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

Oral Therapy In DM
With Pregnancy
By
Prof. ADEL A EL-SAYED MD
Prof. of Internal Medicine
Sohag Faculty of Medicine
Sohag-EGYPT
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.
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.
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, 1975:205-20.

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;42:824-825
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;139:441-445
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;338:866-869.
- 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;182:313-320
Interpretation problems !! What is the primary
teratogen, the treatment or the disease?
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.
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.
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.
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.
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.
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.

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.
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
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.

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.
The Case of Glyburide (Glibenclamide)
The Problem
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.
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.
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.
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.
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.
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 insulindependent 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.
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 insulinindependent 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.
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.
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.
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.
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.
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.

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, 2002..

Acarbose appears to be promising for the
treatment of gestational diabetes.
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.
Conclusions

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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.
THANK YOU