] Diab Cony, 6:69
Editorial
Aldose Reductase hzhibitors--Hope or Hype
I
n this issue of theJournal of Diabetes and Its Complications you will find two articles describing the effect of the aldose reductase inhibitor agent, ponalrestat, on the progression of diabetic neuropathy and retinopathy. Essentially no benefit accrued to the diabetic patients who were treated with the drug as compared with those who were treated with placebo. Sundkvist et al. treated 259 diabetic patients with peripheral diabetic neuropathy with 600 mg per day of ponalrestat or placebo for 18 months. No beneficial effect of ponalrestat was seen in electrophysiological tests or vibration perception thresholds. There was a suggestion that the drug might prevent further deterioration of abnormal autonomic nerve function. Arauz-Pacheco et al. treated 49 diabetic patients with diabetic retinopathy with either 600 mg of ponalrestat per day or placebo. Both treatment groups showed progression of retinopathy over the 18 months of study. Ponalrestat treatment had no clinically significant effect on the progression of diabetic retinopathy. These two reports can be added to an increasingly long list of studies that have failed to show a significant beneficial clinical effect of aldose reductase inhibitor drugs. Ponalrestat is only one of several such drugs to be taken to clinical trials, found to be ineffective or toxic, and then withdrawn from further development. Sorbinil, the first aldose reductase inhibitor drug to be tested, was withdrawn primarily because of excessive side effects. Personally, I had never been convinced that the human data were strong enough to pass Food and Drug Administration (FDA) muster had it not been so toxic. Tolrestat is still in clinical trials in the United States, although it is presently available clinically in some other countries. It, too, has failed to pass FDA muster on its first attempt to gain approval. Are these drugs really no good? There are several
0 1992 ]ournal of Diabetes and Its Complications
possible explanations for the results of Sundkvist et al. and Arauz-Pacheco et al. The most obvious is that the drug was ineffective or was given in an inadequate dose. Another explanation, that has more global implications, is that the polyol hypothesis as a mechanism for tissue damage by hyperglycemia is incorrect. This hypothesis has been extant for almost 30 years. Yet to date, no one has been able to show clear-cut effects of agents which block aldose reductase on the development or progression of the complications of diabetes in humans. Before we turn our backs on the polyol hypothesis, we must look at the nature of most of the studies in humans. The two published in this issue of the Journal of Diabetes and Its Complications lasted for only 18 months. Others have been of even shorter duration. From my perspective it seemsimpossible to expect to see an effect in 1.5 years in disorders like retinopathy and neuropathy that take 20-30 years to develop. Despite what I’ve written so far, I am bullish on aldose reductase inhibitor drugs as potential treatment for diabetic patients. I do believe that a safe effective inhibitor of aldose reductase will eventually be found and given approval by the FDA. Tolrestat may be close to achieving that goal, already. However, I think it is clear that we cannot continue indefinitely to fail to show clinical efficacy with aldose reductase inhibitor drugs. Eventually the FDA will not be willing to put people at risk in testing a class of drug that has failed to show efficacy on repeated attempts. I would agree with that decision. Thus, as new drugs become available for clinical evaluation, the trials must be well designed and the data collection immaculate. I also believe they must last a sufficient length of time to provide a better chance of success. I don’t believe patients with diabetes can stand many more failures. Philip Raskin, MD
0891-6632/92/$5.00
Editorial
Aldose Reductase hzhibitors--Hope or Hype
I
n this issue of theJournal of Diabetes and Its Complications you will find two articles describing the effect of the aldose reductase inhibitor agent, ponalrestat, on the progression of diabetic neuropathy and retinopathy. Essentially no benefit accrued to the diabetic patients who were treated with the drug as compared with those who were treated with placebo. Sundkvist et al. treated 259 diabetic patients with peripheral diabetic neuropathy with 600 mg per day of ponalrestat or placebo for 18 months. No beneficial effect of ponalrestat was seen in electrophysiological tests or vibration perception thresholds. There was a suggestion that the drug might prevent further deterioration of abnormal autonomic nerve function. Arauz-Pacheco et al. treated 49 diabetic patients with diabetic retinopathy with either 600 mg of ponalrestat per day or placebo. Both treatment groups showed progression of retinopathy over the 18 months of study. Ponalrestat treatment had no clinically significant effect on the progression of diabetic retinopathy. These two reports can be added to an increasingly long list of studies that have failed to show a significant beneficial clinical effect of aldose reductase inhibitor drugs. Ponalrestat is only one of several such drugs to be taken to clinical trials, found to be ineffective or toxic, and then withdrawn from further development. Sorbinil, the first aldose reductase inhibitor drug to be tested, was withdrawn primarily because of excessive side effects. Personally, I had never been convinced that the human data were strong enough to pass Food and Drug Administration (FDA) muster had it not been so toxic. Tolrestat is still in clinical trials in the United States, although it is presently available clinically in some other countries. It, too, has failed to pass FDA muster on its first attempt to gain approval. Are these drugs really no good? There are several
0 1992 ]ournal of Diabetes and Its Complications
possible explanations for the results of Sundkvist et al. and Arauz-Pacheco et al. The most obvious is that the drug was ineffective or was given in an inadequate dose. Another explanation, that has more global implications, is that the polyol hypothesis as a mechanism for tissue damage by hyperglycemia is incorrect. This hypothesis has been extant for almost 30 years. Yet to date, no one has been able to show clear-cut effects of agents which block aldose reductase on the development or progression of the complications of diabetes in humans. Before we turn our backs on the polyol hypothesis, we must look at the nature of most of the studies in humans. The two published in this issue of the Journal of Diabetes and Its Complications lasted for only 18 months. Others have been of even shorter duration. From my perspective it seemsimpossible to expect to see an effect in 1.5 years in disorders like retinopathy and neuropathy that take 20-30 years to develop. Despite what I’ve written so far, I am bullish on aldose reductase inhibitor drugs as potential treatment for diabetic patients. I do believe that a safe effective inhibitor of aldose reductase will eventually be found and given approval by the FDA. Tolrestat may be close to achieving that goal, already. However, I think it is clear that we cannot continue indefinitely to fail to show clinical efficacy with aldose reductase inhibitor drugs. Eventually the FDA will not be willing to put people at risk in testing a class of drug that has failed to show efficacy on repeated attempts. I would agree with that decision. Thus, as new drugs become available for clinical evaluation, the trials must be well designed and the data collection immaculate. I also believe they must last a sufficient length of time to provide a better chance of success. I don’t believe patients with diabetes can stand many more failures. Philip Raskin, MD
0891-6632/92/$5.00
