Kendall on TZDs
In the current Diabetes Care (Jan 1), there is a piece by Dr. David Kendall that reviews and supports early TZD use, based on: 1) improved insulin sensitivity and beta cell secretory function; 2) role of TZDs to improve CVD risk factors (hyperglycemia, hypertension, dyslipidemia, endothelial inflammation markers [c reactive protein, white blood cell count, fibrinogen, TNF alpha] and markers of elevated thrombotic risk) and to reduce CVD events.
Strangely, there's a line about how the ability of glitazones to improve insulin secretion is unique among current diabetes therapies - this strikes us as odd because Byetta does this also, in the presence of hyperglycemia. However, it may be that this paper is based on the ADA 2004 debate with Dr. Philip Home - in that case, at that time, Byetta wasn't approved. The article notes that there was supposed to be a "counterpoint" to this paper but that the author didn't submit it.
Back on TZDs! Kendall's piece notes that metformin probably just masks hyperglycemia but how TZDs appear to both prevent and delay diabetes onset. Kendall suggests that this is explained by an "off-loading" of the beta cell due to reduced insulin requirements resulting from increased insulin sensitivity in peripheral tissue. Theoretically, he says, off-loading preserves beta cell mass and improves secretory response, allowing secretion of insulin for a longer period, and effectively preventing diabetes development. There are a bunch of trials in process examining TZD use for pre-diabetes; DREAM is probably the highest profile. We are following the trials with bated breath!
The implications for Byetta on early TZD use and eventually early DPPIV use are of interest - right now, SFUs seem relatively tough early therapy due to tolerability although the A1C drop is decent at ~ 1.0.
Since TZD use is associated with weight gain, edema, and congestive heart failure (to what extent is controversial), it seem particularly important to get alternatives out, especially for early therapy. That said, it appears that edema/CHF is seen less when TZDs are taken early in disease progression, though the impact of taking over a longer period hasn't yet been reported.
We expect TZDs to get a major boost from pre-diabetes progression data; evidence from these trials won't be available for some time, however.