Block 1 Lecture 4 -- Thiazolidinediones

Question 1

What was the first TZD?

Answer 1

troglitazone

Question 2

What are the currently available TZDs?

Answer 2

rosiglitazone

pioglitazone

Question 3

Why is troglitazone no longer available?

Answer 3

development of rare, idiosyncratic liver toxicity that progressed from hepatic failure to death

Question 4

When was troglitazone removed?

Answer 4

2000

Question 5

What is PPAR-gamma?

Answer 5

peroxisome proliferator-activated receptor-gamma

– nuclear hormone receptor (transcription factor)

Question 6

What are the endogenous ligands of PPAR-gamma?

Answer 6

oxidized fatty acids

Question 7

Where is PPAR-gamma mainly expressed?

Answer 7

adipose

Question 8

How were TZDs discovered?

Answer 8

during screening for lipid-lowering agents

Question 9

What is the function of PPAR-gamma?

Answer 9

regulate glucose- and lipid-metabolism genes

Question 10

What is PPAR-gamma’s effect on insulin resistance?

Answer 10

1) decreased lipolysis –> decreased FFA release
- - fat cell differentiation
- - liver/muscle TG –> SubQ
2) decreased [TNF-alpha] release

Question 11

What is PPAR-gamma’s effect on muscle?

Answer 11

increased [GLUT-4]

– indirect effect…not exposed to high concentrations of FFAs

Question 12

How is pioglitazone different from rosiglitazone?

Answer 12

pioglitazone cross-reacts with PPAR-alpha

Question 13

What are the effects of PPAR-alpha agonism (pioglitazone)?

Answer 13

• • slight decrease in plasma TG
• • slight increase in HDL
• • minor decrease in CV endpoints

Question 14

What is the MoA of TZDs?

Answer 14

synthetic ligands of PPAR-gamma

– reduce insulin resistance (via lipolysis & TNF; and via GLUT-4 in muscle)

Question 15

What conclusions have been made about rosiglitazone’s CV ADRs?

Answer 15

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

Question 16

What are the ADRs of TZDs?

Answer 16

1) fluid retention, weight gain

2) increased heart failure risk

Question 17

Why don’t TZDs produce hypoglycemia?

Answer 17

lower [glucose] only in presence of insulin by improved sensitivity

Question 18

What are contraindications of TZDs?

Answer 18

moderate-severe (NYHA Class III/IV) heart failure

Question 19

Describe the onset of TZDs.

Answer 19

slow onset

• • 1-3 months until max effect
• • longer-lasting effects (years) compared to sulfonylureas

Question 20

Describe the absorption of TZDs.

Answer 20

well-absorbed without regard to food

Question 21

Describe the metabolism of TZDs.

Answer 21

hepatic (CYP2C8)

– does not affect kinetics of other drugs

Question 22

Why do TZDs carry a heart failure risk?

Answer 22

plasma volume expansion, edema (not macrovascular/atherosclerotic)

Question 23

What restrictions are on TZDs?

Answer 23

none (REMS removed)

Question 24

What does REMS stand for?

Answer 24

Risk Evaluation and Mitigation Strategy

Question 25

Is there a box warning for TZDs?

Answer 25

yes – heart failure

liver toxicity no longer a boxed warning

Question 26

Quantify the risk for TZDs and heart failure.

Answer 26

chronic use = 2x increase; most often when combined with insulin

Question 27

Why do TZDs cause fluid volume expansion?

Answer 27

PPAR-gamma in kidney has these effects

Question 28

When are TZDs used?

Answer 28

after secondary failure (for patients not controlled by other agents)
– NOT FIRST LINE

Question 29

Describe the effectiveness of TZDs.

Answer 29

effective in majority of new patients

effective when combined with metformin, sulfonylureas, insulin

Question 30

What testing is recommended for TZDs?

Answer 30

routine liver enzyme tests (recommended by FDA)

Question 31

Why is liver toxicity no longer a labeled warning?

Answer 31

no evidence of liver toxicity with either agent

Question 32

What is the indication for TZDs?

Answer 32

t2dm