Oral Hypoglycemic Agents in
Pregnancy
Nafisa Dajani, M.D
Department of Obstetrics and Gynecology
Maternal Fetal Medicine Division
University of Arkansas for Medical Sciences
Feb 2005
History of Oral Hypoglycemic
agents in obstetrics
• First generation sulfonylurea (e.g.
chlorpropramide,tolbutamide)became
available in 1955
• Second generation sulfonylurea (e.g.
glypizide, glyburide) introduced in 1984
• Why do we still not know what to do in
2005
Oral hypoglycemics
• Several initial reports with the first
generation oral hypoglycemic agents
associated with congenital malformations,
hyperbilirubinemia, neonatal
hypoglycemia, polycythemia and neural
tube defects both in vitro mouse model
and in limited observational studies in
humans
Oral Antidiabetic Agents
Sulfonyl
ureas
Generic Glyburide
name
Glipizide
Chlopropr.
Tolbutam.
Glimepride
Action
Incr.
pancreatic
insulin
secretion
chronically
Biguanides Alpha
Glucosida
se
inhibitors
Metformin Acarbose
Miglitol
Thiazolidi Meglitini
nediones des
Rosiglitaz
one
Pioglitazo
ne
Repaglin
ide
Nateglini
de
Dec.HGP
Dec. PIR
Dec. IG
absorption
DEC.PIR
Incr.
Glucose
disposal
Dec HGP
Incr.pan
creatic
insulin
acutely
Delays PP
CHO
digestion
& IG
absorption
Sulfonyl ureas
• Stimulate
secretion of
insulin from
the
pancreatic
beta cells
Glyburide
• Sulfonylurea
• Enhance insulin sensitivity in peripheral
tissue
• Reduces glucose output from the liver
• Insulin increases 15-60 minutes after
injestion, peaks in 2-4 hours ,duration is
<24 hours, elimination half life 5-16 hours
Glyburide- cont’d
• Adverse effects: headache, dizziness,
pruritis, rash, photosensitivity,
hypoglycemia, hyponatremia, nausea,
hepatitis, arthralgia, blurred vision,
aplastic anemia and agranulocytosis
• 2.5-5mg initial, increase by 2.5mg q week
to a maximum of 20 mg/day after 11
weeks gestation
• Crosses the placenta in negligible amounts
due to high protein binding and short half
life
Comparison Of Glyburide and
insulin in women with GDM
• RCT
• N=404
• Randomized between 11-33 weeks
• Singleton, FBS 95-140 ( OGTT )
• No difference in the LGA (12%),
hypoglycemia ,NICU admission and
congenital anomalies
• Failure rate 4%-needed insulin
Glyburide
• Glyburide was not detected in cord serum
• The study did not evaluate first trimester
use
• Did not evaluate use in type 2 diabetics
• Did not evaluate other hypoglycemics
Langer NEJM2000oct19;343(16):1134-8
Other glyburide study
• N=197 , beyond the first trimester, diet
• 124 responded to diet, 73 glyburide
• 81% satisfactory control, 75% required
7.5mg/day or less.
• 19% macrosomic infants
• 11% side effects
Kremer,AJOG2004may;190(5):1438-9
Does stimulation of beta cells
eventually lead to pancreatic
cell failure ?
Does the use of sulfonylureas
eventually lead to Type 2
DM?
Metformin
• Biguanid
• Decreased hepatic glucose production,
decreased glucose intestinal absorption,
increased peripheral utilization
• maximum effect may take 2 weeks
• Dose: starting 500 mg daily up to max
2550mg/day
Metformin –2
• Most common side effects are
gastrointestinal, the potentially lethal side
effect is lactic acidosis. Contraindicated in
patients with renal failure and should be
avoided in patients with liver dysfunction
or excessive alcohol intake. Avoid in
situations leading to hypoxemia such as
CHF
• Crosses the placenta. Negligible protein
binding
Metformin-3
• Metformin concentrates in the jejunal and ileal
wall 10x higher than liver and 60x higher than
muscle or fat. These high concentrations can
result in anaerobic metabolism of glucose and
release of lactic acidosis into the portal vein
• Vitamin B12 defficiencey 10-30% with >3month
treatment duration
• B12, folic acid and other micronutrient
defficiencies may have serious perinatal effects
Why is Metformin attractive?
• Cellular uptake of glucose is the primary
•
•
mechanism , therefore hypoglycemia is not a
side effect
Fortunately the cellular uptake of glucose does
not appear to occur in the placenta (Elliott and
langer 1997)
Unfortunately because of its low protein binding
and low molecular weight it partially crosses to
the fetus
Classified as category B, with no
anomalies in animals, however it
did cause a delay in neural tube
closure or growth in mouse
embryos that was overcome with
continued growth.
Are there fetal implications for
micronutrient deficiencies of B12,
folic acid , iron and calcium that
may occur with metformin use ?
Experience with Metformin
• South Africa has used metformin for 30 years
•
with no bad effects, the reports are small
however . Australia have been using metformin
for years also, no reported bad effects however
no good studies either.
The first RCT has been initiated in Australia MiG
trial aiming to recruit 750 patients
S. Afr. Med. J 56,467(1979)
MJA vol180 3 may 2004
The Australian DIP Group
• Metformin is not to be used routinely in women
•
•
•
with pregnancies complicated by diabetes ( type
2, or GDM )
When benefits from metformin therapy outweigh
the risks e.g. patient refusing insulin, or
requiring large doses of insulin, then its use may
be appropriate
Diabetics conceiving on metformin: discuss risk
and options for other therapies, do not
discontinue metformin until other treatments are
started, reassure patient no teratogenesis
No comment On PCO and first trimester use
MJA 3may2004 volume 180,number9
ACOG cautions against
Metformin Use
Metformin and PCOS Systematic
review
• Cochrane systematic review confirmed
that metformin increases the ovulation
rate by a factor of 3.9 and the pregnancy
rate by 3.3
• Combined with clomide it improves
ovulation and the pregnancy rate by a
factor of 6.7
• The evidence of metformin in decreasing
miscarriage rate is weak and based on few
observational studies.
Cochrane review issue 3 2003,BMJ oct25 2003
Metformin and PCOS-Systematic
Review
• Associated with nausea, vomiting
•
•
•
•
,gastrointestinal disturbances, vitamin B12
deficiency
No literature about the safety of long term use
in young women with PCO
Safety in the first trimester needs further
evaluation, does not appear teratogenic
No evidence it reduces BMI
Equal or better ovulation rate has been reported
by using lifestyle changes to achieve weight loss
Should Insulin Sensitizing Drugs be used for
women with Type2 or GDM
• No randomized control trial available.
there are only small pilot studies of 30-40
patients
• All the available published data are of
small number and the results are all
reassuring EXCEPT for one study
Cohort Study type 2 pregnant
50 metformin
68 sulfonyl ureas
42 insulin
Preeclampsia 32%,7%,10%
Perinatal mortality 11.65%,1.3%
Criticism: Not blinded, not well
controlled ,death cannot be
attributed to metformin
Hellmuth,Diabetic med July 2000,17 ;507-511
Should metformin be used
prophylactically to decrease the
incidence of GDM in PCOS
• Most ,but not all studies agree that the
incidence of GDM is higher in PCOS than
in healthy women (20%-40%)
• No RCT to date that metformin decreases
the incidence of gestational diabetes
• The evidence available comes from cohort,
non randomized non blinded small pilot
studies
GDM and PCOS
• Cohort study n=33 pts with PCOS
conceived and continued metformin, vs a
historical control that included the 33
patients in their prior pregnancy total
n=72 control
• Conclusion:
10 fold reduction in GDM from 31-3%
Glueck,fertilitysterility77(3)march2002
520-525
Are there any adverse effects on the
newborn?
Neonatal Outcome
• 122 live births to 109 patients with PCOS
• Conceived on and continued metformin
throughout pregnancy
• Prospective evaluation of infants for 18
months , with historic controls
• No difference in height, weight or motor
development scores
Glueck, human reprod June 200419(6):1323-30
Are there other insulin sensitizers ?
Troglitazone withdrawn due to liver toxicity,
had a dose dependent effect on ovulation
in a large RCT
Rosiglitazone and pioglitazone have been
tried in PCOS but are not advisable in
pregnancy due to lack of safety data and
their long lasting effects
Alpha glucosidase inhibitors
• Acarbose
• Inhibits intestinal alpha
glugosidase,increased starch reaches the
colon, ,the colonic flora will produce
increasedbutyrate, which can upregulate
prostaglandin E series production. Lobor
inducing potential of PG E . To be avoided
in pregnancy until safety data is available
On study published from Mexico
describing six pregnancies with
GDM . All fasting and post
prandials were normalized. All
newborns were normal.
Intestinal discomfort persisted
throughout the whole
pregnancy
Ginecologia y obstetrica de mexico 68:42-5 2000jan
RCT of adequate power are
urgently needed to establish
safety of oral hypoglycemics
use in pregnancy.