Improved insulin sensivity and beta cell responsivity suggested by HOMA analysis of pioglitazone therapy

Track 2. Clinical Research & Care

P299 Improved Insulin Seusivity and Beta Cell Responsivity Suggested by HOMA Analysis of Pioglitazone Therapy JULIO M. ROSENSTOCK 1. The Pioglitazone 001 Study Group Aims: Pioglitazone HC1 (PIO) was recently introduced in the United States and Japan for treatment of type 2 diabetes as monotherapy (MONO) and in combination with sulfonylurea (SU) or metformin (MET) therapy. The purpose of this study was to assess insulin resistance (IR), and beta cell function (BCF) in three studies by homeostasis model assessment (HOMA) analysis in response to PIO therapy. Material and Methods: In each of the studies, the intermediate dose (30 mg once daily) of PIO was used as the maximum active intervention and the duration of each study was 16 weeks. In the MONO study, PIO was compared to placebo (PBO). In the combination studies, either PIO or PBO were added to the pre-existing therapy without change in the therapeutic dose of the existing agent. Results: The results are expressed as percentage at endpoint vs. baseline. Treatment(n) Monotherapy(LS Mean) PlO 30mg(96) PBO (81) SU Combo(LS Mean) SU+ PIO 30 mg (177) SU + PBO (172) MET Combo(LS Mean) MET + PIO 30 mg (157) MET + PBO (148)

% changein R vs. baseline

p

% changein beta cell functionvs. baseline

p

-12.49 30.34

0.045 0.002

41.41 23.38

<0.00t 0.027

-30.13 20.05

<0.001 0.001

38.04 8.23

<0.001 0.07

-18.16 17.60

0.039 0.100

37.56 36.79

<0.001 0.051

Conclusion: These data suggest that PIO therapy is associated with a statistically significant improvement in insulin sensitivity and improvement in beta cell responsivity when used as either monotherapy or in combination with metformin or sulfonylurea.

P300 Efficacy and Safety of RosigUtazone Combined with Glibenclamide Is Effective and Well Tolerated in Type 2 Diabetes Patients Inadequately Controlled on Maximum-Dose Glibendamide JULIO ROSENSTOCK j , Margaret M. Kreider 2, Lisa Menci 2, Mark Heise 2, Martin I. Freed 2. l Dallas Diabetes and Endocrine Center,

Dallas, IX, United States of America; 2 SmithKline Beecham Pharmaceuticals, Collegeville, PA, United States of America Purpose: A potent PPAR)/ agonist, rosiglitazone (RSG) improves glycemic control in patients with type 2 diabetes (T2DM). RSG (2 or 4mg/d)+glibenclamide (GLB) produced significant dose-related reductions in H b A l c compared with baseline or with GLB in clinical trials. This study evaluated the efficacy, safety, and tolerability of maximum dose RSG 8mg+GLB in T2DM patients inadequately controlled on maximum dose GLB. Methods: During a 6- to 7-week, single-blind, placebo (PBO) run-in period, GLB was titrated from half maximum to the maximum daily dose (20 mg). Following the run-in, 114 patients with FPG _>7.8 mmol/L and <15 mmol/L were randomly assigned to either PBO+GLB 10mg/bid or RSG 4mg/bid+GLB 10mg/bd for 26 weeks. Results: RSG+GLB produced significant decreases in mean H b A l c and F I ~ from baseline and also when compared with GLB alone at 26 weeks. Higher doses resulted in larger decreases in HbAlc. Further, greater reductions in mean H b A l c (-1.7%) and F I ~ (-4.9 mmol/L) were observed in the subset of patients with baseline H b A l c >9%. A total of 47% of patients in the RSG+GLB group achieved an FPG <7.0 mmol/L and 64% of RSG-treated patients had a decrease in H b A l c _>1%. The proportion of patients reporting adverse events was similar in both treatment groups. In the RSG group, 5.4% of patients withdrew due to lack of efficacy compared with 20.7% in the GLB group. Hypoglycemia, which was effectively managed by GLB

$61

dose reduction, was more common during treatment with combination RSG. Parameter/TreatmentGroup HbAle (%) (Baseline=9.0) PBO + GLB (n = 56) RSG 8rag + GLB (n = 53) FPG (mmol/L)(Baseline=l1.6) PBO + GLB (n = 56) RSG 8rag+ GLB (n = 53)

Changefrom Baseline (mean :t: SEM)

Treatment Effect (mean ± 95% C1)

-0.0 4- 0.13 -1.4 ± 0.15"

-1.3 (-1.66, -0.9*)

+0.5 ± 0.29 -3.5 ± 0.43*

-3.9 (-4.8, -2.9)*

*P <0.0001.

Conclusions: RSG 8mg/d+GLB was well tolerated and effective, producing marked improvement in glycemic control in patients with T2DM previously inadequately controlled on GLB monotherapy.

P301 Effect of Pioglitazone on Abdominal Fat Distribution and Insulin Sensitivity in Patients with Type 2 Diabetes YOSHINORI MIYAZAKI, Archana Mahankali, Masafumi Matsuda, Srikanth Mahankali, Kenneth Cusi, Lawrence Mandarino, Ralph A. Defronzo. We examined the effect of pioglitazone on abdominal fat distribution to elucidate the mechanisms via which pioglitazone improves insulin resistance in T2DM patients. 13 patients with T2DM (MF=9/4, age=524-3 y, BMI=29.0+1.2 kg/m2), who were on a stable dose of sulfonylurea, received treatment with pioglitazone (45mg/day) for 4 months. 6 sulfonylurea-treated T2DM patients (M/F=3/3, age=59+4 y, BMI=29.2-4-1.2), received placebo. Before and after 4 months of pioglitazone, subjects received 75g OGTT and 2-step euglycemic insulin clamp (insulin infusion rates: 40 and 160 mU/m2.min) with 3H-glucose. Abdominal fat distribution was evaluated using magnetic resonance imaging at the level of L4-5. After 4 months, F t ~ (1804-10 to 1404-10 mg%, P<0.01), mean PG during OGTT (P<0.01), and H b A l c (8.64-0.4 to 7.24-0.5%, p<0.01) decreased without change in fasting or post-OGTT insulin or C-peptide levels. Fasting plasma FFA (P<0.05) and mean FFA (P<0.01) during OGTT decreased after pioglitazone. Basal hepatic glucose production (bHGP: 824-5 to 734-2 mg/m2.min, P<0.05) and HGP during 1st insulin clamp step ( 1stHGP: 31 4-4 to 164-4, P<0.05) decreased after pioglitazone, while total glucose disposal during 2nd insulin clamp step increased (2ndTGD: 231 4-31 to 291 4-32 mg/m2.min, P<0.01). No significant changes in HGP or TGD were observed in the placebo group. The improvements in hepatic and peripheral insulin sensitivity occurred despite an increase in body weight (824-4 to 864-5 kg, p<0.01) and fat mass (244-3 to 294-2 kg, p<0.01). After pioglitazone, subcutaneous fat area at L4-5 (SFA: 300444 to 3424-44 cm2, P<0.01) increased, while visceral fat area (VSA: 1444-13 to 1314-16 cm2, P<0.05) and V/S ratio (0.594-0.08 to 0.444-0.06, P<0.01) decreased. In stepwise multiple regression analysis with SFA, VSA, and V/S ratio as independent variables, the change in V/S ratio correlated with the changes in bHGP and 1stHGP, and the change in VSA correlated with the change in 2ndTGD. Conclusion: A shift of fat distribution from visceral to subcutaneous adipose depots following pioglitazone is associated with improvements in hepatic and peripheral insulin sensitivity.

P302 Effect of Pioglltazone on Glucose Tolerance and Insulin Sensitivity in Diet.Controlled "l~pe 2 Diabetic Subjects ARCHANA MAHANKALI, Yoshinori Miyazaki, Masafumi Matsuda, Kenneth Cusi, Lawrence Mandarino, Ralph A. Defronzo. Pioglitazone is a newly approved insulin sensitizing thiazolidinedione, for the treatment of Type 2 Diabetes Mellitus (T2DM). The aim of the present