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| Glitazones in Type 2 Diabetes Rosiglitazone and pioglitazone are relatively recent additions to the therapeutic options for type 2 diabetes. Both drugs are able to reduce levels of hemoglobin A1c (A1c), but their effects on lipids differ significantly. Pioglitazone reduces triglycerides and increases high-density lipoprotein cholesterol (HDL-C), whereas rosiglitazone increases low-density lipoprotein cholesterol (LDL-C), has modest effects on HDL-C and has no effect on triglycerides[1]. Pioglitazone: the PROactive trial In the PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events) study, pioglitazone or placebo was given to 5238 patients with both type 2 diabetes and existing cardiovascular disease. Notably, there was an insignificant reduction of 10% in the primary composite endpoint, which comprised cardiac, cerebrovascular and peripheral vascular events [2]. A main secondary endpoint of death, myocardial infarction (MI) and stroke, defined shortly before the study was completed, was significantly reduced by 16%. Subgroup analysis has demonstrated a significant reduction in further MIs in patients who have had a previous MI [3], and strokes in patients who have had a previous stroke [4]. The main side-effects were weight gain and fluid retention, mediated by renal mechanisms, and indeed in some patients this unmasked cardiac failure[2]. Rosiglitazone: the DREAM, ADOPT and RECORD trials In the DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) trial, rosiglitazone was used in patients with typical prediabetic states of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) [5]. A 60% reduction in the progression to diabetes was demonstrated while patients were still being treated with rosiglitazone. Furthermore, patients in this study had no pre-existing vascular disease, and in comparison with the placebo group, there was a significant increase in cardiac failure. An insignificant increase in other vascular outcomes such as MI and new angina was also demonstrated. The largest study investigating the glycemic effects of rosiglitazone has been the ADOPT (A Diabetes Outcome Progression Trial) study [6], which compared rosiglitazone with metformin and glibenclamide as the initial treatment in diabetic patients who were mostly free of vascular disease at baseline. The primary endpoint was an increase in fasting blood glucose (FBG) concentration to more than 10 mmol/l, at which point it was deemed that combination therapy was required. Rosiglitazone significantly reduced the monotherapy failure rate compared with that of metformin, which in turn performed better than glibenclamide. Statistical differences in HbA1c levels were observed, but clinically these differences were not impressive. Treatment with rosiglitazone in the ADOPT study resulted in weight gain and cardiac failure side-effects similar to those observed after treatment with pioglitazone in the PROactive study. In addition, there was a non-significant increase in other vascular events, including MI, similar to observations in the DREAM study. A new side-effect, fracture of long bones in women, was also seen with rosiglitazone therapy, and moreover retrospective analysis showed that this was also a consequence of pioglitazone therapy. Nissen article in NEJM May 21 2007: Media interest was stimulated upon publication of meta-analysis that included data from DREAM and ADOPT, as well as from 40 other studies that investigators identified from the Food and Drug Administration (FDA) and GlaxoSmithKline (GSK) websites as having the following requisites:
Eighty six MIs were observed in 15,565 patients being treated with rosiglitazone, compared with 72 MIs in 12,282 patients in the comparator group, an odds ratio of 1.43 (95% confidence interval, 1.03-1.98; P=0.03). The odds ratio for cardiovascular death was insignificantly increased. It should be pointed out that although the relative risk for MI in the Rosiglitazone group was increased by 43% compared to placebo that the absolute risk was very small in the order of ½ of 1% and the increased risk was of the order of 4/100ths of 1%. Assuming that treatment with Rosiglitazone results in a 1% decrease in A1c and that the UKPDS results have shown that a 1% A1c reduction leads to a 16% reduction in incidence of MI. Netting out the increased with the decreased risk leads to a net reduction of 15.6% in MI risk. Other meta-analyses done subsequently have shown somewhat inconsistent results. It needs to be kept in mind that the meta-analysis is a poor second cousin to the randomized controlled trial (RCT) in the hierarchy of evidence and that the RECORD trial was set up specifically to look at the question of cardiovascular outcomes. The RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycaemia in Diabetes) trial, due for completion in 2009, is a cardiovascular endpoint study that was prospectively established to examine the cardiovascular effects of rosiglitazone. An interim analysis showed no significant differences between the rosiglitazone group and the control group regarding MI and death from cardiovascular causes, but an increase in these events could not be excluded [8]. This highlights major deficiencies in study design. The RECORD trial is an open-label, ‘non-inferiority’ study and is not double-blind. To date, as many as 10% of patients have been lost to follow-up, and the primary event rate is much lower than predicted. Interestingly, when these data are added to the meta-analysis, there remains a significant increase in MIs with rosiglitazone. There are concerns that subjects may not wish to continue with open-label rosiglitazone following the adverse publicity, so the study may not provide a clear answer as to whether MIs are increased with rosiglitazone or not. Conclusions: The Glitazones; Pioglitazone (Actos) and Rosiglitazone (Avandia) have been licensed and approved for the treatment of Type 2 Diabetes for about 10 years. They have shown efficacy in reducting glycemia with the ability to lower A1c by 1-1.5%. The unique property of these drugs has been the ability to prolong the function of the beta cell, the failure of which had been a feature of Type 2 Diabetes irrespective of other treatment choices. The DREAM study showed that Rosiglitazone treatment can prevent diabetes in 65% of people with pre-diabetes. The ADOPT study demonstrated preservation of beta cell function by showing that Rosiglitazone was the treatment that lasted longest without failure. The PROACTIVE study showed that Pioglitazone extended the time before insulin was required. These medications have unique advantages, particularly in the early stages of Type 2 Diabetes when there is still pancreatic function to preserve. The downside is weight gain and an increased incidence of Congestive Cardiac Failure, the medications should be avoided in individuals with heart disease who may not be able to handle the increased fluid load. Both Glitazones need a period of months before full benefits are seen and we must be alert to discontinue the medications if the risks outweigh the benefits. References
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