Hypoglycemia in Diabetes

Transcription

1 - a major challenge for better disease management Kirsten Nørgaard Chief Physician, MD, DrMedSci, MHPE Department of Endocrinology Hvidovre University Hospital Denmark

2 Outline Occurrence and impact of hypoglycemia Treatment approaches to avoid and treat hypoglycemia Insulin pumps and CGM influence on hypoglycemia? What can s.c. glucagon potential add to the treatment: In closed-loop systems In open-loop systems

3 Outline Occurrence and impact of hypoglycemia Treatment approaches to avoid and treat hypoglycemia Insulin pumps and CGM influence on hypoglycemia? What can s.c. glucagon potential add to the treatment: In closed-loop systems In open-loop systems

4 Definitions Mild hypoglycemia: a person can self-treat Detected by the person because of symptoms or a random low BG measurement BG limit vary (<3.0, <3.5, <3.9 mmol/l) or May be detected by others because of person s appearance Severe hypoglycemia: need for third party assistance Always detected by others due to the person s appearance 25 % in coma 50% occur at nighttime

5 Mild hypoglycemia Definition not universal Patients do not recall very well Limited data on occurrence Overall average: 1-2 episodes per patient per week Low HbA1c More episodes of mild hypoglycemia

6 Consequences of hypoglycemia Short-term: Unpleasant for patients Associated with psychological distress Affects driving ability, working ability etc. Acute morbidity: injuries, cardiovascular and cerebrovascular events Increased mortality (up to 4-10 % of T1D die from SH) Long-term: Fear of hypoglycemia Reduce life quality Linked with increased morbidity Dementia? Linked to overweight (>50% BMI>25) Main limitation for good metabolic control

7 Dilemma 1) Any rise in A1c causes more damage - any fall helps Better 2) Severe hypoglycemia is the downside

8 Chillaron et al, Metabolism, 2014

9 DCCT: randomized study in 1500 type 1 patients treated conventionally (insulin twice daily) or intensively (MDI/insulin pumps)

10 Severe hypoglycemia: results from the T1D Exchange Clinic Registry * Weinstock et al. J Clin Endocrin Metab 2013

11 Severe hypoglycemia in Type 1 and Type 2 patients depending on diabetes treatment and duration Frier, Nat Rev Endocrinol 2014

12 Severe hypoglycemia is frequent but few patients account for most attacks Pedersen-Bjerggard et al. Diabetes Metabol Res Rev, 2004

13 Outline Occurrence and impact of hypoglycemia Treatment approaches to avoid and treat hypoglycemia Insulin pumps and CGM influence on hypoglycemia? What can s.c. glucagon potential add to the treatment: In closed-loop systems In open-loop systems

14 How to avoid severe hypoglycemia Re-education 2-3 weeks completely avoidance of hypoglycemia Decreasing HbA1c goals Increase blood glucose measurements Changing insulin regimen to insulin pumps +/- continuous glucose measurements

15 Treating episodes of severe hypoglycemia 1. Sc. or im. glucagon injection by caregivers at home Studies have shown: Requires 9 steps before use Glucagon is underused Prescription of glucagon reduce emergency visits for severe hypoglycemia 2. Iv. glucose injection by HCPs in hospital settings

16 How to avoid mild hypoglycemia? Fear of hypoglycemia leads to: Patients under-bolus with insulin Eat more than needed- especially at night Avoidance of physical activity Increase self-measurements of blood glucose Change insulin and diet regimen

17 Treating episodes of mild hypoglycemia Extra carbohydrates Reducing insulin (Or in the future: maybe a microdose of glucagon)

18 Outline Occurrence and impact of hypoglycemia Treatment approaches to avoid and treat hypoglycemia Insulin pumps and CGM influence on hypoglycemia? What can s.c. glucagon potential add to the treatment: In closed-loop systems In open-loop systems

19 Insulin pump treatment

20 Connection with infusion set to the abdominal subcutaneous tissue

21 Plasma insulin Principle for insulin pump treatment: Analogue insulin as a continuous infusion + bolus insulin Breakfast Lunch Dinner Bolus Bolus Bolus Basal infusion 4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00

22 Intra-individual variability in insulin action Short acting analogues: 15 % Short acting human insulin: 24 % NPH: 68 % Long acting analogues: Glargine: appr. 38 % Detemir: appr. 38 % Tresiba: 25 % Short acting analogues in insulin pumps: 5%

23 Severe hypoglycaemia and glycaemic control in Type 1 diabetes: meta analysis of multiple daily insulin injections compared with continuous subcutaneous insulin infusion Pickup. Diabetic Medicine, 2008 Insulin pumps reduce SH by 80 %

24 Interstitiel glucose vs BG Interstitial fluid glucose (G 2) is alm ost alw ays com parable w ith blood glucose (G 1) G lucose Sensor 9

25 Glukose-oxidase sensors D escr iption - Sensor G lucose O xidase G luconic A cid 0.6 volts G lucose + O 2 H 2 O 2 2H + + O 2 + 2e - Sensor contains the enzyme e glucose oxidase, which conver ts glucose into an electr onic signal 7

26 CGM with an insulin pump or as stand alone Animas+Dexcom Medtronic VEO Minimed 640G Medtronic Guardian Abbott Navigator Dexcom

27 Annual rates of SH, requiring third-party help at baseline and 12 months after starting CGM Choudhary et al. Dia Care 2013

28 95 patients known with severe hypoglycemia randomized to insulin pump or insulin pump with sensor and Low Glucose Suspend Ly et al. JAMA 2013

29 Outline Occurrence and impact of hypoglycemia Treatment approaches to avoid and treat hypoglycemia Insulin pumps and CGM influence on hypoglycemia? What can s.c. glucagon potential add to the treatment: In closed-loop systems In open-loop systems

30 Closed Loop

31 A closed loop system with one hormone Insulin

32 16 type 1 Age: years Closed loop: Time in hypo Mean BG night Mean BG 24 h Den kunstige bugspytkirtel

33 A closed loop with dual hormone! Glucagon Insulin

34 Randomised study in 52 Type (adults and adolescents) in 5 days CSII- open loop or dual-hormone closed loop Open-loop Closed-loop Mean BG 7,8 mmol/l 7,4 mmol/l * % time lower than 3.9 mmol/l Intervention with glucose due to hypo 7,3 % 4,1 % * 0.6 /day 0.3/day

35 33 children 8-18 years 3 nights in camps: - Control night with insulin pump only - Closed loop: single hormone - insulin - Closed loop: dual hormone insulin and glucagon

36 Time

37 DiaCon Danish approach use two hormones: insulin and glucagon

38 Open-Loop +

39 Glucose response to different sc. doses of glucagon to type 1 patients after hypoglycemia due to a small over dose of insulin Ranjan and Nørgaard, Submitted to Diabetes Obesity and Metabolism, 2015

40 p m o l/l m U / L M e a n + S E M P la s m a g lu c a g o n S a lin e g g lu c a g o n g g lu c a g o n g g lu c a g o n p < S e r u m in s u lin a s p a r t p > T im e (m in ) T im e (m in ) Ranjan and Nørgaard, Submitted to Diabetes Obesity and Metabolism, 2015

41 Advanced Open-Loop? or

42 Conclusions Fear and risk of hypoglycemia are still major problems in diabetes treatment Glucagon in soluble form is needed to treat more episodes of severe hypoglycemic attacks at home Soluble glucagon as a treatment tool for mild hypoglycemia in open loop systems should be further explored Dual-hormone artificial pancreas with glucagon seems very promissing