Block 1 Lecture 4 -- Thiazolidinediones Flashcards
What was the first TZD?
troglitazone
What are the currently available TZDs?
rosiglitazone
pioglitazone
Why is troglitazone no longer available?
development of rare, idiosyncratic liver toxicity that progressed from hepatic failure to death
When was troglitazone removed?
2000
What is PPAR-gamma?
peroxisome proliferator-activated receptor-gamma
– nuclear hormone receptor (transcription factor)
What are the endogenous ligands of PPAR-gamma?
oxidized fatty acids
Where is PPAR-gamma mainly expressed?
adipose
How were TZDs discovered?
during screening for lipid-lowering agents
What is the function of PPAR-gamma?
regulate glucose- and lipid-metabolism genes
What is PPAR-gamma’s effect on insulin resistance?
1) decreased lipolysis –> decreased FFA release
- - fat cell differentiation
- - liver/muscle TG –> SubQ
2) decreased [TNF-alpha] release
What is PPAR-gamma’s effect on muscle?
increased [GLUT-4]
– indirect effect…not exposed to high concentrations of FFAs
How is pioglitazone different from rosiglitazone?
pioglitazone cross-reacts with PPAR-alpha
What are the effects of PPAR-alpha agonism (pioglitazone)?
- slight decrease in plasma TG
- slight increase in HDL
- minor decrease in CV endpoints
What is the MoA of TZDs?
synthetic ligands of PPAR-gamma
– reduce insulin resistance (via lipolysis & TNF; and via GLUT-4 in muscle)
What conclusions have been made about rosiglitazone’s CV ADRs?
1) no beneficial CV effects
2) no increased risk of MI if combined with metformin or sulfonylurea (vs. metformin OR sulfonylurea)
heart failure, stroke, etc. not addressed
What are the ADRs of TZDs?
1) fluid retention, weight gain
2) increased heart failure risk
Why don’t TZDs produce hypoglycemia?
lower [glucose] only in presence of insulin by improved sensitivity
What are contraindications of TZDs?
moderate-severe (NYHA Class III/IV) heart failure
Describe the onset of TZDs.
slow onset
- 1-3 months until max effect
- longer-lasting effects (years) compared to sulfonylureas
Describe the absorption of TZDs.
well-absorbed without regard to food
Describe the metabolism of TZDs.
hepatic (CYP2C8)
– does not affect kinetics of other drugs
Why do TZDs carry a heart failure risk?
plasma volume expansion, edema (not macrovascular/atherosclerotic)
What restrictions are on TZDs?
none (REMS removed)
What does REMS stand for?
Risk Evaluation and Mitigation Strategy
Is there a box warning for TZDs?
yes – heart failure
liver toxicity no longer a boxed warning
Quantify the risk for TZDs and heart failure.
chronic use = 2x increase; most often when combined with insulin
Why do TZDs cause fluid volume expansion?
PPAR-gamma in kidney has these effects
When are TZDs used?
after secondary failure (for patients not controlled by other agents)
– NOT FIRST LINE
Describe the effectiveness of TZDs.
effective in majority of new patients
effective when combined with metformin, sulfonylureas, insulin
What testing is recommended for TZDs?
routine liver enzyme tests (recommended by FDA)
Why is liver toxicity no longer a labeled warning?
no evidence of liver toxicity with either agent
What is the indication for TZDs?
t2dm
