WO2003011273A1 - Metformin in the treatment of hyperglycemic conditions - Google Patents

Abstract

Administering a therapeutically effective dose of antiglycemic antidiabetic agent relieves symptoms of impaired glucose tolerance (IGT), or inhibits an onset of type II diabetes in subjects having increased risks of developing type II diabetes. The antidiabetic agent is administered to the subject for a period sufficient to alleviate IGT or inhibit the onset ot type II diabetes. A particular example of a useful antihyperglycemic antidiabetic agent is a biguanide anitdiabetic agent, such as metformin. A substantial risk for developing type II diabetes may be identified in subjects demonstrating one or more diabetes risk factors, such as having IGT or a body mass index (BMI) greater than about 25kg/m2, or in subjects having particular physiological conditions associated with diabetes or IGT. Subjects within a particular demographic group, such as subjects aged about 45 years or less or subjects of particular ethnic backgrounds, also may be selected for treatment.

Description

METFORMIN IN THE TREATMENT OF HYPERGLYCEMIC CONDITIONS

RELATED CASES

This application claims the benefit of pending U.S. Provisional Patent

Application 60/309,194, filed July 31, 2001, which is incorporated herein in its entirety.

FIELD The methods provided relate to treating metabolic disorders, including treating a pre-diabetic condition to inhibit or delay the onset of diabetes.

BACKGROUND

Diabetes is linked to over 200,000 deaths annually and diabetes-related health care costs total over $100 billion per year. Type II (non-insulin dependent) diabetes is one classification of diabetes mellitus, the other two being type I (insulin-dependent) diabetes and gestational diabetes. Type II diabetes, which occurs in 90 to 95% of all diabetics, arises when the body does not respond to or cannot use its own insulin. Type II diabetes affects more than 8% of people in the United States, contributing to kidney and heart disease, vision problems, hypertension, and neurological disease.

Various treatments for type II diabetes exist, including drug therapies such as antihyperglycemic therapies based on biguanide antidiabetic drugs. Metformin, the only currently commercially available biguanide antidiabetic drug, has been available throughout Eurorpe for over 40 years. This drug gained approval from the United States Food and Drug Administration (FDA) in 1995 and is marketed under the name Glucophage^® (Bristol-Myers Squibb Company, Princeton, NJ). Various pharmaceutical compositions containing metformin, such as time-release tablets or combination-therapy formulations, have been disclosed. For example, see WO 00/28989, WO 01/26639, and WO 01/32157. Impaired glucose tolerance (IGT), previously known as "borderline" or

"chemical" diabetes, is related to diabetes and affects about 11% of people aged 20 to 74 in the United States. The pathogenesis of IGT is controversial, especially the question of whether insulin resistance or insulin deficiency is the predominant cause of IGT. However, studies have shown that approximately 10% of persons with IGT convert to type II diabetes annually. Very few studies have investigated the link between IGT and type II diabetes and addressed the question of how IGT can (or should) be treated to delay onset of type II diabetes.

One study of a small group of Chinese factory workers reported that administration of metformin to individuals having IGT reduced the rate of conversion from IGT to type II diabetes. Li, et al., Diabetic Medicine, 16:477-81 (1999). The Li study involved 70 subjects, aged 30-60 years old, randomized under double-blind conditions into two groups: one group of 33 individuals received metformin at a dosage of 250 milligrams (mg) three times daily, and 37 individuals received a placebo. These individuals were identified as having IGT using older, less accurate criteria for diagnosis developed by the World Health Organization (WHO). In fact, under the newer American Diabetes Association (ADA) criteria, over half of the subjects studied would be classified as diabetic, not IGT.

SUMMARY OF THE DISCLOSURE

Administering a therapeutically effective dose of an antihyperglycemic antidiabetic agent inhibits an onset of type II diabetes in a subject with an increased risk of developing type II diabetes who has not yet developed the disease. Once a subject is selected, the therapeutically effective dose of the antidiabetic agent is administered to the subject for a period of time sufficient to delay or inhibit the onset of type II diabetes in the subject. An antihyperglycemic antidiabetic agent also may be used to treat impaired glucose tolerance (IGT) in those subjects with this condition.

Antihyperglycemic antidiabetic agents include biguanide antidiabetic agents of the formula:

Formula 1 wherein R_t and R₂ are independently selected from alkyl, lower alkyl, alkenyl, lower alkenyl, cycloalkyl, aryl, or an arylalkyl of the formula:

wherein X is hydrogen or halogen and n = 0, 1 or 2; R₃ and P^ are independently selected from hydrogen, alkyl, lower alkyl, alkenyl, lower alkenyl, cycloalkyl, alkoxy, lower alkoxy, alkoxyalkyl; and pharmaceutically acceptable salts thereof. In particular embodiments, the biguanide antidiabetic agent is metformin.

An increased or substantial risk for developing type II diabetes may be identified in subjects demonstrating one or more diabetes risk factors, such as having impaired glucose tolerance (IGT) or a body mass index (BMI) greater than about 24 kg/m², or in subjects having particular physiological conditions associated with diabetes or IGT, such as hyperinsulemia, hypertriglyceridemia, or a raised hemoglobinAι_c concentration. Subjects within a particular demographic group, such as subjects aged about 45 years or less, or subjects of particular ethnic backgrounds, such as blacks and or Asians, also may be selected based on observed differential treatment effects or an increased risk of developing type II diabetes.

Administration of the therapeutically effective amount of the antidiabetic agent may vary by dosage regimen, periodicity, and duration, so long as the therapeutic effect is observed. The exact amount of antidiabetic agent administered may depend on the antidiabetic agent being used, the characteristics of the subject being treated, the severity and type of the affliction, and the manner of administration, though the therapeutically effective dose can be determined by various methods. In some embodiments, the antidiabetic agent is administered in amounts of at least about 1000 mg per day, such as at least about 1500 mg per day, or even at least about 1700 mg per day, in single or divided doses. In alternative embodiments, the antidiabetic agent is administered in amounts of about 500 mg or less per day. In particular embodiments, the total amount of agent is divided into smaller doses, such as two or three doses per day, for example 850 mg twice a day (b.i.d.) or 500 mg three times a day (t.i.d.). Additionally, the agent may be carried in a pharmaceutically acceptable carrier and administered by any means that achieve its intended purpose. In some embodiments, the antidiabetic agent is orally administered as a pill.

Administration of the antidiabetic agent may be supplemented by inducing the subject to modify certain lifestyle aspects — such as diet and exercise — to enhance the overall effect of the antidiabetic agent.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph illustrating the cumulative incidence (expressed as a percentage of the population) of diabetes over time in the three treatment groups of the Diabetes Prevention Program (DPP).

FIG. 2 is a graph illustrating the cumulative incidence (expressed as a percentage of the population) of elevated fasting plasma glucose (FPG) levels over time in the three treatment groups of the DPP.

FIG. 3 is a graph illustrating the cumulative incidence (expressed as a percentage of the population) of elevated hemoglobinAι_c (HbAlc) levels over time in the three treatment groups of the DPP. FIG. 4 is a bar graph illustrating a change in average weight for participants in the DPP ananged by treatment group.

FIG. 5 is a bar graph illustrating a change in average weight for participants in the DPP ananged by years from randomization into one of the three treatment groups.

FIG. 6 is a bar graph illustrating a change in average weight for participants in the DPP ananged by months from randomization into one of the three treatment groups. FIG. 7 is a bar graph illustrating a change in average FPG for participants in the DPP ananged by treatment group.

FIG. 8 is a bar graph illustrating a change in average FPG for participants in the DPP ananged by years from randomization into one of the three treatment groups. FIG. 9 is a bar graph illustrating a change in average FPG for participants in the

DPP ananged by months from randomization into one of the three treatment groups.

FIG. 10 is a bar graph illustrating a change in average HbAlc concentration for participants in the DPP ananged by treatment group.

FIG. 11 is a bar graph illustrating a change in average HbAlc concentration for participants in the DPP ananged by years from randomization into one of the three treatment groups.

FIG. 12 is a bar graph illustrating a change in average HbAlc concentration for participants in the DPP ananged by months from randomization into one of the three treatment groups. FIG. 13 is a graph illustrating the population of participants in the DPP, ananged by treatment group, distributed according to density of overall weight change.

FIG. 14 is a graph illustrating the population of participants in the DPP, ananged by treatment group, distributed according to density of overall FPG change. FIG. 15 is a graph illustrating the population of participants in the DPP, ananged by treatment group, distributed according to density of overall HbAlc change. In each of these figures, the three treatment groups of the DPP are indicated by "lifestyle" (for those participants receiving instructions on intensive antidiabetic lifestyle modifications), "metformin" (for those participants receiving the metformin), and "placebo" (for those participants receiving a placebo).

DETAILED DESCRIPTION Disclosed is a method for treating impaired glucose tolerance (IGT), or for inhibiting onset of type II diabetes in a subject that does not yet have type II diabetes. A subject with IGT or a substantial risk of developing type II diabetes is selected, and a therapeutically effective dose of a antidiabetic agent, such as an antihyperglycemic antidiabetic agent, is administered to the subject for a period of time sufficient to alleviate the IGT or inhibit the onset of type II diabetes.

Abbreviations ADA = American Diabetes Association

BMI = body mass index DPP = Diabetes Prevention Program FPG = fasting plasma glucose IGT = impaired glucose tolerance OGTT = oral glucose tolerance test

Explanations of Terms

The following explanations of terms are provided to better illustrate certain features of the invention. Chemistry terms herein are used according to conventional usage in the art, as exemplified by The McGraw-Hill Dictionary of Chemical Terms (1985) and The Condensed Chemical Dictionary (1981).

As used herein, the singular forms "a," "an," and "the," refer to both the singular as well as plural, unless the context clearly indicates otherwise. For example, the term "an agent" includes single or plural agents and can be considered equivalent to the phrase "at least one agent."

Alkyl. The term "alkyl" refers to a cyclic, branched, or straight chain alkyl group containing only carbon and hydrogen, which, unless otherwise described, contains 1 to 12 carbon atoms. This term is further exemplified by groups such as methyl, ethyl, n-propyl, isobutyl, t-butyl, pentyl, pivalyl, heptyl, adamantyl, and cyclopentyl. Alkyl groups can be unsubstituted or substituted with one or more substituents, for example halogen, alkyl, alkoxy, alkylthio, trifluoromethyl, acyloxy, hydroxy, mercapto, carboxy, aryloxy, aryloxy, aryl, arylalkyl, heteroaryl, amino, alkylamino, dialkylamino, morpholino, piperidino, pyrrolidin-1-yl, piperazin-1-yl, or other functionality. A "lower alkyl" refers to a cyclic, branched or straight chain monovalent alkyl radical of 1 to 10 carbon atoms, for example 1 to 6 carbon atoms. This term is further exemplified by such radicals as methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i- butyl (or 2- methylpropyl), sec-butyl, n-pentyl, cyclopropylmethyl, i-amyl, n-amyl, n- pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl. Lower alkyl groups can be unsubstituted or substituted. One specific example of a substituted alkyl is 1,1 -dimethyl propyl.

A "cycloalkyl" is a cyclic alkyl.

Alkenyl. The term "alkenyl" refers to a cyclic, branched, or straight chain alkenyl group having 2 to 12 carbon atoms and also having at least one carbon-carbon double bond. This term is further exemplified by groups such as ethylene, n-propylene, isobutylene, t-butylene, pentylene, pivalylene, heptylene, adamantylene, and cyclopentylene. Alkenyl groups can be unsubstituted or substituted with one or more substituents, for example halogen, alkyl, alkoxy, alkylthio, trifluoromethyl, acyloxy, hydroxy, mercapto, carboxy, aryloxy, aryloxy, aryl, arylalkyl, heteroaryl, amino, alkylamino, dialkylamino, morpholino, piperidino, pyrrolidin-1-yl, piperazin-1-yl, or other functionality.

The term "lower alkenyl" refers to a cyclic, branched, or straight chain alkyl radical containing 2 to 10 carbon atoms, such as 2 to 6 carbon atoms, and also having at least one carbon-carbon double bond including, but not limited to: vinyl, 2-propenyl, 2- methyl-2-propenyl, 3-butenyl, 4-pentenyl, and 5-hexenyl.

A "cycloalkenyl" is a cyclic alkenyl.

Animal. A living multicellular vertebrate organism, including mammals, fish, and birds. A "mammal" includes both human and non-human mammals. Antidiabetic agent. A chemical or pharmaceutical antihyperglycemic agent or drug capable of treating type II diabetes, or alleviating the symptoms associated with type II diabetes. Antidiabetic agents are generally categorized into six classes: biguanides; thiazolidinediones; sulfonylureas; inhibitors of carbohydrate absorption; fatty acid oxidase inhibitors and anti-lipolytic drugs; and weight-loss agents. The antidiabetic agents include those agents disclosed in Diabetes Care, 22(4):623-34, herein incorporated by reference. One common class of antidiabetic agents is the sulfonylureas, which are believed to increase secretion of insulin, decrease hepatic glucogenesis, and increase insulin receptor sensitivity.

Another class of antidiabetic agents is the biguanide antihyperglycemics, which decrease hepatic glucose production and intestinal absorption, and increase peripheral glucose uptake and utilization, without inducing hyperinsulinemia.

The biguanide antidiabetic agents include compounds defined by the chemical formula of Formula 1 (see below), such as the biguanides disclosed in U.S. Pat. Nos. 3,960,949; 4,017,539; and 6,011,049, herein incorporated by reference. One specific, non-limiting example of a biguanide antidiabetic agent is metformin.

Antidiabetic lifestyle modifications. Changes to lifestyle, habits, and practices intended to alleviate the symptoms of diabetes or IGT. Obesity and sedentary lifestyle may both independently increase the risk of a subject developing type II diabetes, so antidiabetic lifestyle modifications include those changes that will lead to a reduction in a subject's BMI, increase physical activity, or both. Specific, non-limiting examples include the lifestyle interventions of the DPP described in Diabetes Care, 22(4):623-34 at pages 626-27, herein incorporated by reference.

Aryl. The term "aryl" refers to a monovalent unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl, benzyl) or multiple condensed rings (e.g., naphthyl or anthryl), which can optionally be unsubstituted or substituted with, for example, halogen, alkyl, alkoxy, mercapto (-SH), alkylthio, trifluoromethyl, acyloxy, hydroxy, carboxy, aryloxy, aryl, arylalkyl, heteroaryl, amino, alkylamino, dialkylamino, morpholino, piperidino, pynolidin-1-yl, piperazin-1-yl, or other functionality.

Body mass index (BMI). A measurement of the relative percentages of fat and muscle mass in the human body, in which weight in kilograms is divided by the square of height in meters and the result used as an index of obesity.

Diabetes mellitus. A disease caused by a relative or absolute lack of insulin leading to uncontrolled carbohydrate metabolism, commonly simplified to "diabetes," though diabetes mellitus should not be confused with diabetes insipidus. As used herein, "diabetes" refers to diabetes mellitus, unless otherwise indicated. Type I diabetes (sometimes refened to as "insulin dependent diabetes" or "juvenile onset diabetes") leads to a total or near total lack of insulin and may be associated with an autoimmune response to pancreatic cells. In type II diabetes (sometimes refened to as "non-insulin dependent diabetes" or "adult onset diabetes"), the body does not respond to insulin, though it is present. Symptoms of diabetes include: excessive thirst (polydipsia); frequent urination (polyuria); extreme hunger or constant eating (polyphagia); unexplained weight loss; presence of glucose in the urine (glycosuria); tiredness or fatigue; changes in vision; numbness or tingling in the extremities (hands, feet); slow-healing wounds or sores; and abnormally high frequency of infection. Diabetes may be clinically diagnosed by a fasting plasma glucose (FPG) concentration of greater than or equal to 7.0 mmol/L (126 mg/dL), or a plasma glucose concentration of greater than or equal to 11.1 mmol/L (200 mg/dL) at about two hours after an oral glucose tolerance test (OGTT) with a 75 g load. A more detailed description of diabetes may be found in Cecil Textbook of Medicine, J.B. Wyngaarden, et al., eds. (W.B. Saunders Co., Philadelphia, 1992, 19^th ed.).

A subject exhibiting one or more of the following risk factors is considered to have a heightened or substantial risk of developing type II diabetes:

1. Obesity, such as a BMI greater than or equal to about 30 kg/m²;

2. Elevated fasting blood glucose levels; 3. Impaired glucose tolerance (IGT);

4. Non-caucasian ethnicity;

5. Hyperinsulinemia;

6. Hypertriglyceridemia;

7. Family history of diabetes; 8. History of gestational diabetes;

9. Sedentary lifestyle;

10. In humans, middle age or elderly status (i.e., 40 years old and older). Ethnicity. For human subjects, ethnicity describes the racial group to which the subject is tied or from which the subject is descended, such as the ethnic identification categories commonly used in a population census. Non-limiting examples of ethnic groups include blacks, who are persons of African ethnicity, such as African- Americans and Afro-Europeans; Asians; Native Americans; Hispanics (including Latinos); and Caucasians (whites). However, because ethnicity is based on race, ethnicity is not considered equivalent to national origin. For example, Afrikaaners are considered to belong to the Caucasian ethnic group because they descended from Northern

Europeans, while Haitian blacks are considered members of the African ethnic group because they are descended from African blacks. Ethnicity may be identified by ancestry, physical, or genetic characteristics (e.g., skin and hair pigmentation, facial characteristics, allelic frequencies possessed by the group, etc.). Fasting plasma glucose (FPG) test. A diagnostic test for diabetes. The blood glucose concentration or level of a subject is analyzed in a blood sample obtained from a subject after the subject has fasted overnight or undergone a fast of at least 8 hours. A diabetic subject will often show a heightened blood glucose level, compared to a non- diabetic subject. Halogen. Refers to the elements fluourine, bromine, chlorine, and iodine, and the term "halo" refers to fluoro, bromo, chloro and iodo substituents.

Hyperglycemia. Too high a level of glucose (sugar) in the blood, and an indicator of diabetes. Hyperglycemia occurs when the body either lacks sufficient insulin or cannot use available insulin to metabolize glucose. Symptoms of hyperglycemia include a great thirst, a dry mouth, and frequent urination.

Hyperinsulemia. A physiological disorder in which a subject's body produces more insulin than metabolically needed.

Hypertriglyceridemia. A physiological disorder in which a subject's body produces more triglycerides than metabolically needed. Impaired glucose tolerance (IGT). Formerly known as "chemical diabetes" or

"borderline diabetes," IGT is identified by a higher than normal blood glucose level (hyperglycemia) that is not high enough to be classified as diabetes. IGT may be clinically diagnosed according to the American Diabetes Association (ADA) criteria adopted in June 1997: a fasting plasma glucose (FPG) concentration of less than about 7.0 millimole per liter (mmol/L) (126 mg/dL), and a plasma glucose concentration of about 7.77 to 11.04 mmol/L (140-199 mg/dL) about two hours after a 75 g OGTT. Diabetes Care, 20(7): 1183-97 (1997). These ADA criteria are similar to the World Health Organization (WHO) criteria adopted in 1985: FPG concentration less than 7.8 mmol/L (140 mg/dL), and a plasma glucose concentration of about 7.77 to 11.04 mmol/L (140-199 mg/dL) 2 h post 75 g OGTT. Diabetes Medicine, 15:539-54 (1998). Oral glucose tolerance test (OGTT). A diagnostic test for diabetes. After fasting overnight, a subject is provided a concentrated sugar solution, usually containing 50 to 100 g of glucose, to drink. The subject's blood is sampled periodically over the next few to several hours to test blood glucose levels over time. In a non-diabetic subject, blood glucose concentration shows a slight upward shift and returns to normal within 2-3 hours. In a diabetic subject, blood glucose concentration is generally higher than normal after fasting, rises more after the subject drinks the glucose solution, and may take several hours to return to normal.

Pharmaceutical agent. A "pharmaceutical agent," "pharmaceutical composition," or "drug" refers to a chemical compound or composition capable of inducing a desired therapeutic (including a prophylactic effect) when properly administered to a subject. The pharmaceutically acceptable salts of the compounds of this invention include, but are not limited to, those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N- benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide. These salts may be prepared by standard procedures, for example by reacting the free acid with a suitable organic or inorganic base. Any chemical compound recited in this specification may alternatively be administered as a pharmaceutically acceptable salt thereof. This term refers to pharmaceutical agents, pharmaceutical compositions, and drugs acceptable for both human and veterinary uses.

Subject. Includes both human and veterinary subjects, for example mammals, such as humans. Therapeutic agent. A substance that demonstrates some therapeutic effect by restoring or maintaining health, such as by alleviating the symptoms associated with a disease or physiological disorder, or delaying (including preventing) progression or onset of a disease. In some instances, the therapeutic agent is a chemical or pharmaceutical agent, or a prodrug. A therapeutic agent may be an antidiabetic agent — which includes an antihyperglycemic agent, such as an agent capable of regulating insulin levels or glucose tolerance. As one non-limiting example, the antidiabetic agent is a biguanide antidiabetic agent suitable for administration to humans.

A "therapeutically effective amount" or "therapeutically effective dose" is that amount or dose sufficient to inhibit or prevent onset or advancement, or to cause regression, of a disease. The therapeutically effective amount or dose also can be considered as that amount or dose capable of relieving symptoms caused by the disease. Thus, a therapeutically effective amount or dose of an antidiabetic agent is that amount or dose sufficient to achieve a stated therapeutic effect. As one specific, non-limiting example, a therapeutically effective amount of an antidiabetic agent is an amount that reduces the signs of, symptoms of, or laboratory findings associated with IGT; delays the progression of IGT to diabetes; or lowers FPG or 2-h OGTT plasma glucose levels.

Antidiabetic Agents An antihyperglycemic antidiabetic agent may be used to inhibit or delay the onset or progression of type II diabetes. In some embodiments, the antidiabetic agent contains a biguanide of the formula:

Formula 1 wherein Ri and R₂ are independently selected from alkyl, lower alkyl, alkenyl, lower alkenyl, cycloalkyl, aryl, or an arylalkyl of the formula:

wherein X is hydrogen or halogen and n = 0, 1 or 2; R₃ and R₄ are independently selected from hydrogen, alkyl, lower alkyl, alkenyl, lower alkenyl, cycloalkyl, alkoxy, lower alkoxy, alkoxyaUcyl; and pharmaceutically acceptable salts thereof. In particular embodiments, the biguanide antidiabetic agent is metformin. Metformin is manufactured by Lyonnaise Industrielle Pharmaceutique SA (Lyons, France), also known by its acronym LIPHA S A, and commercially distributed in the United States as a hydrochloride salt by the Bristol-Myers Squibb Company (Princeton, New Jersey) as GLUCOPHAGE^® XR. Additionally, Bristol-Myers Squibb distributes a pharmaceutical having a combination of metformin and glyburide as GLUCO VANCE^®.

Antidiabetic agents other than biguanides may be used. For example, in alternative embodiments, the antidiabetic agent is a thiazolidinedione, such as troglitazone.

Selecting a Subject

A subject that does not have type II diabetes, but does have an increased or substantial risk for developing type II diabetes, is selected. In some embodiments, the subject has impaired glucose tolerance (IGT). In other embodiments, the subject has been identified with some other diabetes risk factor, such as having a body mass index (BMI) greater than or equal to 24 kg/m , for example a BMI greater than or equal to 30 kg/m . In still other embodiments, a subject having a particular physiological condition associated with diabetes or IGT — such as hyperinsulemia, hypertriglyceridemia, raised hemoglobinAi_c concentration, an age greater than 40, non-caucasian ethnicity, previous history of gestational diabetes, or family history of diabetes — is selected.

The efficacy of a particular antidiabetic agent in delaying or preventing development of type II diabetes may be influenced by the age of the subject. Therefore, in some embodiments, subjects within a particular age range are selected, such as subjects aged about 45 years or less, or subjects aged about 25 to about 45 years old. As one specific, non-limiting example, metformin has been shown to be more effective in inhibiting or delaying the onset of diabetes in humans aged about 45 years or less (see Example 2).

The effectiveness of a particular antidiabetic agent also may be influenced by genetic or physiological attributes. As one specific, non-limiting example, metformin may be used to treat IGT, or inhibit or delay the onset of diabetes, in specific ethnic sub-populations, such as Caucasians, blacks, Hispanics, American Indians, or Asians, for example in black or Asian persons.

Administering an Antidiabetic Agent

A therapeutically effective amount of an antidiabetic agent may be administered in a single dose, or in several doses, for example daily, during a course of treatment. The course of treatment may last for any length of time, such as a day or several days, a week or several weeks, a month or several months, or a year or several years, so long as the therapeutic effect is observed, such as inhibiting the onset of type II diabetes in a subject diagnosed with IGT, or inducing a subject diagnosed with IGT to revert to a normal glucose tolerance. The therapeutically effective amount will depend on the antidiabetic agent being used, the characteristics of the subject being treated (e.g., age, BMI, physiological condition, etc.), the severity and type of the affliction, and the manner of administration of the agent. The therapeutically effective dose can be determined by various methods, including generating an empirical dose-response curve, predicting potency and efficacy by using quantitative structure activity relationships (QSAR) methods or molecular modeling, and other methods used in the pharmaceutical sciences. In certain, non- limiting examples, the therapeutically effective amount of metformin (or a related biguanide analog or homolog) is at least about 1000 mg per day, such as at least about 1500 mg per day, or even at least about 1700 mg per day. In certain other, non-limiting examples, the total amount of metformin is divided into smaller doses, such as two or three doses per day, for example 850 mg twice a day (b.i.d.) or 500 mg three times a day (t.i.d.). In alternative, non- limiting examples, the total amount of metformin is about 500 mg or less per day.

For administration to animals, purified therapeutically active agents are generally combined with a pharmaceutically acceptable carrier. Pharmaceutical preparations may contain only one type of antidiabetic agent, or may be composed of a combination of several types of antidiabetic agents, such as a combination of two or more antidiabetic agents.

In general, the nature of the carrier will depend on the particular mode of administration being employed. For instance, parenteral formulations usually comprise injectable fluids that include pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle. For solid compositions (e.g., powder, pill, tablet, or capsule forms), conventional non-toxic solid carriers can include, for example, pharmaceutical grades of mannitol, lactose, starch, or magnesium stearate. In addition to biologically- neutral carriers, pharmaceutical compositions to be administered can contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like, for example sodium acetate or sorbitan monolaurate. Antidiabetic agents may be administered by any means that achieve their intended purpose. For example, the antidiabetic agents may be administered to a subject through systemic administration, such as intravenous or intraperitoneal administration; intralesionally; by suppository; or orally.

The antidiabetic agent may be administered alone or in combination with another antidiabetic agent. In certain embodiments, the antidiabetic agent is administered in the absence of administering any other antidiabetic agent.

In addition to administering an antidiabetic agent, other measures may be taken to inhibit or delay the onset of type II diabetes in subjects at a heightened risk of developing the disease. For example, in some embodiments, a subject may be instructed, trained, or induced to adopt antidiabetic lifestyle modifications. EXAMPLES

Example 1 The Diabetes Prevention Program

The Diabetes Prevention Program (DPP) is a 27-center randomized clinical trial with 3,234 participants designed to evaluate the safety and efficacy of interventions that may delay or prevent the development of diabetes in people at increased risk for type II diabetes. The DPP is described in Diabetes Care, 22(4):623-34 (1999) and Diabetes Care, 23(13):1619-29 (2000), both articles herein incorporated by reference.

Additionally, the Protocol for the Diabetes Prevention Program (Protocol) Version 4.1 (July 20, 2001), describing the study design, enrollment of participants, participant management protocols, adverse event reporting, data processing, statistical considerations, study administration, and schedule of procedures is herein incorporated by reference. The Protocol is available from the DPP Coordinating Center, George Washington University Biostatistics Center, 6110 Executive Blvd., Suite 750, Rockville, Maryland, 20852, U.S.A. More recent versions of the Protocol are available on the DPP Study Documents Web Site www.bsc.gwu.edu/dpp/protocol.htmlvdoc.

Example 2

Metformin Reduces the Risk of Developing Diabetes

Data obtained from the DPP (see Example 1) demonstrates that administration of metformin inhibits or delays onset of type II diabetes in person at increased risk of developing this disease.

Participants

Eligibility criteria for participation in the DPP included age > 25 years; body mass index > 24 kg/m²; FPG level of 5.27 to 6.94 mmol/L (95-125 mg/dl); and OGTT plasma glucose level of 7.77 to 11.04 mmol/L (140-199 mg/dl) at 2 hours after a 75 g glucose load. These plasma glucose levels were elevated, but not diagnostic of diabetes according to the 1997 American Diabetes Association criteria. Diabetes Care, 20(7): 1183-97 (1997). A national recruitment goal was for half the participants to be from minority racial-ethnic groups. At enrollment, participants could not take medicines known to alter glucose tolerance, such as systemic glucocorticoids, thiazide diuretics, or beta-adrenergic blocking agents, and they had no illnesses that could seriously limit lifespan or ability to participate in the interventions. A 4-step recruitment process included a 3 -week run-in or practice period prior to randomization. Diabetes Care, 22(4):623-34 (1999); Diabetes Care, 23(13): 1619-29 (2000).

Interventions

After giving written informed consent, eligible participants were randomized with equal probabilities to one of three interventions:

(1) standard lifestyle intervention recommendations plus active metformin 850 g twice daily; (2) standard lifestyle intervention recommendations plus placebo, indistinguishable from active metformin, twice daily; or

(3) intensive lifestyle intervention recommendations without medication. The early part of the study included a fourth treatment arm — standard lifestyle recommendations plus troglitazone — that was later discontinued. All participants, regardless of treatment assignment, received standard lifestyle intervention recommendations, consisting of written information and a 20-30 minute individual session with a case manager addressing the importance of a healthy lifestyle for the prevention of type II diabetes. Participants in the medication arms of the study were encouraged to follow the Food Pyramid guidelines (On Your Way to Fitness, C. Everett Koop Foundation (1995)); to consume the equivalent of a National Cholesterol

Education Program Step 1 diet (see, e.g., Am J Med., 21;90(2A):32S-35S (1991); to lose 5-10% of their initial weight through a combination of diet and exercise; to increase their activity gradually with a goal of adding at least 30 minutes of an activity, such as walking, five days each week; and to avoid smoking and excessive alcohol intake. These recommendations were reviewed annually. The goals of the intensive lifestyle intervention were similar to those of the standard lifestyle intervention, but the implementation was much more intensive. The goals were to: (a) achieve and maintain a weight reduction of at least 7% of initial body weight through healthy eating and physical activity, and (b) increase the level of physical activity by at least 150 minutes per week (equivalent to approximately 700 kcal/week) through moderate intensity activity, such as walking. A structured 16-lesson program, conducted during the first 24 weeks after randomization, was designed to achieve these goals. The program included training in diet, exercise, and behavior modification skills; interventions that were flexible, sensitive to cultural differences, and acceptable in the specific communities in which they were implemented; a combination of individual and group intervention; and emphasis on self-esteem, empowerment, and social support. Frequent, usually monthly, visits with lifestyle case managers reinforced the behavior changes.

Metformin and its conesponding placebo were started at 850 mg once daily and increased to 850 mg twice daily. The dosage was adjusted if necessary because of gastrointestinal symptoms. Adherence was assessed by pill counts and a structured interview.

Outcome measures. The primary outcome was the development of diabetes diagnosed with an annual OGTT or semi-annual FPG measurement using the 1997 criteria of the American Diabetes Association: FPG > 7.0 mmol L (> 126 mg/dl) or an OGTT plasma glucose level > 11.1 mmol/L (> 200 mg/dl) at 2 hours after a 75 g glucose load. Additionally, an FPG was administered if a participant showed symptoms suggesting diabetes. An initial diagnosis of diabetes required confirmation by the same criteria within 6 weeks.

When diabetes was confirmed, the participants and their physicians were informed, glucose tolerance tests were discontinued, but measurement of FPG was continued every 6 months and HbA]_C was measured annually. As long as the FPG was < 7.77 mmol L (<140 mg/dl), the participant was asked to continue the assigned study treatment, supplemented with self-monitoring of blood glucose. If FPG was > 7.77 mmol/L (> 140 mg/dl) when diabetes diagnosis was confirmed, or anytime thereafter, study medication was discontinued and the participant was refened to her personal physician for treatment. Secondary metabolic outcomes, defined a priori (Diabetes Care, 22(4):623-34

(1999)), included development of fasting hyperglycemia at a level > 140 mg/dl as well as measures of lipid level, raised hemoglobinA_lc concentration, artherosclerotic risk factors, and quality of life issues. The primary outcome was defined as diabetes regardless of type; i.e., based only on glycemic criteria. Although autoimmunity and diabetes susceptibility genes have not been evaluated in this study, on clinical grounds the vast majority of subjects who developed diabetes had type 2 diabetes.

Most baseline and outcome laboratory measurements, including plasma glucose, were performed centrally. Results were masked to participants and investigators unless they exceeded action values specified by protocol, in which case participants and investigators were informed and refenals for treatment were made.

Statistical methods and study administration.

Randomization of individuals to treatment groups followed a standard urn biased-coin design, stratified by clinical center. Controlled Clinical Trials, 9:345-64 (1988). Clinic personnel were masked to the allocation sequence and, after obtaining informed consent and entering eligibility variables, received randomization assignments from the coordinating center via computer. Analyses employed an "intent-to-treat" approach (Statistics in Medicine, 15:1185-95 (1993)), in which all subjects were included in their original randomly assigned groups, regardless of adherence to treatment regimen.

Three pair-wise comparisons among treatment groups were conducted. The overall Type I enor was set at α = 0.05 with a Bonfenoni adjustment (R. G. Miller, Simultaneous Statistical Inference (Springer- Verlag, New York, 1981)), requiring p < 0.0167 for significance of the pair-wise comparisons among treatment groups. Nominal (unadjusted) p-values are presented for all analyses. The study was designed to have 90% power to detect a 33% reduction in the hazard rate for diabetes for each pair- wise comparison, assuming a control group hazard rate of 6.5 per 100 person-years and a loss-to-follow-up rate of 10% per year.

Time to outcome events was assessed by life-table methods. Separate modified product-limit life-table estimated cumulative incidence curves were calculated for the three treatment groups, and the groups were compared using a log-rank test (J. M. Lachin, Biostatistical Methods: The Assessment of Relative Risks (John Wiley and Sons, New York, 2000). The estimated cumulative incidence at three years, and the Greenwood estimate of the standard error, were employed to compute the number needed to treat to prevent one case of confirmed diabetes within three years (Lachin, 2000). A proportional hazards regression model was used to evaluate effects of covariates. Homogeneity of treatment group differences over strata was assessed by a likelihood ratio test of a fully stratified model versus the non-stratified model.

A normal enors fixed effect model fit by maximum likelihood was employed to conduct analyses of longitudinal quantitative measures over time, assuming either an autoregressive or compound symmetry covariance structure as appropriate, but using the empirical information sandwich estimates for tests and confidence intervals (P. J. Diggle, et al., Analysis of Longitudinal Data (Oxford University Press, New York, 1994). Models included a group-by-time interaction when significant. Interim analyses, reported to the external Data Monitoring Board, used group-sequential methods applied to the primary outcome comparison to control the Type I enor of the study under repeated looks. An alpha-spending function (Biometrika, 70:659-63 (1983)) was employed to control the Type I enor of repeated sequential log-rank tests comparing the hazard rates of developing diabetes between each pair of treatment groups. The group sequential log-rank test comparing any two of the three groups required p < 0.0159 for significance at the 0.05 level, adjusted for repeated tests and three pairwise tests. Results — Study cohort and follow-up.

The 3,234 participants were randomly assigned to one of the three interventions: 1082 received placebo, 1073 received metformin, and 1079 underwent intensive lifestyle modifications. Average age of all participants at baseline was 51 years, with 20% aged 60 years or more. Among all participants, 68% were women, and 45% were from racial-ethnic minority groups. Average BMI was 34.0 kg/m². Participant characteristics are shown in Table 1.

Baseline variables, including risk factors for diabetes, were well balanced between treatment groups. Participants were followed for an average of 2.8 years (range 1.8 to 4.6). As of the closing date, 99% of participants were alive, of whom 93% had attended a scheduled outcome visit within the previous 5 months.

Table 1 Participant Characteristics at baseline

Mean SD

Age (years) 50.6 10.7

Weight (kg) 94.2 20.3

Body mass index

34.0 6.7 (kg/m²)

Fasting plasma glucose

106.5 8.3 (mg/dl)

2-hour post challenge

164.6 17.0 glucose (mg/dl)

HbA_lc (%) 5.9 0.5

Fasting serum insulin

26.7 15.2 (μU/ml)

30-minute post- challenge serum insulin 100.5 64.1

(μU/ml) Results — Adherence to interventions.

The lifestyle intervention was successful, on average, in producing weight loss and increased physical activity. One year after randomization, mean weight change was -0.4 kg (-0.4% of baseline weight) in the placebo group, -2.7 kg (-2.9% of baseline weight) in the metformin group, and -6.7 kg (-7.1% of baseline weight) in the intensive lifestyle modifications group. Among the 510, 502, and 498 participants followed for 3 years in the placebo, metformin and lifestyle groups, weight change was +0.4, -1.2 and —4.1 kg. Differences among the three groups over time were highly significant (p < 0.001). Similarly, fasting and 30-minute post-challenge insulin concentrations declined over time in the metformin and lifestyle groups. The mean change in weight during the first year was conelated with the change in fasting (r = 0.30) and 30-minute (r = 0.18) insulin. Over all time periods, there were significant treatment effects on change in fasting insulin, accounting for weight change (with significantly greater declines in the lifestyle and metformin groups than the placebo group, and a greater decline in the lifestyle group than the metformin group). However, 86% of the treatment effect on fasting insulin concentrations was attributable to group differences in changes in weight. Self-reported exercise increased, on average, only in the lifestyle group, by 6.2 MET-hours/week, compared with decreases of 4.7 and 2.5 MET-hours/week in the metformin and placebo groups (p < 0.0001). In the first year, reported daily energy intake decreased, on average, by 249 kcal for the placebo group, 296 kcal for the metformin group, and 450 kcal for the lifestyle group (p < 0.001). Reported fat intake, as a fraction of total calories, decreased by 0.8% for the placebo and metformin groups and 6.6%) for the lifestyle group (p < 0.001).

Prevention of diabetes.

Both the metformin and lifestyle groups experienced lower cumulative incidence rates of diabetes than the placebo groups at each year of follow-up. Absolute hazard rates for developing type II diabetes were: 11.0 incidences per 100 person-years for the placebo group; 7.8 incidences per 100 person-years for the metformin group; and 4.8 incidences per 100 person-years for the intensive lifestyle intervention group. Compared with the placebo group, the proportional risk of developing type II diabetes was reduced, on average, by 31% (95% confidence interval = 17% to 43%) in the metformin group, and 58% (95% confidence interval = 48% to 66%) in the intensive lifestyle intervention group. The diabetes hazard rate was 39% lower (95% Cl = 24 to 51%) in the lifestyle than in the metformin group.

All three pairwise group comparisons were statistically significant by the group sequential log-rank test. None of these results was materially affected by adjustment for baseline characteristics. The number needed to treat to prevent one case of diabetes developing during 3 years was 6.9 (95% Cl = 5.4 to 9.5) for the lifestyle group and 13.9 (95% Cl = 8.9 to 28.6) for the metformin group.

The criteria by which the 623 cases of diabetes were diagnosed are shown in Table 2. Among the placebo and lifestyle groups, diagnoses were equally likely to be made by FPG or 2-hour OGTT. Participants in the metformin group, however, were more likely to be diagnosed by the 2-hour OGTT with the FPG levels remaining below the diagnostic threshold. This difference parallels this group's lower mean fasting plasma glucose and HbA_lc at diagnosis. Diabetes diagnosis was based on plasma glucose results prompting a confirmation for diagnosis, regardless of which criteria were met for the confirmation. At the three-year follow-up examination of 1 ,495 participants, diabetes had been diagnosed in 25% of the placebo group participants, 18% of the metformin group participants, and 12% of the intensive lifestyle modifications group participants. Additionally, normal glucose tolerance (fasting glucose < 110 mg/dl and 2-hour glucose < 140 mg/dl) was restored in 19% of the placebo group participants, 21% of the metformin group participants, and 32% of the intensive lifestyle modifications group participants. The remainder (56%, 62%, and 55%) had impaired glucose regulation or a diabetic test result that was not confirmed on repeat testing. Results — treatment effects among subgroups.

Table 3 summarizes the treatment effects among subgroups of participants identified by age, gender, ethnicity, BMI, initial FPG level, and initial 2-h OGTT level. In Table 3, "RR" stands for risk reduction and "Cl" stands for confidence interval, and in the entries marked with a double asterisk (**), heterogeneity was present among the strata (p < 0.05). The "24 to < 30" category of BMI includes Asian Americans enrolled with BMFs of 22 to less than 24 kg/m², according to eligibility criteria. The "95 to 100" category for fasting plasma glucose includes American Indian participants enrolled with fasting plasma glucose levels below 95 mg/dl, according to eligibility criteria, and the "111 to 125" category for fasting plasma glucose includes 54 participants enrolled with fasting plasma glucose levels of 126 to 139 mg/dl, prior to the change in ADA criteria in June, 1997. In general, reductions in hazard rates for the development of diabetes were similar among men and women and across racial-ethnic groups for each of the treatments, although the data suggest non-Caucasian ethnic groups may respond even better to the treatments than do Caucasians. For example, African, Asian, Hispanic, and Native American groups each experienced a greater percentage reduction in risk than did Caucasians. The effect of lifestyle intervention versus placebo increased as a function of baseline age, analyzed as a continuous variable. Conversely, the effect of metformin versus placebo diminished as a function of greater baseline age. In younger subjects (i.e., less than about 45 years of age), treatment with metformin was essentially equivalent with lifestyle intervention, whereas lifestyle intervention was more effective than metformin in older age groups (i.e., 45 years of age or more). The effect of metformin versus placebo was greater with higher baseline BMI, with no significant effect among participants with baseline BMI less than 30 kg/m². In the highest BMI group, treatment with metformin was essentially equivalent with lifestyle intervention, whereas in the lower BMI groups lifestyle intervention was more effective than metformin. The interaction of age and treatment effects persisted when controlled for BMI, and the interaction of body mass index and treatment effects persisted when controlled for age. Results— fasting plasma glucose and HbAlc.

As shown in Table 4, the treatments also affected other clinically relevant measures of hyperglycemia, specifically FPG > 140 mg/dl, confirmed by a repeat test within 6 weeks, and HbAι_c > 7%>. As in Table 3, "RR" stands for risk reduction and "Cl" stands for confidence interval. The "Fasting glucose" row includes persons first treated with non-study diabetes drugs before the fasting plasma glucose was > 140 mg/dl at an outcomes visit, and the "HbAι_c" data excludes 94 participants with HbAι_c > 7%> at baseline and 2 participants with no HbAι_c measure post-randomization. In contrast to metformin' s effects on diabetes prevention, in which it produced about half the risk reduction achieved by lifestyle, metformin was nearly as effective as the lifestyle intervention in preventing the onset of marked fasting hyperglycemia (> 140 mg/dl), (reduction in hazard rates, compared with placebo, were 51% by metformin and 61% by lifestyle, with no significant difference between metformin and lifestyle) or of HbAlc > 7.0% (reduction of 61% by metformin and 71% by lifestyle).

Table 2 — Distribution of Study Population on Criteria for Diagnosis of Diabetes

Placebo Metformin Lifestyle

Participants diagnosed at semi-annual visit (only N % N % N % fasting plasma glucose performed)

Total sample size 80 - 42 - 36 -

Fasting only, > 126 mg/dl 80 100 42 100 36 100

Glucose values at diagnosis Mean (SD) Mean (SD) Mean (SD)

Fasting glucose, mg/dl 140 (30) 141 (26) 136 (11)

Participants diagnosed at an annual visit (complete N % N % N %

OGTT performed)

Total sample size 203 — 164 ~ 98 — 1

Fasting only, > 126 mg/dl 36 17.8 19 11.6 19 19.4 1

2-hour only, > 200 mg/dl 117 57.6 115 70.1 54 55.1

Both 50 24.6 30 18.3 25 25.5

Glucose values at diagnosis Mean (SD) Mean (SD) Mean (SD)

Fasting glucose, mg/dl 123 (24) 115 (19) 124 (26)

2-hour glucose, mg/dl** 220 (46) 222 (31) 216 (30)

HbA,_c, %** 6.4 (0.8) 6.2 (0.5) 6.3 (0.6)

All participants diagnosed with diabetes N % N % N %

Total sample size 283 - 206 — 134 ~

Fasting only, > 126 mg/dl 116 41.0 61 29.6 55 41.0

2-hour only, > 200 mg dl 117 41.3 115 55.8 54 40.3

Both 50 17.7 30 14.6 25 18.7

Glucose values at diagnosis Mean (SD) Mean (SD) Mean (SD)

Fasting glucose, mg/dl 128 (27) 121 (23) 127 (23)

Table 3 — Effects of Treatment, Stratified by Covariates, at Baseline Hazard Rates and Percent Reduction in Hazards for Diabetes

Lifestyle versus Metformin versus Lifestyle versus

Hazard rates

Sample sizes (%) Placebo Placebo Metformin

Placebo Metformin Lifestyle % RR (95% Cl) ' % RR (95% Cl) % RR (95% Cl)

Overall 3234 (100) 1 1.0 7.8 4.8 57.8 (48, 66) 31.1 ( 17, 43) 39.2 (24, 51)

Age at baseline, years

25 to < 45 1000 (30.9) 11.6 6.7 6.2 48.1 (27, 63) 44.0 ( 21, 61) 7.5 (-36, 37) **

45 to <60 1586 (49.0) 10.8 7.6 4.7 59.0 (44, 70) 30.5 ( 10, 47) 40.8 (18, 57) **

> 60 648 (20.0) 10.8 9.6 3.1 71.4 (51, 83) 11.2 ( -33, 41) 68.8 (47, 82) **

Gender

Men 1043 (32.3) 10.3 7.6 5.0 65.1 (49, 76) 36.8 ( 14, 54) 45.7 (20, 63)

Women 2191 (67.7) 12.5 8.1 4.6 53.7 (40, 64) 28.2 ( 10, 43) 35.8 (16, 51)

Race-Ethnicity 1

Caucasian 1768 (54.7) 10.3 7.8 5.2 51.3 (35, 63) 24.5 ( 3, 41) 35.8 (14, 52) ^

African American 645 (19.9) 12.4 7.1 5.1 60.8 (37, 76) 44.5 ( 16, 63) 29.3 (-18, 58)

Hispanic American 508 (15.7) 11.7 8.4 4.2 65.8 (41, 80) 30.7 ( -9, 56) 51.1 (13, 73)

American Indian 171 (5.3) 12.9 9.7 4.7 64.7 (7, 87) 25.4 ( -72, 68) 52.2 (-35, 83)

Asian American 142 (4.4) 12.1 7.5 3.8 71.0 (24, 89) 38.4 ( -55, 75) 52.0 (-46, 84)

Body mass index, kg/m²

24 to < 30⁺ 1045 (32.3) 9.0 8.8 3.3 64.7 (46, 77) 2.9 ( -36, 31) ** 63.3 (44, 76) **

30 to < 36 1174 (36.3) 9.8 7.3 4.3 57.9 (39, 71) 26.7 ( -1, 47) ** 42.7 (16, 61) **

> 36 1015 (31.4) 14.3 7.2 7.3 52.0 (34, 65) 51.2 ( 33, 65) ** 1.0 (-43, 31) **

Fasting plasma glucose, mg/dl

95 to 100^ 845 (26.1) 5.5 4.4 2.0 64.5 (34, 81) 20.2 ( -30, 51) ** 56.5 (18, 77)

101 to 110 1447 (44.7) 7.3 6.7 3.8 49.6 (28, 65) 9.2 ( -24, 33) ** 44.8 (20, 62) l l l to l25^w 942 (29.1) 23.9 12.4 9.2 64.7 (53, 74) 52.2 ( 38, 64) ** 27.8 (1. 47)

2-hour plasma glucose, mg/dl

140 to 150 857 (26.4) 6.7 4.1 2.1 70.2 (47, 83) 39.4 ( 4, 62) 51.8 (11, 74)

151 to 175 1445 (44.7) 10.3 6.8 4.0 63.1 (48, 74) 36.2 ( 15, 52) 41.9 (17, 59)

175 to 199 932 (28.8) 16.6 12.8 9.0 48.7 (30, 63) 25.1 ( 0, 44) 31.7 ( 6, 51)

Table 4 Hazard Rates and Percent Reduction in Hazards for Diabetes and Secondary Glycemic Outcomes

Metformin vs. Lifestyle vs.

. ^ψ Hazard rates per 100 person- years Lifestyle vs. Placebo size Placebo Metformin

Placebo Metformin Lifestyle % RR (95% CI) ^* % RR (95% Cl) % RR (95% Cl)

Diabetes 3234 11.0 7.8 4.8 57.8 (48, 66) 31.1 (17, 43) 39.2 (24, 51) Fasting glucose > 140 mg/dl 3234 2.7 1.3 1.1 60.8 (40, 74) 51.4 (28, 67) 19.9 (-29, 50) HbA_lc > 7% 3140 5.4 2.1 1.6 70.7 (55, 81) 61.1 (43, 73) 24.8 (-22, 54)

I

00 I

Claims

WE CLAIM:

1. A method for inhibiting or delaying an onset of type II diabetes in a subject, comprising: selecting a subject at risk for developing type II diabetes; and administering to the subject a therapeutically effective amount of an antihyperglycemic antidiabetic agent, or pharmaceutically acceptable salts thereof, sufficient to inhibit or delay onset of type II diabetes, wherein the antihyperglycemic antidiabetic agent comprises a biguanide antidiabetic agent of the formula

^R

N-C - -NH-C-NH₂

R II II ^R2 N N

R₃ R₄

wherein R_\ and R₂ are independently selected from alkyl, lower alkyl, alkenyl, lower alkenyl, cycloalkyl, aryl, or an arylalkyl of the formula

wherein X is hydrogen or halogen and n = 0, 1 or 2, and R₃ and R₄ are independently selected from hydrogen, alkyl, lower alkyl, alkenyl, lower alkenyl, cycloalkyl, alkoxy, lower alkoxy, alkoxyalkyl.

2. The method of claim 1, wherein biguanide antidiabetic agent is metformin.

3. The method of claim 2, wherein the therapeutically effective amount is at least about 1000 milligrams per day.

4. The method of claim 2, wherein the therapeutically effective amount is at least about 1500 milligrams per day.

5. The method of claim 2, wherein the therapeutically effective amount is at least about 1700 milligrams per day.

6. The method of claim 2, wherein the therapeutically effective amount is administered in at least two doses per day.

7. The method of claim 5, wherein the at least about 1700 milligrams per day is administered in doses of at least about 850 milligrams.

8. The method of claim 1, wherein the biguanide antidiabetic agent is administered for a period of at least one year.

9. The method of claim 1 , wherein the biguanide antidiabetic agent is administered in the absence of any other antidiabetic agent.

10. The method of claim 1, wherein the biguanide antidiabetic agent is administered orally.

11. The method of claim 10, wherein the biguanide antidiabetic agent is administered in a pill.

12. The method of claim 1, wherein administering the therapeutically effective amount of antihyperglycemic antidiabetic agent inhibits or delays the onset of type II diabetes by at least about 20%.

13. The method of claim 12, wherein administering the therapeutically effective amount of antihyperglycemic antidiabetic agent inhibits or delays the onset of type II diabetes by at least about 30%.

14. The method of claim 1, further comprising instructing the subject about antidiabetic lifestyle modifications.

15. The method of claim 1, wherein selecting a subject at risk for developing type II diabetes comprises selecting a subject that has an impaired glucose tolerance.

16. The method of claim 15, wherein an impaired glucose tolerance is characterized by a fasting plasma glucose level of from about 5.2 millimoles per liter to about 6.9 millimoles per liter, or a plasma glucose level of from about 7.7 millimoles per liter to about 11.0 millimoles per liter about two hours after a 75 gram oral glucose tolerance test.

17. The method of claim 1, wherein selecting a subject at risk for developing type II diabetes comprises selecting a subject with a non-Caucasian ethnicity.

18. The method of claim 17, wherein the non-Caucasian ethnicity is Asian.

19. The method of claim 17, wherein the non-Caucasian ethnicity is African.

20. The method of claim 17, wherein the non-Caucasian ethnicity is Native American.

21. The method of claim 17, wherein the non-Caucasian ethnicity is Hispanic.

22. The method of claim 1, wherein selecting a subject at risk for developing type II diabetes comprises selecting a subject with a body mass index greater than about 24 kilograms/meter².

23. The method of claim 22, wherein selecting a subject at risk for developing type II diabetes further comprises selecting a subject with a body mass index greater than about 30 kilograms/meter .

24. The method of claim 1, wherein the subject has an age of less than 60 years.

25. The method of claim 1, wherein the subject has an age of less than 45 years.

26. The method of claim 1, wherein selecting a subject at risk for developing type II diabetes comprises selecting a subject with hyperinsulemia.

27. The method of claim 1, wherein selecting a subject at risk for developing type II diabetes comprises selecting a subject with hypertriglycemia.

28. The method of claim 1, wherein selecting a subject at risk for developing type II diabetes further comprises selecting a subject with raised hemoglobinAι_c concentration.

29. The method of claim 1, wherein selecting a subject at risk for developing type II diabetes comprises selecting a subject with a previous history of gestational diabetes or a family history of diabetes.

30. The method of claim 1, wherein the selecting the subject at risk for developing type II diabetes comprises selecting a subject that is about 40 years of age or more.

31. A method for inhibiting or delaying an onset of type II diabetes in a subject, comprising: selecting a subject with a body mass index greater than about 24 kilograms/meter , and an impaired glucose tolerance characterized by a fasting plasma glucose level of from about 5.2 millimole per liter to about 6.9 millimole per liter or a plasma glucose level of from about 7.7 millimole per liter to about 11.0 millimole per liter about two hours after a 75 grams oral glucose tolerance test; and administering to the subject an antidiabetic drug comprising metformin in an amount of at least about 1700 milligrams of metformin per day for at least about a year.

32. The method of claim 31 , further comprising selecting a subject having an age of less than 45 years.

33. The method of claim 31, further comprising selecting a subject having a body mass index of more than 30 kilograms/meters².

34. The method of claim 31 , further comprising selecting a subject having non-Caucasian ethnicity.

35. The method of claim 34, wherein the non-Caucasian ethnicity is African.

36. The method of claim 34, wherein the non-Caucasian ethnicity is Asian.

37. The method of claim 34, wherein the non-Caucasian ethnicity is Native American.

38. The method of claim 34, wherein the non-Caucasian ethnicity is Hispanic.

39. The method of claim 32, wherein administering the metformin occurs in the absence of administration of any other antidiabetic drug.

40. The method of claim 33, wherein administering the metformin occurs in the absence of administration of any other antidiabetic drug.

41. The method of claim 34, wherein administering the metformin occurs in the absence of administration of any other antidiabetic drug.