Carl Erik Mogensen
Professor of Medicine
Aarhus University Hospital
Among glucose-lowering agents currently available, none has conclusively been proven to be effective at reducing cardiovascular events in diabetic patients. A positive effect with metformin was strongly suggested in the UKPDS, but this was uncovered in post-hoc analysis.
The glitazones reduce blood glucose to a similar extent as other oral agents, but are interesting because they may have additional beneficial effects, such as decreasing insulin resistance by activating the PPAR-gamma receptor . Since insulin resistance is a major pathological feature in Type 2 diabetes, these drugs could provide a logical approach to treating the underlying metabolic disorder.
The PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive trial) was a randomized, double-blind, placebo-controlled trial assessing the effect of pioglitazone on macrovascular events in 5238 patients with Type 2 diabetes. The primary composite endpoint was the time to first occurrence of all-cause mortality, non-fatal myocardial infarction (MI), stroke, leg amputation, acute coronary syndrome, coronary bypass, or leg artery bypass.
The 3-year intervention in PROactive provided a relatively short period for any benefit in diabetic patients with advanced cardiovascular disease to become apparent. Nevertheless, in an unhealthy population, with a high event rate, a treatment benefit is more likely to be observed than it would be in patients with less advanced disease. The study would thus have been of greater clinical relevance had the results been more positive [3,4].
Absolute numbers of serious events observed in PROactive are shown in the table. The main problem with the study is that there was no significant effect on the composite primary endpoint.In retrospect the primary endpoint components could have been more wisely selected from a diabetologist’s point of view, with less emphasis on procedural events.
Table. Total number of serious events in the PROactive study
Glitazone group (n=2605)
Placebo group (n=2633)
Heart failure needing hospital admission*
*See also reference 19 (also a tendency with insulin treatment).
Some effect was seen on secondary endpoints, but this is difficult to evaluate and may be a post-hoc phenomenon. It is surprising, though, that there was no effect on all-cause mortality: quite unexpected since there were over 350 deaths in the trial.
Pioglitazone caused a significant reduction not only in HbA1c (difference of 0.5 %) but also in blood pressure (3 mmHg), the low density lipoprotein to high density lipoprotein ratio, and triglycerides, and therefore a positive effect on all end-points would be expected simply due to reduction in these important risk factors. The reduction in blood pressure alone is important, but this is not carefully discussed in the paper. Furthermore, we already have other means in reducing these risk factors more effectively in the clinical setting.
On the negative side, there was an increase in body weight (4 kg), which is not beneficial, especially in patients with cardiac impairment. As the reviewer, Dr. Hannele Yki-Jarvinen, pointed out , the results may be good for some patients who do not develop heart failure, but how can this be predicted?
A planned subgroup analysis of PROactive focused on those patients with a previous MI (approximately 50% of the population). The results, presented at the AHA annual congress in November, showed a greater benefit in both the primary endpoint and in MI in this “more sick” group. Nevertheless, this was a post-hoc analysis and the aforementioned drawbacks in interpreting the results remain.
Ideally, to assess its impact properly, a glitazone should be compared with the current best treatment for these patients. A comparison with metformin, as in some other glitazone studies, would have been more informative since this would adjust for glycemia. The ideal trial would probably be a placebo-controlled study on top of best evidence-based therapies, including statins, RAAS modulators, and aspirin, with non-glitazone oral antidiabetic agents in the control arm for glycemic control.A study adding glitazone or insulin treatment to metformin treatment would be interesting, but cannot be blinded.
Surprisingly, the glitazones are much more widely used in the USA than in Europe, despite the fact that we are still lacking studies with evidence for any beneficial effect on hard endpoints. Rosiglitazone and pioglitazone currently account for 5% of oral antihyperglycemic medication use in Europe, compared with about 20% of that in the USA . Why is there such a difference? Are those of us in the old world becoming skeptical? It seems so, given that guidelines in the UK and throughout the European Union limit the their place in therapy, on the basis of insufficient evidence of cost-effectiveness.
Another important point in PROactive was that no additional benefit of pioglitazone was seen in patients already treated with statins, which are now standard treatment in Type 2 diabetes, irrespective of the presence of cardiovascular disease. Therefore, one could argue that there would be no further effect of glitazones in patients with Type 2 diabetes managed according to current practice.
However, an important positive finding was that there were no very severe side effects of the drug, particularly because an earlier glitazone, troglitazone, had been associated with liver-toxicity, which was not seen in this study.
The results of PROactive raise doubts that glitazones are any solution for the immense problem we are facing with the increasing number of patients who have poorly controlled Type 2 diabetes. We know that we can control complications more effectively with a multifactorial intervention strategy , tight control of blood glucose and blood pressure, and aggressive cholesterol lowering treatment, and we still have to await the outcome of ongoing studies to determine whether glitazones deserve a major role in this strategy.
There is scope for improvement in the management of diabetic patients with cardiovascular disease. They certainly have a poor prognosis  and many of the patients are not diagnosed before they enter a cardiology unit.
For Type 2 diabetes in general, we still use the traditional drugs, both as monotherapy and in combination to try to improve their overall treatment effects. Sulfonylureas are still widely used, although less so than previously, and in Europe there is less fear of cardiovascular side effects, which may be the case in the US. Metformin has been used increasingly in Europe for many years and has now also become very popular in the US.
Insulin is still a cornerstone in the treatment of many patients with Type 2 diabetes, including patients with cardiovascular disease, who need to be treated with insulin in order to obtain better glycemic control. A few patients may benefit from glitazones if they cannot accept treatment with insulin, but generally insulin is preferable because it usually provides the better control and the dose can easily be adjusted, also to high doses. It has been argued that the glitazones may have an insulin sparing effect, but this is not particularly relevant in practice.
There are many other trials being conducted in Type 2 diabetes, for which we are still awaiting endpoint results. For example, a series of outcome studies with rosiglitazone are underway. One of these is ACCORD, a 5.5-year study including over 10,000 patients that will compare the effect on major cardiovascular events of intensive versus standard glucose lowering, as well as intensive versus standard lipid control and blood-pressure lowering . Another is RECORD, a 6-year study comparing the effect on long-term cardiovascular events of rosiglitazone, metformin, and sulfonylurea, as add-on therapy in over 4,000 patients with uncontrolled glucose on either metformin or sulfonylurea alone . Both these trials are due to report around 2010.
The ADDITION study is looking at a short-acting insulin-stimulating drug in patients found after screening . Another interesting study is the VADT study  using a multifactorial intervention strategy. Interestingly, the ADVANCE study is assessing a more traditional strategy using sulfonylurea with ACE inhibitors, drugs that have proved very useful independently for glucose and blood-pressure lowering, respectively, and will be assessed for their combined impact on hard endpoints in this important study.Meanwhile, the ADVANCE study will provide some important additional information to complement the UKPDS study, as it is assessing patients with longer diabetes duration .
Interestingly the DIGAMI-II Study  did not reveal any superiority of insulin treatment in patients with myocardial infarction. It was rather a traditional risk factor underlying this result, namely glycemic control. Patients treated with sulfonylurea, in fact, had a better prognosis than patients treated with insulin, although the difference was not significant.
Whether the glitazones have an effect on diabetic nephropathy is still uncertain . There was no effect on microalbuminuria in the PROactive Study, as evaluated by the Micral-test , and we are still awaiting results from a number of trials that may shed light on long-term effects on cardiovascular disease in comparison with multifactorial intervention[8,9,15-17].
Finally the costs of pioglitazone may be around US $2000 per year for an average patient (based upon costs in Denmark). Readers are referred to the Editorial by Jay S. Skyler in DOC News on that subject , and a study showing increased hospitalizations for heart failure associated with thiazolidinedione therapy .
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