CLINICAL-TRIALS OF DIABETIC NEUROPATHY - PAST, PRESENT, AND FUTURE

This article reviews current knowledge of the etiology of diabetic neu ropathy and the outcomes and Limitations of previous trials and discus ses future directions for the investigation of its prevention and trea tment. Proposed mechanisms for the development of diabetic neuropathy have been widely studied. It has been shown that there is improvement of nerve function associated with some short-term clinical trials of t reatments that address a number of possible etiologic pathways. Improv ement of morphometry has also been demonstrated in some shortterm clin ical trials. However, with the exception of the Diabetes Control and C omplications Trial (DCCT), longterm trials with adequate statistical p ower to evaluate clinical outcome endpoints have not been conducted. T he changes in nerve function are similar in most of the clinical trial s. For instance, in four clinical trials directed at separate mechanis ms (improved glucose control, high myo-inositol diet, therapy with an aldose reductase inhibitor, and therapy with supplementary gamma-linol enic acid), a similar improvement in peroneal motor velocity of 1-2 m/ s is observed. This implies that each of the proposed mechanisms contr ibutes equally to the development of neuropathy or that there is some redundancy to their mechanisms. In addition to an etiologic approach, nonspecific neural stimulants, such as gangliosides and nerve growth f actors, have also been investigated for the treatment of diabetic neur opathy. with the exception of the prevention of neuropathy by intensiv e glycemic control, the modest improvements with all other treatments have not led to sufficient evidence to approve any approach. Subanalys es of previous clinical trials suggest that treatment effects are grea test and most clear in patients with mild-to-moderate early neuropathy (stage I or early stage II). Thus, variation in composition and sever ity of base-line neuropathic disease in past clinical trials may have ''washed out'' any potential treatment effect. It is encouraging that more recent clinical trials have established more rigid inclusion and exclusion criteria so as to recruit only those patients with early or mild-to-moderate disease and a more homogeneous study population. Impr ovement with treatment has been measured with several markers includin g nerve conduction velocity, quantitative sensory testing, autonomic f unction testing, and morphometric changes. Presumably, the combined fi nding of improved nerve function and improved nerve morphometry will p redict improvement in long-term clinical outcomes such as impaired sen sation, painful neuropathy, insensitive feet, neurotrophic ulceration, and/or amputation. However, data to support this possibility are stil l lacking. It is our opinion that the overall design of neuropathy tri als must consider present knowledge about complications in general and neuropathy specifically. We recommend that future trials be conducted over long periods with clinically significant outcomes as in the angi otensin-converting enzyme-inhibitor nephropathy trials and the DCCT wi th the recognition that reducing the development, rather than reversal , of complications is the best that can be reasonably expected. Patien ts with mild-to-moderate neuropathy (stage I or early stage II) with p resumably more metabolic than structural neuropathy would be preferred subjects, and follow-up of 3-5 years is likely to be needed.