21511 Oral antidiabetics

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Oral antidiabetics are not hormones and do not work in the way that insulin does; they are not substitutes. The most commonly used sulfonylurea derivatives merely stimulate those ,i-cells in the pancreas that still have the ability to function. Among these medications arc the second-generation sulfonylureas glibenchamide (glyburide), glibor-nuride, gliclazide, glimepiride, glipizide, gliquidone, and glisoxepide. First-generation sulfonylureas are acetohexamide, chlorpropamide, tolazamide, and tolbutamide.

In contrast, the biguanide derivatives, metformin and phenfomiin, decrease glucose synthesis in the liver, delay glucose resorption from the gut, and increase glucose utilization in the muscular system.

Acarbose and miglitol, as glucosidase inhibitors, inhibit carbohydrate absorption in the intestine - a controversial therapy for diabetes. Nateglinide and repaglinide regulate postprandial blood sugar by a short increase in insulin secretion from the ii-cells. Pioglitazone and rosiglitazone increase the sensitivity to insulin. Muraglitazar belongs to the same group, but results of studies have shown an increased risk for serious cardiovascular adverse effects, so there is no approval by the FDA for the USA. Sitagliptin and vildagliptin mimic incretin hormones, which naturally work in the gut and increase insulin production, dependent on meal supply. In diabetics, less incrctin hormones than normal arc produced. Both substances are still being tested in clinical trials.

These drugs have in common the fact that there is no evidence so far of effective prevention of diabetic late complications. Insulin, metformin, and sulfonylureas are the only antidiabetic substances where evidence-based data have shown positive effects on the late diabetic complications, such as neuropathy, nephropathy, etc., or coronary sclerosis and others.

Because oral antidiabetics have not been shown to regulate blood sugar as reliably as insulin, they are not considered suitable for treating diabetes during pregnancy. Studies on use during pregnancy only exist for glyburide and metformin.

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Hypoglycemia of the newborn may be noted if treatment has been continued until delivery. In older studies, an increased risk for congenital malformations was described (Piacquadio 1991), which at first was taken as a suggestion that oral antidiabetics might have a teratogenic risk (Towner 1995). Currently, the results are interpreted differently: other studies did not confirm such an association, but stated that inadequately treated hyperglycemia and associated metabolic disruption lead to an increase in birth defects (Gutzin 2001). More recently published case reports do not report an increased rate of malformations, but they do not allow a differentiated risk assessment either. Therefore, substance-specific differences in placental permeability (e.g. tolbutamide is more placenta permeable than glipizide) are of less relevance. Recently published results of perfusion studies examine why the transplacental transfer of glyburidc is low, and what might influence it (Kraemer 2006, Nanovskaya 2006).

Randomized studies have compared several hundred women with gestational diabetes on glyburide to those on insulin therapy, and have not found any differences concerning the course of pregnancy and the well-being of the newborns. Therapy was started after embryogenesis. Glyburide was not detected in umbilical cord blood samples, and there was no significant difference concerning the number of hypoglycemic newborn infants or birth weight (Jacobson 2005, Langcr 2005, Krcmcr 2004). Jacobson (2005) reported an increased need for neonatal phototherapy and a higher rate of pre-eclampsia on glyburide. This latter finding is of particular concern in light of recent findings by Crowther (2005) that pre-eclampsia is more prevalent among patients with untreated gestational diabetes. It is doubtful whether the positive results are yet sufficient to question the current recommendation, regarding therapy of gestational diabetes, in favor of insulin (Rand 2006, Greene 2000).

In contrast to glibenclamide, metformin does not stimulate insulin secretion and thus does not lead to hypoglycemia of the pregnant woman or newborn. In overweight patients, diabetic therapy with metformin, which raises insulin sensitivity and decreases the insulin requirement, is more logical than therapy with glyburide.

Metformin is not only indicated for diabetes type II, but also for women with polycystic ovary syndrome (PCOS) in order to improve poor conception rates and decrease high pregnancy loss rates during first trimester. Gestational diabetes is also a frequent symptom of PCOS, which might be another indication for metformin. No teratogenic risk was reported in a study on 179 retrospectively ascertained pregnancies (Thatcher 2006) and in a case scries of 50 pregnancies (Turner 2006). A meta-analysis of eight studies (five with retrospective and three with prospective data collection) published until 2004, and including 172 pregnancies, arrived at the same result (Gilbert 2006). A retrospective case-control study compared the neonatal outcome of 33 women with PCOS, treated with metformin in the first trimester, with 66 normal healthy women. There was a slight but statistically significant lower mean birth weight in the former (Kovo 2006). Some studies reported a decrease in the rate of miscarriage in women with PCOS on metformin (Thatcher 2006, Palomba 2005, Jakubowicz 2002). There is a debate concerning the duration of therapy in cases of PCOS: how long should metformin be maintained in order to "stabilize a pregnancy"? There is no evidence that therapy after gestational weeks 6-8 is correlated with a better pregnancy outcome. Glueck (2004), who has collected data on 126 intrauterine metformin-exposed infants of mothers with PCOS (of whom sonic are included in the above-mentioned meta-analysis), postulated that metformin, if taken throughout pregnancy, has a preventive effect concerning the occurrence of gestational diabetes, but this could not be confirmed by a randomized prospective study (Vanky 2004). The results from a recent study indicate that metformin freely passes the placenta and that the fetus is exposed to therapeutic concentrations, but it does not seem to influence pH levels in umbilical artery blood (Vanky 2005). Further research is necessary.

There are only a few case reports concerning the use of rosiglita-zone and acarbose in pregnancy (Kalyoncu 2005, Yaris 2004). No data arc available concerning the other oral antidiabetics.

Recommendation. As in type I diabetes, type II diabetics should be controlled with insulin therapy before a planned pregnancy. Nevertheless, when therapy with oral antidiabetics has been carried out during pregnancy, this is not an indication to terminate the pregnancy. A detailed ultrasound examination to verify normal morphologic development of the fetus is recommended. Whether the sulfonylureas glyburide (glibendamide) or metformin are alternatives for insulin in gestational diabetes after the first trimester should be evaluated with reserve. Regular insulin is still the substance of choice. If metformin was taken to stabilize a pregnancy in cases of PCOS, therapy should be stopped by gestational weeks 6-8.

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