WO2008098318A1 - Treatment and medication to reduce body adiposity with low-dose pioglitazone - Google Patents

Treatment and medication to reduce body adiposity with low-dose pioglitazone Download PDF

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WO2008098318A1
WO2008098318A1 PCT/BE2008/000005 BE2008000005W WO2008098318A1 WO 2008098318 A1 WO2008098318 A1 WO 2008098318A1 BE 2008000005 W BE2008000005 W BE 2008000005W WO 2008098318 A1 WO2008098318 A1 WO 2008098318A1
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pioglitazone
dose
administration
treatment
adiposity
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PCT/BE2008/000005
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French (fr)
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Francis De Zegher
Lourdes Ibanez
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Katholieke Universiteit Leuven
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone

Definitions

  • the present invention relates generally to a medication or a treatment to reduce body adiposity without changing body weight.
  • the present invention concerns 1) a low dose of pioglitazone for use in a treatment of high body adiposity and 2) a treatment of high body adiposity through the administration of a low dose of pioglitazone in non-diabetic patients.
  • the treatment with a low dose of pioglitazone was particularly effective in women with androgen excess.
  • Peroxisome proliferator activated receptor-gamma (PPAR- ⁇ ) agonists [thiazolidinediones (TZDs)] are a novel class of insulin-sensitizing agents that are used in the treatment of type 2 diabetes, but have also been shown to improve the endocrine state and the ovulatory performance of women with androgen excess (Bloomgarden ZT 2005 Care. 28:488-493; Romualdi D, et al. 2003 Hum Reprod. 18:1210-1218 and Glintborg D et al., 2006 Fertil Steril. 86:385-397.).
  • TZDs inhibit peripheral lipolysis and have anti-inflammatory, anti-oxidant and anti-procoagulant properties (Bloomgarden ZT 2005 Thiazolidinediones. Diabetes Care. 28:488-493, Romualdi D, et al. 2003 Hum Reprod. 18:1210-1218; Glintborg D, et al. 2006 Fertil Steril. 86:385-397 and Martens FM, et al. 2002 Drugs. 62:1463-1480.).
  • TZDs The clinical use of TZDs is limited by potential side-effects including weight gain, which is mostly due to edema and/or gain of fat mass; these side effects are partly dose- and host-dependent (Belcher G, et al. 2005 Diabetes Res Clin Pract. 70:53-62.). Gain of weight confined to a (further) gain of fat is a cumbersome side- effect of pioglitazone treatment (Yki-Jarvinen H 2004 Thiazolidinediones.
  • hyperinsulinemic hyperandrogenism in non-obese women is combined androgen-receptor blockade (with flutamide; Flu), insulin- sensitization (with metformin; Met) plus an estro-progestagen contraceptive.
  • flutamide with flutamide
  • Met insulin- sensitization
  • estro-progestagen contraceptive We tested whether adding low-dose pioglitazone (Pio 7.5 mg/d) confers more benefit.
  • This double-blind study enrolled 38 young women with hyperinsulinemic hyperandrogenism [mean body mass index (BMI) 24 Kg/m 2 ], all of whom started on Flu (62.5 mg/d), Met (850 mg/d) plus a transdermal estro-progestagen, each for 21/28 d over 6 mo.
  • BMI body mass index
  • PioFluMet treatment was followed by a leaner body composition and a loss of visceral fat (both p ⁇ 0.001).
  • the changes included not only decreases in WHR, hirsutism score and testosterone (all P ⁇ 0.001), but also minor drops in ALT, AST, ⁇ -GT and LDH (all P ⁇ 0.005), indicating absence of hepatotoxicity; BMI remained unchanged. Clinical side- effects were not detected.
  • a cumbersome side-effect of pioglitazone treatment is a gain of weight, which appears to be confined to a (further) gain of fat (Yki-Jarvinen H 2004 Thiazolidinediones. N Engl J Med 351 :1106-18 and Balas B, Belfort R, Harrison SA 1 Darland C, Finch J, Schenker S, Gastaldelli A, Cusi K 2007 Pioglitazone treatment increases whole body fat but not total body water in patients with nonalcoholic steatohepatitis. J Hepatol 47:565-70).
  • this invention is the first report on the effect of low-dose pioglitazone in non-diabetic patients, and is the first demonstrating (in any patient population) that such a low pioglitazone dose (below 14 mg/d) reduces body adiposity without changing body weight, more specifically, reduces adiposity in part by increasing lean mass.
  • the present invention relates to the use of pioglitazone in a dose range between 1 and 14 mg/day (between 17 ⁇ g/kg body weight per day to 239 ⁇ g/kg body weight per day), more preferably between 5 and 10 mg/day (between 85 ⁇ g/kg body weight and 170 ⁇ g/kg body weight per day) , for instance 7.5 mg/day (128 ⁇ g/kg body weight per day), for the reduction of body adiposity in non-diabetic patients.
  • a dose range between 1 and 14 mg/day (between 17 ⁇ g/kg body weight per day to 239 ⁇ g/kg body weight per day), more preferably between 5 and 10 mg/day (between 85 ⁇ g/kg body weight and 170 ⁇ g/kg body weight per day) , for instance 7.5 mg/day (128 ⁇ g/kg body weight per day), for the reduction of body adiposity in non-diabetic patients.
  • such use of pioglitazone proove
  • the present invention concerns the use of pioglitazone for the reduction of adiposity in non-diabetic patients wherein pioglitazone is administered at a dose lower than 14 mg/day (239 ⁇ g/kg body weight per day ) or the same use of pioglitazone at a dose between 1 and 14 mg/day (between 17 ⁇ g/kg body weight per day to 239 ⁇ g/kg body weight per day) in non-diabetic patients, and preferably the same use of pioglitazone at a dose between 5 and 10 mg/day (between 85 ⁇ g/kg body weight and 170 ⁇ g/kg body weight per day).
  • Such use to reduce adiposity is preferably for women with androgen excess.
  • Yet another embodiment of invention concerns pioglitazone for use in the reduction of body adiposity, without changing body weight by more than 2%, in non-diabetic patients and particularly in women with androgen excess, whereby pioglitazone is administered in a dose lower than 14 mg/day.
  • Such reduction of body adiposity is achieved by combining a gain of lean mass with a loss of body fat.
  • the administration of low-dose of pioglitazone was combined with the administration of an appropriate dose of either an other insulin sensitizer such as metformin, an androgen receptor blocker such as flutamide or an estroprogestagen contraceptive.
  • an other insulin sensitizer such as metformin
  • an androgen receptor blocker such as flutamide or an estroprogestagen contraceptive.
  • the administration of a low dose pioglitazone was combined with the administration of an appropriate dose of an other insulin sensitizer, an androgen receptor blocker and an estroprogestagen contraceptive.
  • the administration of pioglitazone is combined with the administration of an insuline sensitizer.
  • a particular embodiment of present invention is also a dosage unit of less than 14 mg of Pioglitazone for use in a treatment to reduce body adiposity of non-diabetic patients by administration of pioglitazone.
  • a further embodiment of present invention is a dosage unit of less than 14 mg of Pioglitazone in combination with a dosage unit of another insulin sensitizer for use in a treatment to reduce body adiposity of non-diabetic patients by administration of the combination.
  • a further embodiment of present invention is a dosage unit of less than 14 mg of Pioglitazone in combination with a dosage unit of metformin or use in a treatment to reduce body adiposity of non-diabetic patients by administration of the combination.
  • a further embodiment of present invention is a dosage unit of less than 14 mg of Pioglitazone in combination with a dosage unit of an androgen-receptor blocker for use in a treatment to reduce body adiposity of non-diabetic patients by administration of the combination.
  • a further embodiment of present invention is a dosage unit of less than 14 mg of Pioglitazone in combination with a dosage unit of an androgen-receptor blocker is a compound the group consisting of flutamide, bicalutamide, spironolactone and drospirenone for use in a treatment to reduce body adiposity of non-diabetic patients by administration of the combination.
  • a further embodiment of present invention is a dosage unit of less than 14 mg of Pioglitazone in combination with a dosage unit of an estroprogestagen contraceptive for use in a treatment to reduce body adiposity of non-diabetic patients by administration of the combination.
  • Body adiposity in the meaning of this invention is the fat fraction of the body.
  • a high body adiposity can thus be reduced without changing weight, either by lowering the amount of fat or by increasing the amount of fat-free mass (the latter consisting mostly of lean mass).
  • High body adiposity is in the meaning of this invention a body fat fraction above 26.5 %, preferably above 30 %, more preferably above 33.5 % and most preferably 37%, as measured by validated techniques (for example, by absorptiometry) or estimated by anthropometric techniques (for example, skinfold assessments).
  • Non-diabetic patients for the meaning of this invention are subjects who do not have or are not suffering of diabetes, in particular, type 2 diabetes.
  • the present invention concerns the use of pioglitazone for the treatment of high body adiposity in non-diabetic patients, in particular of excessive body adiposity in patients not suffering of Type Il diabetes, to whom pioglitazone is given in a dose lower than 14 mg/day.
  • pioglitazone can be administered in a dose between 1 and 14 mg/day and most preferably pioglitazone is administered in a dose between 5 and 10 mg/day.
  • Such use of pioglitazone is prefarably in the treatment of women with androgen excess and such administration of pioglitazone can be combined with the administration of an insulin sensitizer.
  • yet another embodiment of present invention concerns the use of pioglitazone for the treatment of high body adiposity in non-diabetic patients, in particular of of excessive body adiposity in patients not suffering of Type Il diabetes, to whom pioglitazone is given in a dose lower than 14 mg/day in a combination with an androgen receptor blocker and in yet another embodiment such use of pioglitazone is combined with the administration of an estroprogestagen contraceptive.
  • the present invention also concerns a dosage form comprising less than 14 mg pioglitazone which is a one day portion for a patient for use in a treatment to reduce the body adiposity of non-diabetic patients by adminsitration of such dosage form of pioglitazone.
  • the present invention concerns a dosage unit of pioglitazone or a kit for peroral uptake by a subject or patient comprising an amount of pioglitazone which is lower than 14 mg for use in a treatment to reduce body adiposity of non- diabetic patients by adminsitration of such dacco units of pioglitazone so that the subject or patients receives an amount lower than 14 mg/day.
  • the present invention also involves a kit comprising dosage units of pioglitazone wherein each dosage unit of pioglitazone comprises pioglitazone in a dose therapeutically equivalent to a dose of pioglitazone lower than 14, preferably from about 1 mg to 13 mg, more preferably from about 2 to 10 mg, yet more preferably from about 4 to 9 mg, even more preferably about 6 to 8 mg, most preferably 7 mg.
  • the kit of present invention can further comprise a second dosage unit of an insulin sensitizer, a third dosage unit of an androgen receptor blocker and or a fourth dosage unit of an estroprogestagen contraceptive. Furthermore pioglitazone and the insulin sensitizer; pioglitazone and the androgen receptor blocker; pioglitazone and the estroprogestagen contraceptive; or pioglitazone, the insulin sensitizer and/or the androgen receptor blocker and/or the estroprogestagen contraceptive can be combined in one dosage unit.
  • Figure 1 displays the changes (0-6 mo) in endocrine-metabolic indices, visceral fat, inflammation markers and carotid intima media thickness of young women with androgen excess, treated with low-dose FluMet (21/28 d), a transdermal estro- progestagen (21/28 d), and either placebo or low-dose pioglitazone (7.5 mg/d;
  • BMI body mass index
  • Vise fat visceral fat section at lumbar vertebra 3 level
  • WHR waist-to-hip ratio
  • Testo testosterone
  • LDL low-density cholesterol
  • HDL high-density cholesterol
  • Neutro neutrophil count
  • Lympho lymphocyte count
  • CRP C-reactive protein
  • IMT carotid intima media thickness
  • Figure 2 displays the clinical study design over 18 months.
  • Inclusion criteria were: [1] hyperinsulinemia on a standard 2-h oral glucose tolerance test, defined as peak serum insulin levels >150 U/mL and/or mean serum insulin >84 ⁇ U/mL (Vidal-Puig A, Moller DE. In: Azziz R, Nestler JE, Dewailly D, eds. Androgen excess disorders in women. Philadelphia: Lippincott-Raven Publishers; 1997;227-236 and Ibanez L, de Zegher F 2004 J Clin Endocrinol Metab); [2] ovarian androgen excess, as defined by
  • Exclusion criteria were: evidence of thyroid dysfunction, Cushing's syndrome or hyperprolactinemia; glucose intolerance (The Expert Committe on the Diagnosis and Classification of Diabetes Mellitus 1997 Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 20:1183-1197.); personal history of diabetes mellitus; late-onset adrenal hyperplasia (New Ml, et al. 1983 J Clin Endocrinol Metab. 56:320-325 and Mermejo LV, et al. 2005 J Clin Endocrinol Metab. 90:1287-1293.); anemia; abnormal serum electrolytes; abnormal screening results for liver or kidney function; abnormal echocardiogram. This study was registered as IS RCTN 12871246 and conducted in
  • DHEAS C-reactive protein
  • IGF-I insulin-like growth factor-l
  • the IMT of the posterior (far) wall of both common carotid arteries was measured as the distance between the junction of the lumen and intima and the junction of the media and adventitia (Ibanez L, et al. 2006 Hum Reprod (E-Pub Oct 24, 2006)., O'Leary DH, Polak JK 2002 Am J Cardiol. 90:18L-21L). IMT was on each side recorded as the mean of 5 measures. The intra-observer coefficient of variation (CV) was ⁇ 10%.
  • Body Composition was assessed by dual-energy X-ray absorptiometry
  • Total subcutaneous and visceral adipose tissue areas were measured by magnetic resonance imaging (MRI) using a whole-body multi-slice MRI 1.5 Tesla device (Signa LX Echo Speed Plus Excite, General Electric Healthcare, Milwaukee, Wl). Subjects were placed on the platform with arms extended above the head, according to standard imaging procedures (Park YW, et al. lnt J Obes Relat Metab Disord. 26:978-983.). All patients were scanned using a T1 -weighted spin-echo sequence with 360 ms repetition time, 21 ms echo-time, 40 cm field of view, and 256 x 224 matrix.
  • transverse slices of 10-mm thickness were acquired beginning at the L4-L5 intervertebral space.
  • SAT and VAT areas were measured by fitting a spline curve to points on the border of the subcutaneous and visceral regions, selected by the same operator (LdR, blinded to treatment allocation).
  • Non-fat regions within the visceral region were also outlined with a spline fit and subtracted from the total visceral region.
  • the visceral fat region was subdivided into retroperitoneal and intra-peritoneal areas using the ascending and descending colon, the psoas muscles on each side of the spine, and the top of the vessels above the vertebrae as guides for the spline fit.
  • VAT area was calculated by subtracting the organ areas from the intra-peritoneal area (Gallagher D, et al. Am J Physiol Endocrinol Metab. 279.E124-131).
  • CVs for SAT and VAT were 7.2% and 8.8%. These CVs were obtained by repeating the scan three times within 6 mo in 10 young women, and were calculated by dividing the standard error of the estimate (SEE) from linear regression analysis, by the mean of the measurements.
  • Serum glucose was measured by the glucose oxidase method.
  • Immunoreactive insulin was assayed by IMx (micro-particle enzyme immunoassay, Abbott Diagnostics, Santa Clara, CA); the mean intra- and interassay coefficients of variation (CVs) were 4.7% and 7.2%, respectively.
  • Serum testosterone, 17-OHP, DHEAS, androstenedione, and SHBG were measured by immuno-chemiluminescence (IMMULITE 2000; Diagnostic Products, Los Angeles, CA).
  • Table 1 summarizes the results in both subgroups at baseline and after 6 mo.
  • the placebo subgroup confirmed the known effects of intermittent (21/28 d) therapy with low-dose FluMet plus a transdermal estro-progestagen (Ibanez L, et al. Hum Reprod. 21:451-456), extended those findings over time (from 3 mo to 6 mo), and disclosed that hematocrit and circulating IGF-1 are lowered (P ⁇ 0.001), that serum ALT falls reassuringly (P ⁇ 0.05), and that carotid IMT is reduced (P ⁇ 0.001). None of the adiposity markers, however, changed detectably within 6 mo.
  • Pio addition to FluMet was followed by additional benefits such as a leaner body composition and a loss of visceral fat (baseline vs 6 mo; p ⁇ 0.001 for both), a further reduction of IMT and body adiposity (PioFluMet vs FluMet; p ⁇ 0.05 for 0-6 mo changes in both markers).
  • 0-6 mo changes included not only decreases in insulin, glucose, IGF-I, visceral fat, WHR, hirsutism score, testosterone, LDL-to- HDL ratio, Neutrophil-to-Lymphocyte ratio, CRP and IMT (Figure 1), but also minor drops in serum ALT, AST, y-GT and LDH (all P ⁇ 0.005) indicating absence of hepatotoxicity. Clinical side-effects were not detected.
  • low-dose pioglitazone further improved markers of endocrine and cardiovascular health, including C-reactive protein, carotid intima media thickness, and high-molecular-weight adiponectin.
  • Table 2 and Figure 3 show the results after 18 months.
  • Carotid intima media thickness was high-normal at study start (mean 0.47 mm); with add-on placebo, it decreased towards normal (mean 0.36 mm; P ⁇ 0.001 vs start); with add-on pioglitazone, it even dropped into low- normal range (mean 0.29 mm; P ⁇ 0.001 vs start; P ⁇ 0.01 vs placebo).
  • Total weight did not change over 18 months in the placebo or the pioglitazone group.
  • Pio and other TZDs downregulate the expression of CRP and other endothelial activation markers, reduce platelet activity in the circulation, and delay atheromatous plaque progression.
  • Pio therapy (30 mg/d) is known to be associated with a robust weight gain, that is mainly ascribed to gain of subcutaneous fat which, in turn, seems to develop despite augmented growth hormone secretion and despite maintained serum levels of IGF-I (Brettenthaler N, 2004 J Clin Endocrinol Metab. 89:3835-3840; Ortega-Gonzalez C, et al. 2005 J Clin Endocrinol Metab. 90:1360-1365 and Glintborg D, et al. 2005 J Clin Endocrinol Metab. 90:5605-5612.).
  • low-dose Pio as detected within 6 mo in this relatively small study population, may be statistically subtle, but they were achieved on top of striking changes (P ⁇ 0.001 for IGF-1 , CRP and IMT) obtained in the "placebo" group, which actually received one of the most effective treatments known so far.
  • low-dose Pio amplified the benefits of flutamide- metformin (plus an estro-progestagen) by another ⁇ 50% to ⁇ 100%; integrated changes of such magnitude are unprecedented in young women with androgen excess.
  • a estro-progestagen contraceptive is a contraceptive that is based on a comination of a estradiol like compound and a progestagen for instance ike medroxyprogesterone acetate with estradiol or norgestrel and ethinyl estradiol or norgestrel mixed with ethinyl estradiol or norgestrel-ethinyl estradiol or a transdermal contraceptive with ethinylestradiol 600 meg plus norelgestromin 6 mg
  • SHBG sex hormone-binding globulin
  • DHEAS dehydroepiandrosterone-sulfate
  • IMT carotid intima media thickness
  • Neutro neutrophil count
  • Lympho lymphocyte count
  • Subc subcutaneous
  • Vise visceral
  • L3 lumbar vertebra 3 level.
  • HDL-cholesterol and LDL-cholesterol by 38.7.
  • SHBG sex hormone-binding globulin
  • DHEAS dehydroepiandrosterone-sulfate
  • ALT alanine aminotransferase
  • CRP C-reactive protein
  • IMT intima media
  • compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal administration although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.
  • pioglitazone can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
  • any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed.
  • tablets may be coated by standard aqueous or nonaqueous techniques.
  • Such compositions and preparations should contain at least 0.1 percent of active compound.
  • the percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit.
  • the amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained.
  • the active compounds can also be administered intranasally as, for example, liquid drops or spray.
  • the tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as com starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin.
  • a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
  • tablets may be coated with shellac, sugar or both.
  • a syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
  • Pioglitazone may also be administered parenterally.
  • Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

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Abstract

Present invention concerns pioglitazone for use in the reduction of body adiposity, without changing body weight by more than 2%, in non-diabetic patients and particularly in women with androgen excess, whereby pioglitazone is administered in a dose lower than 14 mg/day. Such reduction of body adiposity is achieved by combining a gain of lean mass with a loss of body fat.

Description

TREATMENT AND MEDICATION TO REDUCE BODY ADIPOSITY WITH LOW-DOSE PIOGLITAZONE
Field of the Invention
The present invention relates generally to a medication or a treatment to reduce body adiposity without changing body weight. In particular the present invention concerns 1) a low dose of pioglitazone for use in a treatment of high body adiposity and 2) a treatment of high body adiposity through the administration of a low dose of pioglitazone in non-diabetic patients. The treatment with a low dose of pioglitazone was particularly effective in women with androgen excess.
Background of the invention
One of the treatments for hyperinsulinemic, ovarian hyperandrogenism is combined androgen-receptor blockade (with flutamide; Flu), insulin-sensitization
(with metformin; Met) and, if needed, lifestyle changes and contraceptive measures (Sam S, Dunaif A 2003 Trends Endocrinol Metab. 14: 365-370;
Ehrmann DA 2005 N Engl J Med. 352:1223-1236; Ehrmann DA, et at. 2006. J Clin
Endocrinol Metab. 91:48-53; Ibanez L1 de Zegher F 2006 Human Reproduction Update. 12:243-252 and Gambineri A, et al. 2006 J Clin Endocrinol Metab.
91 :3970-3980.).
Peroxisome proliferator activated receptor-gamma (PPAR-γ) agonists [thiazolidinediones (TZDs)], are a novel class of insulin-sensitizing agents that are used in the treatment of type 2 diabetes, but have also been shown to improve the endocrine state and the ovulatory performance of women with androgen excess (Bloomgarden ZT 2005 Care. 28:488-493; Romualdi D, et al. 2003 Hum Reprod. 18:1210-1218 and Glintborg D et al., 2006 Fertil Steril. 86:385-397.).
TZDs inhibit peripheral lipolysis and have anti-inflammatory, anti-oxidant and anti-procoagulant properties (Bloomgarden ZT 2005 Thiazolidinediones. Diabetes Care. 28:488-493, Romualdi D, et al. 2003 Hum Reprod. 18:1210-1218; Glintborg D, et al. 2006 Fertil Steril. 86:385-397 and Martens FM, et al. 2002 Drugs. 62:1463-1480.).
The clinical use of TZDs is limited by potential side-effects including weight gain, which is mostly due to edema and/or gain of fat mass; these side effects are partly dose- and host-dependent (Belcher G, et al. 2005 Diabetes Res Clin Pract. 70:53-62.). Gain of weight confined to a (further) gain of fat is a cumbersome side- effect of pioglitazone treatment (Yki-Jarvinen H 2004 Thiazolidinediones. N Engl J Med 351 :1106-18 and Balas B, Belfort R, Harrison SA, Darland C, Finch J, Schenker S, Gastaldelli A, Cusi K 2007 Pioglitazone treatment increases whole body fat but not total body water in patients with non-alcoholic steatohepatitis. J Hepatol 47:565-70).
Here, we explored whether the addition of the TZD pioglitazone (Pio) in low dose (7.5 mg/d; commonly used doses are 4- to 6-fold higher) added benefit to the effects of low-dose Flutamide-Metformin (FluMet) in women with androgen excess and found that such treatment resulted in an unexpected reduction of adiposity.
Summary of the invention
One of the treatments for hyperinsulinemic hyperandrogenism in non-obese women is combined androgen-receptor blockade (with flutamide; Flu), insulin- sensitization (with metformin; Met) plus an estro-progestagen contraceptive. We tested whether adding low-dose pioglitazone (Pio 7.5 mg/d) confers more benefit. This double-blind study enrolled 38 young women with hyperinsulinemic hyperandrogenism [mean body mass index (BMI) 24 Kg/m2], all of whom started on Flu (62.5 mg/d), Met (850 mg/d) plus a transdermal estro-progestagen, each for 21/28 d over 6 mo. Patients were randomly assigned to receive, in addition, placebo (n=19) or Pio (n=19; 7.5 mg/d), for the same 21/28 d over 6 mo. BMI, waist-to-hip ratio (WHR), hirsutism score, fasting endocrine-metabolic markers, body composition, abdominal fat (visceral versus subcutaneous), and carotid intima media thickness (IMT) at study start and after 6 mo. PioFluMet reduced IMT more than FluMet, and lowered glucose, IGF-I and C- reactive protein more, as well as the ratio of LDL-to-HDL cholesterol and the ratio of Neutrophils-to-Lymphocytes. PioFluMet treatment was followed by a leaner body composition and a loss of visceral fat (both p<0.001). In the total group, the changes included not only decreases in WHR, hirsutism score and testosterone (all P<0.001), but also minor drops in ALT, AST, γ-GT and LDH (all P<0.005), indicating absence of hepatotoxicity; BMI remained unchanged. Clinical side- effects were not detected.
In this proof-of-concept study, addition of Pio to FluMet plus an estro-progestagen led to improvements in the endocrine-metabolic condition, in low-grade inflammation, in total and visceral adiposity, and in markers of cardiovascular health.
A cumbersome side-effect of pioglitazone treatment is a gain of weight, which appears to be confined to a (further) gain of fat (Yki-Jarvinen H 2004 Thiazolidinediones. N Engl J Med 351 :1106-18 and Balas B, Belfort R, Harrison SA1 Darland C, Finch J, Schenker S, Gastaldelli A, Cusi K 2007 Pioglitazone treatment increases whole body fat but not total body water in patients with nonalcoholic steatohepatitis. J Hepatol 47:565-70).
However this invention is the first report on the effect of low-dose pioglitazone in non-diabetic patients, and is the first demonstrating (in any patient population) that such a low pioglitazone dose (below 14 mg/d) reduces body adiposity without changing body weight, more specifically, reduces adiposity in part by increasing lean mass.
Therefore, in a first embodiment the present invention relates to the use of pioglitazone in a dose range between 1 and 14 mg/day (between 17 μg/kg body weight per day to 239 μg/kg body weight per day), more preferably between 5 and 10 mg/day (between 85 μg/kg body weight and 170 μg/kg body weight per day) , for instance 7.5 mg/day (128 μg/kg body weight per day), for the reduction of body adiposity in non-diabetic patients. In a particular embodiment such use of pioglitazone prooved very effective in the treament of the characteristic adiposity in women with androgen excess.
The present invention concerns the use of pioglitazone for the reduction of adiposity in non-diabetic patients wherein pioglitazone is administered at a dose lower than 14 mg/day (239 μg/kg body weight per day ) or the same use of pioglitazone at a dose between 1 and 14 mg/day (between 17 μg/kg body weight per day to 239 μg/kg body weight per day) in non-diabetic patients, and preferably the same use of pioglitazone at a dose between 5 and 10 mg/day (between 85 μg/kg body weight and 170 μg/kg body weight per day). Such use to reduce adiposity is preferably for women with androgen excess.
Yet another embodiment of invention concerns pioglitazone for use in the reduction of body adiposity, without changing body weight by more than 2%, in non-diabetic patients and particularly in women with androgen excess, whereby pioglitazone is administered in a dose lower than 14 mg/day. Such reduction of body adiposity is achieved by combining a gain of lean mass with a loss of body fat.
In a preferred embodiment, the administration of low-dose of pioglitazone was combined with the administration of an appropriate dose of either an other insulin sensitizer such as metformin, an androgen receptor blocker such as flutamide or an estroprogestagen contraceptive. In a more preferred embodiment, the administration of a low dose pioglitazone was combined with the administration of an appropriate dose of an other insulin sensitizer, an androgen receptor blocker and an estroprogestagen contraceptive. For instance in a particular embodiment the administration of pioglitazone is combined with the administration of an insuline sensitizer. In yet another particular embodiment the administration of pioglitazone is combined with the administration of an androgen receptor blocker and in yet another particular embodiment the administration of pioglitazone is combined with the administration of an estroprogestagen contraceptive. A particular embodiment of present invention is also a dosage unit of less than 14 mg of Pioglitazone for use in a treatment to reduce body adiposity of non-diabetic patients by administration of pioglitazone.
A further embodiment of present invention is a dosage unit of less than 14 mg of Pioglitazone in combination with a dosage unit of another insulin sensitizer for use in a treatment to reduce body adiposity of non-diabetic patients by administration of the combination.
A further embodiment of present invention is a dosage unit of less than 14 mg of Pioglitazone in combination with a dosage unit of metformin or use in a treatment to reduce body adiposity of non-diabetic patients by administration of the combination.
A further embodiment of present invention is a dosage unit of less than 14 mg of Pioglitazone in combination with a dosage unit of an androgen-receptor blocker for use in a treatment to reduce body adiposity of non-diabetic patients by administration of the combination.
A further embodiment of present invention is a dosage unit of less than 14 mg of Pioglitazone in combination with a dosage unit of an androgen-receptor blocker is a compound the group consisting of flutamide, bicalutamide, spironolactone and drospirenone for use in a treatment to reduce body adiposity of non-diabetic patients by administration of the combination.
A further embodiment of present invention is a dosage unit of less than 14 mg of Pioglitazone in combination with a dosage unit of an estroprogestagen contraceptive for use in a treatment to reduce body adiposity of non-diabetic patients by administration of the combination. DETAILED DESCRIPTION
Definitions • Body adiposity in the meaning of this invention is the fat fraction of the body. A high body adiposity can thus be reduced without changing weight, either by lowering the amount of fat or by increasing the amount of fat-free mass (the latter consisting mostly of lean mass).
• Change of body weight in the meaning of this invention is an increase or a decrease of >2 %.
• High body adiposity is in the meaning of this invention a body fat fraction above 26.5 %, preferably above 30 %, more preferably above 33.5 % and most preferably 37%, as measured by validated techniques (for example, by absorptiometry) or estimated by anthropometric techniques (for example, skinfold assessments).
• Non-diabetic patients for the meaning of this invention are subjects who do not have or are not suffering of diabetes, in particular, type 2 diabetes.
The present invention concerns the use of pioglitazone for the treatment of high body adiposity in non-diabetic patients, in particular of excessive body adiposity in patients not suffering of Type Il diabetes, to whom pioglitazone is given in a dose lower than 14 mg/day. For instance pioglitazone can be administered in a dose between 1 and 14 mg/day and most preferably pioglitazone is administered in a dose between 5 and 10 mg/day. Such use of pioglitazone is prefarably in the treatment of women with androgen excess and such administration of pioglitazone can be combined with the administration of an insulin sensitizer.
In yet another embodiment of present invention concerns the use of pioglitazone for the treatment of high body adiposity in non-diabetic patients, in particular of of excessive body adiposity in patients not suffering of Type Il diabetes, to whom pioglitazone is given in a dose lower than 14 mg/day in a combination with an androgen receptor blocker and in yet another embodiment such use of pioglitazone is combined with the administration of an estroprogestagen contraceptive.
The present invention also concerns a dosage form comprising less than 14 mg pioglitazone which is a one day portion for a patient for use in a treatment to reduce the body adiposity of non-diabetic patients by adminsitration of such dosage form of pioglitazone.
Moreover the present invention concerns a dosage unit of pioglitazone or a kit for peroral uptake by a subject or patient comprising an amount of pioglitazone which is lower than 14 mg for use in a treatment to reduce body adiposity of non- diabetic patients by adminsitration of such doase units of pioglitazone so that the subject or patients receives an amount lower than 14 mg/day.
The present invention also involves a kit comprising dosage units of pioglitazone wherein each dosage unit of pioglitazone comprises pioglitazone in a dose therapeutically equivalent to a dose of pioglitazone lower than 14, preferably from about 1 mg to 13 mg, more preferably from about 2 to 10 mg, yet more preferably from about 4 to 9 mg, even more preferably about 6 to 8 mg, most preferably 7 mg.
The kit of present invention can further comprise a second dosage unit of an insulin sensitizer, a third dosage unit of an androgen receptor blocker and or a fourth dosage unit of an estroprogestagen contraceptive. Furthermore pioglitazone and the insulin sensitizer; pioglitazone and the androgen receptor blocker; pioglitazone and the estroprogestagen contraceptive; or pioglitazone, the insulin sensitizer and/or the androgen receptor blocker and/or the estroprogestagen contraceptive can be combined in one dosage unit. Legends to the figures
Figure 1 displays the changes (0-6 mo) in endocrine-metabolic indices, visceral fat, inflammation markers and carotid intima media thickness of young women with androgen excess, treated with low-dose FluMet (21/28 d), a transdermal estro- progestagen (21/28 d), and either placebo or low-dose pioglitazone (7.5 mg/d;
21/28 d). Changes are expressed as standard deviation (SD) scores, calculated by dividing the individual values by the corresponding baseline SD in the study subjects. Plots represent means ± 95% Cl.
*p<0.05; **p<0.01 and ***p<0.001 , for 0-6 mo changes within the total group.
#p<0.05 for differences in 0-6 mo changes between subgroups.
BMI: body mass index; Vise fat: visceral fat section at lumbar vertebra 3 level;
WHR: waist-to-hip ratio; Testo: testosterone; LDL: low-density cholesterol; HDL: high-density cholesterol; Neutro: neutrophil count; Lympho: lymphocyte count;
CRP: C-reactive protein; IMT: carotid intima media thickness.
Figure 2 displays the clinical study design over 18 months.
Figure 3 displays the changes in lean body mass (by dual X-ray absorptiometry), intima media thickness (IMT; left carotid artery), abdominally subcutaneous and visceral fat (by magnetic resonance imaging) in hyperinsulinemic women with androgen excess, all of whom started on triple treatment (metformin; low-dose flutamide; estro-progestagen) at time 0, and were then randomly allocated to receive, in addition, either placebo (21/28 d; n=19; open circles) or pioglitazone (7.5 mg/d; 21/28 d; n=19; closed circles) for 18 mo. Mean and 95% Cl are shown.
# p<0.05, ** p<0.01 and m# p<0.001 , for difference between groups by Student t- test ** p<0.01 and *** p<0.0001 for difference in rate of change between groups by repeated-measures ANOVA Example
Study Subjects & Methods
Study Population In this proof-of-concept study, the population consisted of 38 young women with hyperinsulinemic hyperandrogenism [mean + SEM; age 19.6 ± 0.3 yr; range 18-24 yr; body mass index (BMI) 23.7 ± 0.5 Kg/m2, range 19.5-29.0 Kg/m2; 5-12 yr post-menarche; Table 1].
Inclusion criteria were: [1] hyperinsulinemia on a standard 2-h oral glucose tolerance test, defined as peak serum insulin levels >150 U/mL and/or mean serum insulin >84 μU/mL (Vidal-Puig A, Moller DE. In: Azziz R, Nestler JE, Dewailly D, eds. Androgen excess disorders in women. Philadelphia: Lippincott-Raven Publishers; 1997;227-236 and Ibanez L, de Zegher F 2004 J Clin Endocrinol Metab); [2] ovarian androgen excess, as defined by
• hirsutism [Ferriman-Gallwey score > 8 (Ferriman D, Gallwey JD 1961 J Clin Endocrinol Metab. 21 :1440-1447.)], amenorrhea (menses absent for >3 mo) or oligomenorrhea (menstrual cycles >45 days), and
• high serum androstenedione, total testosterone or free androgen index [testosterone x 100/sex hormone-binding globulin (SHBG)] (Ibanez L, de
Zegher F 2004 J Clin Endocrinol Metab 89:1592-1597.), and
• a 17-hydroxy-progesterone hyperresponse (17-OHP >160 ng/dL) to a GnRH agonist (leuprolide acetate 500 meg sc) (Ibanez L, de Zegher F 2004 J Clin Endocrinol Metab 89:1592-1597 and -Ibanez L, de Zegher F 2004 Hum Reprod. 19:1725-1727).
Prior to study start, none of the patients was receiving a contraceptive or another medication known to affect gonadal or adrenal function, or carbohydrate or lipid metabolism, for at least 9 mo.
Exclusion criteria were: evidence of thyroid dysfunction, Cushing's syndrome or hyperprolactinemia; glucose intolerance (The Expert Committe on the Diagnosis and Classification of Diabetes Mellitus 1997 Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 20:1183-1197.); personal history of diabetes mellitus; late-onset adrenal hyperplasia (New Ml, et al. 1983 J Clin Endocrinol Metab. 56:320-325 and Mermejo LV, et al. 2005 J Clin Endocrinol Metab. 90:1287-1293.); anemia; abnormal serum electrolytes; abnormal screening results for liver or kidney function; abnormal echocardiogram. This study was registered as IS RCTN 12871246 and conducted in
Barcelona, without support from industry, after approval by the Institutional Review Board of Sant Joan University Hospital, and after informed consent by each of the patients. None of the results in the present manuscript has been reported previously.
Study Design
In this double-blind, placebo-controlled study, all women started on metformin (850 mg/d) and flutamide (62.5 mg) once daily (21/28 d), at dinner time, and a transdermal contraceptive with ethinylestradiol 600 meg plus norelgestromin 6 mg, via a weekly patch (Evra, Janssen-Cilag, 21/28 d) for 6 mo. After stratification for BMI, patients were randomly assigned [1:1 ratio, Gran Mos program, Barcelona Medical Research Institute (Ibanez L, de Zegher F 2004 J Clin Endocrinol Metab 89:1592-1597 and Ibanez L, VaIIs C, Cabre S, de Zegher F 2004 J Clin Endocrinol Metab. 89:4716-4720)] to receive, in addition, placebo (21/28 d; n=19) or pioglitazone (7.5 mg, 21/28 d; n=19), at breakfast time, for 6 mo. FluMet and Pio/placebo were all discontinued (7/28 d) during the cyclic week off contraception.
The randomization sequence was known only to a pharmacist independent to the study, and was thus unknown to the clinically involved investigators. Pioglitazone and placebo were packaged in similar tablets; renewals were scheduled 3-monthly. All patients and investigators, except for the study statistician (ALB), have so far been - and still are - blinded for the treatment allocations.
Clinical and endocrine-metabolic variables, carotid intima media thickness (IMT), body composition and abdominal fat distribution were all assessed at study start (0 mo), and again after 6 mo during the off-treatment week. Clinical Assessment
Height (by Harpenden stadiometer), weight, BMI [ratio of weight (in Kg) to height squared (in meter)], waist-to-hip ratio (WHR), and hirsutism score (Ferriman D, Gallwey JD 1961 J Clin Endocrinol Metab. 21 :1440-1447.) were in each subject assessed by the same investigator (Ll, blinded to treatment allocation).
Endocrine-Metabolic Assessment
Fasting blood glucose, neutrophil and lymphocyte count, serum insulin, LDL- and HDL-cholesterol, SHBG, testosterone, dehydroepiandrosteronesulfate
(DHEAS), C-reactive protein (CRP), and insulin-like growth factor-l (IGF-I), were measured together with alanine- and aspartate aminotransferase (ALT, AST), gamma glutamyl transpeptidase (GGT), and a screening of renal function.
Baseline assessments were performed in the follicular phase (day 3-7) or after 2 mo of amenorrhea.
Carotid lntima Media Thickness
Longitudinal ultrasound scans of the carotid arteries were obtained by the same investigator (GE, blinded to treatment allocation) who used a high-resolution apparatus with colour and power Doppler capabilities (Acuson Sequoia 512 SHA, Medisales, Los Alamitos, CA) and a high-frequency 10 MHz linear probe (Ibanez L, et al. de Zegher F 2006 Hum Reprod (E-Pub Oct 24, 2006).). The right and left common carotid arteries, and the bifurcation-bulb areas were scanned in multiple planes. Images were obtained from the distal portions of both common carotid arteries, 1-2 cm away from the bulb and immediately proximal to the origin of the bifurcation. The IMT of the posterior (far) wall of both common carotid arteries was measured as the distance between the junction of the lumen and intima and the junction of the media and adventitia (Ibanez L, et al. 2006 Hum Reprod (E-Pub Oct 24, 2006)., O'Leary DH, Polak JK 2002 Am J Cardiol. 90:18L-21L). IMT was on each side recorded as the mean of 5 measures. The intra-observer coefficient of variation (CV) was <10%. In line with a previous paper on IMT in women with androgen excess (Ibanez L1 et al; 2006 Hum Reprod (E-Pub Oct 24, 2006).), we report IMT results of the left carotid, the slice volumes of which are similar to those on the right side (Adams GJ, et al; 2002 Bilateral symmetry of human carotid atherosclerosis. Stroke. 23:2575-2580.).
Body Composition Body composition was assessed by dual-energy X-ray absorptiometry
(DXA) with a Lunar Prodigy and Lunar software (version 3.4/3.5, Lunar Corp, Wl) (Ibafiez L, de Zegher F 2004 et al. J Clin Endocrinol Metab 89:1592-1597.). Total irradiation dose per assessment was 0.1 mSievert; CVs for scanning precision are 2.2% and 2.6% for fat and lean mass (Kiebzak GM, et al; J Clin Densitometry. 3:35-41.).
Assessment of abdominal fat distribution
Total subcutaneous and visceral adipose tissue areas (SAT, VAT) were measured by magnetic resonance imaging (MRI) using a whole-body multi-slice MRI 1.5 Tesla device (Signa LX Echo Speed Plus Excite, General Electric Healthcare, Milwaukee, Wl). Subjects were placed on the platform with arms extended above the head, according to standard imaging procedures (Park YW, et al. lnt J Obes Relat Metab Disord. 26:978-983.). All patients were scanned using a T1 -weighted spin-echo sequence with 360 ms repetition time, 21 ms echo-time, 40 cm field of view, and 256 x 224 matrix. To obtain abdominal MRI fat values, transverse slices of 10-mm thickness were acquired beginning at the L4-L5 intervertebral space. SAT and VAT areas were measured by fitting a spline curve to points on the border of the subcutaneous and visceral regions, selected by the same operator (LdR, blinded to treatment allocation). Non-fat regions within the visceral region were also outlined with a spline fit and subtracted from the total visceral region. The visceral fat region was subdivided into retroperitoneal and intra-peritoneal areas using the ascending and descending colon, the psoas muscles on each side of the spine, and the top of the vessels above the vertebrae as guides for the spline fit. VAT area was calculated by subtracting the organ areas from the intra-peritoneal area (Gallagher D, et al. Am J Physiol Endocrinol Metab. 279.E124-131). CVs for SAT and VAT were 7.2% and 8.8%. These CVs were obtained by repeating the scan three times within 6 mo in 10 young women, and were calculated by dividing the standard error of the estimate (SEE) from linear regression analysis, by the mean of the measurements.
Assays & Statistics Neutrophil and lymphocyte counts were assessed by cell counter (ABX
Pentra 120, ABX Diagnostics, Montpellier, France) (Ibanez L, Jaramillo A, Ferrer A, de Zegher F 2005 et al. Hum Reprod. 20:2457-2462). Serum glucose was measured by the glucose oxidase method. Immunoreactive insulin was assayed by IMx (micro-particle enzyme immunoassay, Abbott Diagnostics, Santa Clara, CA); the mean intra- and interassay coefficients of variation (CVs) were 4.7% and 7.2%, respectively. Serum testosterone, 17-OHP, DHEAS, androstenedione, and SHBG were measured by immuno-chemiluminescence (IMMULITE 2000; Diagnostic Products, Los Angeles, CA). All methods had intra- and interassay CVs between 4-8% within the relevant concentration ranges. CRP was measured by a highly sensitive method (Architect c8000, Abbott, Wiesbaden, Germany) with intra- and inter-assay CVs below 2%; the detection limit was 0.1 mg/L. Serum samples were stored at -2O0C until assay. Statistical analyses were performed with SPSS 12.0. For uniformity, results are expressed as mean ± SEM. Non-Gaussian variables were mathematically transformed to improve symmetry before statistical analyses. Two-sided t-tests were used for comparisons between groups, and for paired samples within groups; significance level was set at p<0.05.
Examples Results
6 month results
Table 1 summarizes the results in both subgroups at baseline and after 6 mo. The placebo subgroup confirmed the known effects of intermittent (21/28 d) therapy with low-dose FluMet plus a transdermal estro-progestagen (Ibanez L, et al. Hum Reprod. 21:451-456), extended those findings over time (from 3 mo to 6 mo), and disclosed that hematocrit and circulating IGF-1 are lowered (P<0.001), that serum ALT falls reassuringly (P<0.05), and that carotid IMT is reduced (P<0.001). None of the adiposity markers, however, changed detectably within 6 mo.
Pio addition to FluMet was followed by additional benefits such as a leaner body composition and a loss of visceral fat (baseline vs 6 mo; p<0.001 for both), a further reduction of IMT and body adiposity (PioFluMet vs FluMet; p<0.05 for 0-6 mo changes in both markers). Other effects of Pio addition were a lowering of fasting glycemia and LDL-to-HDL ratio, as well as further reductions of circulating IGF-I and of inflammatory markers such as CRP and neutrophil-to-lymphocyte ratio (PioFluMet vs FluMet; P<0.05 for 0-6 mo changes in all these indices), while the reassuring ALT drop was maintained (Figure 1).
In the total study population, 0-6 mo changes included not only decreases in insulin, glucose, IGF-I, visceral fat, WHR, hirsutism score, testosterone, LDL-to- HDL ratio, Neutrophil-to-Lymphocyte ratio, CRP and IMT (Figure 1), but also minor drops in serum ALT, AST, y-GT and LDH (all P<0.005) indicating absence of hepatotoxicity. Clinical side-effects were not detected.
18 months results
We randomized 38 non-obese women with hyperinsulinemic androgen excess into a placebo-controlled trial (ISRCTN12871246; Figure 2) Either placebo or low-dose pioglitazone was added to a triad of metformin (850 mg/d, 21/28 d), flutamide (62.5 mg/d, 21/28 d) and an estro-progestagen (21/28 d; Evra [Janssen-Cilag] for 12 months, followed by Yasmin [Bayer-Schering] for 6 months)
Within 12 months, low-dose pioglitazone further improved markers of endocrine and cardiovascular health, including C-reactive protein, carotid intima media thickness, and high-molecular-weight adiponectin. Table 2 and Figure 3 show the results after 18 months. Carotid intima media thickness was high-normal at study start (mean 0.47 mm); with add-on placebo, it decreased towards normal (mean 0.36 mm; P<0.001 vs start); with add-on pioglitazone, it even dropped into low- normal range (mean 0.29 mm; P<0.001 vs start; P<0.01 vs placebo). Total weight did not change over 18 months in the placebo or the pioglitazone group. With addon placebo, neither lean nor fat mass changed. With add-on pioglitazone, however, lean mass - not fat mass - increased consistently (P<0.0001 vs placebo), thereby markedly reducing body adiposity (P<0.001 vs start; P<0.01 vs placebo).
The results indicate that low-dose pioglitazone can reduce intima media thickness in women with androgen excess, while attenuating - not aggravating - body adiposity. Marked shifts in adipocytokine profiles, including in the circulating levels of visfatin and adiponectin, are among the potential mediators of the effects of low- dose pioglitazone. We conclude that low-dose pioglitazone warrants further attention as a prime candidate to enhance the long-term efficacy of triple therapy (metformin, anti-androgen, estro-progestagen) in hyperinsulinemic women with androgen excess
Discussion
In women with androgen excess, the addition of low-dose Pio (21/28 d) to a combination of low-dose FluMet and a transdermal estro-progestagen (21/28 d) resulted in additional reductions of LDL-to-HDL ratio, CRP, neutrophil-to- lymphocyte ratio and carotid IMT, which are markers of metabolic and cardiovascular health over the longer term. CRP promotes atherothrombosis through direct effects on endothelial cells and vascular smooth muscle cells, and neutrophils enhance coagulation in localised areas of inflammation, for example, on injured endothelium or at sites of platelet aggregate deposition (Venugopal SK, et al; 2005 Curr Opin Nephrol Hypertens. 14:33-37; Tsai JC, et al. 2006 Diabetes Metab Res Rev. May 16; [Epub ahead of print] and Home BD, et al. 2005 J Am Coll Cardiol. 45:1638-1643.). Pio and other TZDs downregulate the expression of CRP and other endothelial activation markers, reduce platelet activity in the circulation, and delay atheromatous plaque progression. The atheroprotective effects of TZDs, as reflected in a reduction of IMT, could thus result not only through insulin sensitization but also through other pathways, for example, via a direct TZD effect on the vessel wall or from a TZD-mediated fall in the LDL-to-HDL ratio (Satoh N, et al. 2003 Diabetes Care. 26:2493-2499 and Mazzone T, Meyer PM, Feinstein SB, Davidson MH, Kondos GT, D'Agostino RB, Perez A, Provost JC, Haffner SM 2006 Effect of pioglitazone compared with glimepiride on carotid intima-media thickness in type 2 diabetes. A randomized trial. JAMA [e-pub November 13].).
In hyperandrogenic women, Pio therapy (30 mg/d) is known to be associated with a robust weight gain, that is mainly ascribed to gain of subcutaneous fat which, in turn, seems to develop despite augmented growth hormone secretion and despite maintained serum levels of IGF-I (Brettenthaler N, 2004 J Clin Endocrinol Metab. 89:3835-3840; Ortega-Gonzalez C, et al. 2005 J Clin Endocrinol Metab. 90:1360-1365 and Glintborg D, et al. 2005 J Clin Endocrinol Metab. 90:5605-5612.). Here, we found that the addition of a much lower Pio dose to FluMet plus an estro-progestagen is in hyperandrogenic women followed by a paradoxal reduction of body adiposity and by a further fall of circulating IGF-1. We speculate that Pio's dose-effect curves for insulin sensitization and non-visceral adipogenesis are respectively shaped so that, if Pio is given in low dose, its insulin-sensitizing effects prevail over its adipogenic effects. Nocturnal profiling of growth hormone (GH) secretion may clarify whether low-dose Pio reduces circulating IGF-1 here by acting as a partial GH antagonist (Towns R, et al. 1994 Endocrinology. 134:608-613.) or rather as an IGF-I sensitizer. The mechanisms whereby co-therapy with low-dose Pio elicits additional benefits are likely to be multiple and intertwined, and they clearly require more research in women with androgen excess.
In line with other studies, we observed a small but consistent fall in hematocrit under low-dose FluMet treatment, either with or without Pio addition (Hollenberg NK 2003 Am J Med. 115 Suppl 8A:111S-115S). These falls in hematocrit are thought to be mainly attributable to concomitant drops in circulating androgens and thus in androgen-driven hematopoiesis (Berria R, et al. 2006 Clin Pharmacol Ther. 80:105-114.).
Women with androgen excess are at risk for transaminase elevations, which have been attributed to non-alcoholic steatohepatitis (Setji TL, et al. 2006 J Clin Endocrinol Metab. 91 :1741-1747.) or to the hepatotoxicity of high-dose flutamide (Ibanez L, et al; 2005 Hum Reprod. 20:1833-1836.). Both low-dose FluMet and low-dose PioFluMet were here reassuringly accompanied by minor - but consistent - drops in the serum levels of ALT, AST, γ-GT and/or LDH. It should be emphasized that the study design included several measures to reduce hepatic risk. Firstly, Flu (62.5 mg/d) and Pio (7.5 mg/d) were each given in the lowest dose known to be effective; for both compounds, this low dose is associated with a virtual absence of side-effects (Ibanez L, de Zegher F 2006 Human Reproduction Update. 12:243-252, Ibanez L, de Zegher F 2004 J Clin Endocrinol Metab 89:1592-1597, Ibanez L, et al; 2004 J Clin Endocrinol Metab. 89:4716-4720., Ibanez L, VaIIs C, de Zegher F 2006 Hum Reprod. 21:451-456., Ibanez L1 de Zegher F 2003 J Clin Endocrinol Metab. 88:4720-4724; Ibanez L, de Zegher F 2005 J Clin Endocrinol Metab. 90:39 and Majima T, et al. 2006 Endocr J. 53:325- 330.). Secondly, as the combination of Pio and Flu is unprecedented, the respective doses were daily given with a maximal intra-diem interval (morning vs evening). Thirdly, in order to avoid a hepatic first-pass effect of orally ingested estro-progestagens, we used a transdermal contraceptive that was previously studied in a combination with FluMet (Ibanez L, VaIIs C, de Zegher F 2006 Hum Reprod. 21 :451-456.). Finally, there was a complete medication-free week after every 3-week episode on estro-progestagen plus either FluMet or PioFluMet.
The additive effects of low-dose Pio, as detected within 6 mo in this relatively small study population, may be statistically subtle, but they were achieved on top of striking changes (P<0.001 for IGF-1 , CRP and IMT) obtained in the "placebo" group, which actually received one of the most effective treatments known so far. For some indices, low-dose Pio amplified the benefits of flutamide- metformin (plus an estro-progestagen) by another ~50% to ~100%; integrated changes of such magnitude are unprecedented in young women with androgen excess.
In this proof-of-concept study, the addition of low-dose Pio to FluMet plus an estro-progestagen led to improvements in the endocrine-metabolic condition, in low-grade inflammation, in total and visceral adiposity, and in markers of cardiovascular health. Larger trials of longer duration are warranted to assess the long-term efficacy and safety of low-dose PioFluMet therapy in women with androgen excess.
A estro-progestagen contraceptive is a contraceptive that is based on a comination of a estradiol like compound and a progestagen for instance ike medroxyprogesterone acetate with estradiol or norgestrel and ethinyl estradiol or norgestrel mixed with ethinyl estradiol or norgestrel-ethinyl estradiol or a transdermal contraceptive with ethinylestradiol 600 meg plus norelgestromin 6 mg
Table 1. Clinical, endocrine-metabolic, carotid ultrasound, body composition (by absorptiometry) and abdominal MRI indices in young women with androgen excess, who received treatment with low-dose FluMet (Flu, 62.5 mg/d, Met, 850 mg/d) and a transdermal estro-progestagen, and who were randomized to receive in addition either placebo (21/28 d, π=19) or low-dose pioglitazone (Pio, 7.5 mg/d, 21/28 d, n=19) for 6 mo
10
Figure imgf000019_0001
Values are mean ± SEM.
SHBG, sex hormone-binding globulin; DHEAS, dehydroepiandrosterone-sulfate,
IMT, carotid intima media thickness; Neutro, neutrophil count, Lympho, lymphocyte count; Subc, subcutaneous; Vise, visceral; L3, lumbar vertebra 3 level.
Indicative values from 24 asymptomatic young women: testosterone, 31 ± 3 ng/dL; androstenedione, 156 + 14 ng/dL; DHEAS, 125 + 12 μg/dL (Ibafiez L, VaIIs C, de Zegher F 2006 Hum Reprod. 21:451-456.).
* Indicative values from 16 asymptomatic young women: 0.39 + 0.02 mm (Ibafiez
L, et al. 2006 Hum Reprod (E-Pub Oct 24, 2006).).
To convert units to Sl, multiply the concentrations of testosterone by 0.03467; those of androstenedione by 0.0349; those of DHEAS by 0.02714; divide the concentrations of SHBG by 0.0288; those of triglycerides by 88.5, and those of
HDL-cholesterol and LDL-cholesterol by 38.7.
a absence of significant differences between randomized subgroups at 0 mo bp < 0.05, cp < 0.01 , dp ≤ 0.001 vs baseline (0 mo) ep < 0.05 for 0-6 mo change (Δ) vs placebo.
Table 2. Results in hyperinsulinemic women with androgen excess, who received treatment with low-dose flutamide (Flu, 62.5 mg/d), metformin (Met, 850 mg/d) and an estro-progestagen, and were randomized to receive in addition either placebo (21/28 d; n=19) or pioglitazone (Pio, 7.5 mg/d; 21/28 d; n=19) for 18 mo.
Figure imgf000021_0001
Values are mean ± SEM.
After 18 mo, blood sampling was performed in a cyclic off-treatment week (7/28 d).
SHBG, sex hormone-binding globulin; DHEAS, dehydroepiandrosterone-sulfate, ALT, alanine aminotransferase; CRP, C-reactive protein, IMT, intima media
10 thickness in left carotid artery; Neutro, neutrophil count; Lympho, lymphocyte count; L3, lumbar vertebra 3 level.
To convert units to Sl, multiply the concentrations of testosterone by 0.03467; those of androstenedione by 0.0349, those of DHEAS by 0.02714; and divide the
15 concentrations of SHBG by 0.0288. Indicative values from asymptomatic young women: testosterone, 31 ± 3 ng/dL
(n=24); androstenedione, 156 + 14 ng/dL (n=24); DHEAS, 125 + 12 μg/dL
(n=24); IMT 0.39 ± 0.02 mm (n=16).
a absence of significant differences between randomized subgroups at baseline. bp ≤ 0.05, cp ≤ 0.01 , dp ≤ 0.001 vs baseline, by paired t-test. ep ≤ 0.01 , fp ≤ 0.0001 for 0-18 mo change (Δ) vs Placebo, by two-way (time and group) repeated-measures ANOVA.
The results of present invention can be obtained by transdermal or oral delivery of the compounds for the adiposity treatment. Other delivery routes and delivery forms can be used. Suitable compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.
In practical use pioglitazone can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained. The active compounds can also be administered intranasally as, for example, liquid drops or spray.
The tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as com starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. When a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
Pioglitazone may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

Claims

Treatment and Medication to Reduce Body AdiposityCLAIMS
1. Pioglitazone for use in a treatment to reduce body adiposity of non-diabetic patients by administration of pioglitazone in an amount lower than 14 mg/day per patient.
2. Pioglitazone according to claim 1 wherein pioglitazone is administered in a dose between 1 and 14 mg/day.
3. Pioglitazone according to claims 1 or 2 wherein pioglitazone is administered in a dose between 5 and 10 mg/day.
4. Pioglitazone according to any of the claims 1 to 3 in the treatment of women with androgen excess.
5. Pioglitazone according to claim 4 wherein the administration of pioglitazone is combined with the administration of an insulin sensitizer.
6. Pioglitazone according to claim 5 wherein the insulin sensitizer is metformin
7. Pioglitazone according to any of the claims 1 to 6 wherein the administration of pioglitazone is combined with the administration of an androgen-receptor blocker.
8. Pioglitazone according to claim 7 wherein the androgen-receptor blocker is a compound the group consisting of flutamide, bicalutamide, spironolactone and drospirenone.
9. Pioglitazone according to any of the claims 1 to 8 wherein the administration of pioglitazone is combined with the administration of an estroprogestagen contraceptive.
10. Pioglitazone for use in a treatment of the reduction of total fat mass or total body adiposity of non-diabetic patients by administration of pioglitazone in an amount lower than 14 mg/day per patient.
11. Pioglitazone for use in a treatment to induce relative decrease in body adiposity and increase in lean body mass in a non-diabetic patient by administration of pioglitazone in an amount lower than 14 mg/day per patient.
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