Diabetes in Young Women

1. Diabetes in Young Women Francine R. Kaufman, M.D. Professor of Pediatrics The Keck School of Medicine of USC Head, Center for Diabetes and Endocrinology Childrens Hospital Los Angeles

2. Life Goes on …. • Diabetes does not have to stop you • That can only happen if you face your diabetes • 24/7 • Just do it • If people react negatively • They are uninformed – you need to educate them • If they cannot be enlightened – you don’t need them • Make it a positive – or at least a neutral

3. Points of Discussion • Practical Strategies for Managing Diabetes • Leaving Home – Taking Risks • Colleges Life and Employment • Dating - Marriage • Pregnancy • Avoiding Complications

4. Question What are the Targets?

5. Glycemic TargetsGlucose values are plasma (mg/mL)

6. HbA1c Statistics for CHLA 2003 Type 1: Diabetes > 1 year, followed > 1 yearEnrolled in Long-term study – total n 1800

7. Question Strategies for Diabetes Management?

8. Managing Diabetes • In DCCT, intensively treated adolescents (13-17 yrs of age) manifested a greater absolute rate of severe hypoglycemia and higher mean HbA1c levels. • Why? • Adolescents are faced with rapid physiological and psychological modifications with the onset of puberty which may destabilize glycemic control.

9. DCCT Results: Comparison of Adults Versus Adolescents Adults Adolescents Intensive Therapy Intensive Therapy Glycemia Mean BG (mg/dL) 155 ± 30 171 ± 31 HbA1c (%) 7.12 ± 0.03 8.06 ± 0.03 Change in HbA1c 1.7 ± 0.1 1.7 ± 0.2 Risk Reduction Retinopathy 63% 61% Microalbuminuria 54% 35% Hypoglycemia Episodes/100 pt-yrs 61.2 85.7 Relative Risk 3.3 2.8

10. Insulin management • Fixed dose regimens: • requires scheduled meals and snacks and is not flexible enough for most lifestyles • Basal: bolus regimens: • Long-acting relatively peak free analogue with pre-food injection of rapid acting analogue useful only if child is willing to take frequent injections • Insulin pumps being increasingly used in all age groups but child must be willing to wear the device

11. 8 7 6 <5% 5 5%-6% A1C (%) 4 6%-7% 3 7%-8% 2 >8% 1 0 >10/day 8-10/day 6-8/day 4-6/day <4/day Number of Blood Glucose Levels per Day Relationship Between Number of Blood Glucose Determinations and A1C

12. Question Does Good Diabetes Control Interfere with My Life?

13. Metabolic Control and Quality of Life • The study involved 20 centres in 17 countries in Europe, Japan and North America. • Adolescents aged 10-18 yrs at each study centre were invited to participate. • 2,101 adolescents were enrolled. • Samples and information from 79% of all patients registered at the centres were obtained.

14. Patient characteristics on insulin management Daily insulin regimen 1 injection 2 injections 3 injections 4 or more injections Premixed insulin, n (%) Insulin dose (U/kg/day) Boys(n=1085) 8 472 295 307 445 (41) 0.94 ± 0.32 Girls(n=1016) 10 380 287 339 407 (40) 1.01 ± 0.32 P-value <0.05 0.66 <0.0001# Results as means ± SD# Adjusted for center, age and duration of diabetes.

15. Worries about diabetes in adolescents by age, gender and HbA1C

16. Metabolic Control and Quality of Life • Key messages • First large international study evaluating the relationship between metabolic control and QOL in 2,101 adolescents with diabetes • Lower HbA1c associated with better QOL of adolescents and lesser perceived family burden

17. Question Leaving Home? Taking Risks

18. Adolescent Issues • Desire for peer acceptance • Rebellion against authority • Expectations of increasing responsibilities outside of home

19. Taking Risks • Alcohol • Drugs • Driving • Hiding diabetes – impacts on it all

20. Question College Life

21. College Life • Fun • Food • Friends • Fraternity • Focus

22. Keeping in Touch • Stay with health care provider who knows you versus changing at college or before you go • Email program • Less frequent visits • Stressors and stress reduction

23. Question Dating and Marriage

24. Dating • When to tell about diabetes • What to tell • Where to find information • How do you handle different responses • MARRIAGE

25. Question Pregnancy

27. More than 135,000 GDM + 200,000 T2DM + 6,000 T1DM pregnancies annually Prevalence of Diabetes in Pregnancyin the United States of America Diabetes 8% Non-diabetes 92% American Diabetes Association. Diabetes Care. 1998;21(Suppl. 2).

28. Fetal Hyperglycemia • Glucose Stimulates fetal pancreas Insulin Placenta Fetal Hyperinsulinemia Fetus Mother

29. Data At CHLA225 Teens at Risk • 5-6 pregnancies / year • >50% interrupted or SAB • 2-3 Live Births / year • 1/3 Require Prolonged Hospitalization • Last 3 years – no anomalies Overall increased rate of anomalies 6-12% compared to 2-3% - a 2-5 fold increase But this can be modified by pre-conception planning and meticulous diabetes control

30. Question How To Avoid Complications

31. DCCT Results: Comparison of Adults Versus Adolescents Adults Adolescents Intensive Therapy Intensive Therapy Glycemia Mean BG (mg/dL) 155 ± 30 171 ± 31 HbA1c (%) 7.12 ± 0.03 8.06 ± 0.03 Change in HbA1c 1.7 ± 0.1 1.7 ± 0.2 Risk Reduction Retinopathy 63% 61% Microalbuminuria 54% 35% Hypoglycemia Episodes/100 pt-yrs 61.2 85.7 Relative Risk 3.3 2.8

32. Relative Risk of Progression of Diabetic Complications by Mean HbA1c Based on DCCT Data RELATIVE RISK HbA1c

33. Intensive Therapy for Diabetes:Reduction in Incidence of Complications T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus. *Not statistically significant due to small number of events. †Showed statistical significance in subsequent epidemiologic analysis. DCCT Research Group. N Engl J Med. 1993;329:977-986; Ohkubo Y, et al. Diabetes Res Clin Pract. 1995;28:103-117; UKPDS 33: Lancet. 1998;352: 837-853; Stratton IM, et al. Brit Med J. 2000;321:405-412.

34. Recommendations For Treatment Of Retinopathy • Annual screening should be done when the child is ≥ 10 years old and has diabetes for 3-5 years Questions: • Is this early enough for a child with poorly controlled diabetes for longer than 3-5 years?

35. Recommendations For Microalbuminuria Testing • Annual screening for urinary albumin should begin when • Child is ≥ 10 yrs old • DM of 5 years duration • If urine albumin: creat ratio on spot urine is abnormal (30-299 mg/gm creatinine) • Confirm with 2 additional urine specimens • Obtain up: down urine specimen to rule out orthostatic proteinuria

36. Recommendations For Microalbuminuria Treatment • ACE Inhibitors may reverse microalbuminuria or delay rate of progression to macro-albuminuria • Treat BP aggressively • Questions: • Should these children all be referred to a nephrologist for evaluation and treatment? • Should children with poorly controlled DM be evaluated sooner? • Should children with HTN be evaluated sooner?

37. BP Recommendations • Repeat with child sitting and relaxed on 2 more occasions • HTN defined as BP≥ 95% for age, sex and height measured on at least 3 separate days • High normal BP is ≥ 90% but < 95% • Rule out non-diabetes causes

38. BP: When to Treat • High normal BP • Diet (limit salt) and exercise for 3-6 months • If still high normal, treat with ACE inhibitor • Consider adding ARBs if 90% on maximal doses • Hypertension (confirmed) • Treat with ACEI to achieve BP< 90% Questions Remaining: At what age to treat? At what level to treat?

39. Children with diabetes have increased muscle thickness & stiffness • Carotid artery intima media thickness is significantly increased in youth with diabetes compared to controls matched for age and gender -correlated with LDL-C levels • Brachial artery reactivity is decreased in children with diabetes compared to matched controls • Radial artery tonometry → stiffer vessels in children with diabetes compared to BMI, age, sex matched controls

40. Cardiovascular Disease Risk Factors in Adolescents with Type 1 Diabetes Mellitus M.V. Karantza, S. Bababeygy, H.N. Hodis, W.J. Mack, C.-R. Liu, C.-H. Liu, and F.R. Kaufman Division of Endocrinology, Diabetes, and Metabolism, Childrens Hospital Los Angeles Supported by ADA Clinical Research Award 1-01-CR-06

41. Background Atherosclerosis is a Major Cause of Morbidity and Mortality in Patients with T1DM • May be initiated early • Accelerated by traditional CVD factors • Hig blood pressure, dyslipidemia, cigarette smoking, obesity • Inflammatory and prothrombotic factors

42. Background Previous Investigations • Atherosclerosis assessed by IMT measurement • 142 subjects with T1DM Mean age 16.0 ± 2.6 yr, mean T1DM duration 6.6 ± 7.9 yr • 87 matched healthy subjects • Results: • Adolescents with T1DM had increased atherosclerosis compared to controls • Risk factors for increased IMT included diabetic complications, and HDL and LDL/HDL ratio Krantz JS, et al, J Pediatr 2004;145: 452-457

43. IMT vs HbA1c .75 P<0.05, r=0.34 .7 .65 IMT mm .6 .55 .5 6 8 10 12 14 HbA1c (%)

44. IMT and Tobacco Exposure in Males with T1DM .8 P=0.02 0.624 ± .042 .7 0.575 ± .048 IMT mm .6 .5 .4 No Tobacco Exposure Tobacco Exposure

45. IMT vs Lipids in T1DM In males, IMT is significantly associated with • Total Cholesterol (r=0.32, p<0.05) • Apolipoprotein B (r=0.41, p<0.05) In females, IMT is negatively correlated with • HDL (r=-0.30, p<0.05)

46. The Continuum Of Vascular Damage in T1DM • Conventional CVD risk factors result in increased IMT and probably cause the initial endothelial dysfunction in our cohort of youth with T1DM • The subsequent loss of normal endothelial homeostatic properties leading to a proinflammatory, proadhesive, and procoagulant endothelial surface is not yet present in our cohort • Early treatment of modifiable risk factors could avert the chronic inflammatory process which, if unabated, will result in the advanced atherosclerotic plaque formation

47. Recommendations For Lipid Management • When to test • Pre-pubertal children >2 years old should have • Fasting lipids at diagnosis if there is positive FH of increased lipids or early cv event (<50 males, < 60 females) • If initial LDL-c < 100 mg/dl, repeat every 5 years • If initial LDL-c > 100 mg/dl, begin therapeutic lifestyle change (TLC) • Fasting lipids at puberty or at age 12 yrs if FH normal • Pubertal children or > 12 years old should have fasting lipid profile done at time of diagnosis after BG control established

48. Recommendations For Lipid Management • LDL-c > 100 mg/dl • Step 2 diet (< 7% saturated fat, < 200 mg/d chol) • Exercise 60 minutes daily • Intensify efforts to normalize BG • Repeat 3-6 months • LDL-c >130 mg/dl & ≤ 160 mg/dl after 3-6 mos • Consider treatment • LDL-c > 160 mg/dl after 3-6 months • Treat

49. Pittsburgh Epidemiology of Diabetes Complications Study • 10 year follow up of patients with Type 1 diabetes diagnosed before age 17 • Showed that increased LDL is an independent factor of microvascular disease, macrovascular disease, and mortality LDL 100-129 RR 5.3 LDL 130-159 RR 5.6 LDL >160 RR 12.1 (p<0.01 in all)

50. Unanswered Questions • At what age should we begin medication to decrease lipids? • Should we wait until glycemic control is achieved before initiation of lipid lowering medications • At what level of LDL-c should we treat? • Should we be monitoring hsCRP? • What drugs should we use?