Effects of short-term treatment with metformin on markers of endothelial function and inflammatory activity in type 2 diabetes mellitus: a randomized, placebo-controlled trial.
OBJECTIVE
The UK Prospective Diabetes Study (UKPDS) showed that treatment with metformin decreases macrovascular morbidity and mortality independent of glycaemic control. We hypothesized that metformin may achieve this by improving endothelial function and chronic, low-grade inflammation. Data on this issue are scarce and we therefore tested, in the setting of a randomized, placebo-controlled trial, whether metformin can affect endothelial function and low-grade inflammation.


METHODS
The Hyperinsulinaemia the Outcome of its Metabolic Effects (HOME) trial is a double-blind trial, in which all patients were randomized to receive either metformin or placebo in addition to insulin therapy. At the beginning and the end of a 16-week treatment period fasting blood samples were drawn and a physical examination was carried out.


METHODS
The trial was conducted in the outpatient clinics of three nonacademic hospitals (Hoogeveen, Meppel and Coevorden; the Netherlands).


METHODS
Patients were included if they were between 30 and 80 years of age; had received a diagnosis of diabetes after the age of 25; had never had an episode of ketoacidosis; and their blood glucose-lowering treatment previously consisted of oral agents but now only consisted of either insulin (n = 345) or insulin and metformin (n = 45). We excluded pregnant women and women trying to become pregnant, patients with a Cockroft-Gault-estimated creatinine clearance <50 mL min(-1), or low plasma cholinesterase (reference value <3.5 units L(-1)), patients with congestive heart failure (New York Heart Association class III/IV), or patients with other serious medical or psychiatric disease. A total of 745 eligible patients were approached; 390 gave informed consent and were randomized (196 metformin, 194 placebo). About 353 patients completed 16 weeks of treatment (171 metformin, 182 placebo).


METHODS
The HOME trial was designed to study the metabolic and cardiovascular effects of metformin during a follow-up of 4 years. Presented here are the results of an interim analysis after 16 weeks of treatment.


RESULTS
When compared with placebo, metformin treatment was associated with an increase in urinary albumin excretion of 21% (-1 to +48; P = 0.06); a decrease in plasma von Willebrand factor of 6% (-10 to -2; P = 0.0007); a decrease in soluble vascular cell adhesion molecule-1 of 4% (-7 to -2; P = 0.0002); a decrease in soluble E-selectin of 6% (-10 to -2; P = 0.008); a decrease in tissue-type plasminogen activator of 16% (-20 to -12; P < 0.0001); and a decrease in plasminogen activator inhibitor-1 of 20% (-27 to -10; P = 0.0001). These changes could not be explained by metformin-associated changes in glycaemic control, body weight or insulin dose. Markers of inflammation, i.e. C-reactive protein and soluble intercellular adhesion molecule-1, did not change with metformin treatment.


CONCLUSIONS
In patients with type 2 diabetes treated with insulin, metformin treatment was associated with improvement of endothelial function, which was largely unrelated to changes in glycaemic control, but not with improvement of chronic, low-grade inflammation.
De Jager
J
J
Department of Internal Medicine, Bethesda General Hospital Hoogeveen, Hoogeveen, The Netherlands.
Kooy
A
A
Lehert
Ph
P
Bets
D
D
Wulffelé
M G
MG
Teerlink
T
T
Scheffer
P G
PG
Schalkwijk
C G
CG
Donker
A J M
AJ
Stehouwer
C D A
CD
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000419:Albuminuria / Q000150:complications; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000032:analysis; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D019040:E-Selectin / Q000097:blood; D004730:Endothelium, Vascular / Q000503:physiopathology; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D007328:Insulin / Q000008:administration & dosage; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D008297:Male; D008687:Metformin / Q000008:administration & dosage*; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood; D010959:Tissue Plasminogen Activator / Q000097:blood; D019010:Vascular Cell Adhesion Molecule-1 / Q000097:blood; D014841:von Willebrand Factor / Q000032:analysis
D015415:Biomarkers; D019040:E-Selectin; D007004:Hypoglycemic Agents; D007328:Insulin; D017395:Plasminogen Activator Inhibitor 1; D019010:Vascular Cell Adhesion Molecule-1; D014841:von Willebrand Factor; D018799:Intercellular Adhesion Molecule-1; D002097:C-Reactive Protein; D008687:Metformin; D010959:Tissue Plasminogen Activator