# Presentation: 710851

## NATIVE WOMEN’S HEALTH AND MCH CONFERENCE, 2007

** ****WORKSHOP:**** **
**Use of Oral Antidiabetic Agents in Obstetrics**

**DONALD R. COUSTAN, MD**
**AUGUST 16, 2007**

## ORAL ANTIDIABETIC AGENTS

**I have no relevant financial relationships with any commercial interest relative to the subject of this lecture.**

**Donald R. Coustan, MD**

## ORAL ANTIDIABETIC AGENTS

**At the conclusion of this presentation, the participant will be able to... **
**Describe three types of oral antidiabetic agents**
**Outline the use of glyburide during pregnancy**
**Evaluate the use of metformin during pregnancy**

## ORAL ANTIDIABETIC AGENTS

**Classes of agents**
**Use in pregnancy**

## Insulin

**Sensitizers**

**Insulin**
**Secretogogues**

**α****-glucosidase**
**inhibitors**

## INSULIN SECRETOGOGUES

**SULFONYLUREAS**
**MEGLITINIDES**

## SULFONYLUREAS

**Bind to sulfonylurea receptors in ****β****-cells, ****	****stimulating insulin secretion at all blood ****	****glucose levels**
**Patient must have residual ****β****-****cell function**
**Not effective in type 1 diabetes or long ****	****standing type 2 diabetes in stage of ****	****insulinopenia**
**Side effect: hypoglycemia**

## SULFONYLUREAS

**Suppress hepatic glucose production**
**Diminish glucotoxicity**
**Improve insulin secretion after meals**
**Usually lower blood glucose by ****~20%**
**Work best in patients of normal or slightly ****	****increased body weight**

## SULFONYLUREAS

**First generation: tolbutamide, chlorpropamide, ****	****tolazamide**
**Second generation**
**Glipizide (shorter acting - Glucotrol****®****)**
**Glyburide (longer acting – Diabeta ****®****, Micronase ****®****)**
**Glimepride (longer acting - Amaryl ®)**

## BIGUANIDES

**Enhance insulin action, stimulating ****	****glucose uptake in liver and ****	****periphery, and suppressing ****	****hepatic glucose output**
**Only work when insulin is present**
**Do not stimulate insulin secretion and ****	****release, nor cause hypoglycemia**

## BIGUANIDES

**Used for type 2 diabetes, with residual ****β****-****	****cell function, when diet and exercise ****	****don’t do the trick**
**Useful in insulin resistance syndrome**
**Patients do not tend to gain weight**

## BIGUANIDES

**Phenformin taken off the market in ‘60s (lactic acidosis)**
**Metformin (Glucophage ****®**** )is the ****	****only agent currently available**
**Can be used alone or in combination ****	****with other oral agents or insulin**
**Often used for PCOS, insulin ****	****resistance syndrome**

## THIAZOLIDINEDIONES

**Enhance peripheral insulin action**
**Useful for type 2 diabetes with ****	****adequate endogenous insulin**
**Can be used alone or in combination ****	****with other oral agents or insulin**
**Only useful if insulin resistance present**

## THIAZOLIDINEDIONES

**Troglitazone – taken off market in 2000 ****	****because 2% had to D/C drug due to ****	****hepatotoxicity, and a number of deaths ****	****occurred**
**Rosiglitazone (QD or BID - Avandia ****®****) and ****	****pioglitazone (QD - Actos ****®****) are less ****	****hepatotoxic but still require monitoring ****	****LFTs**

## α-GLUCOSIDASE INHIBITORS

**Slow the absorption of sugars in the upper ****	****GI tract, decreasing postprandial ****	****glucose excursions**
**Major side effects are GI, including ****	****flatulence – start at low dosage and ****	****work up**
**Don’t depend on presence of endogenous ****	****insulin**

## α-glucosidase inhibitors

**Miglitol – highly absorbed from ****	****GI tract**
**Acarbose – very little is absorbed ****	****from GI tract**

## ORAL AGENTS IN PREGNANCY

## ORAL AGENTS IN PREGNANCY

**Sulfonylureas: if they stimulate ****	****insulin production in fetus, ****	****would make diabetic ****	****fetopathy worse**
**Mainly case series’ and anecdotes ****	****with first generation agents**
**Glyburide crosses placenta poorly**

## ORAL AGENTS IN PREGNANCY

**Glyburide study: **
**Randomized trial glyburide vs insulin**
**404 GDMs FPG >95 but <140 mg/dl or 2-****	****hr pp >120 on diet**
**Similar success of glucose control in both ****	****groups**

**Langer et al: NEJM  200:343:1134**

## ORAL AGENTS IN PREGNANCY

**Glyburide study: **
**4% of glyburide group had to go on insulin**
**Rates of C/S, macrosomia, neonatal ****	****hypoglycemia all similar**
**No glyburide detected in cord blood ****	****despite measurable levels in moms’ blood**

**Langer et al: NEJM  200:343:1134**

## ORAL AGENTS IN PREGNANCY

**Subsequent glyburide study: **
**16% of 75 glyburide treated women had to go on insulin**
**Risk factors not very predictable, although if fasting plasma glucose ****≥110 mg/dl 24% needed insulin**

**Conway et al: J MF-Neo Med  2004 15:51**

## ORAL AGENTS IN PREGNANCY

**Is glyburide safe in *****early***** pregnancy?**

## THIAZOLIDINEDIONES

**Increasing use in PCO and insulin ****	****resistance syndrome**
**No controlled data in pregnancy**
**Rosiglitazone crossed placenta at 10-12 ****	****weeks in one human study; fetal ****	****tissue levels about half of maternal ****	****serum levels.**

## α-GLUCOSIDASE INHIBITORS

**Slow the absorption of sugars in the ****	****upper GI tract, decreasing ****	****postprandial glucose excursions**
**Major side effects are GI, including ****	****flatulence – start at low dosage ****	****and ****	****work up**
**Don’t depend on presence of endogenous ****	****insulin**

## α-GLUCOSIDASE INHIBITORS

**CASE SERIES OF 6 GDMs IN ****	****MEXICO CITY**
**ACARBOSE 50MG TID WITH ****	****MEALS**

**Zarate et al: Ginec Obstet Mex  68:42-5, 2000**

## α-GLUCOSIDASE INHIBITORS

**RESULTS:**
**GLUCOSE NORMALIZED**
**ALL BABIES NORMAL**
**ALL MOMS HAD GI ****	****DISCOMFORT**

**Zarate et al: Ginec Obstet Mex  68:42-5, 2000**

## α-GLUCOSIDASE INHIBITORS

**RANDOMIZED TRIAL **
**91 GDMs FAILED DIET >20 WKS**
**45 RECEIVED ACARBOSE, ****	****START ****	****AT 25 MG TID; MAX ****	****100 MG TID**
**46 RECEIVED INSULIN ****	****(NPH/LISPRO)**

**de Veciana et al: ObGyn 99(suppl): 5s**

## α-GLUCOSIDASE INHIBITORS

**PRELIMINARY RESULTS ****	****(ABSTRACT): **
**6% OF ACARBOSE GROUP ****	****REQUIRED INSULIN (GI SIDE ****	****EFFECTS)**
**GLUCOSE CONTROL, HbA1c ****	****RESULTS SIMILAR**

**de Veciana et al: ObGyn 99(suppl): 5s**

## α-GLUCOSIDASE INHIBITORS

**ACARBOSE NOT WELL ABSORBED ****	****SYSTEMICALLY**
**THEORETICALLY, LITTLE SHOULD ****	****REACH FETUS**
**SHOWS PROMISE**

## METFORMIN

**How about metformin?**
**Small molecule, crosses placenta; might enhance insulin action in fetus**
**Could this cause macrosomia and other aspects of diabetic fetopathy?**

## METFORMIN

**Is metformin teratogenic?**
**Not teratogenic in rats and rabbits at doses 2-6X maximum recommended daily exposure**
**“****Partial placental barrier” demonstrated by fetal concentrations**

## DOES METFORMIN CROSS THE PLACENTA?

**Plasma metformin levels measured in 7 women taking median daily dose of 2000 mg metformin, on 19 occasions.**
**Cord plasma metformin levels measured in 23 babies whose mothers took metformin during pregnancy**

**HAGUE ET AL, BMJ, 4 DEC 2003 (WEB SITE)**

## DOES METFORMIN CROSS THE PLACENTA?

**Median (range) plasma metformin levels:**
**Mothers 1.05 mcg/ml (0.06-2.93)**
**Cord blood 0.63 mcg/ml (0.08-2.55)**
**Conclusion: significant amounts of metformin can cross the placenta**

**HAGUE ET AL, BMJ, 4 DEC 2003 (WEB SITE)**

## DOES METFORMIN CROSS THE PLACENTA?

**15 PREGNANCIES IN PCOS PATIENTS**
**12 MOTHERS TOOK 850 MG METFORMIN BID THROUGHOUT PREGNANCY; 3 ON LOWER DOSE**
**MATERNAL SERUM, CORD ARTERY AND VEIN METFOPRMIN LEVELS MEASURED SIMULTANEOUSLY**

**VANKY ET AL: *****FERTIL STERIL***** 83:1575, 2005**

## DOES METFORMIN CROSS THE PLACENTA?

**METFORMIN DETECTABLE IN SERUM OF 13 MOTHERS AT DELIVERY**
**ALL 13 CORD BLOODS CONTAINED METFORMIN**
**MEDIAN CONCENTRATIONS (****ųmol/L)**

**VANKY ET AL: *****FERTIL STERIL***** 83:1575, 2005**

| MATERNAL | CORD VEIN | CORD ARTERY |
| --- | --- | --- |
| 1.50 | 2.81 | 3.16 |

*** ******FETAL METFORMIN LEVELS EXCEED ***
***MATERNAL LEVELS!***

## METFORMIN IN PREGNANCY 	

**Copenhagen Study**
**Retrospective chart review**
**1966-1984: trial of oral agents in GDM**
**31 subjects on metformin**
**39 subjects on sulfonylurea**
**35 subjects on insulin (including 1984-1991)**
**Another 19 subjects with type 2 DM, 7 of whom were taking metformin at conception and 12 started metformin at week 13-38**

**Hellmuth et al  **_**Diab Med**_**  2000; 17:507**

## METFORMIN IN PREGNANCY 	

**Copenhagen Study**

**Hellmuth et al  **_**Diab Med**_**  2000; 17:507**

|  | Metformin (N=50) | Sulphonylurea (N=68) | Insulin (N=42) |
| --- | --- | --- | --- |
| Pre-eclampsia | 16(32%) | 5(7%) | 4(10%) |
| Chronic HTN | 0 | 1(1%) | 1(2%) |
| Stillbirths | 4(8%) | 0 | 1(2%) |

*****

**@p=0.042**

***p<0.001**

**@**

## METFORMIN IN PREGNANCY 	

**Copenhagen Study problems**
**Not randomized**
**Controls generally in different era**
**Only 7 subjects with first trimester metformin**
**Nevertheless, authors suggest avoiding metformin in pregnant women with type 2 diabetes**

**Hellmuth et al  **_**Diab Med**_**  2000; 17:507**

## DOES METFORMIN PREVENT SPONTANEOUS ABORTION?

**Open label case series**
**22 PCOS patients conceived on metformin, 1.5-2.55 g/day**
**Control group: previous pregnancy outcomes among 125 PCOS patients who did not take metformin during the pregnancies **

**Gluek et al, **_**Fertil Steril**_**  2001;75:46**

## DOES METFORMIN PREVENT SPONTANEOUS ABORTION? 	

**Bottom line:**
**16 completed pregnancies where metformin used at least through 4-6 wks gestation**
**3/16 (19%) spontaneous abortions**
**10  had 22 previous pregnancies without metformin; 73% ended in spontaneous abortion**
**Among 125 women in “control group” there were 265 previous pregnancies without metformin**
**103/265 (39%) spontaneous abortions**

**Gluek et al, **_**Fertil Steril**_**  2001;75:46**

## METFORMIN IN PREGNANCY 	

**Problems**
**Small sample size (16 completed pregnancies)**
**Not randomized**
**Not even a contemporaneous control group (regression toward the mean)**

**Gluek et al, **_**Fertil Steril**_**  2001;75:46**

## METFORMIN & SPONTANEOUS AB	

**Case series of 48 anovulatory PCO patients treated with metformin**
**20 conceived; metformin continued for first 12 weeks**
**35% (7/20) spontaneous abortions**

**Heard MJ et al  *****Fert Steril*****  2002;77:669**

## METFORMIN & SPONTANEOUS AB		

**Retrospective study of PCOS patients All nondiabetic, all offered metformin**
**31 controls (declined or D/C’d metformin), **
**65 taking metformin at conception and throughout pregnancy**

**Jakubowicz et al  **_**JCEM**_**  2002; 87:524**

## METFORMIN & SPONTANEOUS AB		

**Early pregnancy loss rate (****≤****12 weeks)**
**Metformin group 6/68 (9%)**
**Control group 13/31 (42%)**
**P<0.001**

**Jakubowicz et al  **_**JCEM**_**  2002; 87:524**

## METFORMIN & SPONTANEOUS AB		

**Hypothesis: decreasing insulin resistance in pregnancy decreases spontaneous abortion rate**
**Problems:**
**Not randomized**
**No data on development of GDM in the two groups**
**Randomized trial would be helpful**

**Jakubowicz et al  **_**JCEM**_**  2002; 87:524**

## METFORMIN & SPONTANEOUS AB		

**Randomized blinded trial of metformin (N=45) vs clomiphene (N=47) to treat nonobese anovlulatory PCO patients**
**Ovulation rates similar**
**Pregnancy rate higher in metformin (15%) than clomiphene group (7.2%)**

**Palomba et al: **_**JCEM**_** 90:4068, 2005**

## METFORMIN & SPONTANEOUS AB		

**Randomized blinded trial (continued)**
**Spontaneous abortion rate lower (3/31, 10%) in metformin than clomiphene group (6/16, 38%), p=0.045**
**METFORMIN WAS STOPPED AS SOON AS PREGNANCY DIAGNOSED!**

**Palomba et al: **_**JCEM**_** 90:4068, 2005**

## METFORMIN & SPONTANEOUS AB		

**Randomized blinded trial of metformin (N=60) vs laparoscopic ovarian diathermy (N=60) to treat obese anovlulatory PCO patients**
**Ovulation rates similar**
**Pregnancy rate higher in metformin (22%) than placebo (13%) group**

**Palomba et al: **_**JCEM**_** 89:4801, 2004**

## METFORMIN & SPONTANEOUS AB		

**Randomized blinded trial (continued)**
**Spontaneous abortion rate lower (4/43, 9%) in metformin than placebo group (6/16, 29%), p<0.05**
**METFORMIN WAS STOPPED AS SOON AS PREGNANCY DIAGNOSED!**

**Palomba et al: **_**JCEM**_** 89:4801, 2004**

## METFORMIN & SPONTANEOUS AB		

**RCT METFORMIN VS CLOMIPHENE**
**NIH REPRODUCTIVE MEDICINE NETWORK**
**626 INFERTILE PCOS SUBJECTS**
**THREE TREATMENT ARMS**
**METFORMIN/PLACEBO (n=208)**
**CLOMIPHENE/PLACEBO (n=209)**
**METFORMIN/CLOMIPHENE (n=209)**
**METFORMIN EXTENDED RELEASE (2 g/d)**
**METFORMIN D/C’D AT DX OF CONCEPTION**
**CLOMIPHENE 50-150 MG/D x 5 DAYS**

**Legro RS et al, 2006**

## METFORMIN & SPONTANEOUS AB		

**RANDOMIZED TRIAL METFORMIN VS CLOMIPHENE**
**LIVE BIRTH RATE **
**METFORMIN 7.2% (15/208) (P<0.001 VS EACH GROUP)**
**CLOMIPHENE 22.5% (47/209)**
**COMBINED 26.8% (56/209)**
**SPONTANEOUS ABORTION RATES**
**METFORMIN 21% (NS)**
**CLOMIPHENE 8%**
**COMBINED 9%**
**MULTIPLES METFORMIN 0%, CLOMIPHENE 6%, COMBINED 3%**

**Legro RS et al, 2006**

## METFORMIN	

**Conclusions**
**Metformin crosses the placenta**
**Fetal effects of metformin not known; could be good or bad; animal studies would be helpful**
**Preliminary data suggest that metformin:**
**Improves pregnancy rate in IVF with PCOS**
**May mprove early pregnancy loss rate in PCOS - even if discontinued at time of diagnosis of pregnancy**
**May or may not prevent GDM in PCOS**

## METFORMIN	

**Conclusions**
**Currently available level 1 data do not support continuing the use of metformin after conception in order to prevent spontaneous abortion.**

## METFORMIN	

**Conclusions**
**Currently available data do not support the use of metformin in pregnancy except with fully informed consent, and/or in the context of a well designed study.**

## REFERENCES

**Gluek et al: Continuing metformin throughout pregnancy in women with PCOS appears to safely reduce first trimester Sab. *****Fertil Steril*****  2001;75:46-52**
**Glueck CJ et al: Pregnancy outcomes among women with PCOS treated with metformin.  *****Hum Reprod*****  2002;17:2858-2864**

## REFERENCES

**Gluek et al: Metformin throughout pregnancy reduces the development of GDM in women with PCOS. *****Fertil Steril*****  2002;75:46-52**
**Heard MJ et al: Pregnancies following use of metformin for ovulation induction in patients with PCOS.  *****Fert Steril*****  2002;77:520-525.**

## REFERENCES

**Hague, WM, Davoren PM, McIntyre D et al: Metformin crosses the placenta: a modulator for fetal insulin resistance?  *****British Medical Journal***** 4 Dec 2003; rapid response to editorial from BMJ 327:880-881, 2003.  Published online.**

## REFERENCES

**Hellmuth E et al: Oral hypoglycaemic agents in 118 diabetic pregnancies.  *****Diab Med*****  2000; 17:507-511**
**Jakubowicz DJ et al: Effects of metformin on early pregnancy loss in the PCOS.  *****JCEM*****  2002;87:524-529.**

## REFERENCES

**Langer O et al: A comparison of glyburide and insulin in women with GDM.  *****NEJM***** 2000;343:1134-1138**
**Legro, RS.  Clinical Crossroads: A 27-year-old woman with a diagnosis of polycystic ovary syndrome.  *****JAMA*****  2007;297:509-519.**
**McCarthy EA et al: Metformin in obstetric and gynecologic practice: a review.  *****Ob Gyn Survey*****  2004;59:118-127**

## REFERENCES

**Vanky E, Salvesen KA, Heimstad R et al: Metformin reduces pregnancy complications without affecting androgen levels in pregnant polycystic ovary syndrome women: results of a randomized study.  *****Human Reproduction*****  2004;19:1734-1740**
**Vanky E, Zahlsen K, Spigset O, Carlsen SM: Placental passage of metformin in women with polycystic ovary syndrome.  *****Fertility Sterility*****  2005;83:1575-1578**

## REFERENCES

**Radon PA et al: Impaired glucose tolerance in pregnant women with PCOS.*****  Obstet Gynecol*****  1999:94:194-197.**
**Palomba S et al: Prospective parallel randomized, double-blind, double-dummy controlled clinical trial comparing clomiphene citrate and metformin as first-line treatment for ovulation induction in nonobese anovulatory women with PCOS.  *****JCEM*****  2005; 90:4068-4074.**

## REFERENCES

**Palomba S et al: Metformin administration versus laparoscopic ovarian diathermy in clomiphene citrate-resistant women  with PCOS: A prospective parallel randomized double-blind placebo-controlled trial.  *****JCEM*****  2004; 89:4801-4809.**
**Stadtmauer LA et al: Metformin treatment of patients with PCOS undergoing IVF improves outcomes and is associated with modulation of the IGFs.  *****Fertil Steril*****  2001; 75:505-509**