Cyclosporin and other immunosuppressive agents have been proposed as a preventive treatment against the development of insulin-dependent diabetes mellitus (IDDM) in relatives at increased risk for the disease, based on the understanding that its etiology is an ongoing process of autoimmune β-cell destruction. We used an epidemiological approach to evaluate several recent trials of cyclosporin in newly diagnosed IDDM patients to determine the degree of benefit that is to be expected. We assessed these and other studies to estimate the potential adverse effects of such treatment, were it to be used in the future, either in newly diagnosed subjects or healthy high-risk relatives. Standard sample-size calculations were used to quantify the number of study subjects necessary to allow adequate statistical power to test the positive and negative effects of a future treatment (α = 0.05, β = 0.20). The estimates were based on the data available from published studies of cyclosporin treatment. The importance of conducting an adequate trial of such a therapy, both from an ethical and a practical viewpoint, is discussed. Five small immunosuppression trials were evaluated. Remission rates in treated subjects exceeded those in control subjects by 15-59%. Variability in defining remission may account for the differences in rates across the studies. Estimates of the major beneficial and adverse effects of cyclosporin were derived from these trials and studies of patients who have undergone long-term immunosuppression. Indicators of kidney damage associated with cyclosporin treatment were reported in 5-47% of treated subjects. A threefold increase in the rate for all cancers and an eightfold increase in the rate for non-Hodgkin's lymphoma were reported in immunosuppressed autoimmune patients. To detect a beneficial effect such as that described for cyclosporin, between 14 and 2598 subjects would be required in a clinical trial. Sample-size calculations demonstrated that between 1200 and 156,000 subjects would need to be enrolled in such a trial to detect a twofold increase over baseline levels of the adverse effects reported in the studies reviewed herein. Of critical importance are not the specific findings concerning the risks and benefits of cyclosporin but rather the use of an epidemiological approach for evaluating any future immunosuppressive treatments designed to prevent or cure IDDM.
