your insulin dose pre exercise 
by up to 25% 
• 
Reduce your insulin dose post exercise 
by up to 25% 
• 
If it is high intensity then you will need 
to take extra CHO before or during and 
after exercise 
• 
Check blood glucose levels regularly 
• 
www.runsweet.com 
 
 
 

Protocol version 1: 10th January 2012 
 
Appendix 3B 
 
 
Carbohydrate awareness 
 
Your diet is made up of Protein, Fat and Carbohydrate  
 
 
What are carbohydrate foods? 
STARCHY FOODS  
 
SUGARS 
Bread  
 
 
 
sugar 
Potato 
 
 
 
glucose 
Rice 
 
 
 
 
sweetened drinks 
Pasta  
 
 
 
sweets, chocolate 
Breakfast cereals 
 
 
sweet puddings 
Biscuits and other   
 
fruit 
flour products 
 
 
milk 
 
 
 
 
 
yoghurt 
 
 
How does CHO affect my blood glucose? 
CHO will increase blood glucose depending on… 
• 
Whether it is quick or slow acting 
• 
The amount you eat 
• 
Your sensitivity to insulin 
• 
Your activity level  
 

Protocol version 1: 10th January 2012 
 
 
 
WHAT IS glycemic index (GI)? 
The glycaemic index of foods is simply a ‘ranking’ of foods 
based on their immediate effect on blood glucose levels.  
• 
Starch type  
• 
Particle/grain size  
• 
Processing methods 
• 
Cooking methods 
• 
Intact fibre 
• 
Type of sugar present 
• 
Ripeness of fruit 
• 
Fat & protein content 
 
 
SLOW ACTING CARBOHYDRATES 
• 
Granary bread 
• 
Boiled potatoes 
• 
Pasta and noodles 
• 
Pitta bread 
• 
Porridge 
• 
All Bran 
• 
Small portion Fruit ‘n Fibre 
• 
Basmati rice 
• 
Pulse vegetables 
• 
Ryvita 
• 
Oatcakes 
• 
Fruit 
• 
Milk 
• 
Yoghurt 
STARCHY FOODS
SUGARS
GLUCOSE
Blood Stream
Insulin
Cells of body
CARBOHYDRATE

Protocol version 1: 10th January 2012 
 
QUICK ACTING CARBOHYDRATES 
• 
White bread, wholemeal bread 
• 
Mashed potato, jacket potato, chips 
• 
Cornflakes, rice krispies 
 
 
Daily Carbohydrate Intake 
Calorie intake (kcal)           
CHO (grams) 
• 
    1500                       
180 – 240 (Male / Female, inactive) 
• 
    2000                       
240 – 320 ( Male / Female moderate activity) 
• 
    2500              
 
300 -  400 (Male / Female active) 
 
ARE SNACKS NECESSARY? 
• 
For those on DIET ALONE, especially if overweight, snacks are not really 
necessary 
• 
If having a snack, a portion of fruit, diet yogurt or slice of bread are good 
choices 
• 
Those on certain oral hypoglycaemic agents or insulin may need between 
meal &/or bedtime snacks  
 
FAQ’S 
What about bananas? 
• 
Like all fruit, bananas form part of a healthy diet 
• 
Weight for weight they have a higher CHO content than many other fruit  
• 
A medium banana contains approx. 30g CHO & 130 kcals 
• 
A medium apple contains 10 – 15g CHO & 50 kcals 
• 
Bananas are fine for those with diabetes but there is no reason to suggest 
that they are more beneficial than other fruits 
 
And grapes? 
• 
Again, a higher CHO fruit; 10–12 grapes are the same as an apple. Fine in 
moderation but eat the whole bunch & expect BG to rise! 
 
Dried fruit? 
• 
Concentrated source of CHO so modest portions 
 
Fruit juice 
 
Contains sucrose & fructose so take as small portions (125ml) 
 
Encourage  
 
3-4 portions fruit spread out over the day 
 

Protocol version 1: 10th January 2012 
 
Appendix 3c 
 
Diabetes medications and the risk of hypoglycemia 
 
 
 
Low 
High 
 
Metformin 
All agents in the sulphonylurea group 
(gliclazide and glimepiride are the most 
widely used in the UK) 
 
Pioglitazone 
 
Nateglinide and repaglinide 
Sitagliptin 
 
 
Vildagliptin 
 
 
Saxagliptin 
 
 
Linagliptin 
 
 
Acarbose 
 
 
GLP-1 analogues (exenatide and 
liraglutide) 
 
 
 
 
 
Circle any medication the patient is taking and discuss potential 
side effects. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol version 1: 10th January 2012 
 
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