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Oral Therapy In DM With Pregnancy

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1 Oral Therapy In DM With Pregnancy
By Prof. ADEL A EL-SAYED MD Prof. of Internal Medicine Sohag Faculty of Medicine Sohag-EGYPT

2 Classic Statement If diet and exercise do not lead to adequate glycemic control in a woman with gestational diabetes, then insulin should be given. Oral hypoglycemic drugs, particularly the sulfonylurea drugs, are contraindicated during pregnancy. Davis SN, Granner DK. Insulin, oral hypoglycemic agents, and the pharmacology of the endocrine pancreas. In: Hardman JG, Limbird LE, eds. Goodman and Gilman's the pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill, 1996:1509.

3 Classic Statement In a recent policy statement by the American Diabetes Association and the American College of Obstetricians and Gynecologists, “Oral glucose lowering agents have generally not been recommended during pregnancy”. American Diabetes Association: Gestational diabetes mellitus. Diabetes Care 27 (Suppl. 1):S88 –S90, 2004.

4 Problems With Oral Therapy Hyperinsulinemia
First-generation sulfonylureas (tolbutamide and chlorpropamide) can easily cross the placenta leading to almost similar cord and maternal serum concentrations. Stowers JM, Sutherland HW. The use of sulphonylureas biguanides and insulin in pregnancy. In: Sutherland HW, Stowers JM, eds. Carbohydrate metabolism in pregnancy and the newborn. Edinburgh, Scotland: Churchill Livingstone, 1975: Early experience with these drugs included numerous cases of profound and prolonged neonatal hypoglycemia. Zucker P, Simon G. Prolonged symptomatic neonatal hypoglycemia associated with maternal chlorpropamide therapy. Pediatrics 1968;42:

5 Problems With Oral Therapy Hyperinsulinemia
Furthermore, fetal hyperinsulinemia can lead to macrosomia and hypoxemia. Both macrosomia and fetal hypoxemia can be induced experimentally by inducing fetal hyperinsulinemia without maternal or fetal hyperglycemia. Philipps AF, Dubin JW, Raye JR. Fetal metabolic response to endogenous insulin release. Am J Obstet Gynecol 1981;139:

6 Problems With Oral Therapy? Teratogenicity
Retrospective studies of series of women with type 2 diabetes mellitus suggested an association between first-trimester sulfonylurea therapy and major congenital malformations - Piacquadio K, Hollingsworth DR, Murphy H. Effects of in-utero exposure to oral hypoglycaemic drugs. Lancet 1991;338:   - Schaefer-Graf UM, Buchanan TA, Xiang A, Songster G, Montoro M, Kjos SL. Patterns of congenital anomalies and relationship to initial maternal fasting glucose levels in pregnancies complicated by type 2 and gestational diabetes. Am J Obstet Gynecol 2000;182: Interpretation problems !! What is the primary teratogen, the treatment or the disease?

7 Why Oral Therapy Still needed?
Insulin therapy is associated with: - The fear of injections (particularly when multiple). - The issue of compliance. - The risks of hypoglycemia. - The increase in appetite and weight. In spite of all these problems the search for oral therapy did not stop

8 What to do? One of two options:
1- Oral drugs which do not cross the placenta. 2- Oral drugs which cross the placenta without causing fetal: - Hypoglycemia. - Hyperinsulinemia. - Teratogenic effects. Actually we have a very good example for both options, and every example has a case. I shall try to focus a little bit on these cases.

9 The Case of Glyburide (Glibenclamide)
Using an isolated perfused human placental model, Elliott et al. demonstrated minimal placental transfer of glyburide, but greater transport of glipizide and particularly chlorpropamide and tolbutamide. 1- Elliott BD, Langer O, Schenker S, Johnson RF: Insignificant transfer of glyburide occurs across the human placenta. Am J Obstet Gynecol 165:807–812, 1991. 2- Elliott BD, Langer O, Schenker S, Johnson RF, Prihoda T: Comparative placental transport of oral hypoglycemic agents in humans: a model of human placental drug transfer. Am J Obstet Gynecol 171:653–660, 1994. In the early 90s Elliott and his group used an in vitro placental model to study the ability of different sulphonylureas to cross the placenta

10 The Case of Glyburide (Glibenclamide) A comparison of glyburide and insulin in women with gestational diabetes mellitus. N Engl J Med 343:1134–1138, 2000 404 women with GDM were randomized to glyburide or insulin treatment. Insulin was given 0.7 units/kg subcutaneously three times daily, and the dose was modified weekly as necessary. The starting glyburide dose was 2.5 mg orally in the morning and escalated weekly to 5mg and then 5 mg twice daily. The twice-daily glyburide regimens were escalated to a total of 20 mg to achieve glycemic control.

11 The Case of Glyburide (Glibenclamide) A comparison of glyburide and insulin in women with gestational diabetes mellitus. If the woman did not achieve the target blood glucose within two weeks, she was switched to insulin. The blood glucose targets for both groups were fasting 90 mg/dl and 2-h postprandial 120 mg/dl.

12 The Case of Glyburide (Glibenclamide) The Trial Results
there were no significant differences in mean neonatal glucose concentrations, macrosomia, neonatal intensive care unit (NICU) admission, or fetal anomalies. Glyburide was not detected in the cord serum of any infant. Only 4% of the glyburide group required insulin therapy. Regarding the neonatal outcome

13 The Case of Glyburide (Glibenclamide) The Trial Results
Of the maternal outcome variables assessed, none were significantly different between groups except the dramatic (P 0.03) reduction in maternal hypoglycemic episodes in the glyburide-treated group (2%) compared with the 20% rate for insulin. Now regarding the …….

14 The Case of Glyburide (Glibenclamide) Further Reports
five small retrospective reports of glyburide use for GDM have been published since 2000: 1- Jacobson GF, Ramos GA, Ching JY, Kirby RS, Ferrara A, Field DR: Comparison of glyburide and insulin for the management of gestational diabetes in a large managed care organization. Am J Obstet Gynecol 193:118–124, 2005 2. Conway DL, Gonzales O, Skiver D: Use of glyburide for the treatment of gestational diabetes: the San Antonio experience. J Matern Fetal Neonat Med 15:51–55, 2004 3. Kremer CJ, Duff P: Glyburide for the treatment of gestational diabetes. Am J Obstet Gynecol 190:1438–1439, 2004 4. Chmait R, Dinise T, Moore T: Prospective observational study to establish predictors of glyburide success in women with gestational diabetes mellitus. J Perinatol 24:617– 622, 2004 5. Fines VL, Moore TR, Castle S: Comparison of Glyburide and Insulin Treatment in Gestational Diabetes Mellitus on Infant Birth Weight and Adiposity. Society for Maternal-Fetal Medicine Annual Meeting 2004,New Orleans, LA

15 The Case of Glyburide (Glibenclamide) Summary of Further Reports Results
Results of glyburide treatment, compared with insulin: For the mother: Better glycemic control – less hypoglycemic episodes. For the fetus: lower mean glucose values (?? More hypoglycemia) - ?? Less macrosomia.

16 The Case of Glyburide (Glibenclamide) The Problem
In July 2007, Thomas and Moore Published a (critical appraisal) article about this trial in: DIABETES CARE, VOLUME 30, SUPPLEMENT 2, JULY 2007 They stated that the main problem here arises from the undersized study population which resulted in the loss of the power to analyze the results of the key variables of interest. They noticed that major specialty bodies continue to advocate caution in adopting oral agents as an acceptable modality for management of GDM

17 The Case of Glyburide (Glibenclamide) The Problem

18 The Case of Glyburide (Glibenclamide) The Problem
In 2005 Langer reanalyzed the results of his trial Langer O, Yogev Y, Xenakis EM, Rosenn B: Insulin and glyburide therapy: dosage, severity level of gestational diabetes, and pregnancy outcome. Am J Obstet Gynecol 192:134–139, 2005 Patients were grouped into low (less than 10 mg) and high (More than 10 mg) daily glyburide dose groups. The rate of macrosomia was 16 vs. 5% (P 0.01), respectively, in the high and low glyburide dose groups.

19 The Case of Glyburide (Glibenclamide) The Present Situation
In the recent policy statement by the American Diabetes Association and the American College of Obstetricians and Gynecologists, “Glyburide is not FDA approved for the treatment of GDM and further studies are needed in a larger patient population to establish its safety”. American Diabetes Association: Gestational diabetes mellitus. Diabetes Care 27 (Suppl. 1):S88 –S90, 2004. The clinical experience with glyburide treatment of GDM has moved ahead of the science.

20 What to do? One of two options:
1- Oral drugs which do not cross the placenta. 2- Oral drugs which cross the placenta without causing fetal: - Hypoglycemia. - Hyperinsulinemia. - Teratogenic effects. Actually we have a very good example for both options, and every example has a case. I shall try to focus a little bit on these cases.

21 The Case of Metformin Why Metformin?
Metformin was shown to be able to significantly cross the placenta, with fetal concentrations in the range of half of maternal concentrations. Hague WM, et al: Metformin crosses the placenta: a modulator for fetal insulin resistance? (Letter) Br Med J. 4 December 2003. However, it does not stimulate insulin secretion or release, and does not cause hypoglycemia. Metformin enhances insulin action, stimulating glucose uptake in the liver and in the periphery and also suppressing hepatic glucose output.

22 The Case of Metformin Why Metformin?
It is also useful in the insulin resistance syndrome and constitute an increasingly popular treatment for polycystic ovarian syndrome, often inducing ovulation and resulting in pregnancy.

23 The Case of Metformin Teratogenicity
Several trials did not report any major congenital malformations in infants born to mothers who received metformin throughout pregnancy, whether those mothers were diabetics 1- Reece EA, Homko CJ. Metformin in pregnancy: Ready or not. Curr Opin Endocrinol Diabetes 2006;13:185–190. 2- Coetzee EJ, Jackson WP. Metformin in management of pregnant insulin-dependent diabetics. Diabetologia 1979;16: 241. or non diabetics. 1-Glueck CJ, et al. Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first trimester spontaneous abortion: A pilot study. Fertil Steril 2001;75:46–52. 2- Glueck CJ, et al. Metformin therapy throughout pregnancy reduces the development of gestational diabetes in women with polycystic ovary syndrome. Fertil Steril 2002;77:520–525.

24 The Case of Metformin The Practice
Several studies: - South Africa more than 20 years ago 1- Coetzee EJ, Jackson WP: Metformin in management of pregnant insulin-independent diabetics. Diabetologia 16:241–245, 1979 2- Coetzee EJ, Jackson WP: Pregnancy in established non-insulin-dependent diabetics. S Afr Med J 58:795– 802, 1980 3- Coetzee EJ, Jackson WP: The management of non-insulin-dependent diabetes during pregnancy. Diabetes Res 1:281–287, 1986 - New Zealand 2006 Hughes R, Rowan J: Pregnancy in women with type 2 diabetes: who takes metformin and what is the outcome? Diabet Med 23:318 –322, 2006 No adverse pregnancy outcomes have been reported.

25 The Case of Metformin The Problem
The studies are small, retrospective and non-randomised. What are the long term effects of exposing the fetus to metformin?. ……………..???? Glueck et al. Human Reprod 2004;19:1323–1330. have followed for 18 months a cohort of 126 neonates to mothers with PCOS who received metformin through pregnancy. They found no differences in height weight and motor social growth over this period.

26 The Case of Metformin The MiG Trial (still in progress) DIABETES CARE, VOLUME 30, SUPPLEMENT 2, JULY 2007 The Metformin in Gestational Diabetes (MiG) trial is a prospective randomized multicenter trial in women with gestational diabetes mellitus (GDM). It includes 750 women with GDM from Australia and New Zealand. The trial started in October 2002 and finished recruiting in October 2006.

27 The Case of Metformin The MiG Trial (still in progress)
It will address the efficacy and detailed safety of metformin compared with insulin in women with GDM. Long-term follow-up of offspring will examine whether treatment influences later health.

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29 Other Oral Agents Thiazolidinediones
No controlled data available. One study reported that rosiglitazone crossed the placenta in early human pregnancy at 10–12 weeks, with fetal tissue levels measured at about half of maternal serum levels. Chan LY, Yeung JH, Lau TK: Placental transfer of rosiglitazone in the first trimester of human pregnancy. Fertil Steril 83: 955–958, 2005.

30 Other Oral Agents Alpha-Glucosidase inhibitors
Acarbose is minimally absorbed from GIT. Two reports: 1- a case series of six gestational diabetic patients treated with 50 mg acarbose three times daily with meals. In these six patients, glucose levels were normalized, and all six babies were apparently normal. All mothers reported gastrointestinal discomfort. Ginecol Obstet Mex 68:42–45, 2000.

31 Other Oral Agents Alpha-Glucosidase inhibitors
2- A randomized trial of acarbose versus insulin in 91 gestational diabetic women failing diet therapy, glucose control and glycohemoglobin results were similar. Gastrointestinal side effects were common. Obstet Gynecol 99 (Suppl.):5S, Acarbose appears to be promising for the treatment of gestational diabetes.

32 Other Agents Exenatide
No available data about its use in pregnancy. Human placental perfusion studies detected minimal levels on the fetal side (fetal:maternal ratio 0.017). Hiles RA, Bawdon RE, Petrella EM: Ex vivo human placental transfer of the peptides pramlintide and exenatide. Hum Exp Toxicol 22:623– 628, 2003 However, being injectable may decrease the interest of its use in pregnancy.

33 Conclusions There is a growing interest in the use of oral drugs in pregnant diabetic women. There are at least three drugs which are promising regarding effectiveness and safety which are: glebinclamide, metformin and acarbose. More studies (some are in progress) are needed before the use of oral therapy in DM with pregnancy is recommended.

34 THANK YOU


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