Feb 2005Feb 2005

Oral Hypoglycemic Agents Oral Hypoglycemic Agents in Pregnancyin Pregnancy

Nafisa Dajani, M.DNafisa Dajani, M.DDepartment of Obstetrics and Department of Obstetrics and

GynecologyGynecologyMaternal Fetal Medicine DivisionMaternal Fetal Medicine Division

University of Arkansas for Medical University of Arkansas for Medical SciencesSciences

History of Oral History of Oral Hypoglycemic agents in Hypoglycemic agents in obstetricsobstetrics• First generation sulfonylurea (e.g. First generation sulfonylurea (e.g.

chlorpropramide,tolbutamide)becamchlorpropramide,tolbutamide)became available in 1955e available in 1955

• Second generation sulfonylurea (e.g. Second generation sulfonylurea (e.g. glypizide, glyburide) introduced in glypizide, glyburide) introduced in 19841984

• Why do we still not know what to do Why do we still not know what to do in 2005in 2005

Oral hypoglycemicsOral hypoglycemics

• Several initial reports with the first Several initial reports with the first generation oral hypoglycemic agents generation oral hypoglycemic agents associated with congenital associated with congenital malformations, hyperbilirubinemia, malformations, hyperbilirubinemia, neonatal hypoglycemia, polycythemia neonatal hypoglycemia, polycythemia and neural tube defects both in vitro and neural tube defects both in vitro mouse model and in mouse model and in limited limited observational studiesobservational studies in humans in humans

Oral Antidiabetic AgentsOral Antidiabetic AgentsSulfonylSulfonyl

ureasureasBiguanideBiguanidess

Alpha Alpha GlucosidGlucosidase ase inhibitorinhibitorss

ThiazoliThiazolidinediondinedioneses

MeglitiMeglitinidesnides

GeneriGeneric c namename

GlyburideGlyburide

GlipizideGlipizide

ChlopropChlopropr.r.

TolbutamTolbutam..

GlimepridGlimepridee

MetforminMetformin AcarboseAcarbose

MiglitolMiglitolRosiglitaRosiglitazonezone

PioglitazPioglitazoneone

RepagliRepaglinidenide

NategliNateglinidenide

ActionAction Incr. Incr. pancreatipancreatic insulin c insulin secretion secretion chronicallchronicallyy

Dec.HGPDec.HGP

Dec. PIRDec. PIR

Dec. IG Dec. IG absorptioabsorptionn

Delays Delays PP CHOPP CHO

digestion digestion & IG & IG absorptiabsorptionon

DEC.PIRDEC.PIR

Incr. Incr. Glucose Glucose disposaldisposal

Dec HGPDec HGP

Incr.paIncr.pancreatincreatic c insulin insulin acutelyacutely

Sulfonyl ureasSulfonyl ureas

• Stimulate Stimulate secretion secretion of insulin of insulin from the from the pancreatic pancreatic beta cellsbeta cells

GlyburideGlyburide

• SulfonylureaSulfonylurea

• Enhance insulin sensitivity in Enhance insulin sensitivity in peripheral tissueperipheral tissue

• Reduces glucose output from the Reduces glucose output from the liverliver

• Insulin increases 15-60 minutes after Insulin increases 15-60 minutes after injestion, peaks in 2-4 injestion, peaks in 2-4 hours ,duration is <24 hours, hours ,duration is <24 hours, elimination half life 5-16 hourselimination half life 5-16 hours

Glyburide- cont’dGlyburide- cont’d

• Adverse effects: headache, dizziness, Adverse effects: headache, dizziness, pruritis, rash, photosensitivity, pruritis, rash, photosensitivity, hypoglycemia, hyponatremia, nausea, hypoglycemia, hyponatremia, nausea, hepatitis, arthralgia, blurred vision, hepatitis, arthralgia, blurred vision, aplastic anemia and agranulocytosisaplastic anemia and agranulocytosis

• 2.5-5mg initial, increase by 2.5mg q 2.5-5mg initial, increase by 2.5mg q week to a maximum of 20 mg/day week to a maximum of 20 mg/day after 11 weeks gestationafter 11 weeks gestation

• Crosses the placenta in negligible Crosses the placenta in negligible amounts due to high protein binding amounts due to high protein binding and short half lifeand short half life

Comparison Of Glyburide Comparison Of Glyburide and insulin in women with and insulin in women with GDM GDM • RCTRCT• N=404N=404• Randomized between 11-33 weeks Randomized between 11-33 weeks • Singleton, FBS 95-140 ( OGTT )Singleton, FBS 95-140 ( OGTT )• No difference in the LGA (12%), No difference in the LGA (12%),

hypoglycemia ,NICU admission and hypoglycemia ,NICU admission and congenital anomaliescongenital anomalies

• Failure rate 4%-needed insulinFailure rate 4%-needed insulin

GlyburideGlyburide

• Glyburide was not detected in cord Glyburide was not detected in cord serumserum

• The study did not evaluate first The study did not evaluate first trimester usetrimester use

• Did not evaluate use in type 2 Did not evaluate use in type 2 diabetics diabetics

• Did not evaluate other hypoglycemicsDid not evaluate other hypoglycemics

Langer NEJM2000oct19;343(16):1134-8

Other glyburide studyOther glyburide study

• N=197 , beyond the first trimester, N=197 , beyond the first trimester, dietdiet

• 124 responded to diet, 73 glyburide124 responded to diet, 73 glyburide

• 81% satisfactory control, 75% 81% satisfactory control, 75% required 7.5mg/day or less.required 7.5mg/day or less.

• 19% macrosomic infants19% macrosomic infants

• 11% side effects11% side effectsKremer,AJOG2004may;190(5):1438-9

Does stimulation of beta Does stimulation of beta cells eventually lead to cells eventually lead to pancreatic cell failure ?pancreatic cell failure ?

Does the use of Does the use of sulfonylureas eventually sulfonylureas eventually lead to Type 2 DM?lead to Type 2 DM?

MetforminMetformin

• BiguanidBiguanid

• Decreased hepatic glucose Decreased hepatic glucose production, decreased glucose production, decreased glucose intestinal absorption, increased intestinal absorption, increased peripheral utilizationperipheral utilization

• maximum effect may take 2 weeksmaximum effect may take 2 weeks

• Dose: starting 500 mg daily up to max Dose: starting 500 mg daily up to max 2550mg/day2550mg/day

Metformin –2Metformin –2

• Most common side effects are Most common side effects are gastrointestinal, the potentially lethal gastrointestinal, the potentially lethal side effect is lactic acidosis. side effect is lactic acidosis. Contraindicated in patients with renal Contraindicated in patients with renal failure and should be avoided in failure and should be avoided in patients with liver dysfunction or patients with liver dysfunction or excessive alcohol intake. Avoid in excessive alcohol intake. Avoid in situations leading to hypoxemia such as situations leading to hypoxemia such as CHFCHF

• Crosses the placenta. Negligible protein Crosses the placenta. Negligible protein bindingbinding

Metformin-3Metformin-3• Metformin concentrates in the jejunal and ileal Metformin concentrates in the jejunal and ileal

wall 10x higher than liver and 60x higher than wall 10x higher than liver and 60x higher than muscle or fat. These high concentrations can muscle or fat. These high concentrations can result in anaerobic metabolism of glucose and result in anaerobic metabolism of glucose and release of lactic acidosis into the portal vein release of lactic acidosis into the portal vein

• Vitamin B12 defficiencey 10-30% with Vitamin B12 defficiencey 10-30% with >3month treatment duration>3month treatment duration

• B12, folic acid and other micronutrient B12, folic acid and other micronutrient

defficiencies may have serious perinatal defficiencies may have serious perinatal effectseffects

Why is Metformin Why is Metformin attractive?attractive?• Cellular uptake of glucose is the primary Cellular uptake of glucose is the primary

mechanism , therefore hypoglycemia is mechanism , therefore hypoglycemia is not a side effectnot a side effect

• Fortunately the cellular uptake of glucose Fortunately the cellular uptake of glucose does not appear to occur in the placenta does not appear to occur in the placenta (Elliott and langer 1997)(Elliott and langer 1997)

• Unfortunately because of its low protein Unfortunately because of its low protein binding and low molecular weight it binding and low molecular weight it partially crosses to the fetuspartially crosses to the fetus

Classified as category B, with Classified as category B, with no anomalies in animals, no anomalies in animals, however it did cause a delay in however it did cause a delay in neural tube closure or growth neural tube closure or growth in mouse embryos that was in mouse embryos that was overcome with continued overcome with continued growth. growth.

Are there fetal implications Are there fetal implications for micronutrient deficiencies for micronutrient deficiencies of B12, folic acid , iron and of B12, folic acid , iron and calcium that may occur with calcium that may occur with metformin use ?metformin use ?

Experience with MetforminExperience with Metformin

• South Africa has used metformin for 30 South Africa has used metformin for 30 years with no bad effects, the reports are years with no bad effects, the reports are small however . Australia have been using small however . Australia have been using metformin for years also, no reported bad metformin for years also, no reported bad effects however no good studies either.effects however no good studies either.

• The first RCT has been initiated in The first RCT has been initiated in Australia MiG trial aiming to recruit 750 Australia MiG trial aiming to recruit 750 patientspatients

S. Afr. Med. J 56,467(1979)

MJA vol180 3 may 2004

The Australian DIP GroupThe Australian DIP Group• Metformin is not to be used routinely in Metformin is not to be used routinely in

women with pregnancies complicated by women with pregnancies complicated by diabetes ( type 2, or GDM )diabetes ( type 2, or GDM )

• When benefits from metformin therapy When benefits from metformin therapy outweigh the risks e.g. patient refusing outweigh the risks e.g. patient refusing insulin, or requiring large doses of insulin, insulin, or requiring large doses of insulin, then its use may be appropriatethen its use may be appropriate

• Diabetics conceiving on metformin: discuss Diabetics conceiving on metformin: discuss risk and options for other therapies, do not risk and options for other therapies, do not discontinue metformin until other treatments discontinue metformin until other treatments are started, reassure patient no teratogenesisare started, reassure patient no teratogenesis

• No comment On PCO and first trimester useNo comment On PCO and first trimester use

MJA 3may2004 volume 180,number9

ACOG cautions against ACOG cautions against Metformin UseMetformin Use

Metformin and PCOS Metformin and PCOS Systematic reviewSystematic review• Cochrane systematic review Cochrane systematic review

confirmed that metformin increases confirmed that metformin increases the ovulation rate by a factor of 3.9 the ovulation rate by a factor of 3.9 and the pregnancy rate by 3.3and the pregnancy rate by 3.3

• Combined with clomide it improves Combined with clomide it improves ovulation and the pregnancy rate by ovulation and the pregnancy rate by a factor of 6.7a factor of 6.7

• The evidence of metformin in The evidence of metformin in decreasing miscarriage rate is weak decreasing miscarriage rate is weak and based on few observational and based on few observational studies. studies. Cochrane review issue 3 2003,BMJ oct25

2003

Metformin and PCOS-Metformin and PCOS-Systematic ReviewSystematic Review

• Associated with nausea, Associated with nausea, vomiting ,gastrointestinal disturbances, vomiting ,gastrointestinal disturbances, vitamin B12 deficiencyvitamin B12 deficiency

• No literature about the safety of long term No literature about the safety of long term use in young women with PCOuse in young women with PCO

• Safety in the first trimester needs further Safety in the first trimester needs further evaluation, does not appear teratogenicevaluation, does not appear teratogenic

• No evidence it reduces BMINo evidence it reduces BMI• Equal or better ovulation rate has been Equal or better ovulation rate has been

reported by using lifestyle changes to reported by using lifestyle changes to achieve weight lossachieve weight loss

Should Insulin Sensitizing Should Insulin Sensitizing Drugs be used for women with Drugs be used for women with Type2 or GDMType2 or GDM• No randomized control trial available. No randomized control trial available.

there are only small pilot studies of there are only small pilot studies of 30-40 patients30-40 patients

• All the available published data are All the available published data are of small number and the results are of small number and the results are all reassuring EXCEPT for one study all reassuring EXCEPT for one study

Cohort Study type 2 pregnantCohort Study type 2 pregnant 50 metformin 50 metformin 68 sulfonyl ureas 68 sulfonyl ureas 42 insulin 42 insulin Preeclampsia 32%,7%,10%Preeclampsia 32%,7%,10%Perinatal mortality Perinatal mortality 11.65%,1.3% 11.65%,1.3% Criticism: Not blinded, not well Criticism: Not blinded, not well controlled ,death cannot be controlled ,death cannot be attributed to metformin attributed to metformin

Hellmuth,Diabetic med July 2000,17 ;507-511

Should metformin be used Should metformin be used prophylactically to prophylactically to decrease the incidence of decrease the incidence of GDM in PCOSGDM in PCOS

• Most ,but not all studies agree that the Most ,but not all studies agree that the incidence of GDM is higher in PCOS incidence of GDM is higher in PCOS than in healthy women (20%-40%)than in healthy women (20%-40%)

• No RCT to date that metformin No RCT to date that metformin decreases the incidence of gestational decreases the incidence of gestational diabetesdiabetes

• The evidence available comes from The evidence available comes from cohort, non randomized non blinded cohort, non randomized non blinded small pilot studiessmall pilot studies

GDM and PCOSGDM and PCOS

• Cohort study n=33 pts with PCOS Cohort study n=33 pts with PCOS conceived and continued metformin, conceived and continued metformin, vs a historical control that included vs a historical control that included the 33 patients in their prior the 33 patients in their prior pregnancy total n=72 controlpregnancy total n=72 control

• Conclusion:Conclusion:

10 fold reduction in GDM from 31-10 fold reduction in GDM from 31-3%3%

Glueck,fertilitysterility77(3)march2002

520-525

Are there any adverse Are there any adverse effects on the newborn?effects on the newborn?

Neonatal OutcomeNeonatal Outcome

• 122 live births to 109 patients with 122 live births to 109 patients with PCOSPCOS

• Conceived on and continued Conceived on and continued metformin throughout pregnancymetformin throughout pregnancy

• Prospective evaluation of infants for Prospective evaluation of infants for 18 months , with historic controls18 months , with historic controls

• No difference in height, weight or No difference in height, weight or motor development scoresmotor development scores

Glueck, human reprod June 200419(6):1323-30

Are there other insulin Are there other insulin sensitizers ?sensitizers ?

Troglitazone withdrawn due to liver Troglitazone withdrawn due to liver toxicity, had a dose dependent effect toxicity, had a dose dependent effect on ovulation in a large RCTon ovulation in a large RCT

Rosiglitazone and pioglitazone have Rosiglitazone and pioglitazone have been tried in PCOS but are not been tried in PCOS but are not advisable in pregnancy due to lack of advisable in pregnancy due to lack of safety data and their long lasting safety data and their long lasting effectseffects

Alpha glucosidase inhibitorsAlpha glucosidase inhibitors

• AcarboseAcarbose

• Inhibits intestinal alpha Inhibits intestinal alpha glugosidase,increased starch reaches glugosidase,increased starch reaches the colon, ,the colonic flora will produce the colon, ,the colonic flora will produce increasedbutyrate, which can upregulate increasedbutyrate, which can upregulate prostaglandin E series production. Lobor prostaglandin E series production. Lobor inducing potential of PG E . To be inducing potential of PG E . To be avoided in pregnancy until safety data is avoided in pregnancy until safety data is availableavailable

On study published from On study published from Mexico describing six Mexico describing six pregnancies with GDM . All pregnancies with GDM . All fasting and post prandials fasting and post prandials were normalized. All were normalized. All newborns were normal. newborns were normal. Intestinal discomfort Intestinal discomfort persisted throughout the persisted throughout the whole pregnancywhole pregnancy

Ginecologia y obstetrica de mexico 68:42-5 2000jan

RCT of adequate power are RCT of adequate power are urgently needed to urgently needed to establish safety of oral establish safety of oral hypoglycemics use in hypoglycemics use in pregnancy.pregnancy.