Effect of Combination Glipizide GITS/Metformin on Fibrinolytic and Metabolic Parameters in Poorly Controlled Type 2 Diabetic Subjects
- William T. Cefalu, MD1,
- David J. Schneider, MD1,
- Harold E. Carlson, MD2,
- Phyllis Migdal, MD2,
- Leonil Gan Lim, MD2,
- Meriam P. Izon, MD2,
- Anoop Kapoor, MD3,
- Audrey Bell-Farrow, MBA, MHA4,
- James G. Terry, MS4 and
- Burton E. Sobel, MD1
- 1Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont
- 2Department of Medicine, State University of New York at Stony Brook, Stony Brook, New York
- 3Medical Service, Northport VA Medical Center, Northport, New York
- 4Wake Forest University School of Medicine, Winston-Salem, North Carolina
Abstract
OBJECTIVE—Epidemiological studies have implicated increased plasminogen-activated inhibitor 1 (PAI-1) as a marker or predictor of accelerated coronary atherosclerotic disease in type 2 diabetes. We sought to determine whether metabolic control, independent of its oral mode of implementation, affects PAI-1 in patients with marked hyperglycemia.
RESEARCH DESIGN AND METHODS—A total of 91 subjects were screened, subjected to a 4-week drug washout, and randomized to daily treatment with glipizide GITS (maximum 20 mg, n = 46) or metformin (maximum 2,550 mg, n = 45) as monotherapy. After monotherapy, combination therapy was initiated by adding the second agent to the regimen. Plasma glucose (fasting and postprandial), HbA1c, fructosamine, and PAI-1 were assayed before and after randomization and sequentially thereafter in all subjects; hepatic glucose output (HGO) and abdominal fat distribution were each measured in a subset of subjects.
RESULTS—Glycemic control was markedly impaired at baseline (mean HbA1c 10.4 ± 0.2% glipizide GITS; 10.0 ± 0.2% metformin) but improved comparably with each agent as monotherapy and in combination (P < 0.0001 vs. baseline), as assessed with meal tolerance studies, fructosamine values, and HGO. Body weight and abdominal fat distribution did not change significantly in either group. PAI-1 concentrations were extraordinarily high (5- to 10-fold more than normal) at baseline (202 ± 12 ng/ml glipizide GITS; 201 ± 13 ng/ml metformin) but declined comparably, and significantly, after treatment with either agent as monotherapy and decreased further with combination therapy.
CONCLUSIONS—When hyperglycemia is profound, increases in PAI-1 are also profound. Control of hyperglycemia with either glipizide GITS, an insulin secretagogue, or metformin as monotherapy comparably ameliorates elevated PAI-1.
- ACS, acyl-CoA synthase
- AUC, area under the curve
- CVD, cardiovascular disease
- ELISA, enzyme-linked immunosorbent assay
- FBG, fasting blood glucose
- FFA, free fatty acid
- FPG, fasting plasma glucose
- HGO, hepatic glucose output
- LOCF, last observed clinical finding
- MRI, magnetic resonance imaging
- NEFA, nonesterified (free) fatty acids
- PAI-1, plasminogen-activated inhibitor 1
- SUNY, State University of New York at Stony Brook
- t-PA, tissue-type plasminogen activator
- UKPDS, U.K. Prospective Diabetes Study
- WFU, Wake Forest University
Footnotes
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Address correspondence and reprint requests to William T. Cefalu, Associate Professor of Medicine, University of Vermont College of Medicine, UHC Campus, Arnold 3433, One South Prospect Street, Burlington, VT 05401. E-mail: william.cefalu{at}uvm.edu.
Received for publication 2 April 2002 and accepted in revised form 1 September 2002.
A.K. owns stock in, H.E.C. has received honoraria from, and W.T.C. has received honoraria and grant research support from Pfizer.
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.
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