Gestational diabetes mellitus (GDM) complicates 3–15% of pregnancies depending upon the geographic location and ethnic groups, and its incidence is estimated to increase even further due to the increasing rates of obesity in the general population and the trend towards advanced maternal age in pregnancy. GDM is associated with adverse pregnancy outcome such as an increased rate of fetal macrosomia, neonatal metabolic disturbances, and maternal injuries. It has been shown that there is an inverse relation between maternal glycemic control and the risk of complications. When diet and exercise therapy fail in achieving good glycemic control, pharmacological intervention is warranted. This chapter deals with the evidence regarding the various pharmacological interventions for glycemic control in women with GDM, when to start, and what pharmacological agent to use.
Gestational diabetes, glycemic control, and adverse outcome
Although the association between gestational diabetes mellitus (GDM) and the risk of adverse pregnancy outcome is axiomatic, only in the last decade a positive relationship between the levels of maternal glycemia and perinatal morbidity and mortality was established. Langer et al. have shown that in a matched control study of 555 gravidas with GDM diagnosed after 37 weeks who were compared with 1110 subjects treated for GDM and 1110 nondiabetic subjects, the composite adverse outcome was 59% for untreated, 18% for treated, and 11% for nondiabetic subjects. Moreover, a two- to fourfold increase in metabolic complications and macrosomia/large for gestational age was found in the untreated group with no difference between the nondiabetic and treated subjects . Crowther et al. randomly assigned 1000 women between 24 and 34 weeks of gestation who had GDM to receive dietary advice, blood glucose monitoring, and insulin therapy as needed (the intervention group) or routine care. The rate of serious perinatal complications was significantly lower among the infants of the 490 women in the intervention group than among the infants of the 510 women in the routine-care group (1% vs. 4%, p = 0.01) although higher rates of induction of labor and neonatal nursery admission were found in the intervention group . Moreover, even in mild GDM (i.e., an abnormal result on an oral glucose tolerance test (OGTT) but a fasting glucose level <95 mg/dl), treatment was shown to reduce the risks of fetal overgrowth, shoulder dystocia, cesarean delivery, and hypertensive disorders . Surprisingly, despite the fact that additional drug support with oral agents or insulin is administered in 20–60% of pregnancies compromised by GDM , scant evidence on glucose data and pregnancy outcome persists, as only a small percent of the thousands of published studies provided glycemic data on patients, and even in these studies, the majority did not provide the pregnancy outcome based on whether or not glycemic targets were reached, method of testing, and mean levels of glycemic data throughout pregnancy .
Although a thorough review regarding the effect of different glycemic targets and diabetes-related complications is beyond the scope of this chapter, before elaborating on various treatment modalities, it is prudent to understand the goals needed to be reached. Several authoritative bodies have recommended varying levels of glycemia that need to be targeted in patients with diabetes in pregnancy. The sources of these recommendations utilized the concept of isolated normality based on nondiabetic glucose profiles and are usually well-defined cutoff levels . However, glucose values are best described as a continuous variable, and the risk to the fetus increases in direct relation to the increased level of maternal glycemia. For example, while maintaining mean blood glucose <100 mg/dl is associated with a similar risk of neonatal metabolic complications as the general population, levels >114 mg/dl increases the risk approximately twofold and >141 mg/dl over sevenfold compared to nondiabetic gravidas . Thus, even if the optimal glycemic goals cannot be reached, it is important to keep on struggling as it would still minimize the risk of complications even if not abolishing it.
Oral antihyperglycemic and hypoglycemic agents
Several groups of oral agents for lowering blood glucose levels are currently available, and each group has a different set of pharmacological characteristics and mechanism of action allowing for the possibility of combining drug therapies.
Sulfonylureas
Sulfonylureas have been used in the treatment of type 2 diabetes since 1942. The major effect of this group of agents is to enhance insulin secretion from beta cells of the pancreas . Moreover, sulfonylureas may further increase insulin levels by reducing hepatic clearance of the hormone, which is the main contributor to fasting hyperglycemia. They act by binding to specific receptors on the beta-cell membrane, closing potassium adenosine triphosphate (ATP) channels and opening calcium channels. The resulting increase in cytoplasmic calcium stimulates insulin release. A diminished glucose toxicity and improved insulin secretion following meals and, thus, reduction of postprandial hyperglycemia are achieved by enhanced insulin secretion. These drugs can also enhance peripheral tissue sensitivity to insulin . The sulfonylureas influence insulin secretion in direct proportion to plasma glucose levels from 3.3 to 10 mmol/l (60–180 mg/dl). However, the stimulation of insulin secretion by sulfonylureas does not occur when the plasma glucose is <3.3 mmol/l (60 mg/dl) . Thus, profound hypoglycemia is uncommon. The sulfonylureas act to facilitate rapid insulin secretion in response to nutritional intake, resulting in minimal to no lag time between the changes in plasma glucose and modification of the insulin secretory rate .
Glyburide
A second generation of hypoglycemic sulfonylurea-class compounds has emerged that include glyburide (also known as glibenclamide and glybenzcyclamide), glipizide, gliclazide, and glimepiride. These agents are considerably more potent than those of the first generation. When administrated alone, the glyburide plasma level peaks within 4 h. Food digestion does not impede the drug absorption and it is metabolized in the liver, with equal metabolite levels in the bile and urine. The elimination half-life of glyburide in nonpregnant individuals is approximately 10 h. Second-generation agents are relatively safe as <4% of patients using them report any adverse effects . The main side effect of glyburide (11–38% of type 2 nonpregnant patients) is hypoglycemia with the severity of the symptoms being dose related. Older patients are at a greater risk of a hypoglycemic episode than the young.
Glimepiride
Glimepiride is a relatively new sulfonylurea agent. Glimepiride and glyburide displace one another from their respective binding sites. Compared to glyburide, glimepiride has a 2.5–3-fold faster rate of association and an eight- to ninefold faster rate of dissociation from the beta-cell sulfonylurea receptor (SUR)-binding site. This results in a more rapid release and a shorter duration of insulin secretion. Glimepiride significantly increases second-phase insulin secretion, whole body glucose uptake, and insulin sensitivity .
Biguanides
Metformin
Metformin is an oral antihyperglycemic agent that is chemically and pharmacologically unrelated to the sulfonylureas and has been shown to be effective in improving the glycemic profile of patients with early-onset and mild diabetes. Its mechanisms of action include decreased intestinal absorption of glucose and hepatic glucose production, and increased peripheral uptake of glucose and utilization. The latter two mechanisms improve insulin sensitivity and, as a result, decrease insulin requirements . Metformin acts by causing the translocation of glucose transporters from the microsomal fraction to the plasma membrane of hepatic and muscle cells . Hypoglycemic episodes are rare as metformin does not stimulate direct insulin secretion. Metformin also has no significant effect on the secretion of glucagon, growth hormone, cortisol, or somatostatin. Although the mechanism by which it reduces hepatic glucose production is controversial, the preponderance of studies indicates it has an inhibitory effect on gluconeogenesis . Metformin is initiated gradually in 500- or 850-mg increments up to a maximum of 2000 mg daily . The peak plasma level of metformin when given as a single agent occurs within 4 h, and the plasma elimination half-life is approximately 6 h. Absorption is reduced by food intake, although it should be administered with meals to minimize gastrointestinal intolerance. Metformin is not metabolized, and is eliminated unchanged in the urine. It is effective in reducing plasma triglyceride and cholesterol levels as well as promoting weight loss in obese diabetic patients. One attractive aspect of metformin during pregnancy is that it does not stimulate the fetal pancreas to oversecrete insulin.
Thiazolidinediones
Thiazolidinediones are another group of agents that provide a pharmacological alternative to insulin therapy. They act by lowering insulin resistance in peripheral tissue; a decrease in systemic and local tissue lipid availability may also contribute to the control of the effects of diabetes. While there are no reports of their use during pregnancy, they remain potentially attractive. Rosiglitazone is more potent than the related troglitazone and offers a lower risk of hepatotoxicity. It is absorbed within about 2 h, but takes 6–12 weeks to achieve the maximum clinical effect. Hepatic function should be tested before and periodically after initiating therapy. Several studies also note considerable weight gain after beginning these drugs . A certain similarity in the pharmacological characteristics of rosiglitazone and glyburide exists, suggesting the former does not cross the placenta well. If true, rosiglitazone, like metformin, may be an ideal agent for the management of GDM and type 2 diabetes in pregnancy either as monotherapy or combined with glyburide.
Alpha-glucosidase inhibitors
Alpha-glucosidase inhibitors, such as acarbose, act by slowing the absorption of carbohydrates from the intestine, thereby reducing the postprandial rise in blood glucose. Frequent gastrointestinal side effects require gradual dose increments over time after the initiation of therapy. The drugs in this group may be useful as monotherapy for older adult patients, but are typically used in combination with other oral, antidiabetic agents and/or insulin. Acarbose, the oral agent currently in use, is often added to most of the other available therapies .
Oral antihyperglycemic and hypoglycemic agents
Several groups of oral agents for lowering blood glucose levels are currently available, and each group has a different set of pharmacological characteristics and mechanism of action allowing for the possibility of combining drug therapies.
Sulfonylureas
Sulfonylureas have been used in the treatment of type 2 diabetes since 1942. The major effect of this group of agents is to enhance insulin secretion from beta cells of the pancreas . Moreover, sulfonylureas may further increase insulin levels by reducing hepatic clearance of the hormone, which is the main contributor to fasting hyperglycemia. They act by binding to specific receptors on the beta-cell membrane, closing potassium adenosine triphosphate (ATP) channels and opening calcium channels. The resulting increase in cytoplasmic calcium stimulates insulin release. A diminished glucose toxicity and improved insulin secretion following meals and, thus, reduction of postprandial hyperglycemia are achieved by enhanced insulin secretion. These drugs can also enhance peripheral tissue sensitivity to insulin . The sulfonylureas influence insulin secretion in direct proportion to plasma glucose levels from 3.3 to 10 mmol/l (60–180 mg/dl). However, the stimulation of insulin secretion by sulfonylureas does not occur when the plasma glucose is <3.3 mmol/l (60 mg/dl) . Thus, profound hypoglycemia is uncommon. The sulfonylureas act to facilitate rapid insulin secretion in response to nutritional intake, resulting in minimal to no lag time between the changes in plasma glucose and modification of the insulin secretory rate .
Glyburide
A second generation of hypoglycemic sulfonylurea-class compounds has emerged that include glyburide (also known as glibenclamide and glybenzcyclamide), glipizide, gliclazide, and glimepiride. These agents are considerably more potent than those of the first generation. When administrated alone, the glyburide plasma level peaks within 4 h. Food digestion does not impede the drug absorption and it is metabolized in the liver, with equal metabolite levels in the bile and urine. The elimination half-life of glyburide in nonpregnant individuals is approximately 10 h. Second-generation agents are relatively safe as <4% of patients using them report any adverse effects . The main side effect of glyburide (11–38% of type 2 nonpregnant patients) is hypoglycemia with the severity of the symptoms being dose related. Older patients are at a greater risk of a hypoglycemic episode than the young.
Glimepiride
Glimepiride is a relatively new sulfonylurea agent. Glimepiride and glyburide displace one another from their respective binding sites. Compared to glyburide, glimepiride has a 2.5–3-fold faster rate of association and an eight- to ninefold faster rate of dissociation from the beta-cell sulfonylurea receptor (SUR)-binding site. This results in a more rapid release and a shorter duration of insulin secretion. Glimepiride significantly increases second-phase insulin secretion, whole body glucose uptake, and insulin sensitivity .
Biguanides
Metformin
Metformin is an oral antihyperglycemic agent that is chemically and pharmacologically unrelated to the sulfonylureas and has been shown to be effective in improving the glycemic profile of patients with early-onset and mild diabetes. Its mechanisms of action include decreased intestinal absorption of glucose and hepatic glucose production, and increased peripheral uptake of glucose and utilization. The latter two mechanisms improve insulin sensitivity and, as a result, decrease insulin requirements . Metformin acts by causing the translocation of glucose transporters from the microsomal fraction to the plasma membrane of hepatic and muscle cells . Hypoglycemic episodes are rare as metformin does not stimulate direct insulin secretion. Metformin also has no significant effect on the secretion of glucagon, growth hormone, cortisol, or somatostatin. Although the mechanism by which it reduces hepatic glucose production is controversial, the preponderance of studies indicates it has an inhibitory effect on gluconeogenesis . Metformin is initiated gradually in 500- or 850-mg increments up to a maximum of 2000 mg daily . The peak plasma level of metformin when given as a single agent occurs within 4 h, and the plasma elimination half-life is approximately 6 h. Absorption is reduced by food intake, although it should be administered with meals to minimize gastrointestinal intolerance. Metformin is not metabolized, and is eliminated unchanged in the urine. It is effective in reducing plasma triglyceride and cholesterol levels as well as promoting weight loss in obese diabetic patients. One attractive aspect of metformin during pregnancy is that it does not stimulate the fetal pancreas to oversecrete insulin.
Thiazolidinediones
Thiazolidinediones are another group of agents that provide a pharmacological alternative to insulin therapy. They act by lowering insulin resistance in peripheral tissue; a decrease in systemic and local tissue lipid availability may also contribute to the control of the effects of diabetes. While there are no reports of their use during pregnancy, they remain potentially attractive. Rosiglitazone is more potent than the related troglitazone and offers a lower risk of hepatotoxicity. It is absorbed within about 2 h, but takes 6–12 weeks to achieve the maximum clinical effect. Hepatic function should be tested before and periodically after initiating therapy. Several studies also note considerable weight gain after beginning these drugs . A certain similarity in the pharmacological characteristics of rosiglitazone and glyburide exists, suggesting the former does not cross the placenta well. If true, rosiglitazone, like metformin, may be an ideal agent for the management of GDM and type 2 diabetes in pregnancy either as monotherapy or combined with glyburide.
Alpha-glucosidase inhibitors
Alpha-glucosidase inhibitors, such as acarbose, act by slowing the absorption of carbohydrates from the intestine, thereby reducing the postprandial rise in blood glucose. Frequent gastrointestinal side effects require gradual dose increments over time after the initiation of therapy. The drugs in this group may be useful as monotherapy for older adult patients, but are typically used in combination with other oral, antidiabetic agents and/or insulin. Acarbose, the oral agent currently in use, is often added to most of the other available therapies .
Insulin – physiology and analogs
Insulin is produced in the beta cells of the islets of Langerhans as a single-polypeptide precursor, preproinsulin, which is then converted to proinsulin, an 86-amino-acid polypeptide. Proinsulin forms equimolar amounts of insulin and C-peptide (i.e., connecting peptide) through the removal of four-amino-acid residues. The resulting insulin consists of a 20-amino-acid A chain and a 31-amino-acid B chain connected by two disulfide bridges, with the addition of a third disulfide bridge within the A chain. The final product that is released from the beta cells into the portal venous system is 90–97% insulin with an equimolar amount of C-peptide . During its first passage, 50% of the insulin that is released into the portal system is removed by the liver . Insulin secretion into the portal system occurs in the basal state at a rate of about 1 U/h in normal adults and is increased five- to tenfold with the intake of food. The total daily secretion of insulin is approximately 40 U.
Insulin secretion rates in either the fasting or the postprandial state decrease rapidly to prevent hypoglycemia with moderate exercise. However, strenuous exercise may lead to hyperglycemia followed by an enhanced insulin secretion in the post-exercise period .
Insulin analogs
The aim of exogenous insulin administration in patients with diabetes is to mimic normal physiology in nondiabetic pregnancies. Normal insulin secretion includes a basal stage and insulin secretion that is related to meals. The basal insulin secretion prevents excessive hepatic production and mobilization of free fatty acids from the adipose tissue stores, and is needed regardless of meals and physical activity. The second component in insulin physiology is related to insulin secretion in association with meals. Importantly, 90% of nutrients are absorbed within 90 min after a meal, and the plasma glucose and insulin levels return to normal premeal values after approximately 2 h .
Since its original discovery in the early 1920s, several generations of insulin have been developed. The most commonly used are human insulin and insulin analogs. Some of the features of regular human insulin prevent it from being entirely successful in imitating physiological insulin secretion. There is a delay in the absorption of subcutaneously administered structurally unchanged insulin due to the fact that, in this preparation, it tends to associate in “clusters” of six molecules (hexamers), and time is needed after injection for these clusters to dissociate to single molecules that can be used by the body . Therefore, it should be administered 30–45 min prior to the ingestion of a meal; its peak effect occurs 2–4 h after the injection and its duration of action lasts 6–8 h. As a result, there is often nonadherence to the insulin protocol due to the inconvenience and limitations of injecting approximately a half hour prior to a meal so the patient ultimately administer the insulin with the meal .
Over the past decades, insulin analogs with improved pharmacokinetic profiles were developed in order to overcome the limitations of the human insulin and improve glycemic control among patients. Insulin lispro is an analog of human insulin in which the amino acids praline and lysine which occupy B28 and B29 positions, respectively, are interchanged. Although insulin lispro, like soluble insulin, forms hexamers, they dissociate more rapidly following subcutaneous injection . In the short-acting insulin analog aspart, aspartic acid replaces praline at position 29 of the B-region. The change reduces the stability of the interactions within the hexane leading to an increased absorption of the insulin after injection . Short-acting insulin analogs are, therefore, absorbed more quickly, achieving peak plasma concentrations about twice as high and within approximately half the time compared to structurally unchanged insulin leading to lower glucose levels in the postprandial period . Moreover, in nonpregnant type 1 diabetic patients, the use of regular insulin has shown to improve overall glycemic control, patient satisfaction, and hemoglobin A 1C values . However, insulin analogs are more expensive than structurally unchanged insulin. Moreover, the structural homology of insulin analogs to insulin-like growth factor I (IGF-I) has raised concern regarding the progression of late complications and even potential mitogenic (induction of cell division) effects, especially with long-term use. IGF-I may affect the progression of retinopathy and certain modified insulin analogs have mitogenic potency in osteosarcoma cells . Studies addressing the potential of insulin analogs to cross the placenta have shown that insulin unilaterally does not cross the placenta . However, it will cross when it complexes to insulin antibodies and the transfer is directly related to the level of anti-insulin antibodies in the mother . In a study of 19 GDM women treated with insulin lispro, four of the subjects received intravenous infusion of the drug in labor; insulin lispro was not detected in the umbilical cord blood of their infants , although others have shown that the ability to cross the placenta is concentration dependent and at concentrations of 580 μU/ml and higher insulin lispro can cross to the fetal side of the placenta .
Intermediate- and long-acting insulin
Intermediate- and long-acting insulin are components of the insulin algorithm in the care of patients. The neutral protamine Hagedorn (NPH) has a concentration pattern, which is not ideal and resembles a bimodal distribution. Yet, it is more commonly used than the lente and the ultralente insulin in pregnancy mainly because its absorption pattern and duration are more accurate.
Insulin glargine and detemir are long-acting insulin analogs that were developed to mirror the basal pancreatic insulin secretion. Glargine has high IGF qualities. It has been reported to have 6.5 times more potency than human insulin in binding the IGF receptors . Insulin glargine is an analog in which glycine is substituted for aspartic acid at position 21 on the alpha chain and two basic argenines are added to the C-terminus of the beta chain. The addition of zinc to the molecule results in stabilization of the hexane (prolongation of molecule action), a decrease in absorption, and an increase in association rates. In contrast to NPH, the glargine has a stable monotonous basal profile which minimizes the peaks and valleys in the former insulin. Thus, it has been suggested that the use of glargine results in decreased hypoglycemic episodes when used as part of the insulin administration algorithm in conjunction with lispro or aspart insulin. In the nonpregnant state, the use of glargine demonstrated a decrease in fasting glucose levels, hemoglobin A 1c , and nocturnal hypoglycemia . As these agents are relatively new, not many studies are published regarding the safety profile of insulin glargine and detemir in pregnancy . In studies in pregnant rats and rabbits with diabetes treated with moderate to high doses of insulin glargine, congenital abnormalities and abortions have been observed but were thought to be caused by hyperglycemia rather than the insulin . Studies in rats and rabbits have not demonstrated embryo toxicity and teratogenicity concerns for insulin detemir . In women with type 1 diabetes, insulin detemir was reported to be as well tolerated and safe as NPH regarding perinatal outcomes .
When to start pharmacological treatment in GDM
The mainstay of treatment of GDM remains nutritional counseling and dietary intervention. In order to decrease the risk of adverse perinatal outcome, the optimal diet should provide caloric and nutrient needs to sustain pregnancy without resulting in significant postprandial hyperglycemia . When a low glycemic index diet and exercise therapy fail to achieve targeted glucose levels, options are either oral antidiabetic drugs or insulin. It seems that as many as 50% of GDM women will eventually require pharmacological therapy . However, in order to identify those women with GDM who need pharmacological therapy, several issues should first be addressed.
What glucose thresholds necessitate pharmacological intervention?
In GDM, there is no consensus among authoritative bodies regarding the threshold of fasting plasma glucose (FPG) for the initiation of pharmacological therapy. Even in practice, uniformity among physicians is lacking. In a survey of obstetricians and maternal–fetal specialists in the United States, Landon et al. reported that 11% of the participants initiate insulin at fasting plasma values of 90–104 mg/dl, 54% at a fasting of 105 mg/dl, 23% at a threshold fasting of 110–119 mg/dl, and 9% at fasting levels in the range of 120–150 mg/dl. Only 22% of the survey respondents used 120 mg/dl as the postprandial threshold for insulin initiation; the remaining 78% used values ranging from 121 to 160 mg/dl. Both the American Congress of Obstetricians and Gynecologists (ACOG) and the American Diabetes Association (ADA) have established guidelines with goal plasma glucose thresholds for postprandial values <140 mg/dl at 1 h and <120 mg/dl at 2 h . The Fifth International Workshop on Gestational Diabetes and the North American Diabetes in Pregnancy Study Group recommended a threshold of fasting glucose ≥95 mg/dl as the glycemic target. The majority of fasting and postprandial plasma glucose thresholds in use, however, are not based on peer-reviewed studies but rather on clinical opinions that are at best Level IV evidence-based practice. Based on a large prospective study by Langer et al. demonstrating that the rate of LGA was similar with either diet or insulin therapies when fasting plasma from the oral glucose tolerance test (OGTT) was <95 mg/dl, in contrast to a threefold higher (27%) rate in diet versus insulin-treated when the fasting plasma level was between 95 and 105 mg/dl, it is preferable to use 95 mg/dl as a threshold in order to decrease the rates of macrosomia and large-for-gestational-age infants.
How long should diet therapy be used before the introduction of pharmacological treatment?
As most patients with GDM are diagnosed in the late second or early third trimester, not much time is left for achieving good glycemic control. Failure to initiate a timely introduction of pharmacological therapy may lead to fetal hyperinsulinemia and associated complications. McFarland et al. evaluated the time required to achieve the desired levels of glycemic control with diet alone during a 4-week study period. Seventy percent of the subjects with initial FPG <95 mg/dl achieved targeted levels of glycemia within a 2-week period with no significant improvement thereafter. Shushan et al. evaluated 60 women with GDM who initiated treatment before 34 completed weeks (early group) and 24 women with GDM who initiated treatment after the 34th week (late group) and found that the rates of macrosomic and large-for-gestational-age infants were 5% and 11%, respectively, in the early group as compared to 25% and 29% in the “late” group ( p < 0.05). Therefore, it is advised to initiate pharmacological therapy in cases when glycemic control cannot be achieved solely with diet and exercise therapy for 2 weeks. Pharmacological therapy should be considered earlier if GDM is diagnosed in late gestation.
Can the fetus provide markers for pharmacological initiation?
As the main aim of therapy in gestational diabetes is to prevent fetal complications, it would be beneficial if fetal parameters could be used as markers for initiation of pharmacological therapy. Weiss et al. suggested the use of amniotic fluid insulin at 29 weeks of gestation as a marker for insulin initiation, although others found no advantage over maternal glucose monitoring for the prevention of GDM-related complications. The measurement of the fetal abdominal circumference (AC) (>70–75th percentile) early in the third trimester has also been suggested as a marker for insulin initiation to prevent macrosomia . In a randomized clinical trial of 98 women with GDM with fasting hyperglycemia of 105–120 mg/dl, glucose plus fetal AC measurements identified pregnancies at a low risk of macrosomia and resulted in the avoidance of insulin therapy in 38% of patients without increasing the rates of neonatal morbidity compared to glucose measurement alone . Yet, data regarding the use of fetal parameters for decision making for pharmacological intervention are not well established and further research is needed.
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