Efficacy and safety of ezetimibe co-administered with simvastatin in thiazolidinedione-treated type 2 diabetic patients.
OBJECTIVE
In patients with type 2 diabetes mellitus (T2DM), combination therapy is usually required to optimize glucose metabolism as well as to help patients achieve aggressive targets for low-density lipoprotein cholesterol (LDL-C) and other lipid parameters associated with cardiovascular risk. The thiazolidinediones (TZDs) are increasingly being used for both their blood glucose-lowering properties and their modest beneficial effects on triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C). Ezetimibe, an intestinal cholesterol absorption inhibitor, has a mechanism of action that differs from that of statins, which inhibit hepatic cholesterol synthesis. We compared the lipid-modifying efficacy and safety of adding ezetimibe to simvastatin, vs. doubling the dose of simvastatin, in TZD-treated T2DM patients.


METHODS
This was a randomized, double-blind, parallel group, multicentre study in T2DM patients, 30-75 years of age, who had been on a stable dose of a TZD for at least 3 months and had LDL-C > 2.6 mmol/l (100 mg/dl) prior to study entry. Other antidiabetic medications were also allowed. Following 6 weeks of open-label simvastatin 20 mg/day, patients were randomized to the addition of either blinded ezetimibe 10 mg/day (n = 104) or an additional blinded simvastatin 20 mg/day (total simvastatin 40 mg/day; n = 110) for 24 weeks. Patients were stratified according to TZD type and dose (pioglitazone 15-30 vs. 45 mg/day; rosiglitazone 2-4 vs. 8 mg/day).


RESULTS
LDL-C was reduced more (p < 0.001) by adding ezetimibe 10 mg to simvastatin 20 mg (-20.8%) than by doubling the dose of simvastatin to 40 mg (-0.3%). Ezetimibe plus simvastatin 20 mg also produced significant incremental reductions in non-HDL-C (p < 0.001), very low-density lipoprotein cholesterol (p < 0.05) and apolipoprotein B (p < 0.001) relative to simvastatin 40 mg. There were no differences between the groups with respect to changes in TG and HDL-C levels, and both treatments were well tolerated.


CONCLUSIONS
Co-administration of ezetimibe with simvastatin, a dual inhibition treatment strategy targeting both cholesterol synthesis and absorption, is well tolerated and provides greater LDL-C-lowering efficacy than increasing the dose of simvastatin in T2DM patients taking TZDs.
Gaudiani
L M
LM
Marin Endocrine Associates, Greenbrae, CA 94904, USA. lmgmd@earthlink.net
Lewin
A
A
Meneghini
L
L
Perevozskaya
I
I
Plotkin
D
D
Mitchel
Y
Y
Shah
S
S
D000328:Adult; D000368:Aged; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D001055:Apolipoproteins B / Q000032:analysis; D001384:Azetidines / Q000627:therapeutic use*; D008078:Cholesterol, LDL / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D000069438:Ezetimibe; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D019821:Simvastatin / Q000627:therapeutic use*; D018709:Statistics, Nonparametric; D045162:Thiazolidinediones / Q000627:therapeutic use*
D000924:Anticholesteremic Agents; D001055:Apolipoproteins B; D001384:Azetidines; D008078:Cholesterol, LDL; D045162:Thiazolidinediones; C089946:2,4-thiazolidinedione; D019821:Simvastatin; D000069438:Ezetimibe