Diabetes drugs- TZDs

Question 1

Thiazolidinediones – molecular mechanism (4)

Answer 1

TZDs are PPARg ligands

Ligand binding results in formation of a complex with a co-activator

Increased transcriptional activation of PPARg target genes

There are 100s of target genes – some beneficial, some adverse

Question 2

Thiazolidinediones – physiological mechanism (6)

Answer 2

Main effect is on adipocytes

1. Increase differentiation from pre-adipocytes to adipocytes
2. Increases fat mass (subcutaneous)
3. ‘lipid steal’ – FFA uptake removes fat from liver and muscle. Reduces lipotoxicity.
   4.Increases adiponectin which acts on liver to increase insulin sensitivity
   5.Net result – increased insulin sensitivity

Question 3

Thiazolidinediones - simply (4)

Answer 3

Otherwise known as glitazones. First licensed 1997.

PPARg agonists – results in switching on 100s of genes

Net effect is to increase fat mass in subcutaneous depots and to ‘suck out’ fat from viscera (liver, pancreas) and muscle

Also increased adiponectin and reduced ‘inflammatory cytokines’ like TNFa and IL-6

Question 4

Thiazolidinediones – clinical use (6)

Answer 4

Good efficacy – 15-20mmol/mol HbA1c reduction; especially potent in obese women

Increase in weight – due to increase in fat mass and fluid retention

Reduction in blood pressure – SBP by 4.7 and DBP by 3.8 mmHg

Only available TZD is Pioglitazone
-Troglitazone was withdrawn soon after licensed due to idiosyncratic liver reactions
-Rosiglitazone was withdrawn after many years of use – due to discovery of potential increase in CV death

Pioglitazone 15-30mg od

Question 5

Thiazolidinediones – side effects (3)

Answer 5

Weight gain

Fluid retention – resulting in peripheral oedema and doubling of risk of hospitalization for cardiac failure.
But absolute risk in younger patients without HF is very low

Fracture risk – fat accumulation in bone marrow and reduction in bone density.Up to doubling of fracture risk esp in the elderly.

Question 6

Thiazolidinediones – CV risk (2)

Answer 6

Pioglitazone (but not rosiglitazone) probably reduces CV risk

PROactive study showed a 16% reduction in main secondary endpoint (all cause mortality, non-fatal MI, stroke)