oral therapy in dm with pregnancy by prof. adel a el-sayed md prof. of internal medicine sohag...

Oral Therapy In DM Oral Therapy In DM With PregnancyWith Pregnancy

ByBy

Prof. ADEL A EL-SAYED MDProf. ADEL A EL-SAYED MDProf. of Internal MedicineProf. of Internal MedicineSohag Faculty of MedicineSohag Faculty of Medicine

Sohag-EGYPTSohag-EGYPT

Classic StatementClassic Statement

If diet and exercise do not lead to If diet and exercise do not lead to adequate glycemic control in a woman adequate glycemic control in a woman with gestational diabetes, then insulin with gestational diabetes, then insulin should be given. Oral hypoglycemic should be given. Oral hypoglycemic drugs, particularly the sulfonylurea drugs, particularly the sulfonylurea drugs, are contraindicated during drugs, are contraindicated during pregnancy.pregnancy.

Davis SN, Granner DK. Insulin, oral hypoglycemic agents, and Davis SN, Granner DK. Insulin, oral hypoglycemic agents, and the pharmacology of the endocrine pancreas. In: Hardman JG, the pharmacology of the endocrine pancreas. In: Hardman JG, Limbird LE, eds. Goodman and Gilman's the pharmacological Limbird LE, eds. Goodman and Gilman's the pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill, basis of therapeutics. 9th ed. New York: McGraw-Hill, 1996:1509. 1996:1509.

Classic StatementClassic 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.

Problems With Oral Problems With Oral TherapyTherapy

HyperinsulinemiaHyperinsulinemia First-generation sulfonylureas First-generation sulfonylureas

(tolbutamide and chlorpropamide) (tolbutamide and chlorpropamide) can easily cross the placenta leading can easily cross the placenta leading to almost similar cord and maternal to almost similar cord and maternal serum concentrations. serum concentrations. Stowers JM, Stowers JM, Sutherland HW. The use of sulphonylureas biguanides and Sutherland HW. The use of sulphonylureas biguanides and insulin in pregnancy. In: Sutherland HW, Stowers JM, eds. insulin in pregnancy. In: Sutherland HW, Stowers JM, eds. Carbohydrate metabolism in pregnancy and the newborn. Carbohydrate metabolism in pregnancy and the newborn.

Edinburgh, Scotland: Churchill Livingstone, 1975:205-20.Edinburgh, Scotland: Churchill Livingstone, 1975:205-20. Early experience with these drugs Early experience with these drugs

included numerous cases of included numerous cases of profound and prolonged neonatal profound and prolonged neonatal hypoglycemia.hypoglycemia.

Zucker P, Simon G. Prolonged symptomatic neonatal Zucker P, Simon G. Prolonged symptomatic neonatal hypoglycemia associated with maternal chlorpropamide therapy. hypoglycemia associated with maternal chlorpropamide therapy. Pediatrics 1968;42:824-825Pediatrics 1968;42:824-825

Problems With Oral Problems With Oral TherapyTherapy

HyperinsulinemiaHyperinsulinemia

Furthermore, fetal hyperinsulinemia Furthermore, fetal hyperinsulinemia can lead to macrosomia and can lead to macrosomia and hypoxemia.hypoxemia.

Both macrosomia and fetal hypoxemia Both macrosomia and fetal hypoxemia can be induced experimentally by can be induced experimentally by inducing fetal hyperinsulinemia inducing fetal hyperinsulinemia without maternal or fetal without maternal or fetal hyperglycemia.hyperglycemia.

Philipps AF, Dubin JW, Raye JR. Fetal metabolic response to Philipps AF, Dubin JW, Raye JR. Fetal metabolic response to endogenous insulin release. Am J Obstet Gynecol endogenous insulin release. Am J Obstet Gynecol

1981;139:441-4451981;139:441-445

Problems With Oral Problems With Oral Therapy?Therapy?

TeratogenicityTeratogenicity Retrospective studies of series of women Retrospective studies of series of women

with type 2 diabetes mellitus suggested an with type 2 diabetes mellitus suggested an association between first-trimester association between first-trimester sulfonylurea therapy and major congenital sulfonylurea therapy and major congenital malformationsmalformations

- - Piacquadio K, Hollingsworth DR, Murphy H. Effects of in-utero Piacquadio K, Hollingsworth DR, Murphy H. Effects of in-utero exposure to oral hypoglycaemic drugs. Lancet 1991;338:866-869.exposure to oral hypoglycaemic drugs. Lancet 1991;338:866-869.

- Schaefer-Graf UM, Buchanan TA, Xiang A, Songster G, Montoro - Schaefer-Graf UM, Buchanan TA, Xiang A, Songster G, Montoro M, Kjos SL. Patterns of congenital anomalies and relationship to M, Kjos SL. Patterns of congenital anomalies and relationship to initial maternal fasting glucose levels in pregnancies complicated initial maternal fasting glucose levels in pregnancies complicated by type 2 and gestational diabetes. Am J Obstet Gynecol by type 2 and gestational diabetes. Am J Obstet Gynecol

2000;182:313-3202000;182:313-320

Interpretation problems !! What is the Interpretation problems !! What is the primary teratogen, the treatment or the primary teratogen, the treatment or the disease?disease?

Why Oral Therapy Still Why Oral Therapy Still neededneeded ? ?

Insulin therapy is associated Insulin therapy is associated with:with:

- The fear of injections - The fear of injections (particularly when multiple).(particularly when multiple).

- The issue of compliance.- The issue of compliance.

- The - The risks of hypoglycemia. - The increase in appetite and

weight.

What to doWhat to do??

One of two options:One of two options: 1- Oral drugs which do not 1- Oral drugs which do not

cross the placenta.cross the placenta. 2- Oral drugs which cross the 2- Oral drugs which cross the

placenta without causing fetal:placenta without causing fetal: - Hypoglycemia.- Hypoglycemia. - Hyperinsulinemia.- Hyperinsulinemia. - Teratogenic effects.- Teratogenic effects.

The Case of Glyburide The Case of Glyburide (Glibenclamide)(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.


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.


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.


The Trial ResultsThe 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.


The Trial ResultsThe 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.


Further ReportsFurther Reportsfive 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


Summary of Further Reports ResultsSummary 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.


The ProblemThe Problem

In July 2007, Thomas and Moore Published a In July 2007, Thomas and Moore Published a (critical appraisal) article about this trial in:(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.



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.

The Case of Glyburide The Case of Glyburide (Glibenclamide)(Glibenclamide)The Present SituationThe 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.

What to doWhat to do??

One of two options:One of two options: 1- Oral drugs which do not 1- Oral drugs which do not

cross the placenta.cross the placenta. 2- Oral drugs which cross the 2- Oral drugs which cross the

placenta without causing fetal:placenta without causing fetal: - Hypoglycemia.- Hypoglycemia. - Hyperinsulinemia.- Hyperinsulinemia. - Teratogenic effects.- Teratogenic effects.

The Case of MetforminThe Case of MetforminWhy MetforminWhy 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.

The Case of MetforminThe Case of MetforminWhy MetforminWhy 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.

The Case of MetforminThe Case of MetforminTeratogenicityTeratogenicity

Several trials did not report any major Several trials did not report any major congenital malformations in infants congenital malformations in infants born to mothers who received born to mothers who received metformin throughout pregnancy, metformin throughout pregnancy, whether those mothers were diabetics 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. 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.

The Case of MetforminThe Case of MetforminThe PracticeThe Practice

Several studies:Several studies: - South Africa more than 20 years ago- 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- 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.

The Case of MetforminThe Case of MetforminThe ProblemThe Problem

The studies are small, retrospective The studies are small, retrospective and non-randomised.and non-randomised.

What are the long term effects of exposing What are the long term effects of exposing the fetus to metformin?.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.

The Case of MetforminThe Case of MetforminThe MiG Trial (still in progress)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.

The Case of MetforminThe Case of MetforminThe MiG Trial (still in progress)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.

Other Oral AgentsOther Oral AgentsThiazolidinedionesThiazolidinediones

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.

Other Oral AgentsOther Oral AgentsAlpha-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.

Other Oral AgentsOther Oral AgentsAlpha-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, 2002..

Acarbose appears to be promising for the treatment of gestational diabetes.

Other AgentsOther AgentsExenatide

No available data about its use in No available data about its use in pregnancy.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.

ConclusionsConclusions

There is a growing interest in the use There is a growing interest in the use of oral drugs in pregnant diabetic of oral drugs in pregnant diabetic women.women.

There are at least three drugs which There are at least three drugs which are promising regarding effectiveness are promising regarding effectiveness and safety which are: glebinclamide, and safety which are: glebinclamide, metformin and acarbose.metformin and acarbose.

More studies (some are in progress) More studies (some are in progress) are needed before the use of oral are needed before the use of oral therapy in DM with pregnancy is therapy in DM with pregnancy is recommended.recommended.

THANK YOUTHANK YOU

oral therapy in dm with pregnancy by prof. adel a el-sayed md prof. of internal medicine sohag...

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