Elsevier

The Lancet

Volume 363, Issue 9413, 20 March 2004, Pages 925-931
The Lancet

Articles
European Nicotinamide Diabetes Intervention Trial (ENDIT): a randomised controlled trial of intervention before the onset of type 1 diabetes

https://doi.org/10.1016/S0140-6736(04)15786-3Get rights and content

Summary

Background

Results of studies in animals and human beings suggest that type 1 diabetes is preventable. Nicotinamide prevents autoimmune diabetes in animal models, possibly through inhibition of the DNA repair enzyme poly-ADP-ribose polymerase and prevention of β-cell NAD depletion. We aimed to assess whether high dose nicotinamide prevents or delays clinical onset of diabetes in people with a first-degree family history of type 1 diabetes.

Methods

We did a randomised double-blind placebo-controlled trial of nicotinamide in 552 relatives with confirmed islet cell antibody (ICA) levels of 20 Juvenile Diabetes Federation (JDF) units or more, and a non-diabetic oral glucose tolerance test. Participants were recruited from 18 European countries, Canada, and the USA, and were randomly allocated oral modified release nicotinamide (1·2 g/m2) or placebo for 5 years. Random allocation was done with a pseudorandom number generator and we used size balanced blocks of four and stratified by age and national group. Primary outcome was development of diabetes, as defined by WHO criteria. Analysis was done on an intention-to-treat basis.

Findings

There was no difference in the development of diabetes between the treatment groups. Of 159 participants who developed diabetes in the course of the trial, 82 were taking nicotinamide and 77 were on placebo. The unadjusted hazard ratio for development of diabetes was 1·07 (95% CI 0·78–1·45; p=0·69), and the hazard ratio adjusted for age-at-entry, baseline glucose tolerance, and number of islet autoantibodies detected was 1·01 (0·73–1·38; p=0·97). Of 168 (30·4%) participants who withdrew from the trial, 83 were on placebo. The number of serious adverse events did not differ between treatment groups. Nicotinamide treatment did not affect growth in children or first-phase insulin secretion.

Interpretation

Large-scale controlled trials of interventions designed to prevent the onset of type 1 diabetes are feasible, but nicotinamide was ineffective at the dose we used.

Introduction

Type 1 diabetes might be a preventable disease. Many successful interventions have been described in the non-obese diabetic (NOD) mouse.1 In human beings, results of prospective studies in high-risk relatives of people with diabetes have shown a long latent period between the first appearance of circulating autoantibodies directed against antigens derived from pancreatic islets and the clinical onset of the disease.2 Multiple autoantibodies are present in most newly diagnosed cases at the time of diagnosis, and their presence is highly predictive of progression to disease in otherwise healthy first-degree relatives.3 Type 1 diabetes is a serious and currently incurable disease with a prodrome that offers a long window of opportunity for screening. Inexpensive validated methods are available. On this basis, screening and intervention before the onset of type 1 diabetes would be justified if there were a cost-effective means of intervention.

Pretreatment with high dose nicotinamide has been known for many years to prevent the development of diabetes in rats treated with streptozotocin. Nicotinamide also prevents or delays the onset of diabetes in the non-obese diabetic mouse, and results of in-vitro studies have shown that it can prevent β-cell damage. Nicotinamide affords a degree of protection to β cells after the diagnosis of diabetes in humans4 and has been reported to prevent the development of diabetes in schoolchildren with islet-cell antibodies (ICA).5 The results of small pilot studies of nicotinamide in high-risk relatives were also promising.6 As the safety profile in humans seems favourable,7 we aimed to assess whether high dose nicotinamide could delay or prevent the onset of diabetes in people at high risk of progression to the disease.

First-degree relatives of a patient with type 1 diabetes provided an accessible and highly motivated population for such an intervention. Furthermore, the risk of progression to disease associated with ICA and other antibody markers has been accurately quantified for this group of people, with remarkable consensus between studies throughout the world.8, 9, 10 However, the logistics of such a study are daunting, since only a small proportion of first-degree relatives are at high enough risk of the disease to justify intervention. Of the 84228 relatives screened for the Diabetes Prevention Trial—Type 1 (DPT-1), only 339 participants were identified for inclusion in the trial of parenteral insulin to prevent type 1 diabetes in high risk individuals.11 A screening exercise of this size needs the resources of a whole continent, and therefore, this investigator-led study included participants from 18 European countries, Canada, and a group in the USA.

Section snippets

Methods

The protocol and outcome of the screening stages of ENDIT have been published elsewhere.12

Results

Between between June, 1994, and May, 1998, we enrolled 552 participants. The interval between collection of samples for ICA positivity and randomisation was less than 18 months in all but 11 participants, and less than 2 years in all but one who was randomly allocated to treatment 26 months after ICA positivity was confirmed. Figure 1 shows the trial profile. Of 552 individuals randomly allocated to a study group, 549started their trial medication.

Participants' baseline characteristics are

Discussion

We have shown that at the doses used, nicotinamide is ineffective in the prevention of type 1 diabetes. The proportion of relatives who developed diabetes within 5 years was almost identical in those treated with nicotinamide and those on placebo, and there was no suggestion of a treatment effect in any of the subgroups defined by well established markers of additional risk. Type 1 diabetes meets every criterion for a disease for which screening would be justified 20 save one: we lack an

References (31)

  • BingleyPJ

    Interactions of age, islet cell antibodies, insulin autoantibodies, and first-phase insulin response in predicting risk of progression to IDDM in ICA+ relatives: the ICARUS data set

    Diabetes

    (1996)
  • Effects of insulin in relatives of patients with type 1 diabetes

    N Engl J Med

    (2002)
  • The European Nicotinamide Diabetes Intervention Trial (ENDIT) group

    Intervening before the onset of Type 1 diabetes: baseline data from the European Nicotinamide Diabetes Intervention Trial (ENDIT)

    Diabetologia

    (2003)
  • WHO

    Diabetes Mellitus: Report of a WHO Study Group

    (1985)
  • BingleyPJ et al.

    Standardization of IVGTT to predict IDDM

    Diabetes Care

    (1992)
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