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Use of exendins and agonists thereof for the treatment of gestational diabetes mellitus

Use of exendins and agonists thereof for the treatment of gestational diabetes mellitus description/claims

This application is a continuation of co-pending U.S. application Ser. No. 10/342,014, filed on Jan. 13, 2003, which is a continuation Application of U.S. application Ser. No. 09/323,867, filed on Jun. 1, 1999, now U.S. Pat. No. 6,506,724.

A paper copy of the Sequence Listing and a computer readable form of the sequence listing on diskette, containing the file named Seq.txt, which can be found in co-pending U.S. application Ser. No. 10/342,014 and which was created on May 7, 2003, are herein incorporated by reference.

The present invention relates to methods for treating gestational diabetes mellitus comprising administration of an effective amount of an exendin or an exendin agonist alone or in conjunction with other compounds or compositions that affect blood glucose control, such as an insulin or an amylin agonist. Pharmaceutical compositions for use in the methods of the invention are also disclosed.

The following description summarizes information relevant to the present invention. It is not an admission that any of the information provided herein is prior art to the presently claimed invention, nor that any of the publications specifically or implicitly referenced are prior art to that invention.

Gestational Diabetes Mellitus

Gestational diabetes mellitus (“GDM”) is a disorder associated with elevated circulating plasma glucose. Although the diagnostic criteria for GDM have been the subject of controversy for decades, it was defined by the Third Workshop Conference on Gestational Diabetes Mellitus as carbohydrate intolerance of varying severity with onset or first recognition during pregnancy, irrespective of the glycemic status after delivery. Metzger (ed.) Proceedings of the Third International Workshop Conference on Gestational Diabetes Mellitus, Diabetes 40(Suppl. 2), 1991. Despite advances in clinical management of GDM, there are problems associated with GDM which persist, including elevated rate of perinatal morbidity and elevated rate of malformations in newborns. Persson et al., Diabetes and Pregnancy, In International Textbook of Diabetes Mellitus, Second Edition, John Wiley & Sons 1997 (Alberti et al. Eds.). For example, it has been reported that, when the mean blood glucose level is greater than 105 mg/dl, there is a greater risk for the development of large-for-gestational age (“LGA”) infants when compared with a control population. Id. Additional reported consequences of untreated GDM include an increased incidence of macrosomia, respiratory distress syndrome, and other abnormalities of fetal metabolism. Langer, Am. J. Obstet. Gynecol. 176:S186, 1997; American Diabetes Association: Self-Monitoring of Blood Glucose Consensus Statement, Diabetes Care 17:81-82, 1994 (“ABA Consensus Statement”); Coetzee & Jackson, S. Afr. Med. J. 56:467-475, 1979. It has been clearly established by those in the field that tight glycemic control can serve as the primary prevention of fetal disease relating to GDM. Drexel et al., Diabetes Care 11:761-768, 1988; Roversi et al., Diabetes Care 3:489-494, 1980; Langer & Mazze, Am. J. Obstet. Gynecol. 159:1478-1483, 1988; Langer et al., Am. J. Obstet. Gynecol. 161:646-653, 1989). GDM results in a greater incidence of intrauterine death or neonatal mortality. Position Statement American Diabetes Association Gestational Diabetes Mellitus, Diabetes Care 21 (Suppl. 1):S60-61, 1998. GDM pregnancies are at an increased risk for fetal macrosomia and neonatal morbidities including neural tube defects, hypoglycemia, hypocalcemiea, hypomagnsemia, polycythemia and hyperbilirubinemia and subsequent childhood and adolescent obesity. Siccardi, Gestational Diabetes. Other complications to the woman include increased rates of cesarean delivery, hypertensive disorders including preeclamsia and urinary tract infections.

It has been reported that approximately 4% of all pregnancies (135,000 cases annually) are complicated by GDM, however, it has been estimated that the incidence may range from 1% to 14% of all pregnancies, depending on the population and diagnostic tests employed. ADA Consensus Statement, supra.

Normally during pregnancy, fasting plasma levels of insulin gradually increase to reach concentrations that are approximately twice as high in the third trimester as they were outside of pregnancy. Women with gestational diabetes mellitus (“GDM”) have fasting insulin levels comparable to or higher than those of normal pregnant women with the highest levels seen in women with GDM who are obese. Insulin secretion also increases gradually in pregnancy and also reaches a maximum during the third trimester. However, the relative increase in secretion is significantly smaller in women with GDM than in normal glucose tolerant (“NGT”) women. The first-phase insulin response in NGT women is significantly higher than in GDM women; second phase insulin response was similarly increased during pregnancy in both groups. This finding is consistent with the finding that GDM women have a later time of peak insulin concentration during an oral glucose tolerance test than do NGT women. Consistent with this observation, the insulin response per unit of glycemic stimulus is significantly higher in NGT women than in GDM women (90% and 40%, respectively). The fact that glucose tolerance deteriorates in both normal and GDM pregnancies while at the same time, insulin secretion increases indicates a decrease in insulin sensitivity. Comparative results from an intravenous glucose tolerance test and a hyperinsulinemic, euglycemic clamp showed a sensitivity decrease during pregnancy in both groups of 50-60%, but GDM women had a slightly lower sensitivity. In another study using radioactive glucose, turnover of glucose and amino acids in GDM women was comparable to NGT women only when insulin concentrations 3-5 fold higher in the GDM group were used. Thus, it appears that GDM is due to a combination of diminished insulin sensitivity and an impaired ability to increase insulin secretion and has, in fact, many features in common with type 2 diabetes. Normal or near normal glycemic control returns upon parturition.

Clinical Diagnosis

It is common clinical practice to screen women for elevated glucose and glucose intolerance between weeks 24 and 28 of gestation, especially women with any one the following four characteristics: age≧25; race/ethnicity of Hispanic, Native American, Asian, African-American or Pacific Islander origin; obese or a family history of diabetes. In addition, women with previous pregnancies with complications due to a large weight fetus/neonate are usually tested. In some medical centers all pregnant women are tested. Indeed, certain investigators have found that historical risk factors account for only roughly half of the women known to have GDM. Carr, Diabetes Care 21(Suppl. 2):B14-B18, 1998. Additionally, there is some reported evidence that advancing maternal age is associated with increased incidence of GDM. Id.

The clinical diagnosis is generally based on a multi-step process. The evaluation is most typically performed by measuring plasma glucose 1 hour after a 50-gram oral glucose challenge test in either the fasted or the unfasted state. If the value in the glucose challenge test is ≧140 mg/dl, a 3-hr 100 g oral glucose tolerance test is done. If two or more of the following criteria are met, the patient is considered in need of glycemic control: fasted venous plasma≧105 mg/dl, venous plasma≧190 mg/dl at 1 hr, venous plasma≧165 mg/dl at 2 hr or venous plasma≧145 mg/dl at 3 hr. Williams et al., Diabetes Care 22: 418-421, 1999. Variations of this test are also used by some. See, e.g., Coustan, Gestational Diabetes In Diabetes in America, 2d ed. National Institutes of Health Publication No. 95-1468, 1995.

Current Clinical Therapy

The current therapeutic approach for GDM is to control plasma glucose for the remainder of the gestation (i.e., the third trimester through parturition). GDM has many features in common with type 2 diabetes. The endocrine (impaired insulin secretion) and metabolic (insulin resistance) abnormalities that characterize both forms of diabetes are similar. In general, pregnancy is characterized by increases in both insulin resistance and insulin secretion. Women with GDM fail to respond with increased insulin to the decrease in insulin sensitivity.

A significant correlation has been shown to exist between late-stage gestational maternal glucose levels and preeclamsia, macrosomia, Cesarean section delivery and phototherapy for hyperbilirubinemia. Sermer et al., Diabetic Care 21 (Suppl. 2):B33-B42, 1998. It has also been determined that the length of hospitalization of the new mother and the length of time the neonate spent in the nursery could be correlated to the degree of elevation of plasma glucose in the pregnant woman. Id. Tallarigo, et al. reported a striking rise in the risk of fetal macrosomia (9.9 vs. 27.5%) and preeclamsia/Cesarean sections (19.9 vs. 40.0%) in women with abnormal glucose tolerance when compared to NGT women. Tallarigo et al., N. Engl. J. Med. 315:989-992, 1986.

Thus, the goals for therapy of GDM are to achieve and maintain as near normal glycemia as feasible with a special emphasis to keep postprandial glucose concentrations within the normal range. Optimal therapeutic strategies are safe and efficacious in achieving a metabolic balancing without creating complications, which may include ketosis and/or hypoglycemia. Jovanovic, Diabetes Care 21(Suppl. 2):B131-B137, 1998. The initial therapeutic approach is through diet. Jovanovic-Peterson & Peterson, J. Am. Coll. Nutr. 9:320-325, 1990.

If diet or diet and exercise are not effective (i.e., failure is fasting glucose≧105 mg/dl and/or a 2-hr postprandial plasma glucose of ≧120 mg/dl on 2 or more occasions within a 1- to 2-week period), then insulin therapy (preferably, human insulin) is considered appropriate. ADA Position Statement, supra.

Oral glucose-lowering agents are not recommended during pregnancy. Kuhl et al., Diabetic Care 21 (Suppl. 2): B19-B26, 1998. Although sulfonylureas are used in the treatment of type 2 diabetes due to their activity in increasing insulin sensitivity, these agents are contraindicated for use in GDM. Jovanovic, Diabetes Care 21 (Suppl. 2):B131-B137, 1998. See also Kahn & Shechter, Insulin, Oral Hypoglycemic Agents, and the Pharmacology of the Endocrine Pancreas, In Goodman & Gilman's The Pharmacological Basis of Therapeutics (8th ed. 1993 Goodman Gilman et al. eds.). Oral hypoglycemic drugs traverse the placenta, and may cause prolonged severe hypoglycemia in the newborn. Persson et al., supra.

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