Differential effects of metformin and troglitazone on cardiovascular risk factors in patients with type 2 diabetes.
OBJECTIVE
Traditional cardiovascular risk factors (CVRF) only partly explain the excessive risk of cardiovascular disease in patients with type 2 diabetes. There is now an increasing appreciation for many novel CVRF that occur largely as a result of insulin resistance and hyperinsulinemia. Therefore, we investigated whether diabetes medications that vary in their mechanism of action and ability to reduce insulin resistance may differ in their effects on both traditional and novel CVRF.


METHODS
We compared the addition of metformin or troglitazone therapy on CVRF in 22 subjects with type 2 diabetes who remained in poor glycemic control (with HbA1c >8.5%) while taking glyburide 10 mg twice daily. Subjects were initially randomized to either metformin 850 mg once daily or troglitazone 200 mg once daily. Both medications were then titrated upward as needed to achieve fasting plasma glucose <120 mg/dl. Measures of glucose control, insulin resistance, and CVRF (blood pressure, lipids, plasminogen activator inhibitor-1, C-reactive protein, fibrinogen, and small dense LDL) were assessed both before and after therapy.


RESULTS
After 4 months of treatment, both metformin and troglitazone led to similar decreases in fasting plasma glucose and HbA1c. The reduction in insulin resistance determined by hyperinsulinemic-euglycemic clamp was nearly twofold greater with troglitazone than metformin. Metformin did not induce significant changes in blood pressure, LDL cholesterol, LDL size, HDL cholesterol, triglycerides, or plasminogen activator inhibitor-1. However, C-reactive protein did decrease by 33% (6 +/- 1 to 4 +/- 1 mg/l; P < 0.01) [corrected]. Troglitazone therapy was associated with increases in LDL size (26.21 +/- 0.22 to 26.56 +/- 0.25 nm; P=0.04) and HDL cholesterol (33 +/- 3 to 36 +/- 3 mg/dl; P=0.05) and decreases in triglycerides (197 +/- 19 to 155 +/- 23 mg/dl; P=0.07) and C-reactive protein by 60% (8 +/- 3 to 3 +/- 1 mg/l, P < 0.01) [corrected].


CONCLUSIONS
For patients with type 2 diabetes in whom maximal sulfonylurea therapy failed, the addition of the insulin sensitizer troglitazone seemed to have greater benefits on several traditional and novel CVRF than metformin therapy. These differences were not related to glycemic improvement but reflected, in part, the greater reduction in insulin resistance obtained with addition of troglitazone. These data suggest that medications that more effectively address this underlying metabolic defect may be more beneficial in reducing cardiovascular risk in type 2 diabetes.
Chu
Neelima V
NV
Department of Endocrinology and Metabolism, VA San Diego Healthcare System/University of California, San Diego, California 92161, USA.
Kong
Alice P S
AP
Kim
Dennis D
DD
Armstrong
Debra
D
Baxi
Sunita
S
Deutsch
Reena
R
Caulfield
Michael
M
Mudaliar
Sunder R
SR
Reitz
Richard
R
Henry
Robert R
RR
Reaven
Peter D
PD
D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure; D002097:C-Reactive Protein / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000453:epidemiology*; D002784:Cholesterol / Q000097:blood; D002839:Chromans / Q000009:adverse effects / Q000627:therapeutic use*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy*; D003925:Diabetic Angiopathies / Q000453:epidemiology*; D005260:Female; D005905:Glyburide / Q000627:therapeutic use; D006442:Glycated Hemoglobin / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D008055:Lipids / Q000097:blood; D008077:Lipoproteins, LDL / Q000097:blood; D008297:Male; D008687:Metformin / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood; D012307:Risk Factors; D013844:Thiazoles / Q000009:adverse effects / Q000627:therapeutic use*; D045162:Thiazolidinediones; D000077288:Troglitazone
D001786:Blood Glucose; D002097:C-Reactive Protein; D002784:Cholesterol; D002839:Chromans; D005905:Glyburide; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D008055:Lipids; D008077:Lipoproteins, LDL; D008687:Metformin; D017395:Plasminogen Activator Inhibitor 1; D013844:Thiazoles; D045162:Thiazolidinediones; D000077288:Troglitazone