Exenatide effects on statin pharmacokinetics and lipid response.
OBJECTIVE
Exenatide is an adjunctive treatment for type 2 diabetes. Many patients with type 2 diabetes have dyslipidemia, which requires treatment with three hydroxy-3-methyl glutaryl coenzyme (HMG-CoA) reductase inhibitors (statins), hence, concurrent use of exenatide and statins is likely. Exenatide slows gastric emptying, which may alter the absorption rate of co-administered oral medications. Thus, the potential interaction between exenatide and statins was evaluated in two study settings.


METHODS
In an open-label, fixed-sequence, clinical pharmacology study, the plasma pharmacokinetics of lovastatin (40 mg after breakfast) in the presence and absence of exenatide (10 microg before breakfast and dinner) was evaluated in 21 healthy subjects. In a second clinical setting, changes in lipid profiles and statin dosage over 30 weeks in patients with type 2 diabetes were retrospectively compared (n = 180 exenatide 10 microg twice daily (BID), n = 168 placebo BID) in a combined analysis of three placebo-controlled, randomized exenatide Phase 3 trials.


RESULTS
In healthy subjects, exenatide decreased mean lovastatin area under the plasma concentration time curve from zero to infinity (AUC0-infinity) and maximum plasma concentration (Cmax) by 40 and 28%, respectively, and increased median time to maximum plasma concentration (tmax) by 4 hours. In the exenatide Phase 3 trials, 30-week changes from baseline for low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol, triglycerides and statin dosage were not significantly different between the exenatide and placebo groups treated with statins.


CONCLUSIONS
Despite observed changes in lovastatin bioavailability in the pharmacokinetic drug interaction study, exenatide did not negatively affect long-term lipid profiles or statin dosage in patients with concurrent statin therapy. Thus, co-administration of exenatide does not require adjustment in statin dosage.
Kothare
P A
PA
Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. kotharep@lilly.com
Linnebjerg
H
H
Skrivanek
Z
Z
Reddy
S
S
Mace
K
K
Pena
A
A
Han
J
J
Fineman
M
M
Mitchell
M
M
D000293:Adolescent; D000328:Adult; D000368:Aged; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D004347:Drug Interactions; D000077270:Exenatide; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008055:Lipids / Q000097:blood*; D008148:Lovastatin / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000494:pharmacology* / Q000627:therapeutic use; D014688:Venoms / Q000494:pharmacology* / Q000627:therapeutic use
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007004:Hypoglycemic Agents; D008055:Lipids; D010455:Peptides; D014688:Venoms; D008148:Lovastatin; D000077270:Exenatide