1. Hypoglycaemia in People with Type 2 Diabetes Angela O’ Riordan CNS Diabetes, Kerry 15 th October, 2014

2. Hypoglycaemia in Type 2 Diabetes Pathophysiology Incidence Causes Treatment & Management Drug Therapies Implications Driving Regulations Case Studies

3. 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)

4. 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 )

5. 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 )

6. 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

7. Defense against hypoglycaemia Glucose counterregulation mechanism Increases glucagon secretion Increases epinephrine secretion

8. ( Bilous & Donnelly), 2010

9. 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)

10. ( Bilous & Donnelly), 2010

12. 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

13. 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)

14. 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 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 longer- acting analogue can carry on working between meals ‒ Human insulin mixture is taken about 30 minutes before a meal so that the short- acting insulin can control the rise in glucose after a meal and the longer-acting insulin can carry on working 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 longer- acting analogue can carry on working between meals ‒ Human insulin mixture is taken about 30 minutes before a meal so that the short- acting insulin can control the rise in glucose after a meal and the longer-acting insulin can carry on working between meals

15. 0 0 0 8 12 18 20 22 24 0 4 24 6 12 24 4 4 8 12 24 0 4 8 18 20 24 Rapid-acting analogue e.g. Humalog®, NovoRapid ®, Apidra ® Short-acting (soluble/human) e.g., Humulin S ®, Actrapid ®, Insuman Rapid ® Intermediate acting (Isophane) e.g. Insulatard ®, Humulin I ®, Insuman Basal ® 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 24 Long acting analogue e.g. Lantus ® or Levemir ® Complete Summary of Product Characteristics available at www.medicines.iewww.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 Onset and Duration of Insulin

16. 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) Why does variable clearance of insulin occur?

17. 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)

18. 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

19. 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)

20. Hypoglycaemia Management in the conscious orientated person 1. 15-20g fasting acting carbohydrate 100mls original lucozade 5-6 Dextrose sweets 150mls coca-cola 200mls fruit juice 3-4 heaped teaspoons of sugar dissolved 2. If a meal is due in 10mins eat CHO containing meal 3. If no meal due 2 slices of wholegrain bread 1 digestive or 2 rich tea biscuits 200-300mls milk 5. 20mins after the eating recheck blood glucose (ADA, 2014)

21. 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 repeat If a meal is due in 10mins eat CHO containing meal recheck blood glucose (ADA, 2014) If no meal due: e.g. 2 slices of wholegrain bread or 1 digestive or 2 rich tea biscuits or 200-300mls milk 10-15 mins > 4mmols 20 mins

22. 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

23. 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?

24. Consequences of hypoglycaemia in diabetes Obstacle to achieving normoglycaemia Cardiovascular risk All cause mortality Cognitive ability Quality of life LOS in hospital Accidents

25. 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.

27. 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 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 Class 2 (Truck, Bus & Trailer Vehicles)

28. 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

29. 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

30. 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

31. 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

32. 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

33. 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

34. 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?

35. Useful websites NHS Diabetes (2011) ‘Recognition, treatment and prevention of hypoglycaemia in the community’, TREND- UK can be accessed on: http://www.trend- uk.org/documents/Trend_report_to_print.pdfhttp://www.trend- uk.org/documents/Trend_report_to_print.pdf www.RSA.ie Medical Fitness to Drive Guidelines www.RSA.ie www.diabetes.ie www.diabetescare.org American Diabetes Association www.diabetescare.org