DESIGNER INSULINS IN GESTATIONAL DIABETES

1. DESIGNER INSULINS IN GESTATIONAL DIABETES DR.T.RAMANI DEVI MD DGO FICS FICOG RAMAKRISHNA NURSING HOME TRICHY

2. Maternal Diabetes Two lives.. Twice as special An oppurtunity for primary prevention -Maternal health -Child health

3. Definition GDM is defined as carbohydrate in tolerance of variable severity with onset or first recognition during pregnancy. The definition is applicable regardless of whether insulin is used to treat the disease or if the condition persists after pregnancy. It does not exclude the possibility that unrecognized glucose intolerance may have antedated the pregnancy

4. Introduction • Incidence of GDM is variable from 17% to 29% of all pregnancies • Associated with maternal and perinatal complications. • 90% of all Diabetics are GDM and 10% are due to pregestational diabetes. • 4 million pregnancies in India are complicated by GDM • This may contribute a part of MMR in India

7. IGT GDM GDM prevalence linked to background IGT rates 2% Agarwal S, Gupta AN. Gestational Diabetes. J Assoc Physicians India 1982;30:203 2% Ramachandran A, et .al., High prevalence of diabetes in an urban population in south India. BMJ 1988;3; 297(6648):587-90 1980s 7.6% Narendra J, Munichoodappa C, et al, Prevalence of glucose intolerance during pregnancy. Int J Diab Dev Countries 1991;11:2-4 8.2% Ramachandran A, Snehalatha c, Dharmaraj D, Viswanathan M. Prevalence of glucose intolerance in Asian Indians. Diabetes Care 1992; 15:1348-55 1990s 14.5% Ramachandran A, Snehalatha C, Kapur A, Vijay V, Mohan V,Das AK, Rao PV, Yajnik CS, Prasanna Kumar KM, Nair JD.For the Diabetes Epidemiology Study Group in India (DESI).Diabetologia 2001;44:1094-1101. 16.6% V Seshiah, V Balaji, Madhuri S Balaji, CB Sanjeevi, A. Green. Gestational Diabetes Mellitus in India. J Assoc Physicians India 2004;52:707 2000s

8. Significance of Diabetes and Pregnancy • Malformation rate in 94/1000 Vs 9.7/1000 in general population • Still birth is 15 times higher 25/1000 Vs 5/1000 • PNM is 3 times higher 19.9/1000 Vs 6.8/1000 • Recent concept of adult diseases having their origin inutero insults has been established. • 1989 WHO/IDF discussed the problem of hyperglycemia in pregnant women. They wanted to achieve pregnancy outcome in diabetic women same as in non diabetic women.

9. FREINKEL HYPOTHESIS Uterine At Birth After Birth placenta Macrosomia Obesity Hypoglycemia Maternal DM Metabolic syndrome IGT/DM A Insulin Fetus A.A Fat CHO CVD

10. Hyperglycaemia during pregnancy is associated with high risk of maternal and perinatal morbidity and mortality and poor pregnancy outcome Maternal hyperglycaemia is associated with development of metabolic problems including type 2 diabetes in the offspring Diagnosis of GDM identifies women at high risk of future diabetes, offers opportunity of primary prevention Diabetes and Pregnancy – Why it is relevant?

11. IUGR & Macrosomia SolutionOptimal nutrition+ Optimal glycemic control=Optimal birth weight 3000 – 3500 g.

13. SCREENING FOR DIABETES

14. WHO Criteria

15. ADA recommendation

16. THRESHOLDS FOR DIAGNOSIS OF GDM

17. GLYCEMIC THRESHOLDS FOR PREVENTION OF DIABETIC COMPLICATION

18. Comparison of the Foetal Outcome in a NGT & GDM Foetal outcome Normal Abortions Still birth Died after birth Congenital anomalies Premature deliveries Sick babies Big baby ( 3.5 kg) NGT (n = 851) 804 6 3 1 8 9 / 831 22 78 GDM (n =211) 122 0 5 5 5 11 / 148 10 90 P value < 0.0001 -- 0.07 0.01 0.23 0.002 0.157 < 0.0001

19. Offspring's of women with GDM, have a 4 to 8 fold increased risk of diabetes. GDM increases the risk of offspring DM Clausen TD et al., Diabetes Care 2008

20. How to reduce this • Early screening for GDM • Monitoring frequently • Proper uses of diet plan , exercise and insulin. • Future concepts of CSII, CGMS, telemedicine, e-health, will revolutionize the management of GDM

21. How to treat? MNT Exercise Insulin Glyburide Metformin Acarbose? Insulin pump

22. Calorie allotment 30 kcal per kg current weight per day in pregnant women who are BMI 22 to 25. 24 kcal per kg current weight per day in overweight pregnant women (BMI 26 to 29). 12 to 15 kcal per kg current weight per day for severely obese pregnant women (BMI >30). 40 kcal per kg current weight per day in pregnant women who are less than BMI 22. Jovanovic-Peterson L, Peterson, CM. Nutritional management of the obese gestational diabetic woman. J Am CollNutr 1992; 11:246.

23. How long MNT? Consensus and hard data are lacking regarding how long diet therapy should be maintained before initiating pharmacologic treatment. 70% of the subjects with initial fasting plasma glucose less than 95 mg/dL achieved targeted levels of glycemia within 2 weeks of dietary management, but no significant improvement occurred thereafter McFarland et al obstet gynecol 1999

24. Exercise Prescription • Can continue prepregnancy activity • Keeping physically active is essential for good glycemic control • Upperbodyergometric exercise useful • Do not start new vigorous exercise for glucose control • Uterine contractions,fetaltachy, maternal heart rate to be monitored

25. ORAL AGENTS IN PREGNANCY Glyburide study: Randomized trial glyburidevs insulin 404 GDMs FPG >95 but <140 mg/dl or 2- hr pp >120 on diet Similar success of glucose control in both groups Langer et al: NEJM 200:343:1134

27. Animal insulin  Insulin Analogues • 1920- Introduction of insulin revolutionized Diabetes Management • 1920- Introduced insulin had impurities and batch to batch variation • 1980- higher quality insulin from bovine and porcine sources . Then came recombinant Insulin

28. IDEAL AGENT SHOULD FULFILL • Mimic physiological control • No adverse effect upon maternal and fetal outcome. • Should not interfere with antenatal , perinatal and post natal care • Insulin Analogues fulfills all the criteria when given in right doses in right manner.

29. ADVANTAGES • Batch to Batch consistency • No allergy, antibody formation • No immune mediated lipoatrophy • Glucose control is similar in endogenous insulin production • Preprandial hypoglycemia and postprandial hyperglycemia are well controlled. • Mealtime flexibility is possible with analogues.

30. Safety issues with Insulin Analogues • Ideal insulin • Mimic physiological insulin secretion • Does not cross placenta • No mitogenic potential • Since IgG bound insulin can cross placenta, therapeutic agent should not induce antibody generation

31. STRUCTURAL MODIFICATION OF INSULIN ANALOGUE

32. Pharmacokinetics of HI and IA

33. RECEPTOR BINDING, METABOLIC AND MITOGENIC POTENCY OF IA

34. HAPO: Hyperglycemia And Adverse Pregnancy Outcome 9 countries, 25 centers, 23,325 patients 7 year study Women were screened between 24-32weeks with fasting glucose, 1 hour and 2 hour post 75 gm glucose . Medical caregivers were blinded to results except that exceeded pre defined cut offs[ 5.8 fasting, 11.1 post 75 gm glucose] and were then removed from the study. Birth weight, maternal complications, operative delivery, insulin levels in newborn were studied. Int J,Gynecology & Obstetrics. 2002,78, (1);69-77

36. GLYCEMIC STATUS IN GDM FASTING HYPOGLYCEMIA POSTPRANDIAL HYPERGLYCEMIA Normalisation of this is possible by Insulin Analogues.

37. Insulin aspart qualifies for use in GDM • Insulin analogues does not cross the placenta but placental concentration is higher than in maternal blood.

38. Insulin Aspart in pregnancy status compared with Human Insulin Moshe Hod et al., Studied insulin aspart in Type I diabetic patient Randomized parallel group open label Multinational study • Decreased hypoglycemic spells • Increased fetal outcome

39. Insulin Aspart in pregnancy status compared with Human Insulin Primary objective – Hypoglycemic attacks Secondary objective – Analyze maternal/fetal outcome - HbA1c - 8 point glucose profile - Number of mild hypoglycemia - cord blood insulin AB

45. Mean cord blood insulin level is lower in IA group

50. INSULIN TACTICS Twice-daily Split-mixed Regimens Regular NPH Insulin Effect B L S HS B 6-23