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ORIGINAL ARTICLE

Primary and Secondary Prevention Strategies of Pre–Type 1 Diabetes

Potentials and pitfalls

Gisela G. Dahlquist, MD, PHD

Over the past decade, a large part of type 1 diabetes research has focused on the possibility of preventing the disease. The objective of this article is to analyze which potential and pitfalls different preventive strategies may involve from the individual, epidemiological, and ethical perspectives. Two potential prevention strategies are considered: 1) to try to arrest or delay an already ongoing immune destruction of the -cells, and 2) to try to intervene with exposures that may initiate this process. In addition to the potential effects of immune modulation, this prevention strategy depends on screening for risk markers. There are inherent ethical problems with screening because of the introduction of awareness of risk in healthy individuals and also because false positivity, the rate of which differs tremendously in high- and low-risk groups. Because of these latter circumstances, the most promising low-risk preventive treatments presently used in trials, i.e., nicotinamide and insulin, will probably only be feasible in high-risk groups, such as family members, though this group covers only 10–15% of potential cases. The second strategy aiming at eradicating environmental initiators of the -cell destruction will avoid the problem of screening and approach a total population at risk. Potential risk factors, such as food components (cow's milk proteins, gliadin or nitroso products) or different viruses, are indicated by animal and epidemiological studies. So far, however, no single environmental risk factor has been proven to be necessary and certainly not sufficient for the disease causation, and the etiological fractions estimated in population-based studies are low. It is concluded that more basic research is warranted before effective and safe prevention can be introduced for type 1 diabetes. Most probably, different preventive strategies must be applied to different groups and populations and in different phases of the -cell destruction.

Diabetes Care 22 (Suppl. 2):B4–B6, 1999

Prevention of type 1 diabetes is an important task for researchers, because the disease most often affects young children and threatens not only the physical development but also the psychological and social development of the child. The life of the whole family is affected. The onset of type 1 diabetes in early childhood also means a threat that severe complications may occur in the most active period of life, that is, in the fourth or fifth decade. The improvements in the care of childhood diabetes during the past decades have significantly improved all aspects of living with the disease, but an effective prevention must still remain a goal, especially since in many countries the incidence of type 1 diabetes is rapidly increasing (1). Thus, during the past decade, a large part of type 1 diabetes research has focused on the possibility of preventing the disease. At this stage of development, it is important to analyze which potentials and pitfalls different preventive strategies may hide. When deciding which preventive strategy might, in a broad sense, be most cost-beneficial, not only facts and probabilities but also ethical values have to be taken into account, and the problem must be regarded in both an individual and a population perspective. This article aims at a critical discussion of present knowledge in the field rather than a review, but it is based on and refers to relevant and extensive published reviews.

CONCEPT AND POTENTIAL  SOLUTION— Primary prevention in the case of pre-type 1 diabetes could be divided into two levels: 1) to try to arrest or delay an already ongoing destruction of the -cells, and 2) to try to intervene with exposures that may initiate this process. For each level, different kinds of knowledge are necessary and different scientific and ethical problems occur. For either potential solution, the general concept must be that any presymptomatic treatment must have a benefit/risk ratio that is not only positive in both the short- and long-term perspectives but also higher than that of the optimal treatment of the clinically overt disease.

DISCOVERIES OF RELEVANCE— To arrest or delay an already ongoing pathogenic process, the mechanism of the -cell destruction must be known. Several different pathogenetic models have been proposed based on extensive experimental research, most of which include immune mechanisms (2). Despite some remaining controversy and the fact that many details are indeed lacking, there is good evidence that the -cell destruction is autoimmune in nature (3,4). Thus, immune modulation might be used for prevention at this stage of the disease (5). Because for most individuals at risk the time span between initiation of autoimmunity and clinically overt disease seems to be long, there is a potential to screen for risk markers and introduce immune-modulating agents while the -cell mass is still rather large.

Screening could be defined as an examination of a population in which the individuals have no clinical symptoms and have not asked for the examination. There are inherent ethical problems with screening: in some individuals, we will introduce an unwanted awareness of a risk for disease. Of those individuals, not all will really develop the disease, i.e., a varying number of individuals will test false-positive. False positivity is a concept that is often confused by both clinicians and researchers. A false-positive rate from the population perspective is one minus the specificity (the fraction of all healthy individuals who have a negative test) of the test. In contrast, false positivity from the individual perspective is one minus the positive predictive value (the frequency of diseased among those individuals who have a positive test). This could mean that if out of 1,000 screened individuals, 51 have a positive test, 50 of whom are without disease, the false-positive rate in this population is 5%. The false-positive rate at the individual level in this case is 98%. A confusion of these two concepts obviously has important ethical implications.

Another common pitfall when discussing screening is that a positive predictive value estimated by testing high-risk groups, e.g., family members, could not be transferred to another group with a different prevalence of disease because the prevalence of the disease in the group under study heavily influences the positive predictive value. For example, a test with a sensitivity and a specificity as high as 99% for both may mean a positive predictive value of around 92% if the prevalence is 10%, whereas the predictive value would decrease to 9% if the prevalence is 0.1% (6).

Each of the risk markers available today for type 1 diabetes screening—HLA alleles, haplotypes or genotypes, islet cell antibodies (ICAs), insulin autoantibodies, GAD, or thyrosine phosphatase (ICA-512, IA₂)—have low predictive values in both high- and low-risk groups. As an example of the classic and still among the highest predictive values is ICA, which with a cutoff of >20 Juvenile Diabetes Foundation units alone could predict ~35% of relatives with ICA who will get type 1 diabetes within 5 years and 60–70% of relatives likely to get type 1 diabetes within 10 years (7,8). By combining different risk markers, however, predictive values approaching 100% could be reached in first-degree relatives (9,10). Because the large majority of type 1 diabetic cases, 80–90%, occur in the general population—i.e., in individuals without first-degree relatives with type 1 diabetes—screening combined with a successful immune modulation in family members would prevent only a small fraction of the potential type 1 diabetic cases. When looking for the most optimal combination of HLA haplotypes together with two of the three antibody markers, a Swedish population-based study found the best positive predictive value in the general population to be 20% (11). Because combining predictive markers will lead to a loss of sensitivity in that study, only 34% of potential cases would be detected using these combined markers. Certainly, this in reality means that about twice as many potential cases will be detected at an early stage compared with approaching only family members, but still 80% of cases with a "positive" test will never get the disease. A slightly modified approach of combining risk markers, a so-called decision tree analysis, has been discussed (12). Using such a model, based on a fairly extreme Finnish gene marker with a very high discrimination potency, a 60% positive predictive value could theoretically be achieved in the general population (12). Still, it is difficult to justify the introduction of unnecessary anxiety and treatment into a very large group of children who lack the ability to give their own informed consent. The conclusion on screening using today's available risk markers for type 1 diabetes is therefore that it is ethically justified in high-risk groups only unless we can find a highly effective and a highly safe treatment.

For the other potential strategy for type 1 diabetes prevention—eradicating exposures that might initiate autoimmunity—the facts are sparse so far. The research to identify exposures that may initiate -cell destruction is promising and might be intensified, because these studies might lead to safe interventions, e.g., vaccinations, nutrition advice, or early introduction of small amounts of oral antigens (oral tolerization) (13). Because of the probably long time lag between the initiation of autoimmunity to the -cell and the onset of clinical disease, research in this field has started to focus on early perinatal events. Epidemiological (14) and animal experiments (15–18) have indicated that food components—such as cow's milk proteins or gliadin but also food containing nitroso products (19–22)—as well as early virus exposures (23–25) could initiate autoimmunity. Population-based studies have clearly indicated that different risk genes are associated with type 1 diabetes in different ethnic groups (2) as well as in different age-groups (26). Thus, different gene–environment interactions may produce the same disease by different mechanisms in different groups. It is then necessary to consider the attributable fraction for each potential risk exposure, i.e., the proportion of cases in the population that might be saved by eradicating a specific possible initiating exposure.

PERSPECTIVES FOR DIABETES CARE— Any method for prevention in prediabetes focusing on the arrest or delay of an already ongoing -cell destruction must include screening. In the general guidelines for screening proposed by the World Health Organization, not only must the disease constitute a major health problem and the test method be acceptable but an accepted treatment must also be available. When evaluating the acceptability of the treatment of presymptomatic individuals, the treatment should not only be efficient in preventing the disease, but the long-term side effects of this treatment must be compared to the overall side effects of having the disease with today's treatment efficiency in light of both acute and long-term complications, as well as quality-of-life aspects. Taking all these aspects into account, screening and treatment of specifically children and young first-degree relatives of type 1 diabetes patients with immunosuppressants such as cyclosporine would be unethical because of serious side effects and only a delay in onset. Treatment with insulin injections is easier to accept, but it means an earlier introduction of the normal treatment with clearly negative effects on quality of life, especially for children. Nicotinamide provides greater hope if it can be proven beneficial in the long-term and harmless to humans. Still, because of the low predictive value of available risk markers in the general population, these strategies will probably be applicable only to a minority of potential cases, i.e., family members.

A strategy aiming at preventing the initiation of -cell damage would approach the whole population at risk and need no screening. However, so far no single environmental risk factor has been proven to be necessary and certainly not sufficient for the disease causation; and the etiological fractions indicated from potential risk factors, such as cow's milk protein, nitrosamines, or enteroviruses, are low. Such calculations also need to be assessed in each country before any intervention at this level would be planned and used in the calculation of the overall cost/benefit ratio. Because such an intervention strategy would approach the whole population, i.e., all potential cases, the frequency of overtreatment would be huge and the level of risk must therefore be almost nil. If the multiple causation theory is true and the attributable proportions for each risk exposure are thereby low, the cost/benefit ratio may also be low with this strategy. The hope must, however, be to go on and find one or some exposures that may be necessary for the initiation of autoimmunity. An attack aimed at such exposures by, e.g., general vaccination programs, would have the potential to eradicate all type 1 diabetes cases.

When critically reviewing the present knowledge on type 1 diabetes etiology and pathogenesis, obviously more facts are needed. Today, no prevention strategy has a basis of knowledge good enough to allow routine prevention in either high-risk or low-risk groups, but interesting clinical trials are going on or are being planned. It is important when planning such trials to carefully consider the above-mentioned potentials and pitfalls, especially considering that a large fraction of individuals taking part in these studies are children who cannot give their own informed consent. According to the Council for International Organization of Medical Services' interpretation of the declaration of Helsinki (27), on research with children, even more strict criteria regarding the risk/benefit ratio must be ensured. It is also stated that children should never be the subjects of research that might equally well be carried out on adults. These rules are particularly strict in nontherapeutic research. If predictive value for, e.g., screening is low, a large proportion of children involved in the study will, in fact, be included in a nontherapeutic trial (i.e., they will not benefit at all). In contrast, a high predictive value in screening means that a larger proportion of children will take part in a therapeutic trial.

In conclusion, we need more basic research before we can start an effective and safe prevention for type 1 diabetes. We clearly need the enthusiastic researchers who at this stage are already promoting or conducting large intervention trials. But the messages provided from these trials must be balanced. The potentials and pitfalls of interventions must be carefully considered in all aspects before applying any results in routine care and also when planning future trials.

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From the Department of Pediatrics, Umeå University, Umeå, Sweden.

Address correspondence and reprint requests to Gisela G, Dahlquist, Department of Pediatrics, Umeå University, S-901 85 Umeå, Sweden. E-mail: gisela.dahlquist@pediatri.umu.se.

Received for publication 27 May 1998 and accepted in revised form 20 August 1998.

Abbreviations: ICA, islet cell antibody.

This article is based on a presentation at a satellite symposium of the 16th International Diabetes Federation Congress. The symposium and the publication of this article were made possible by educational grants from Hoechst Marion Roussel AG.

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