- Email: [email protected]
Dose titration of new metformin-glibenclamide (glyburide) fixed combination in metformin-failure type 2 diabetics
Poster Session 1
$50
InRBC incubations the expected increase in media MG levels was prevented by MF (MF(-)=3.73+2.18, MF(+)=0.444-2.7 nmol/gRBCs, p=0.03) while TP, GAPDH and intracellular MG were not effected by MF therapy. GLX activity also did not differ between MF(+) and MF(-) subjects. TZP was found in the media only in MF(+) subjects and accounted for 70.9% of the reduction in MG levels. In vivo studies demonstrated a significant inverse relationship between plasma TZP and MG (R=0.69, p=0.019), while a significant direct relationship was observed between Urinary levels of TZP and MG (R=0.71, P=0.009). Our results indicate that MF had no effect on cellular MG production or detoxification. Conversely, MF lowers MG levels by formation of a stable condensation product (Triazepinone), and TZP can account for most of the in vitro reduction in MG.In vivo studies also confirm a relationship between TZP and decreased MG levels. In summary, MF appears to act as an extracellular scavenger of MG independent of its antihyperglycemic effect, and could thereby contribute to the prevention of chronic diabetic complications by reduction of dicarbonyl stress.
P262 Dose Titration of New Metformin-Glibenclamide (Glyburide) Fixed Combination in Metformin-Failure "I~pe 2 Diabetics THIERRY ALLAVOINE I, M. Marre 2. / Lipha SA, Lyon, France; 2 Bichat Hospital, Paris, France Objective: The primary objective of this study was to study the efficacy of two fixed combination metformin/glibenclarnide (M/G) tablet dosages compared with metformin (Met) or glibenclamide (Gli) monotherapy on HbAic in patients with inadequate glycaemic control (FPG > 7 retool/l) on at least 1500 mg/day of Met alone. Methods: This was a randomised, 4-month, phase III, controlled, parallel, double-blind, double-dummy study. Four hundred and ninety type-2 patients were enrolled, 411 of whom were randomised to one of four treatment groups: Met 500 mg; Gli 5 mg; M/G 500 mg/2.5 rag; or M/G 500 mg/5 mg. Doses were titrated from one to four tablets a day for the first month, according to self glucose monitoring. Results: Escalation in dose was proportional to the baseline level of HbAic. The HbAnc decrease was higher in the fixed combination groups except for one tablet a day (see Figure). The M/G 500 mg/2.5 mg group achieved a more regular and steady increase of efficacy in line with dose titration.
':I
i ~~t0 '*~g
I I' CL~*S mrj
I, ~3
I
S00s2 6 m~
RI I I ~JVG S00,S
Conclusions: After Met monotherapy failure, titration was more effective in both tested fixed M/G combinations compared with continuation with Met or switch to Gli. This improvement in efficacy was most evident with the M/G 500 mg/2.5 mg dosage.
P263 Effects of Metformin on Fibrinolytic Activity, Insulinemia and Body Weight in Non-Diabetic Obese Subjects JORGE ALVARII~AS J, Julio Mollerach J, Claudio D. Gonzfilez 2, Marcelo Mollerach J, Guillermo E. Burlando t. t Dept. of Nutrition, Tornd
Hospital, Buenos Aires, BA, Argentina; 2 Dept. of Pharmacology, University of Buenos Aires, Buenos Aires, BA, Argentina Objective: to assess the effect of Metformin (M) on PAI- 1 levels (an inhibitor of plasminogen activation), and its association with the actions of the drug on body weight and insulinemia, in non- diabetic obese subjects. Methods: forty non- diabetic obese subjects were included in a double blind placebo (P) controlled trial, 23 of them receiving M. The triad duration after inclusion was 4 months; at baseline, patients in both groups (P and M) did not show significant differences in age (p=0.110) nor BMI (36.3 4- 5.3 in M; 38.1 4- 6.3 in P; p= 0.352). Dietary prescription was similar for both groups. Determinations (at baseline and 4 months after): PAI-1, glycemia, fasting insulinemia, total cholesterol, LDL-c, HDL-c, trygliceridemia, fibrinogenemia, microalbuminuria, hepatic enzymes, creatininemia, arterial blood pressure, BMI. Statistical Analysis: Student t test; Mann- Whitney test; Wilcoxon test; two way ANCOVA (analysis of covariance). Results: after a 4 month treatment, a higher reduction of BMI values was observed in group M regarding P (-3 kg/m2 in M vs. -0.6 kg/m2 in P, p< 0.05). In M, PAI-1 levels were reduced from 16.4 4- 2.9 to 13.5 4- 2.3 ng/ml; in group P, a marginal increase was observed from 16.5 4- 2.5 to 16.9 4- 2.8 ng/ml. In the ANCOVA model, we detected highly significant differences in PAI-I values even after adjustment for BMI (basal and after 4 months) (p= 0.000045). Fasting insulin levels showed a reduction only in M; as above, we also found a significant decrease of PAI-1 levels in M after adjustment by baseline and 4 months fasting insulin levels (p= 0.000003). Conclusions: After 4 months, PAI-I levels were significantly reduced in non- diabetic obese patients treated with M. This reduction may be related to changes in BMI and/or insulin levels; nevertheless, the variance in PAI-1 decrease is only partially explained by weight or insulin reductions.
P264 Response by Dose Level with Metformin/Glyburide Tablets as First-Line Treatment in "l~pe 2 Diabetes DANIEL S. DONOVAN 1, Julio Rosenstock 2, David Henry 3. / College of
Physicians and Surgeons, Columbia University, New York, N y United States of America; 2 Dallas Diabetes and Endocrine Clinic, Dallas, TX, United States of America; 3 Pharmaceutical Research Institute, Bristol-Myers Squibb, Princeton, NJ, United States of America The pathogenesis of type 2 diabetes is multifaceted and involves both impaired insulin secretion and increased insulin resistance. The use of two oral antidiabetic agents with complementary mechanisms of action may result in a synergistic effect, resulting in a greater response than could be obtained with either drug alone. This multicenter study evaluated the efficacy and safety of two fixed combination metformin/glyburide (M/G) tablet dosages, after 20 weeks of oral administration as firstqine therapy Mean changein glycaemicparameters: Tabletnumber Glyburide2.5 mg Metformin500 mg M/G 250/1.25mg M/G 500/2.5mg HbAic (%) 1 2 3 4 FPG (mg/dL) 1 2 3 4
n=141 -1.09 - 1.34 - 1.69 -1.06 n=157 -27.8 -45.2 -50.2 -36.4
n=140 -1.00 -0.90 -0.83 -1.21 n=155 -6.3 -16.8 -18.6 -32.5
n=149 -0.93 - 1.66 - 1.71 -I.92 n=153 -20.3 -44.0 -54.4 -57.9
n=152 -1.30 - 1.70 - 1.94 -2.16 n=154 -28.6 -59.7 -44.0 -58.6
$50
InRBC incubations the expected increase in media MG levels was prevented by MF (MF(-)=3.73+2.18, MF(+)=0.444-2.7 nmol/gRBCs, p=0.03) while TP, GAPDH and intracellular MG were not effected by MF therapy. GLX activity also did not differ between MF(+) and MF(-) subjects. TZP was found in the media only in MF(+) subjects and accounted for 70.9% of the reduction in MG levels. In vivo studies demonstrated a significant inverse relationship between plasma TZP and MG (R=0.69, p=0.019), while a significant direct relationship was observed between Urinary levels of TZP and MG (R=0.71, P=0.009). Our results indicate that MF had no effect on cellular MG production or detoxification. Conversely, MF lowers MG levels by formation of a stable condensation product (Triazepinone), and TZP can account for most of the in vitro reduction in MG.In vivo studies also confirm a relationship between TZP and decreased MG levels. In summary, MF appears to act as an extracellular scavenger of MG independent of its antihyperglycemic effect, and could thereby contribute to the prevention of chronic diabetic complications by reduction of dicarbonyl stress.
P262 Dose Titration of New Metformin-Glibenclamide (Glyburide) Fixed Combination in Metformin-Failure "I~pe 2 Diabetics THIERRY ALLAVOINE I, M. Marre 2. / Lipha SA, Lyon, France; 2 Bichat Hospital, Paris, France Objective: The primary objective of this study was to study the efficacy of two fixed combination metformin/glibenclarnide (M/G) tablet dosages compared with metformin (Met) or glibenclamide (Gli) monotherapy on HbAic in patients with inadequate glycaemic control (FPG > 7 retool/l) on at least 1500 mg/day of Met alone. Methods: This was a randomised, 4-month, phase III, controlled, parallel, double-blind, double-dummy study. Four hundred and ninety type-2 patients were enrolled, 411 of whom were randomised to one of four treatment groups: Met 500 mg; Gli 5 mg; M/G 500 mg/2.5 rag; or M/G 500 mg/5 mg. Doses were titrated from one to four tablets a day for the first month, according to self glucose monitoring. Results: Escalation in dose was proportional to the baseline level of HbAic. The HbAnc decrease was higher in the fixed combination groups except for one tablet a day (see Figure). The M/G 500 mg/2.5 mg group achieved a more regular and steady increase of efficacy in line with dose titration.
':I
i ~~t0 '*~g
I I' CL~*S mrj
I, ~3
I
S00s2 6 m~
RI I I ~JVG S00,S
Conclusions: After Met monotherapy failure, titration was more effective in both tested fixed M/G combinations compared with continuation with Met or switch to Gli. This improvement in efficacy was most evident with the M/G 500 mg/2.5 mg dosage.
P263 Effects of Metformin on Fibrinolytic Activity, Insulinemia and Body Weight in Non-Diabetic Obese Subjects JORGE ALVARII~AS J, Julio Mollerach J, Claudio D. Gonzfilez 2, Marcelo Mollerach J, Guillermo E. Burlando t. t Dept. of Nutrition, Tornd
Hospital, Buenos Aires, BA, Argentina; 2 Dept. of Pharmacology, University of Buenos Aires, Buenos Aires, BA, Argentina Objective: to assess the effect of Metformin (M) on PAI- 1 levels (an inhibitor of plasminogen activation), and its association with the actions of the drug on body weight and insulinemia, in non- diabetic obese subjects. Methods: forty non- diabetic obese subjects were included in a double blind placebo (P) controlled trial, 23 of them receiving M. The triad duration after inclusion was 4 months; at baseline, patients in both groups (P and M) did not show significant differences in age (p=0.110) nor BMI (36.3 4- 5.3 in M; 38.1 4- 6.3 in P; p= 0.352). Dietary prescription was similar for both groups. Determinations (at baseline and 4 months after): PAI-1, glycemia, fasting insulinemia, total cholesterol, LDL-c, HDL-c, trygliceridemia, fibrinogenemia, microalbuminuria, hepatic enzymes, creatininemia, arterial blood pressure, BMI. Statistical Analysis: Student t test; Mann- Whitney test; Wilcoxon test; two way ANCOVA (analysis of covariance). Results: after a 4 month treatment, a higher reduction of BMI values was observed in group M regarding P (-3 kg/m2 in M vs. -0.6 kg/m2 in P, p< 0.05). In M, PAI-1 levels were reduced from 16.4 4- 2.9 to 13.5 4- 2.3 ng/ml; in group P, a marginal increase was observed from 16.5 4- 2.5 to 16.9 4- 2.8 ng/ml. In the ANCOVA model, we detected highly significant differences in PAI-I values even after adjustment for BMI (basal and after 4 months) (p= 0.000045). Fasting insulin levels showed a reduction only in M; as above, we also found a significant decrease of PAI-1 levels in M after adjustment by baseline and 4 months fasting insulin levels (p= 0.000003). Conclusions: After 4 months, PAI-I levels were significantly reduced in non- diabetic obese patients treated with M. This reduction may be related to changes in BMI and/or insulin levels; nevertheless, the variance in PAI-1 decrease is only partially explained by weight or insulin reductions.
P264 Response by Dose Level with Metformin/Glyburide Tablets as First-Line Treatment in "l~pe 2 Diabetes DANIEL S. DONOVAN 1, Julio Rosenstock 2, David Henry 3. / College of
Physicians and Surgeons, Columbia University, New York, N y United States of America; 2 Dallas Diabetes and Endocrine Clinic, Dallas, TX, United States of America; 3 Pharmaceutical Research Institute, Bristol-Myers Squibb, Princeton, NJ, United States of America The pathogenesis of type 2 diabetes is multifaceted and involves both impaired insulin secretion and increased insulin resistance. The use of two oral antidiabetic agents with complementary mechanisms of action may result in a synergistic effect, resulting in a greater response than could be obtained with either drug alone. This multicenter study evaluated the efficacy and safety of two fixed combination metformin/glyburide (M/G) tablet dosages, after 20 weeks of oral administration as firstqine therapy Mean changein glycaemicparameters: Tabletnumber Glyburide2.5 mg Metformin500 mg M/G 250/1.25mg M/G 500/2.5mg HbAic (%) 1 2 3 4 FPG (mg/dL) 1 2 3 4
n=141 -1.09 - 1.34 - 1.69 -1.06 n=157 -27.8 -45.2 -50.2 -36.4
n=140 -1.00 -0.90 -0.83 -1.21 n=155 -6.3 -16.8 -18.6 -32.5
n=149 -0.93 - 1.66 - 1.71 -I.92 n=153 -20.3 -44.0 -54.4 -57.9
n=152 -1.30 - 1.70 - 1.94 -2.16 n=154 -28.6 -59.7 -44.0 -58.6