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Prof. Lars Ryden,
Presenter: Pfeffer, Marc (United States of America)
Discussant report: Ryden, Lars (Sweden)
This is a post hoc (?) subgroup analysis of the ARISE trial testing whether the antioxidant succinobucol may impact on prognosis as regards cardiovascular events in patients with serious atherosclerotic disease. As was shown, the primary outcome of the main study was negative. This means that, in a purely statistical perspective, one may argue that further analyses are obsolete. This would however not give us the interesting opportunity to look for new and potentially useful areas for this novel drug.
The subgroup analysis is based on the hypothesis that there is a link between dysglycaemia, cardiovascular disease and diabetes. This is an interesting concept that still awaits proof, but occupies many investigators. In particular, it has been assumed that postprandial hyperglycaemia, by inducing oxidative stress, may simultaneously have a negative impact on myocardial tissue and vascular structures, but also be harmful for the pancreatic beta cells, thereby in parallel causing cardiovascular disease and type 2 diabetes. If succinobucol protects from the oxidative forces, one may assume a decrease in deterioration towards diabetes and at the same time, less cardiovascular events.
The subgroup analysis is based on a large cohort of patients at very high risk with meticulous background therapy, therefore representative for the purpose. The reported endpoints are solid and well chosen. Looking at the results, a fairly big issue was made of the reduction in fasting glucose and HbA1c, but the factual decreases are indeed small. This means that even if they are highly statistically significant, the clinical value may be questioned. Commonly used glucose lowering agents usually result in a decrease of HbA1c in the range 1.0-2.0%, which is considerably more efficient. It was also said that the decease in HbA1c related to the baseline levels but patients with diabetes were 37% of the population. They were reasonably already on glucose lowering therapy. One may therefore ask how much changed glucose lowering therapy might have been behind the improved glucose control, in particular among subjects with a high glucose level at baseline. Furthermore, and reflecting on patients with an originally low HbA1c, one may ask how many of them actually had diabetes, or impaired glucose tolerance. The Euro Heart Survey on diabetes and the heart revealed that patients of the present composition have a normal glucose regulation only in less than one third, while the vast majority have either already known or hidden diabetes or impaired glucose tolerance. This relates to the most encouraging result of this report, namely the substantial decrease in patients with impaired fasting glucose that progressed to diabetes. We are now discussing a substantial number of patients, more than 1,000 patients with impaired fasting glucose, accordingly at a high risk for type 2 diabetes. It would have been interesting to know exactly how many indeed had impaired glucose tolerance or type 2 diabetes at baseline. Are we looking at a compound with a potential to reverse type 2 diabetes?
Let us finally look at the conclusions presented and let me give my own opinion about their validity:
1) Succinobucol is new adjunctive therapy that may reduce events in patients with coronary artery disease. This is not proven, and hardly likely. 2) Succinobucol is a compound that may reduce the risk of developing diabetes. This assumption is not proven but definitely deserves further exploration. 3) Succinobucol is a compound that may improve glycemic control in diabetes. This is not proven and actually not a key issue. 4) Finally, succinobucol is a compound that may preserve renal function. This is also not proven, and perhaps not clinically very important.
I do however agree with the grand conclusion that succinobucol needs further study in prospective, randomised controlled trials. We should remember that the ACE inhibitor ramipril considered to prevent diabetes as originally reported from the HOPE trial, did not have that capacity when finally tested in the DREAM trial. If uccinobucol is proven to be efficient in retarding or preventing diabetes, it may become a compound for patients with type 2 diabetes or impaired glucose tolerance with an unusually large safety profile data base.
The effect of the novel anti-oxidant AGI-1067 (succinobucol) on glycaemic control, new onset diabetes and clinical events in patients with a recent acute coronary syndrome: the Aggressive Reduction of Inflammation Stops Events study (ARISE).