Emerging Complications Hypoglycemia/ Autonomic Neuropathy

1. Clinical Guidelines to the Transition of Care in Young Adults with Type 1 Diabetes Position Statement Conference Emerging Complications Hypoglycemia/ Autonomic Neuropathy Michael Riddell, PhD Associate Professor Muscle Health Research Centre Physical Activity and Chronic Disease Unit School of Kinesiology and Health Science York University

2. Hypoglycemia-Key Points • Hypoglycemia is common (perhaps 8.5% of nights), with half of these episodes undetected by the patient. • 6% of all deaths in diabetes are due to unrecognized nocturnal hypoglycemia. The “dead in bed syndrome”. • The duration of nocturnal hypoglycemia before a seizure is 2.25-4 hours. • More than two episodes of hypoglycemia per week can lead to loss of counter-regulation and cause the loss of symptom awareness. • Repeated hypoglycemia may impact cognitive function • A fear of hypoglycemia is a barrier to good metabolic control and to healthy behaviours • Exercise participation, energy balance • Hypoglycemia incidence appears to increase at the time of transition. • Factors are unknown

3. Severe hypoglycemia Cognitive dysfunction, loss of consciousness, seizure, death Epidemiology-Severe Hypos In the DCCT, of 1,441 patients with T1DM, there were 3,788 episodes of severe hypoglycemia (requiring assistance); 1,027 of these episodes were associated with coma and/or seizure. A total of 65% percent of patients in the intensive group vs. 35% of patients in the conventional group had at least one episode of severe hypoglycemia by the study end. The overall rates of severe hypoglycemia were 61.2 per 100 patient-years vs. 18.7 per 100 patient-years in the intensive and conventional treatment groups, respectively. (DCCT 1994; 1997)

4. ? Epidemiology-Age and Duration of disease Pickup and Sutton, Diabetic Medicine 2008

5. Epidemiology MDI vs CSII • Severe hypoglycaemia is reduced with CSII compared with MDI [rate ratio 4.19 for all studies]. • In 22 studies, severe hypoglycaemia was related to diabetes duration and was greater in adults than children (100 vs. 36 events/100 patient years). Pickup and Sutton, Diabetic Medicine 2008

6. Hypoglycemia and the adolescent/ young adult Typically, there is a loss of parental supervision of diabetes care with the transition to self care. Attendance to specialty care drops. Several factors may increase risk for hypoglycemia in young patients who are in “transition”: • Busy schedules (work, school) • Lack of diabetes knowledge • Lack of motivation • Alcohol consumption • Changing physical activity levels • Alterations in normal routine (school and work stress) • Poor dietary choices

7. Is Increased Hypoglycemia Associated with Transition of Care? • DM-related hospitalization rates increased from 7.6 to 9.5 cases per 100 patient-years in the 2 years after transition to adult care (P = .03). Previous DM-related hospitalizations, lower income, female gender, and living in areas with low physician supply were associated with higher admission rates. • Hypoglycemia rates did not differ, however. Nakhla M, et al., Transition to adult care for youths with diabetes mellitus: findings from a Universal Health Care System. Pediatrics 124: 6: e1134-41, 2009.

8. What transition do you think worked the best to lower hospital visits? • Transfer to a new physician and allied health care team • Transfer to a new physician but remaining with the same allied health care team • No change in physician or allied health care team • Transfer to a new allied health care team but remaining with the same physician • Transfer to a new physician with no allied health care team follow-up care.

9. True Incidence of Hypoglycemia • Attempts at quantifying the incidence of hypoglycemia in T1DM patients (ages 15-30 years), is challenging as many individuals are symptomless during mild/moderate hypoglycaemia.

10. CGM Data • A recent analysis of 36,467 nights in 176 young subjects with T1DM revealed that hypoglycemic events (2 consecutive CGM readings ≤60mg/dL in 20 minutes) occurred during 8.5% of nights. • The duration of hypoglycemia was ≥2 hours on 23% of hypoglycemic nights. • A higher incidence of nocturnal hypoglycemia was associated with • lower baseline HbA1c levels • the occurrence of hypoglycemia on one or more nights during baseline blinded CGM JDRF CGM Randomized Clinical Trial March, Diabetes Care. 2010 Mar 3. [Epub ahead of print]

11. CGM or microdialysis- Nocturnal Hypo data • On any given night, the incidence has been reported to be between 14% to 47% (depending on the cutoff used), with up to half of the episodes undetected by the subject. • In a 48 hour period, about 1/3rd of patients have nocturnal hypo (<3.9 mmol/L) Kaufman et al., Journal of Pediatrics 2002; Wentholt et al., Diabetic Medicine 2007

12. Both Nights Exercise night only Sedentary night only Neither night Nocturnal hypoglycemia is common following exercise in pediatric T1DM Comparison of nocturnal blood glucose levels between an exercise day vs a sedentary day in 50 children with Type 1 diabetes, reveals that hypoglycemia is common. Incidence of hypoglycemia • Studied on 2 separate days • Ages 11-17 years • Treadmill =140bpm/ 60min • Frequent venous monitoring • Overnight stay in hospital • No insulin adjustments Modified from Tsalikian J Pediatr 2005;147:528-34

13. Screening Even though hypoglycemia is extremely common, screening for severe hypoglycemia should be based on some established risk factors: • Being a male teen or young adult • Low HbA1c • Long duration of diabetes • A history of hypoglycemia • Hypoglycemia unawareness • Recent bouts of severe hypoglycemia • Low C-peptide level, daily insulin dose • insulin dosage >0.85 U/kg/day • Recreationally active (athlete?) Clarke et al., ISPAD Guidelines Pediatric Diabetes 2009

14. Treatment • 15g of carbohydrate, wait 15 minutes, re-treat if BG still <4.5mmol/L (<80mg/dL). • In most adults, 15g of carb can raise a blood glucose level about 2 mmol/L (35mg/dL). • Treatment should be a readily available source of fast acting glucose (tablets) which becomes metabolically available within about 7 minutes. • Glucagon if patient is unable to swallow or is unconscious Clarke et al., ISPAD Guidelines Pediatric Diabetes 2009

15. Interventions • insulin analogs1,MDI, CSII, CGM • Clinical tool vs Real Time • Nutritional Counselling • Exercise Counselling? • Ex carbs 1 Rossetti P et al., DIABETES CARE, VOLUME 31, SUPPLEMENT 2, FEBRUARY 2008

16. Prevention • CSII vs MDI1 • CGM-real time2 Sensor augmented pumps3? • 10PM-3AM risk is high • SMBG is still required to confirm before treatment • Ex carbs • Bedtime snacks • a 2-fold increase in risk of hypoglycemia occurs when the bedtime glucose value is ≤100 mg/dL3 1Misso et al., Cochrane review 2010; 2 JDRF Glucose Monitoring Study Group 2009; 3Hirsch et al., 2008; 4 Kaufman et al., 2002;

17. Gaps in Care • Factors other than A1c and insulin dose need to be identified that influence the risk for hypoglycemia. These may include attitudes of treatment teams, self-care behaviors, educational models, or patient satisfaction. Hvidøre Study Group, Diabetes Care 24:1342–1347, 2001; Scott et al., CJD 2005

18. Antecedent hypoglycemia Glucose counterregulatory failure cardiac autonomic neuropathy Increased risk for hypoglycemia Genetic polymorphisms? Dead in bed syndrome Autonomic Neuropathy Clinical symptoms of autonomic neuropathy do not generally occur until long after the onset of diabetes. There is controversy over whether subclinical signs of autonomic dysfunction can be found in children with diabetes. Sudden cardiac death Verrotti et al., Eur J of Endo, 2009 Tu et al., Human Pathology, 2010

19. Epidemiology- Autonomic Neuropathy • Somewhere between 25-40% of diabetic children and adolescents show one or more abnormal test for cardiovascular autonomic dysfunction (as reviewed by Verrotti 2009). • Non diabetic children can also display these abnormalities

20. Screening for AN 5 simple noninvasive cardiovascular reflex tests: i. Falling systolic blood pressure in response to standing. ii. Heart rate response to standing (30/15 ratio). iii. Heart rate response during deep breathing (expiration:inspiration ratio). iv. Heart rate response to Valsalva maneuver. Verrotti et al, 2009

21. Interventions • Prevention with good glycemic control limits progression of neuropathy • DCCT/EDIC, UK Prospective Diabetes Study, EURODIAB-IDDM Complications Study and the EURODIAB Prospective Study • Trials using aldose reductase inhibitors are not impressive (Chalk; Cochrane Systematic Reviews 2007). • Antioxidants (α-lipoic acid) ? • Ziegler et al. 2004; Huang et., 2008 • C-Peptide • Johansson et al., 2000; and others…

22. Gaps in Care In Canada, 89.2% of respondents indicated they had attended a pediatric diabetes clinic, while only 41.3% had attended an adult diabetes clinic. Time constraints were reported by more than half of responders to be the main reason for not attending or not returning to an adult clinic. When given the freedom to describe their “ideal” diabetes centre, young adults in Canada overwhelmingly pronounced that it would “not [be] in a hospital.” Scott et al., CJD 2005

23. Summary Hypoglycemia Autonomic Neuropathy • Extremely prevalent • The major side effect of lowering A1c • A barrier to many things • Related to transition? • Challenging to detect • (tools for detections do exist and are being used) • Treatment and prevention strategies are reasonably effective • (lowering A1c makes it worse) • Maybe more common that you thought • Probably not related to transition • Can be detected • (tools for detections do exist but are largely not being used) • New treatment and prevention strategies are being tested • Lowering HbA1c is important