Reductions in biomarkers of cardiovascular risk in type 2 diabetes with rosiglitazone added to metformin compared with dose escalation of metformin: an EMPIRE trial sub-study.
OBJECTIVE
To compare the effects of rosiglitazone added to metformin with dose escalation of metformin on cardiovascular risk biomarkers in type 2 diabetes mellitus.


METHODS
Cardiovascular biomarkers were assessed in a sub-population of 122 subjects with type 2 diabetes mellitus (mean age 54.6 and 56.0 years, BMI 34.7 and 32.1 kg/m2; for the rosiglitazone plus metformin and metformin groups, respectively) from the multicenter (63 centers in the USA), double-blind, randomized parallel-group Escalation of Metformin theraPy vs. Initiation of Rosiglitazone Early (EMPIRE) study. Treatment group sizes were slightly imbalanced owing to central, rather than local, randomization. Subjects receiving metformin 1000 mg/day at baseline were randomized to rosiglitazone 4 mg/day plus metformin 1000 mg/day (RSG + MET) or metformin 1500 mg/day (up-titrated MET) for 24 weeks. At 8-weeks, rosiglitazone was increased to 8 mg/day in RSG + MET recipients and metformin to 2000 mg/day in up-titrated MET recipients.


RESULTS
Reductions from baseline in HbA1c at week 24 (mean +/- SD) occurred in both groups (RSG + MET: -0.61% +/- 1.16%; up-titrated MET: -0.65% +/- 1.18%). Post-prandial glucose levels (AUC(0-3h)) decreased with RSG + MET (-3.5 mmol/L.h; 95% confidence interval [CI]: -5.2 to -1.8) and up-titrated MET (-1.3 mmol/L.h; 95% CI: -3.8 to 1.1). Homeostasis Model Assessment (HOMA)-estimated insulin sensitivity increased by 37.7% (95% CI: 22.8 to 54.5) in RSG + MET and 6.9% (95% CI: -6.2 to 21.9) in up-titrated MET recipients. RSG + MET reduced C-reactive protein (CRP; -23.9%; 95% CI: -40.4 to -2.8), plasminogen activator inhibitor-1 (PAI-1) activity (-30.1%; 95% CI: -44.5 to -11.9), PAI-1 antigen (-15.5%; 95% CI: -28.3 to -0.3) and matrix metalloproteinase-9 (MMP-9; -13.8%; 95% CI: -25.1 to -0.9), but increased tumor necrosis factor-alpha (TNF-alpha; 27.0%; 95% CI: 6.8 to 50.9). Corresponding values for up-titrated MET were CRP -9.3% (95% CI: -36.9 to 30.2), PAI-1 activity -7.2% (95% CI: -28.2 to 20.0), PAI-1 antigen -1.5% (95% CI: -17.4 to 17.5), MMP-9 29.0% (95% CI: -1.3 to 68.6) and TNF-alpha -6.0% (95% CI: -22.0 to 13.2).


CONCLUSIONS
These results suggest that rosiglitazone plus metformin has positive cardiovascular effects against a background of similar glycemic improvements.
Goldstein
Barry J
BJ
Division of Endocrinology, Diabetes and Metabolic Diseases, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA, USA.
Weissman
Peter N
PN
Wooddell
Margaret J
MJ
Waterhouse
Brian R
BR
Cobitz
Alexander R
AR
D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D002097:C-Reactive Protein / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000097:blood*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D007333:Insulin Resistance; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000097:blood; D008687:Metformin / Q000008:administration & dosage* / Q000009:adverse effects; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage* / Q000009:adverse effects; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D015415:Biomarkers; D001786:Blood Glucose; D002097:C-Reactive Protein; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D020780:Matrix Metalloproteinase 9; D008687:Metformin; D017395:Plasminogen Activator Inhibitor 1; D000077154:Rosiglitazone; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha