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ORIGINAL ARTICLE

Pharmacological Management of Gestational Diabetes An overview

DONALD R. COUSTAN, MD presumably the fetus is relatively pro- tected from any direct effects. An example of such a would be heparin, OBJECTIVE — To provide a review of the background literature regarding the pharmaco- which as a relatively large and highly logical management of gestational diabetes. charged molecule, does not traverse the placenta to any measurable extent. Hepa- RESEARCH DESIGN AND METHODS — This is a literature review. rin is generally considered to be safe for the fetus, although of course it poses sig- RESULTS — Information is available regarding the use of some, but not all, oral antidiabetes nificant risks such as hemorrhage and agents in pregnancy. bone demineralization for the mother. CONCLUSIONS — Available evidence supports the use of glyburide during pregnancy. If a medication is shown to cross the Evidence is inadequate to support or refute the use of , an agent that has been shown placenta, that is not necessarily a contra- to cross the placenta and thus could be helpful or harmful to the developing fetus. indication to its use in pregnancy. For example, we frequently prescribe dexa- Diabetes Care 30 (Suppl. 2):S206–S208, 2007 methasone or betamethasone to pregnant women to take advantage of transplacen- ecause preparations tested to GUIDING PRINCIPLES — As our tal passage of these , to enhance fetal date have been determined not to understanding of the physiology and lung maturation. The second question is B cross the placenta or to cross mini- pharmacology of both pregnancy and di- whether a medication that reaches the fe- mally, insulin has been the treatment of abetes has increased, some guiding prin- tal compartment is neutral, helpful, or choice in most parts of the world for pa- ciples have emerged to help us decide harmful to the fetus. tients with gestational diabetes whose which are safe and effective The second safety question above also circulating glucose levels exceed prede- for pregnant women. Any medication touches on the subject of efficacy. If a termined thresholds. Although advances must, of course, be safe for the person crosses the placenta and is helpful to have been made in developing who takes it, or at least the benefits of its the fetus without causing harm, it could that may be administered by alternative use must outweigh the risks. However, then be considered to be both safe and routes, insulin is typically injected subcu- when a pregnant woman takes a medica- efficacious. Most often, a drug is pre- taneously. This poses a barrier to utiliza- tion, we are also concerned about that scribed during pregnancy to help the tion and has been one of the factors that medication’s effects on her unborn fetus. mother. The first efficacy question is kindled interest over many years in treat- Starting with the thalidomide experience whether the drug has been shown to help ing gestational diabetes with oral antidia- in the 1960s, our view of the placenta has the condition for which the mother is be- betic agents. This and the following shifted from that of a barrier, serving to ing treated. If the mother has diabetes, presentations describe oral agents that protect the fetus from harm, to that of a and we are considering oral antidiabetic have the potential to be used as alterna- sieve, allowing entry of all kinds of chem- drugs, the answer would generally be yes. tives to insulin for the treatment of gesta- icals and substances to the fetal circula- However, this will not always be the case. tional diabetes. In this overview, I shall tion. Whereas neither point of view is A medication whose mechanism of action outline some guiding principles in deter- entirely accurate, the latter is probably a is to stimulate pancreatic insulin secretion mining whether a particular agent is ap- safer perspective. Thus, the first question and/or release would not be helpful to a propriate for use in pregnancy and then one should ask about a medication to be mother with type 1 diabetes. apply these principles to the most com- used by pregnant women is whether it There are situations where treating monly used oral antidiabetes agents. crosses the placenta. If it does not, then the mother’s condition will also help the ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● fetus indirectly. The second efficacy ques- From the Department of Obstetrics and Gynecology, Brown Medical School, and the Women & Infants tion is whether the drug’s effect on the Hospital of Rhode Island, Providence, Rhode Island. mother will be beneficial, and not harm- Address correspondence and reprint requests to Donald R. Coustan, Chace/Joukowsky Professor and ful, to the fetus. In keeping with the Ped- Chair, Department of Obstetrics and Gynecology, Brown Medical School, Obstetrician and Gynecologist in ersen Hypothesis, any medication that Chief, Women & Infants Hospital of Rhode Island, 101 Dudley St., Providence, RI 02905-2401 E-mail: [email protected]. tends to normalize maternal glycemic lev- Received for publication 28 March 2006 and accepted in revised form 14 June 2006. els should benefit the fetus as well. The This article is based on a presentation at a symposium. The symposium and the publication of this article third efficacy question is whether the were made possible by an unrestricted educational grant from LifeScan, Inc., a Johnson & Johnson company. drug crosses the placenta and has a direct A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion factors for many substances. benefit to the fetus. DOI: 10.2337/dc07-s217 It is my view that all of these questions © 2007 by the American Diabetes Association. should be considered in making a deci-

S206 DIABETES CARE, VOLUME 30, SUPPLEMENT 2, JULY 2007 Coustan sion regarding treatment of gestational di- detected in the cord blood of offspring latter statement. However, Hague et al. abetes with oral antidiabetes agents. whose mothers took the drug as part of a (8) measured plasma metformin levels in randomized trial (4). No information is seven women taking metformin at a me- CLASSES OF ORAL available regarding ; the pack- dian daily dose of 2,000 mg and in the ANTIDIABETES AGENTS — Oral age insert (5) lists the drug as Pregnancy cord blood of 23 babies whose mothers antidiabetes agents are typically classified Category C, but states, “There are no ad- took metformin during pregnancy. Me- as insulin secretagogues, insulin sensitiz- equate and well-controlled studies in dian plasma metformin levels were 1.05 ers, and ␣-glucosidase inhibitors. Re- pregnant women. Starlix should not be ␮g/ml (range 0.06–2.93) in maternal cently, a glucagon-like peptide 1 agonist used in pregnancy.” For , the blood and 0.63 ␮g/ml (range 0.08–2.55) has also been placed on the market. Physicians’ Desk Reference (6) states, in cord blood samples. These data suggest “Prandin should be used during preg- that significant amounts of metformin can Insulin secretagogues nancy only if it is clearly needed.” Given cross the placenta, with fetal concentra- The and are in- the available data, glyburide appears to be tions in the range of half of maternal con- sulin secretagogues. The sulfonylureas the best candidate insulin secretagogue centrations. Because it is unknown bind to receptors in ␤-cells, for use during pregnancy, since it crosses whether metformin is therapeutic or del- stimulating insulin secretion at all blood the placental little or not at all and bene- eterious to the fetus, it would seem pru- glucose levels. For sulfonylureas to be ef- fits the mother directly and the fetus indi- dent to obtain further data (perhaps from fective, the patient must have residual rectly. A subsequent presentation will go animal models) before metformin be- ␤-cell function, so these drugs are not at into detail regarding the use of this drug comes commonly prescribed during all effective in patients with type 1 diabe- for women with gestational diabetes. pregnancy. At the very least, patients tak- tes or longstanding in the ing metformin should be counseled about stage of insulinopenia. The primary side Insulin sensitizers the unknown risks and benefits for the effect of sulfonylureas is hypoglycemia. There are two broad types of insulin sen- fetus. The effect of sulfonylureas is to suppress sitizers: the and the thiazo- The are agonists hepatic glucose production, diminish lidinediones, also called peroxisome for the peroxisome proliferator–activated glucotoxicity, and improve insulin secre- proliferator–activated receptor-␥ agonists. receptor-␥. Such receptors are found in tion after meals. They generally lower cir- The biguanides enhance insulin ac- target tissues for insulin action. These culating glucose levels by ϳ20% and tion, stimulating glucose uptake in the drugs enhance peripheral insulin action work best in patients of normal or slightly liver and in the periphery and also sup- and are useful for patients with type 2 increased body weight. The first- pressing hepatic glucose output. They diabetes who have adequate endogenous generation sulfonylureas include tolbut- only work when insulin is present, do not insulin; they are only useful if insulin re- amide, , and . stimulate insulin secretion or release, and sistance is present. Weight gain is com- Second-generation sulfonylureas include do not cause hypoglycemia. They are mon with these drugs and appears to be (Glucotrol), which is shorter act- used for patients with type 2 diabetes who dose and time dependent. Fluid retention ing; glyburide or (Diabeta have residual ␤-cell function, typically may occur, and peripheral edema devel- and Micronase), which are longer acting; when diet and exercise are insufficient for ops in 2–5% of patients. Heart failure may and gimepride (Amaryl), which is also diabetic control. They are also useful in be precipitated that is not responsive to longer acting. the insulin resistance syndrome and con- diuretics; it does generally respond to dis- are structurally different stitute an increasingly popular treatment continuation of the from sulfonylureas, but act similarly via a for polycystic ovarian syndrome, often in- therapy. was the original different receptor. The meglitinides that ducing ovulation and resulting in preg- thiazolidinedione, but was removed from are currently marketed are nateglinide nancy. was the original the market in 2000 because ϳ2% of those (Starlix) and repaglinide (Prandin). but was removed from the mar- treated had to discontinue the drug be- If insulin secretagogues cross the pla- ket in the 1960s because of reports of fatal cause of hepatotoxicity, and a number of centa, they would be expected to stimu- lactic acidosis. Metformin (Glucophage) deaths occurred. Currently there are two late insulin production in the fetus. is the only biguanide currently available thiazolidinediones on the market: rosigli- Presumably this would make diabetic fe- in the U.S. tazone (Avandia) and (Ac- topathy worse, even if circulating glucose Metformin is a relatively small mole- tos). These drugs are less hepatotoxic levels were lowered. In one study (1), cule with a molecular weight of 105.03. If than troglitazone, but patients still re- which measured levels in it were to cross the placenta, it might be quire monitoring of liver function tests. mothers taking tolbutamide as well as expected to enhance the action of fetal These drugs are increasingly used in treat- their newborns, drug concentrations in insulin, which could be beneficial or del- ing polycystic ovarian syndrome and placental samples and in neonatal blood eterious to the fetus, depending on which other aspects of the insulin resistance syn- samples obtained ϳ3 h after birth were insulin effects are potentiated. According drome. Because they enhance insulin ac- similar to maternal levels. Using an iso- to the package insert (7), metformin is tion, it would be logical to consider their lated perfused human placental cotyle- Pregnancy Category B. The manufacturer use in insulin-resistant states such as don model, Elliott et al. (2) demonstrated also states, “Determination of fetal pregnancy. Unfortunately, there are no minimal placental transfer of glyburide, concentrations demonstrated a partial controlled data available in pregnancy, but greater transport of glipizide and par- placental barrier to metformin.” In con- and one study reported that ticularly chlorpropamide and tolbut- versations with officials at Bristol-Myers crossed the placenta in early human preg- amide (3), from maternal to fetal Squibb, the manufacturer, I have been nancy at 10–12 weeks, with fetal tissue compartments. Glyburide could not be unable to obtain the data supporting the levels measured at about half of maternal

DIABETES CARE, VOLUME 30, SUPPLEMENT 2, JULY 2007 S207 Pharmacological management of gestational diabetes serum levels (9). Use in pregnancy would the Food and Drug Administration for ad- References best await the availability of further data. junctive therapy when patients with type 1. Miller DI, Wishinsky H, Thompson G: 2 diabetes have not been optimally con- Transfer of tolbutamide across the pla- ␣-Glucosidase inhibitors trolled on metformin (12). It is an incretin centa. Diabetes 11 (Suppl.):93–97, 1962 The ␣-glucosidase inhibitors slow the ab- mimetic and potentiates insulin secretion 2. Elliott BD, Langer O, Schenker S, Johnson sorption of sugars in the upper gastroin- while inhibiting glucagon secretion and RF: Insignificant transfer of glyburide oc- testinal tract, decreasing postprandial slowing gastric emptying. It also pro- curs across the human placenta. Am J Ob- glucose excursions. Their major side ef- motes satiety. The drug is administered as stet Gynecol 165:807–812, 1991 fects are gastrointestinal, particularly flat- a subcutaneous injection, generally con- 3. Elliott BD, Langer O, Schenker S, Johnson RF, Prihoda T: Comparative placental ulence and borborygmus. These drugs do comitantly with a sulfonylurea or met- not depend on the presence of endoge- transport of oral hypoglycemic agents in formin. Although it has a modest effect on humans: a model of human placental nous insulin. There are currently two lowering fasting glucose levels, it mark- drug transfer. Am J Obstet Gynecol 171: available preparations: (Glyset) edly reduces postprandial glucose. It is a 653–660, 1994 and (Precose). Although no data polypeptide consisting of 39 amino acids 4. Langer O, Conway DL, Berkus MD, Xe- are currently available concerning placen- with a molecular weight of 4186.6. Ex nakis EM, Gonzales O: A comparison of tal passage, miglitol is highly absorbed vivo human placental perfusion studies glyburide and insulin in women with ges- from the gastrointestinal tract, whereas (13) detected minimal levels on the fetal tational diabetes mellitus. N Engl J Med acarbose is minimally absorbed, so that, side (fetal:maternal ratio Յ0.017). There 343:1134–1138, 2000 on principle, the latter drug would seem 5. Physicians’ Desk Reference. 59th ed. are no data available regarding the use of Montvale, NJ, Thomson PDR, 2005, p. to be preferable in pregnancy. Neverthe- in pregnancy, and the fact that less, there have been reports of transient 2375–2377 it must be injected subcutaneously will elevations in transaminase levels in acar- 6. Physicians’ Desk Reference. 59th ed. probably limit interest. bose-treated individuals, and a few cases Montvale, NJ, Thomson PDR, 2005, p. 2435–2438 of fulminant hepatitis with fatal outcome 7. Package insert for Glucophage. Available have been reported. A literature search re- SUMMARY AND online at http://www.glucophagexr.com vealed only two studies of acarbose in ges- CONCLUSIONS 8. Hague WM, Davoren PM, McIntyre D, tational diabetes. The first (10) was a case — Available data including poor transplacental passage Norris R, Xiaonian X, Charles B: Met- series of six gestational diabetic patients formin crosses the placenta: a modulator treated with 50 mg acarbose three times support the use of an insulin secreta- for fetal insulin resistance? (Letter) Br daily with meals. In these six patients, gogue, glyburide, to treat gestational dia- Med J. 4 December 20003. Available on- glucose levels were normalized, and all six betes. The widespread use of metformin line at http://bmj.bmjjournals.com/cgi/ babies were apparently normal. All moth- should await the demonstration of safety eletters/327/7420/880#42294 ers reported gastrointestinal discomfort. for the fetus, since fetal levels are approx- 9. Chan LY, Yeung JH, Lau TK: Placental In a preliminary abstract of a randomized imately half of maternal levels. Acarbose transfer of rosiglitazone in the first trimes- trial (11) of acarbose versus insulin in 91 may be a worthwhile approach if the pub- ter of human pregnancy. Fertil Steril 83: 955–958, 2005 gestational diabetic women failing diet lished preliminary data from a random- ized trial are confirmed in the final report 10. Za´rate A, Ochoa R, Herna´ndez M, Basurto therapy, glucose control and glycohemo- L: Eficacia de la acarbose para controlar el globin results were similar, and only 6% and if the issue of gastrointestinal distur- deterioro de la tolerancia a la glucose du- of acarbose-treated patients required in- bance can be overcome. Given the avail- rante la gestacio´n. Ginecol Obstet Mex 68: sulin. Gastrointestinal side effects were able evidence regarding placental transfer, 42–45, 2000 common. Acarbose is not systemically ab- and the lack of data from pregnancy, thia- 11. deVeciana M, Trail PA, Lau TK, Dulaney sorbed to an appreciable extent, so trans- zolidinediones should not be used until K: A comparison of oral acarbose and in- placental passage should not be an issue. more information is available. Incretin mi- sulin in women with gestational diabetes It is directly beneficial to the mother and metics do not yet show promise for use in mellitus. Obstet Gynecol 99 (Suppl.):5S, indirectly to the fetus. This medication gestational diabetes. 2002 appears to hold promise for the treatment 12. Exenatide (Byetta) for type 2 diabetes. of gestational diabetes. Med Lett Drugs Therapeutics 47:45–46, 2005 Acknowledgments— This work was pre- 13. Hiles RA, Bawdon RE, Petrella EM: Ex vivo Exenatide sented at the Fifth International Workshop- human placental transfer of the peptides Exenatide (Byetta) is a glucagon-like pep- Conference on Gestational Diabetes, Chicago, and exenatide. Hum Exp Toxi- tide (GLP-1) agonist that was approved by IL, 11–13 November 2005. col 22:623–628, 2003

S208 DIABETES CARE, VOLUME 30, SUPPLEMENT 2, JULY 2007