Current update of use Insulin analogs in pregnancy and diabetes

1. Insulin Analogs in pregnancy Current status ….. Mathew John , MD, D M, DNB Providence Endocrine and Diabetes Specialty Centre, Trivandrum

2. Gestational diabetes Gestational diabetes mellitus (GDM), a common medical complication of pregnancy, is defined as “any degree of glucose intolerance with onset or first recognition during pregnancy” Pre gestational diabetes Diabetes preceding pregnancy

3. Normal glycemic pattern in pregnancy Based on CGMS data and SMPG data Fasting (premeal and overnight values) : 50-99 mg/dl Peak postmeal values : 60-70 minutes after eating Postmeal values : 81-129 mg/dl Hod M, Yogev Y. Goals of metabolic management of gestational diabetes: is it all about the sugar? Diabetes Care. 2007 Jul;30 Suppl 2:S180-7.

4. The Impact of Maternal Hyperglycemia During PregnancyModified Pedersen Hypothesis Maternal hyperglycemia Insulin Fetal pancreas stimulated Fetal hyperinsulinemia IgG-antibody-bound insulin Insulin resistance syndrome Placenta Fetus Mother IgG=immunoglobulin G

5. Why is controlling hyperglycemia important in pregnancy ? ACHOIS study Australian Carbohydrate Intolerance Study in Pregnant Women (ACHOIS) Crowther CA. N Eng J Med 2005: 352; 2477-2486.

6. Why is controlling hyperglycemia important in pregnancy ? A Multicenter, Randomized Trial of Treatment for Mild Gestational Diabetes. MFMU Trial Landon, MB, et al. NEJM, Oct 2009.

7. Increased Second Trimester Maternal Glucose Levels Are Related to Extremely Large-for-Gestational-Age Infants in Women With Type 1 Diabetes Kerssen A, Harold W. de Valk, Diabetes Care May 2007 30:1069-1074;

8. Glycemic targets Simmons D . Gestational Diabetes Mellitus: NICE for the U.S.? Diabetes Care 33:34–37, 2010

9. Insulin in pregnancy Insulin is the preferred pharmacological treatment in pregnancy because it is unable to cross the placenta due to its large molecular weight (6000 Da) Anti-insulin antibodies in response to human insulin in women with gestational diabetes Once bound to these IgG antibodies, insulin can cross the placental barrier and initiate the cascade of events leading to neonatal macrosomia. Elliott B, Schenker S, Langer O, Jonhson R, Prihoda T. Comparative placental transport of oral hypoglycemic agents in humans: a model of human placental drug transfer. Am J ObstetGynecol 1994;171: 653e60. Elliott B, Langer O, Schenker S, Johnson RF. Insignificant transfer of glyburide occurs across the human placenta. Am J ObstetGynecol 1991 ct;165(4 Pt 1):807e12.

10. Short acting insulin analogs Short acting analogs Lispro Aspart Glulisine

11. 24 hour insulin profiles after a single injection Glargine, Detemir More predictable Less variable than NPH insulin Long acting analogs

12. Judging analogs Safety Efficacy

13. Short acting analogs Similar PK and PD Plasma insulin level is reached earlier and greater Better control of post prandial plasma glucose Less risk of post prandial hypoglycemia Gold standard of mealtime insulin replacement in adults Rodbard HW, Jellinger PS, Davidson JA Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control. EndocrPract. 2009 Sep-Oct;15(6):540-59

14. Safety Lispro Greater homology with IGF -1 Low dose lispro: not found in the umbilical cord of infants after low dose infusion in labor High dose 4 hour infusion: small dose dependent transfer In vitro study : placental accumulation, but not transferred to umbilical cord Prospective open label study showing that there are no difference in progression of retinopathy in women on lispro

15. Safety Aspart Comparable receptor affinity to Lispro IGF-1 affinity same as that of human insulin

16. Pregestational diabetes : Aspart 322 pregnant women with type 1 diabetes has been performed Regular insulin or Aspart Aspart showed a lower degree major hypos( 1.4 vs. 2.1 episodes/year ) Risk of minor/major hypoglycemias was 52 % lower with Aspart ( P=0.003 p: 0.044 ) Lower perinatal mortality ( 14 vs. 22 per 1000 births) Congenital malformations ( 6 and 9 ) Mean birth weight ( 3.438 vs. 3.555 P = 0.091 Preterm 20.3 % and 30.6 % ( P=0.053) Hod M, Damm P, Kaaja R, et al. Fetal and perinatal outcomes in type 1 diabetes pregnancy: randomised study comparing insulin aspart with human insulin in 322 subjects. Am J Obstet Gynecol. 2008;198:e1–e7

17. Congenital anomalies : short acting analog vs. regular insulin ( non RCT )

18. Insulin Lispro Controls Postprandial Hyperglycemia in GDM Plasmaglucose(mg/dL) Jovanovic L et al. Diabetes Care. 1999;22:1422-1427

19. Decreased Hypoglycemia With Insulin Lispro 2.5 Mean hypoglycemiarate (blood glucose<55 mg/dL) Regular human insulin Insulin lispro 2.0 1.5 * 1.0 0.5 0 Breakfast Lunch Dinner *P=0.025 Jovanovic L et al. Diabetes Care. 1999;22:1422-1427

20. Insulin Aspart Improves Mean Glucose Concentrations in GDM None Regular human insulin Insulin aspart Glucose (mg/dL) 130 120 110 100 90 80 70 60 –30 0 30 60 90 120 180 240 Time (min) Pettitt DJ et al. Diabetes Care. 2003;26:183-186

21. Neonatal Malformations Are Not Related to Type of Insulin 15.8% Regular human insulin 16 Congenital malformation rate (%) Insulin lispro 14 12 10 7.9% P=0.79 8 6.6% P=0.16 6 3.8% 4 2 0 GDM Preexisting diabetes N=213 N=97 Bhattacharyya A et al. Q J Med. 2001;94:255-260

22. Infant Malformations in Preexisting Diabetes Are Related to First-Trimester A1C Levels, Not Type of Insulin A1C standard deviation from mean at first prenatal visit correlates with major anomaly rate in insulin lispro–treated patients (5.4%, P=0.04) Percentwith major anomalies 14 12 10 8 6 4 2 0 <–2 –2 to <0 0 to <2 2 to <4 4 to <6 6 to <8 8 A1C standard deviation from mean Wyatt JW et al. Diabet Med [online early]. Available at: http://www.blackwell-synergy.com/links/doi/10.1111/j.1464-5491.2004.01498.x/abs/. Accessed December 23, 2004

23. Glargine in pregnancy Reproductive toxicity in animal studies No direct effect on reproduction or embryo fetal development Hypoglycemia related effect ( similar to NPH ) Increased IGF-1 receptor action Increased DNA stimulation No proof of malignancy in humans Hoffman T Int J Toxicol 2002 21;181-189 Kurtzals P Diabetes 2000 :49: 995-1005

24. Glargine : a large retrospective review 240 women in Bronx Diabetes in Pregnancy Programme 184 with GDM, 56 with pregestational diabetes 132 : spontaneous delivery, 108 : LSCS 2 % GDM : macrosomic infants No congenital malformations Henderson C . A retrospective review of Glargine Use in Pregnancy J Rep Med 2009; 54: 208-210

25. Glargine: metaanalysis of observational studies

26. Glargine: metaanalysis of observational studies

27. Concerns about Glargine Glargine has increased affinity for IGF-1 receptor compared to regular insulin ( X 6.5 ) Possible interaction with trophoblast IGF-1 receptor Glargine molecule is large and does not traverse placenta No animal studies in therapeutic doses to substantiate Henderson C . A retrospective review of Glargine Use in Pregnancy J Rep Med 2009; 54: 208-210 Kurtzhals P. Diabetes 2000 ; 49: 999-1005.

28. Detemir in pregnancy Limited studies Safety data limited by limited studies 310 patient data for RCT in Type 1 studies Maternal and fetal data similar between 2 groups M Hod et al. Perinatal Outcomes in a Randomized Trial Comparing Insulin Detemir with NPH Insulin in 310 Pregnant Women with Type 1 Diabetes ADA Abstract 2011 Clinical Experience with Basal Insulin Analogs in Diabetic Pregnancy: Details of a Randomized Controlled Trial in Type 1 Diabetes and a Review of the Literature Accepted Article', doi:10.1002/dmrr.1213 Lapolla A, Di Cianni G, Bruttomesso D, et al. Use of insulin detemir in pregnancy: a report on 10 Type 1 diabetic women. Diabet Med 2009; 26(11): 1181–1182.

29. Pregnancy categories Aspart, Lispro: category B Regular insulin : category B Glargine, Detemir : category C Category A : No increased risk of fetal abnormalities have been demonstrated in adequate, well-controlled studies in pregnant women. Category B : There are no adequate and well-controlled studies in pregnant women; however, animal studies have not revealed evidence of harm to the fetus. Category C: There are no adequate and well-controlled studies in pregnant women;however, an adverse effect has been shown in animal studies. -or- Adequate and well-controlled studies in pregnant women have failed to show a risk to the fetus; however, an adverse effect has been shown in animal studies.

30. Messages Glycemic control is important in pregnancy Short acting analogs are safe in pregnancy and are categorized as B ( same as human insulin) Long acting analogs are category C in pregnancy In a well controlled pregestational diabetes patient, we should weigh the risks vs. benefits with stopping long acting analogs

31. Thank you

32. Can we use Metformin in pregnancy ? Metformin is an insulin sensitizer Used up to 2500 mg/day 751 patients were randomized Neonatal complications — did not differ significantly between groups (32.0% in the metformin group and 32.2% in the insulin group, P = 0.95) No difference in FPG, PPG< HbA1c between the groups with Metformin and Insulin 46.3% of women taking Metformin required supplemental insulin Metformin versus Insulin for the Treatment of Gestational Diabetes N Engl J Med 2008;358:2003-15.

33. Can we use Glibenclamide in pregnancy ? Transplacental transfer is < 4% Drug was undetectable in the cord blood of their neonates Randomised control trials present Start at 2.5 mg/day and hike up doses every 7 days upto 20 mg/day Target levels of sugars and fetal outcomes similar to insulin Increased risk of pre-eclampsia and a higher need for phototherapy in the glyburide group Jacobson GF Am. J. Obstet. Gynecol. 193, 118-124 (2005