GDM analogs


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Current update of use Insulin analogs in pregnancy and diabetes

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  • All of the included studies were observational cohort studies. Each study included pregnant women with either gestational diabetes or pregestational diabetes who were on insulin glargine and a control group of women on NPH insulin in pregnancy. These 8 studies comprised a total of 702 women with pregestational or gestational diabetes in pregnancy treated with either insulin glargine (n = 331) or NPH insulin (n = 371).
  • GDM analogs

    1. 1. Insulin Analogs in pregnancy Current status ….. <br />Mathew John , MD, D M, DNB <br />Providence Endocrine and Diabetes Specialty Centre, Trivandrum <br />
    2. 2. Gestational diabetes <br />Gestational diabetes mellitus (GDM), a common medical <br />complication of pregnancy, is defined as “any degree of <br />glucose intolerance with onset or first recognition during <br />pregnancy”<br />Pre gestational diabetes<br />Diabetes preceding pregnancy <br />
    3. 3. Normal glycemic pattern in pregnancy <br />Based on CGMS data and SMPG data <br />Fasting (premeal and overnight values) : 50-99 mg/dl <br />Peak postmeal values : 60-70 minutes after eating <br />Postmeal values : 81-129 mg/dl <br />Hod M, Yogev Y. Goals of metabolic management of gestational diabetes: is it<br />all about the sugar? Diabetes Care. 2007 Jul;30 Suppl 2:S180-7.<br />
    4. 4. The Impact of Maternal Hyperglycemia During PregnancyModified Pedersen Hypothesis<br />Maternal hyperglycemia<br />Insulin<br />Fetal pancreas stimulated<br />Fetal<br />hyperinsulinemia<br />IgG-antibody-bound insulin<br /> Insulin resistance syndrome<br />Placenta<br />Fetus<br />Mother<br />IgG=immunoglobulin G<br />
    5. 5. Why is controlling hyperglycemia important in pregnancy ? <br />ACHOIS study<br />Australian Carbohydrate Intolerance Study in Pregnant Women (ACHOIS) <br />Crowther CA. N Eng J Med 2005: 352; 2477-2486. <br />
    6. 6. Why is controlling hyperglycemia important in pregnancy ? <br /> A Multicenter, Randomized Trial of Treatment for Mild Gestational Diabetes. MFMU Trial<br />Landon, MB, et al. NEJM, Oct 2009.<br />
    7. 7. Increased Second Trimester Maternal Glucose Levels Are Related to Extremely Large-for-Gestational-Age Infants in Women With Type 1 Diabetes <br />Kerssen A, Harold W. de Valk, <br />Diabetes Care May 2007 30:1069-1074;<br />
    8. 8. Glycemic targets <br />Simmons D . Gestational Diabetes Mellitus: NICE for the U.S.? Diabetes Care 33:34–37, 2010<br />
    9. 9. Insulin in pregnancy <br />Insulin is the preferred pharmacological treatment in<br /> pregnancy because it is unable to cross the placenta due <br /> to its large molecular weight (6000 Da)<br />Anti-insulin antibodies in response to human insulin in <br /> women with gestational diabetes<br />Once bound to these IgG antibodies, insulin can cross the placental barrier and initiate the cascade of events leading to neonatal macrosomia.<br />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.<br />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.<br />
    10. 10. Short acting insulin analogs <br />Short acting analogs<br />Lispro <br />Aspart <br />Glulisine <br />
    11. 11. 24 hour insulin profiles after a single injection <br />Glargine, Detemir <br />More predictable <br />Less variable than NPH insulin <br />Long acting analogs <br />
    12. 12. Judging analogs <br />Safety <br />Efficacy <br />
    13. 13. Short acting analogs<br />Similar PK and PD <br />Plasma insulin level is reached earlier and greater <br />Better control of post prandial plasma glucose <br />Less risk of post prandial hypoglycemia <br />Gold standard of mealtime insulin replacement in adults <br />Rodbard HW, Jellinger PS, Davidson JA Statement by an American Association of Clinical <br />Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes <br />mellitus: an algorithm for glycemic control. EndocrPract. 2009 Sep-Oct;15(6):540-59<br />
    14. 14. Safety <br />Lispro<br />Greater homology with IGF -1 <br />Low dose lispro: not found in the umbilical cord of <br /> infants after low dose infusion in labor <br />High dose 4 hour infusion: small dose dependent transfer <br />In vitro study : placental accumulation, but not transferred to umbilical cord<br />Prospective open label study showing that there are no difference in progression of retinopathy in women on lispro<br />
    15. 15. Safety<br />Aspart <br />Comparable receptor affinity to Lispro <br />IGF-1 affinity same as that of human insulin <br />
    16. 16. Pregestational diabetes : Aspart <br />322 pregnant women with type 1 diabetes has been performed<br />Regular insulin or Aspart<br />Aspart showed a lower degree major hypos( 1.4 vs. 2.1 episodes/year ) <br />Risk of minor/major hypoglycemias was 52 % lower with Aspart ( P=0.003 p: 0.044 ) <br />Lower perinatal mortality ( 14 vs. 22 per 1000 births) <br />Congenital malformations ( 6 and 9 ) <br />Mean birth weight ( 3.438 vs. 3.555 P = 0.091<br />Preterm 20.3 % and 30.6 % ( P=0.053) <br />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<br />
    17. 17. Congenital anomalies : short acting analog vs. regular insulin ( non RCT ) <br />
    18. 18. Insulin Lispro Controls Postprandial Hyperglycemia in GDM<br />Plasmaglucose(mg/dL)<br />Jovanovic L et al. Diabetes Care. 1999;22:1422-1427 <br />
    19. 19. Decreased Hypoglycemia With Insulin Lispro<br />2.5<br />Mean hypoglycemiarate (blood glucose<55 mg/dL)<br />Regular human insulin<br />Insulin lispro<br />2.0<br />1.5<br />*<br />1.0<br />0.5<br />0<br />Breakfast<br />Lunch<br />Dinner<br />*P=0.025<br />Jovanovic L et al. Diabetes Care. 1999;22:1422-1427 <br />
    20. 20. Insulin Aspart Improves Mean Glucose Concentrations in GDM<br />None<br />Regular human insulin<br />Insulin aspart<br />Glucose (mg/dL)<br />130<br />120<br />110<br />100<br />90<br />80<br />70<br />60<br />–30<br />0<br />30<br />60<br />90<br />120<br />180<br />240<br />Time (min)<br />Pettitt DJ et al. Diabetes Care. 2003;26:183-186<br />
    21. 21. Neonatal Malformations Are Not Related to Type of Insulin<br />15.8%<br />Regular human insulin<br />16<br />Congenital malformation rate (%)<br />Insulin lispro<br />14<br />12<br />10<br />7.9%<br />P=0.79<br />8<br />6.6%<br />P=0.16<br />6<br />3.8%<br />4<br />2<br />0<br />GDM<br />Preexisting diabetes<br />N=213<br />N=97<br />Bhattacharyya A et al. Q J Med. 2001;94:255-260 <br />
    22. 22. Infant Malformations in Preexisting Diabetes Are Related to First-Trimester A1C Levels, Not Type of Insulin<br />A1C standard deviation from mean at first prenatal visit correlates with major anomaly rate in insulin lispro–treated patients (5.4%, P=0.04) <br />Percentwith major anomalies<br />14<br />12<br />10<br />8<br />6<br />4<br />2<br />0<br /><–2<br />–2 to <0<br />0 to <2<br />2 to <4<br />4 to <6<br />6 to <8<br /> 8<br />A1C standard deviation from mean<br />Wyatt JW et al. Diabet Med [online early]. Available at: Accessed December 23, 2004<br />
    23. 23. Glargine in pregnancy <br />Reproductive toxicity in animal studies<br />No direct effect on reproduction or embryo fetal development <br />Hypoglycemia related effect ( similar to NPH )<br />Increased IGF-1 receptor action <br />Increased DNA stimulation <br />No proof of malignancy in humans <br />Hoffman T Int J Toxicol 2002 21;181-189<br />Kurtzals P Diabetes 2000 :49: 995-1005 <br />
    24. 24. Glargine : a large retrospective review <br />240 women in Bronx Diabetes in Pregnancy Programme<br />184 with GDM, 56 with pregestational diabetes<br />132 : spontaneous delivery, 108 : LSCS<br />2 % GDM : macrosomic infants <br />No congenital malformations <br />Henderson C . A retrospective review of Glargine Use in Pregnancy J Rep Med 2009; 54: 208-210 <br />
    25. 25. Glargine: metaanalysis of observational studies<br />
    26. 26. Glargine: metaanalysis of observational studies<br />
    27. 27. Concerns about Glargine <br />Glargine has increased affinity for IGF-1 receptor compared to regular insulin ( X 6.5 ) <br />Possible interaction with trophoblast IGF-1 receptor <br />Glargine molecule is large and does not traverse placenta <br />No animal studies in therapeutic doses to substantiate <br />Henderson C . A retrospective review of Glargine Use in Pregnancy J Rep Med 2009; 54: 208-210 <br />Kurtzhals P. Diabetes 2000 ; 49: 999-1005. <br />
    28. 28. Detemir in pregnancy <br />Limited studies<br />Safety data limited by limited studies <br />310 patient data for RCT in Type 1 studies <br />Maternal and fetal data similar between 2 groups <br />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<br />Clinical Experience with Basal Insulin Analogs in Diabetic Pregnancy: Details of a Randomized<br /> Controlled Trial in Type 1 Diabetes and a Review of the Literature Accepted Article', doi:10.1002/dmrr.1213<br />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.<br />
    29. 29. Pregnancy categories <br />Aspart, Lispro: category B <br />Regular insulin : category B <br />Glargine, Detemir : category C <br />Category A : No increased risk of fetal abnormalities have been demonstrated in adequate, well-controlled studies in pregnant women.<br />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.<br />Category C: There are no adequate and well-controlled studies in pregnant women;however, an adverse effect has been shown in animal studies.<br />-or-<br /> Adequate and well-controlled studies in pregnant women have failed to<br /> show a risk to the fetus; however, an adverse effect has been shown in<br /> animal studies.<br />
    30. 30. Messages <br />Glycemic control is important in pregnancy <br />Short acting analogs are safe in pregnancy and are categorized as B ( same as human insulin) <br />Long acting analogs are category C in pregnancy<br />In a well controlled pregestational diabetes patient, we should weigh the risks vs. benefits with stopping long acting analogs <br />
    31. 31. Thank you <br />
    32. 32. Can we use Metformin in pregnancy ? <br />Metformin is an insulin sensitizer<br />Used up to 2500 mg/day <br />751 patients were randomized<br />Neonatal complications — did not differ significantly between groups (32.0% in the metformin group and<br /> 32.2% in the insulin group, P = 0.95)<br />No difference in FPG, PPG< HbA1c between the groups with Metformin and Insulin<br />46.3% of women taking Metformin required supplemental insulin<br />Metformin versus Insulin for the Treatment of Gestational Diabetes N Engl J Med 2008;358:2003-15.<br />
    33. 33. Can we use Glibenclamide in pregnancy ?<br />Transplacental transfer is < 4% <br />Drug was undetectable in the cord blood of their neonates<br />Randomised control trials present <br />Start at 2.5 mg/day and hike up doses every 7 days upto 20 mg/day<br />Target levels of sugars and fetal outcomes similar to insulin<br />Increased risk of pre-eclampsia and a higher need for phototherapy in the glyburide group<br />Jacobson GF Am. J. Obstet. Gynecol. 193, 118-124 (2005<br />