1. Type 1 Diabetes Treatment Options Stanley Schwartz Mark Stolar Emeritus, Univ of Pa Part 1

2. Type 1 Diabetes Diabetes mellitus type 1 (IDDM) Hyperglycemia resulting from the autoimmune destruction of the insulin-producing beta cells in the pancreas- insulin therapy is essential for survival= insulin dependent unlike type 2 diabetes where insulin use defines insulin treated not dependent

3. Pathogenesis of Type 1 Diabetes Variable insulitis  -cell sensitivity to injury Interactions between genes imparting susceptibility and resistance Environmental triggers and regulators Immune dysregulation Pre-diabetes Overt diabetes  -cell Mass Time Loss of first-phase insulin response Glucose intolerance Adapted with permission from Atkinson MA, Eisenbarth GS. Lancet. 2001;358:221 May be relapsing/remitting

4. Type 1 Diabetes Insulin-deficient state Therapeutic goal: replace insulin Strategy: provide replacement insulin in manner that mimics normal fasting/prandial physiology This cannot always be done with current insulin analogues Goal to reduce microvascular complications. Is postprandial hyperglycemia more pathogenic?

5. DCCT Microvascular Complication Event Rates and Risk Reductions Cumulative Incidence (%) 76% 59% 39% 54% 64% 1. DCCT Research Group. Ophthalmology. 1995;102:647 2. DCCT Research Group. Kidney Int. 1995;47:1703 3. DCCT Research Group. Ann Intern Med. 1995;122:561 1 2 2 1 3

6. : 1. Hypoglycemia 2. Weight gain 3. Glycemic, including daytime, variability 4. Doesn’t address non-insulin mediated causes of hyperglycemia in type 1 diabetes The Downside to Intensive Insulin Management

7. DCCT RESULTS Severe Hypoglycemia DCCT Research Group, Diabetes 1997;46:271-286 HbA 1c (%) During Study 100 80 60 40 20 0 567891011121314 Rate/100 Patient Years Conventional Intensive Persistent three-fold increase in INT Increased risk of multiple episodes within same patient (INT = 22%, CON = 4%) Number of prior episodes was strongest predictor of future risk Current A1C not solely predictive of risk

8. Hypoglycemia Unawareness Is a Dangerous Complication of T1DM Each episode of hypoglycemia reduces counterregulatory response to low glucose even after one episode Reduction in catecholamine response decreases awareness/symptoms even after a single episode Nocturnal hypoglycemia is most pathogenic and unrecognized. Hypoglycemic awareness decreases significantly in the elderly

10. CV Consequences of Hypoglycemia Prolonged QT- intervals- Diabetologia 52:42,2009 – Can be of pronged duration IJCP Sup 129, 7/02 – Greater with higher catecholamine levels Europace 10,860 Associated with Angina Diabetes Care 26, 1485, 2003 / Ischemic EKG changes Porcellati, ADA2010 Associated with Arrhythmias Associated with Sudden Death Endocrine Practice 16,¾ 2010 Increased Glycemic Variabilty- Adverse ICU outcomes/Increased vascular inflammation Hirsch ADA2010

11. : 1. Hypoglycemia 2. Weight gain 3.Glycemic, including daytime, variability 4. Doesn’t address non-insulin mediated causes of hyperglycemia in type 1 diabetes The Downside to Intensive Insulin Management

12. Consequences of Intensive Insulin Therapy Intensive Conventional Weight Gain DCCT (Type 1)UKPDS (Type 2) Time (y) 03691215 0 2.5 5.0 7.5 10.0 Δ Weight (kg) Quartile of Weight Gain Δ Weight (kg) 30 25 20 15 10 5 0 -5 1234 Data from Purnell J, et al. JAMA 1998; 280:140-146 Data from UKPDS Group (UKPDS 33). Lancet 1998; 352:837-853

13. Weight Gain 4 0 10 5 6 7 8 9 11 12 A1C (%) Δ Weight (kg) 6 8 4 2 -2.2% -2.6% Yki-Jarvinen 1999Henry 1993 +4.6 kg +8.7 kg BID Insulin Intensive BID Insulin ADA Goal MEALTIME INSULIN THERAPY

14. : 1. Hypoglycemia 2. Weight gain 3. Glycemic, including daytime, variability 4. Doesn’t address non-insulin mediated causes of hyperglycemia in type 1 diabetes The Downside to Intensive Insulin Management