Transcript Why does variable clearance of insulin occur?

Hypoglycaemia in
People with Type 2
Diabetes
Angela O’ Riordan
CNS Diabetes, Kerry
15th October, 2014
Hypoglycaemia in Type 2 Diabetes








Pathophysiology
Incidence
Causes
Treatment & Management
Drug Therapies
Implications
Driving Regulations
Case Studies

Hypoglycaemia includes ‘all episodes of an
abnormally low plasma glucose concentration
(with or without symptoms) that expose an
individual to harm---- defined biochemically
as a blood glucose < 4.0mmol/l’
(IDF, 2014)
Incidence of Hypoglycaemia in
Type 2 Diabetes


UKPDS 1.8% per year insulin treated group
UKPDS 28% per year mild hypoglycaemia
(Gerstein & Hayes, 2010)

9,000 11% severe hypo in the previous year
(Diabetes Care, 2013)

Equivalent levels of severe hypoglycaemia with sulphonylureas
compared with insulin therapy < 2yrs duration
(UK Hypoglycaemia Study, 2007)
Who is at risk?





History of hypoglycaemia
Long duration of diabetes
Impaired counter-regulatory hormone
responses
Impaired awareness of hypoglycaemia
Intensively treated glycated haemoglobin
(Ghosh & Collier, 2012)



The brain is dependent on glucose.
In the person without diabetes,
hypoglycaemia is limited by the inhibition of
insulin release and stimulation of glucagon.
Glucagon and epinephrine release are
probably the main factors that limit
hypoglycaemia & ensure glucose recovery in
normal subjects
Defense against
hypoglycaemia



Glucose counterregulation mechanism
Increases glucagon secretion
Increases epinephrine secretion
(Bilous & Donnelly), 2010
SIGNS AND SYMPTOMS
Autonomic
 Glucose less than 4 mmol/l
 Sweating
 Shaking
 Hungry
 Pale
 Anxious
 Tachycardia
Neuroglycopenic
Glucose <3mmol/l
 Impaired concentration
 Confusion
 Irrational or
uncharacteristic behaviour
 Difficulty in speaking
 Non-cooperation or
aggression
 Convulsions
Hypo unawareness – diminished or no symptoms due to autonomic neuropathy or
frequent hypoglycaemia. = high risk severe hypoglycaemia.
Bilous & Donnelly (2010)
(Bilous & Donnelly), 2010
(Bilous & Donnelly),
2010
Causes of Hypoglycaemia









Delayed or missed meal
Reduced carbohydrate intake
Excessive dose or mismatch of insulin
Lipohypertrophy
Increased physical activity
Alcohol
Hypo unawareness
Weight loss
Reduced renal function
Risks with insulin or insulin
secreting drugs
Sulphonylureas




Gliclazide (Diamicron/ Diabrazide/ Diaglyc)
Glimepiride (Amaryl)
Glipizide (Glibenese)
Glibenclamide (Daonil / Glibenese)**
Glinides


Nateglinide (Starlix)
Repaglinide (Novo norm)
Rapid-acting insulin analogue
 has a rapid onset of action (approximately 15
minutes), allowing it to be given within 15 minutes
of a meal
Short-acting human insulin
 should be injected about 30 minutes before a
meal
Intermediate-acting human insulin
 has an effect that lasts for several hours
and helps to control blood glucose between meals
Long-acting basal analogue
• Has an effect that lasts for several hours and
helps to control blood glucose between meals
Insulin mixtures
 contain either a rapid or short-acting insulin
mixed with a longer-acting insulin
‒ Insulin analogue mixtures should be
injected within 15 minutes of a meal so that
the rapid-acting analogue can control the
rise in glucose after a meal and the longeracting analogue can carry on working
between meals
‒ Human insulin mixture is taken about
30 minutes before a meal so that the shortacting insulin can control the rise in glucose
after a meal and the longer-acting insulin
can carry on working between meals
Onset and Duration of Insulin
Rapid-acting analogue
e.g. Humalog®, NovoRapid®, Apidra®
0
4
4
0
6
8
12
24
12
24
Short-acting (soluble/human)
e.g., Humulin S®, Actrapid®, Insuman
Rapid®
Intermediate acting (Isophane)
e.g. Insulatard®, Humulin I®, Insuman
Basal®
0
8
0
12
18
20
4
22
24
24
Long acting analogue
e.g. Lantus®
or Levemir®
0
0
4
4
24
8
18
20
24
Rapid acting analogue-intermediate
mixture
e.g. Humalog Mix25 / Mix50® or
NovoMix30®
Short acting-intermediate mixture
e.g. Humulin M3®, Insuman Comb® 15, 25,
50
0
4
8
18
20
24
Complete Summary of Product Characteristics available at www.medicines.ie
• Humulin S and Humulin I are registered trademarks of Eli Lilly and Company; Insuman Rapid, Insuman Basal, Insuman Comb and
Lantus are registered trademarks of Sanofi-Aventis ; Insulatard, Novomix30 and Levemir are registered trademarks of Novo Nordisk
Krentz AJ and Bailey CJ. Type 2 Diabetes in Practice. The Royal Society of Medicine Press. London 2001. p12.. Humalog Mix 25/50SPC. Levemir
SPC. Insuman Comb SPC
Why does variable clearance
of insulin occur?

Clearance of insulin is reduced by
decreased renal function

Diabetes & CKD with eGFR <60mls/min


results in prolonged exposure to higher levels of the
drug or its metabolites potentially leading to
hypoglycaemia
frequently have lower insulin requirements
(Moen et Al, 2009)
Therapeutic challenges:
Sulphonylureas

The clearance of both sulphonylureas and its metabolites are
highly dependent on renal function.
 First
generation have been abandoned due to the risk of prolonged
hypoglycaemia.
 Second generation e.g. diamicron MR, glimepiride have shorter half
lives (5-15hours) but their duration may be as long as 24 hours.
 The risk of hypoglycaemia induced by sulphonylureas in CKD is due
to the accumulation of active metabolites which induce
hypoglycaemia.

Pharmaceutical interventions tend to have a longer half life due
to impaired kidney function resulting in hypoglycaemic episodes.
(Moen et Al, 2009)
Prevention of hypoglycaemia









Patient education – written information
Diet review/ timing /dose of medication
Agree individual glucose & Hba1c targets
Patients definition / understanding/ experiences of
hypo
Medication review… SU & Insulin
Reduce / stop SU if commencing insulin
Stop daonil
Carry rapid acting CHO
Identification
Treatment of Hypoglycaemia


Adults with poor glycaemic control may
experience symptoms >4.0mmol/l
To provide symptomatic relief, treat with a
small carbohydrate snack
(NHS, 2010)
Hypoglycaemia Management in
the conscious orientated person
15-20g fasting acting carbohydrate
e.g. 100mls original lucozade
or 3-4 heaped teaspoons of sugar dissolved
or 150mls coca-cola
or 200mls fruit juice
or 5-6 Dextrose sweets
> 4mmols
If a meal is
due in 10mins
eat CHO
containing
meal
20 mins
10-15
mins
< 4mmols repeat
If no meal due:
e.g. 2 slices of wholegrain bread
or 1 digestive or 2 rich tea biscuits
or 200-300mls milk
recheck blood glucose
20 mins
(ADA, 2014)
Severe Hypoglycaemia
 Unconscious person




Do not put anything into mouth/Lay in
recovery position
Check blood glucose
Administer 1mg of Glucagon I.M.
Injection
Less effective in chronic liver disease,
malnourishment & alcoholism
Management after a hypo




Do not omit insulin injection but consider reducing the dose
A larger portion of carbohydrate is required after a glucagon
injection
SMBG regularly for the next 48hours
Consider what caused the hypo?
Consequences of
hypoglycaemia in diabetes
•
•
•
•
•
•
•
Obstacle to achieving normoglycaemia
Cardiovascular risk
All cause mortality
Cognitive ability
Quality of life
LOS in hospital
Accidents
RSA MEDICAL FITNESS TO DRIVE
GUIDELINES (April, 2014)

Drivers with diabetes


must notify the NDLS when treated with sulphonylureas, glinides or insulin
advised to take the following precautions:




Always carry blood glucose meter
Test before driving and every 2 hrs of the journey
Keep oral glucose in the vehicle
ID
If hypoglycaemia develops while driving, STOP as soon as possible.


Switch off the engine, remove the keys from the ignition and move
from the driver’s seat.
Do not start driving until 45 minutes after blood glucose has returned to
normal.
Class 1 (Car, Motorcycle &
Tractor)






Complete a medical form
Duration up to 3yrs
Must have had no more
than one episode of ‘severe’
hypoglycaemia in 12
months
Good understanding and
awareness of
hypoglycaemia
Appropriate SMBG & prior
to driving
Visual standards must be
met
Class 2
(Truck, Bus & Trailer Vehicles)







Complete a medical form
Duration of license 1yr
No episodes of ‘severe’
hypoglycaemia
Good understanding &
awareness of
hypoglycaemia
Demonstrate regular SMBG
BD & prior to driving
At annual endocrinologist
review 3 months of SMBG
Must demonstrate an
understanding of the risks
of hypoglycaemia
Challenges?






Identify people high risk individuals
Develop measures to lower their risks of
driving mishaps
Educate on avoiding & responding
Facts on when it is safe & not safe to drive
Medical fitness to drive guidelines
Patient advisory form
Case Study No.1







John 74 yr
Type 2 Diabetes 30yrs, requiring insulin 20yrs
Basal bolus 10 yrs, does not adjust
Hba1c 85mmol/mol or 9.9%
eGFR 44ml/min
Poor hypoglycaemia awareness
1 episode of severe hypoglycaemia
Case Study No. 2







Michael 62yr
Type 2 Diabetes 8 years
Bus driver…SMBG 7-8 times daily
No episodes of hypoglycaemia
Hba1c 67mmol/mol or 8.3%
Janumet 50/1000mg BD
Diamicron MR 30mg
Case Study No.3






Barbara 41years
Diet controlled diabetes…erratic eater
Hba1c 45mmol/mol or 6.3%
Hx bariatric surgery & OCD
Gyms 1-2hrs 1-5 days per week
Reports blood glucose 3.4mmols 2hr after
lunch
Case Study No.4









Breda 47yrs
Type 2 Diabetes 3 years
BMI 31
eGFR 92mls/min
Hba1c 81mmol/mol or 9.6%
Poor diet
Scuba diver
Jentadueto
Diamicron MR 60mg daily
Case Study No.5








Brian 72 years
Multiple co-morbities
eGFR 50ml/min
Recent diagnosis sleep apnoea
Hba1c 75mmol/mol or 9%
Basal bolus regime & sliding scale
Insulin titration
Ist episode of hypoglycaemia…no record in
SMBG diary
Questions that can be asked to explore a persons understanding of diabetes
What do you understand by the term “hypo” or low blood glucose?
What do you think causes hypoglycaemia?
People with diabetes may not realise they have experienced hypoglycaemia or know
What to look for
How would you recognise a “hypo”?
Have you ever felt shaky and sweaty, maybe when you haven’t eaten for a long time?
People with diabetes may not appreciate the implications of hypoglycaemia
What do you think the effects of hypoglycaemia are?
Do you drive, cycle regularly or operate machinery?
People with diabetes may not understand what to do if they experience hypoglycaemia
Have you ever had a hypo and how did you feel?
How many times have you had a hypo in the last month?
How would you treat a hypo?
People with diabetes may not carry glucose with them in case of hypoglycaemia
If you had a “hypo” now, how would you treat it?
Are you carrying glucose with you now?
Useful websites




NHS Diabetes (2011) ‘Recognition, treatment and
prevention of hypoglycaemia in the community’, TRENDUK can be accessed on: http://www.trenduk.org/documents/Trend_report_to_print.pdf
www.RSA.ie Medical Fitness to Drive Guidelines
www.diabetes.ie
www.diabetescare.org American Diabetes Association