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WO2003011273A1 - Metformine utilisee dans le traitement de conditions hyperglycemiques - Google Patents

Metformine utilisee dans le traitement de conditions hyperglycemiques Download PDF

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Publication number
WO2003011273A1
WO2003011273A1 PCT/US2002/024225 US0224225W WO03011273A1 WO 2003011273 A1 WO2003011273 A1 WO 2003011273A1 US 0224225 W US0224225 W US 0224225W WO 03011273 A1 WO03011273 A1 WO 03011273A1
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WIPO (PCT)
Prior art keywords
diabetes
subject
selecting
metformin
antidiabetic agent
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PCT/US2002/024225
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English (en)
Inventor
Sanford A. Garfield
George A. Bray
Wilfred Y. Fujimoto
Dorothy Gohdes
Edward S. Horton
Steven E. Kahn
William C. Knowler
Boyd E. METZGER
Mark E. Molitch
David M. Nathan
Jerrold M. Olefsky
David S. Schade
Robert S. Schwartz
Harry Shamoon
Julio SANTIAGO
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The Governement Of The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services
The Regents Of The University Of California
SANTIAGO, Ana
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Application filed by The Governement Of The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services, The Regents Of The University Of California, SANTIAGO, Ana filed Critical The Governement Of The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services
Publication of WO2003011273A1 publication Critical patent/WO2003011273A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the methods provided relate to treating metabolic disorders, including treating a pre-diabetic condition to inhibit or delay the onset of diabetes.
  • Type II 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.
  • Type II diabetes 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).
  • 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
  • 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.
  • ITT impaired glucose tolerance
  • R t and R 2 are independently selected from alkyl, lower alkyl, alkenyl, lower alkenyl, cycloalkyl, aryl, or an arylalkyl of the formula:
  • R 3 and P ⁇ are independently selected from hydrogen, alkyl, lower alkyl, alkenyl, lower alkenyl, cycloalkyl, alkoxy, lower alkoxy, alkoxyalkyl; and pharmaceutically acceptable salts thereof.
  • 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/m 2 , or in subjects having particular physiological conditions associated with diabetes or IGT, such as hyperinsulemia, hypertriglyceridemia, or a raised hemoglobinA ⁇ c concentration.
  • diabetes risk factors such as having impaired glucose tolerance (IGT) or a body mass index (BMI) greater than about 24 kg/m 2 , or in subjects having particular physiological conditions associated with diabetes or IGT, such as hyperinsulemia, hypertriglyceridemia, or a raised hemoglobinA ⁇ 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.
  • 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.
  • 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.).
  • the agent may be carried in a pharmaceutically acceptable carrier and administered by any means that achieve its intended purpose.
  • 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.
  • 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).
  • DPP Diabetes Prevention Program
  • 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.
  • FPG fasting plasma glucose
  • FIG. 3 is a graph illustrating the cumulative incidence (expressed as a percentage of the population) of elevated hemoglobinA ⁇ 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
  • 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.
  • 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.
  • IGT impaired glucose tolerance
  • 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.
  • a antidiabetic agent such as an antihyperglycemic antidiabetic agent
  • 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
  • an agent includes single or plural agents and can be considered equivalent to the phrase “at least one agent.”
  • 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.
  • a substituted alkyl is 1,1 -dimethyl propyl.
  • a "cycloalkyl” is a cyclic alkyl.
  • 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.
  • 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
  • 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.
  • 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 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 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.
  • 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.
  • FPG fasting plasma glucose
  • OGTT oral glucose tolerance test
  • 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:
  • Obesity such as a BMI greater than or equal to about 30 kg/m 2 ;
  • 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.
  • 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).
  • ethnicity is not considered equivalent to national origin.
  • SOAMers are considered to belong to the Caucasian ethnic group because they descended from Northern
  • FPG Fasting plasma glucose
  • 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
  • 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).
  • FPG fasting plasma glucose
  • 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.
  • WHO World Health Organization
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a therapeutically effective amount or dose of an antidiabetic agent is that amount or dose sufficient to achieve a stated therapeutic effect.
  • 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.
  • the antidiabetic agent contains a biguanide of the formula:
  • Ri and R 2 are independently selected from alkyl, lower alkyl, alkenyl, lower alkenyl, cycloalkyl, aryl, or an arylalkyl of the formula:
  • R 3 and R 4 are independently selected from hydrogen, alkyl, lower alkyl, alkenyl, lower alkenyl, cycloalkyl, alkoxy, lower alkoxy, alkoxyaUcyl; and pharmaceutically acceptable salts thereof.
  • 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.
  • the antidiabetic agent is a thiazolidinedione, such as troglitazone.
  • a subject that does not have type II diabetes, but does have an increased or substantial risk for developing type II diabetes is selected.
  • the subject has impaired glucose tolerance (IGT).
  • 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 .
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle.
  • physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like
  • 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.
  • 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.
  • 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.
  • antidiabetic agents 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.
  • the Diabetes Prevention Program 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.
  • 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 Boulevard., 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.
  • 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.
  • Eligibility criteria for participation in the DPP included age > 25 years; body mass index > 24 kg/m 2 ; 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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/m 2 . 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 3 summarizes the treatment effects among subgroups of participants identified by age, gender, ethnicity, BMI, initial FPG level, and initial 2-h OGTT level.
  • RR stands for risk reduction
  • Cl stands for confidence interval
  • 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/m 2 , 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.
  • 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 treatments also affected other clinically relevant measures of hyperglycemia, specifically FPG > 140 mg/dl, confirmed by a repeat test within 6 weeks, and HbA ⁇ c > 7%>.
  • RR stands for risk reduction
  • 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 "HbA ⁇ c " data excludes 94 participants with HbA ⁇ c > 7%> at baseline and 2 participants with no HbA ⁇ c measure post-randomization.
  • metformin 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).
  • African American 645 (19.9) 12.4 7.1 5.1 60.8 (37, 76) 44.5 ( 16, 63) 29.3 (-18, 58)
  • Asian American 142 (4.4) 12.1 7.5 3.8 71.0 (24, 89) 38.4 ( -55, 75) 52.0 (-46, 84)

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Abstract

L'administration d'une dose efficace sur le plan thérapeutique d'un agent antidiabétique, antihyperglycémique atténue les symptômes de la diminution de la tolérance au glucose (IGT), ou inhibe un début de diabète de type II chez des sujets présentant un risque accru de développer le diabète de type II. L'agent antidiabétique est administré à un sujet durant une période suffisante à alléger l'IGT ou à inhiber le début du diabète de type II. Un exemple particulier d'un agent antidiabétique, antihyperglycémique utile consiste en un agent antidiabétique biguanide, tel que la metformine. Un risque sensible à développer le diabète de type II peut être identifié chez des sujets présentant un ou plusieurs facteurs de risque du diabète, notamment une IGT ou un indice de masse corporelle (IMC) supérieur à environ 24 kg/m2, ou chez les sujets présentant des conditions physiologiques particulières associées au diabète ou à l'IGT. Des sujets d'un groupe démographique particulier, tels que ceux âgés au plus d'environ 45 ans ou des sujets d'horizons ethniques particuliers, peuvent aussi être choisis pour le traitement.
PCT/US2002/024225 2001-07-31 2002-07-30 Metformine utilisee dans le traitement de conditions hyperglycemiques WO2003011273A1 (fr)

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WO2005033089A1 (fr) * 2003-10-07 2005-04-14 Biocon Limited Sel d'acide 6-(1, 3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoique avec du diamide de n, n-dimethyl-imidodicarbonimidique

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WO2001032157A2 (fr) * 1999-11-03 2001-05-10 Bristol-Myers Squibb Company Procede utilise pour traiter le diabete

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WO2001032157A2 (fr) * 1999-11-03 2001-05-10 Bristol-Myers Squibb Company Procede utilise pour traiter le diabete

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005033089A1 (fr) * 2003-10-07 2005-04-14 Biocon Limited Sel d'acide 6-(1, 3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoique avec du diamide de n, n-dimethyl-imidodicarbonimidique

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