12/24/04njm

Q. Are there alternatives to insulin / diet in diabetes and pregnancy?
Glyburide? Others?

A. Yes, we have successfully used glyburide, and other agents, with
caution.

Initially, please note that the Cochrane Library finds there appears to
be no clear evidence of benefit from very tight glycemic control for
pregnant diabetic women. Since very strict control may have a
substantial impact on lifestyle, this suggests caution in advising such
a degree of control. (Walkinshaw SA.-Cochrane)

The Cochrane Library also finds a comparison of the effects of human and
animal insulin as well as of the adverse reaction profile did not show
clinically relevant differences. Many patient-oriented outcomes like
health-related quality of life or diabetes complications and mortality
were never investigated in high-quality randomized clinical trials.

Some patients will be reluctant to give themselves multiple daily
insulin injections and it would be convenient to be able to offer them
an alternative. Classic teaching is that oral hypoglycemic agents can
cause severe hypoglycemia during pregnancy and are to be avoided.
Currently, investigation is in progress on the use of oral hypoglycemic
agents in pregnancy, but their use at this time can not yet be
considered standard of care.

NB: If you do use the oral hypoglycemic agents below, please inform your
patients that the oral hypoglycemic agents are [not]{.underline} FDA
approved. In addition, follow these patients in some kind of Quality
Assurance project, or monitor their outcomes as a group in some way.

**Glyburide**

The agent that has been most extensively studied in pregnancy is the
sulfonylurea, glyburide. Level I results have been encouraging to date.
([Langer et
al](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11036118&dopt=Abstract))
Glyburide does not cross the placenta because of its molecular size.
Hence, like insulin, it will control the maternal blood sugar without
affecting fetal glucose homeostasis. Nevertheless, its mode of action,
stimulating secretion of insulin from the pancreatic islet cells,
probably does not well address the underlying pathophysiology of this
disorder, which is characterized by insulin resistance and
hyperinsulinemia. (See Other practice strategies and editorial comments
below\*)

If you choose to use glyburide, then I suggest using it according to the
Langer paper, e.g., start low at 2.5 mg qd and don't exceed 10 mg bid.
Continue to monitor the blood glucose (BS) qid.

**Metformin**\
Metformin, a biguanide, would seem to be an ideal choice from a
physiologic standpoint since it works at the "post-receptor" level to
enhance glucose utilization. Metformin is a small molecule and readily
crosses the placenta. This fact has limited its investigation in
pregnancy. Nevertheless, metformin should not cause hypoglycemia in
euglycemic subjects, and fetal effects should theoretically be minimal.
There is a small body of experience with the drug in patients with
infertility secondary to polycystic ovaries. These patients have
conceived on metformin, and then continued it during pregnancy. ([Glueck
et
al](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11872206&dopt=Abstract))
At the present time, it can [not]{.underline} be recommended for routine
clinical use.

**Acarbose**

Acarbose, because it works locally in the gut to decrease glucose
absorption, might also be expected to be safe in pregnancy, but its
effects are limited by its side effects of bloating and diarrhea.
Insulin therefore remains the standard of care for those patients who
cannot maintain euglycemia on medical nutrition therapy.

**Exercise**

Exercise is the best alternative to insulin.

As diet is not actually proven to work with Level I data in the
literature, what is an evidence-based helpful intervention? Exercise has
randomized data to support its benefit in control of fasting and
postprandial glucose. ([Bung et
al](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8515355&dopt=Abstract),
[Jovanovic-Peterson et
al](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2764059&dopt=Abstract))

[Dyck et
al](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10093309&dopt=Abstract)
describe a successful exercise program in Aboriginal women in Saskatoon,
Saskatchewan. An "exercise prescription" is something from which women
with GDM should benefit. Something as simple as walking at a comfortable
pace for 20-30 minutes after meals will usually favorably impact
post-prandial glucose values and result in lower birth weight if done as
part of a regular regimen.

There are also major policy statements supporting exercise in pregnancy
in pregnant women:

-Exercise in Pregnancy and the Postpartum Period. No. 129, June 2003.
Joint SOGC / CSEP Clinical Practice Guideline. Society of Obstetricians
and Gynaecologists of Canada

And

-Exercise during pregnancy and the postpartum period. ACOG Committee
Opinion No. 267. American College of Obstetricians and Gynecologists.
Obstet Gynecol 2002;99:171--173

Lastly, here are two good resources, which also give free CME on this
subject

Diabetes in pregnancy: Screening and diagnosis

[[http://www.ihs.gov/MedicalPrograms/MCH/M/DP01.asp#top]{.underline}](http://www.ihs.gov/MedicalPrograms/MCH/M/DP01.asp#top)

Diabetes in pregnancy: Management and postpartum

[[http://www.ihs.gov/MedicalPrograms/MCH/M/DP21.asp#top]{.underline}](http://www.ihs.gov/MedicalPrograms/MCH/M/DP21.asp#top)

**\*Other** **practice strategies and editorial comments**

Glyburide really just encourages the patient's own insulin to be
secreted. Hence, for those hard to control patients, you may even
consider giving it in combination with insulin.... with careful
monitoring. We use glyburide under a QA protocol because it [is not FDA
approved]{.underline} (even for use without concurrent insulin), so one
may also want to consult a MFM to back you up.

Please note: No one has been able to re-create Langer's success rate
with only 4% failing oral therapy and needing to go on to insulin. Our
institution's failure rate has been about 20%, but at least those 20%
folks got some reprieve from several injections a day before they
ultimately placed on insulin. There have been no significant reports of
fetal complications at this writing, because glyburide does not cross
the placenta.

Physiologically speaking, we are waiting for more studies to back us up
to use metformin in pregnancy. Metformin makes more sense
physiologically. Pregnant patients with glucose intolerance have too
much circulating insulin as they just are resistant to their own
insulin....which is why strategies like exercise and metformin, an
insulin sensitizer, actually work well in these types of patients. While
there is good data that exercise works in pregnancy, there is minimal
data for metformin in pregnancy at this writing, though Metformin is a
Pregnancy Class B drug.

Exercise actually works. We allow patients to get on a treadmill at
clinic visits and check their BS. If their BS was elevated to begin
with, it will often drop 30-40 mg/dL during a short controlled exercise
period. In addition, exercise drives BS into the striated muscle at 35x
the rate without exercise. 'Just walking the nearest streets, a
treadmill, nothing fancy...3x/wk x 20-30 min/day (Level I data).

'Have a nutritionist go over her diet one more time. Reviewing the
glycemic index maybe helpful. Some foods go right into BS (corn, fruit
juice, refined sugars).... others take their time (whole grain bread,
complex carbs). The patient might do better with foods with a lower
glycemic index (slower uptake) There is minimal level I data on this
effect yet, but diet has always been a Level C recommendation, anyway.

A high-fiber diet has also been proposed as helpful for glycemic control
because of its effect on intestinal transit time and decreased nutrient
absorption, but this has not been able to be confirmed in the trials.

[McFarland et
al](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10362166&dopt=Abstract)
reported that women with GDM should be prescribed diet therapy alone for
two weeks before they are prescribed insulin. In those with fasting
glucose above 95 mg/dL insulin may be prescribed after 1 week of therapy
or at diagnosis.

**[References:]{.underline}**

[Bung P, Bung C, Artal R, Khodiguian N, Fallenstein F, Spätling
L](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8515355&dopt=Abstract).
Therapeutic exercise for insulin-requiring gestational diabetics:
effects on the fetus---results of a randomized prospective longitudinal
study. J Perinat Med 1993;21:125--137 (Level II-2)

<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8515355&dopt=Abstract>

[Dyck RF, Sheppard MS, Cassidy H, Chad K, Tan L, Van Vliet
SH](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10093309&dopt=Abstract).
Preventing NIDDM among aboriginal people: is exercise the answer?
Description of a pilot project using exercise to prevent gestational
diabetes. Int J Circumpolar Health 1998;57 Suppl 1:375-8 (Level III)

<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10093309&dopt=Abstract>

Exercise during pregnancy and the postpartum period. ACOG Committee
Opinion No. 267. American College of Obstetricians and Gynecologists.
Obstet Gynecol 2002;99:171--173

Non- ACOG members

<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11777528>

ACOG members

<http://www.acog.org/publications/committee_opinions/co267.cfm>

Exercise in Pregnancy and the Postpartum Period. No. 129, June 2003.
Joint SOGC / CSEP Clinical Practice Guideline. Society of Obstetricians
and Gynaecologists of Canada

[[http://www.sogc.org/SOGCnet/sogc_docs/common/guide/pdfs/ps129.pdf]{.underline}](http://www.sogc.org/SOGCnet/sogc_docs/common/guide/pdfs/ps129.pdf)

[Glueck CJ, Wang P, Kobayashi S, Phillips H, Sieve-Smith
L](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11872206&dopt=Abstract).
Metformin therapy throughout pregnancy reduces the development of
gestational diabetes in women with polycystic ovary syndrome. Fertil
Steril 2002 Mar;77(3):520-5 (Level II-2)

<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11872206&dopt=Abstract>

[Jovanovic-Peterson L, Durak EP, Peterson
CM](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2764059&dopt=Abstract).
Randomized trial of diet versus diet plus cardiovascular conditioning on
glucose levels in gestational diabetes. Am J Obstet Gynecol
1989;161:415--419 (Level II-1)

<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2764059&dopt=Abstract>

[Langer O, Conway DL, Berkus MD, Xenakis EM, Gonzales
O](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11036118&dopt=Abstract).
A comparison of glyburide and insulin in women with gestational diabetes
mellitus. N Engl J Med 2000 Oct 19;343(16):1134-8 (Level I)

<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11036118&dopt=Abstract>

[McFarland MB, Langer O, Conway DL, Berkus
MD](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10362166&dopt=Abstract).
Dietary therapy for gestational diabetes: how long is long enough?
Obstet Gynecol 1999 Jun;93(6):978-82 (Level II-3)

<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10362166&dopt=Abstract>

Walkinshaw SA. Very tight versus tight control for diabetes in
pregnancy. *The Cochrane Database of Systematic Reviews* 1996, Issue 2.
Art. No.: CD000226. DOI: 10.1002/14651858.CD000226.

<http://www.mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD000226/frame.html>