Type 1 diabetes
The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) in the USA has set up the type 1 Diabetes Trial Net, a clinical trials network that will explore new treatments in patients with newly presenting diabetes, in family members at risk of developing type 1 diabetes and, possibly, also in people who are at high genetic risk. At present no such therapy has proven to be effective or clinically safe. On the basis of the theory that immune-mediated type 1 diabetes is believed to result from immunologic destruction of islet p-cells as a consequence of an interplay between genetic susceptibility and a triggering environmental agent or agents, it would seem possible to identify potential targets for prevention of the disease, although we know that the above theory is very much an over-simplification of the true pathological mechanism. The development of type 1 diabetes is a slow process with the best prospect of preventive strategies being early in the disease process. At that stage, disease prediction is less accurate and any treatment would need to be safe and harmless, otherwise individuals may come to harm with treatment who were never going to develop the disease. No such agent yet exists.
Strategies to prevent type 1 diabetes would include (a) identification and elimination of environmental triggers, (b) identification and promotion of environmental protective factors and (c) interruption of the immunologic process leading to p-cell destruction.
Several trials have demonstrated that immunosup-pressive agents can slow or interrupt the disease process, but concern remains about long-term toxicity. Studies with newer agents (e.g. sirolimus, mycopheno-late, etc.) have been initiated. Early studies with anti-CD3 monoclonal antibodies have suggested a beneficial effect on preservation of p-cell function. Nicotinamide has been suggested as a means of protecting p-cells; however, unfortunately a large scale trial (ENDIT: the European Nicotinamide Diabetes Intervention Trial) showed no significant benefit. Expansion of p-cell mass (with exendin, GLP-1 or islet neogenesis-associated protein) is a possible research consideration. Rest of p-cells (with insulin therapy) in early-onset diabetes or ICA-positive relatives has not yet shown conclusively that it delays or prevents the development of type 1 diabetes. More recently several groups have made progress towards the development of a vaccine to prevent the onset of type 1 diabetes.
Given the expanding prevalence rates of type 2 diabetes both in developed and developing nations, the prevention of type 2 diabetes assumes global importance. Clearly the prevention of type 2 diabetes is incestuously related to the prevention of obesity. Type
2 diabetes lends itself to potential preventative action because of the long delay between development of the earliest metabolic defects and full expression of the disease. Lifestyle modification or pharmacologic intervention that can improve insulin sensitivity (reduce insulin resistance) or improve or preserve p-cell function would expect to have an impact on the future development of type 2 diabetes.
The first major trial to show the effect of lifestyle change on the development of diabetes was the Da Qing Study in China where patients with impaired glucose tolerance (IGT) were randomized to a control group and one of three active treatment groups (change in diet, exercise or change in diet plus exercise). The diet group experienced a relative risk reduction of progression to frank diabetes of 31%, the exercise group of 46% and the combined group of 42%.
This study was followed by the Finnish Diabetes Prevention Study which compared lifestyle intervention to a control group in overweight patients with IGT. The lifestyle intervention group received detailed dietary advice and individualized advice on physical activity with supervized training sessions. During the first year of the study, the intervention group achieved a significant loss of 4.2 kg with minimal change in the control group and after 2 years, the cumulative incidence of progression to diabetes was reduced by 58%. Whether such an intensity of lifestyle intervention could be provided, funded and adhered to outside the context of a clinical trial remains open to debate.
In the USA, the investigators in the Diabetes Prevention Program randomly assigned patients with IGT to one of three arms: placebo, lifestyle modification or metformin (850mg twice daily). Patients in the lifestyle intervention group were asked to achieve and maintain a reduction of at least 7% in body weight through a healthy diet and to engage in moderate physical activity for at least 150 min per week. Patients received intensive support and, as for the Finnish study, such a level of support is unlikely to be available in routine clinical practice. The lifestyle group achieved a greater weight loss (5.6 kg) and a greater increase in physical activity than the other groups. At
3 years, the prevalence of type 2 diabetes was reduced by 58% with lifestyle change and by 31% in the metformin group.
The multinational STOP-NIDDM Trial (The Study to Prevent Non-Insulin Dependent Diabetes) used acarbose to prevent progression to diabetes in IGT
subjects. Patients who were randomized to acarbose were 25% less likely to develop diabetes and when the data were corrected to the revised ADA criteria for the diagnosis of diabetes, there was an even greater relative risk reduction of 32%. Treatment with a glitazone has also been shown to reduce the number of patients who develop diabetes 30 months after gestational diabetes with a 55% relative risk reduction in the TRIPOD study (Troglitazone in Prevention of Diabetes Study).
Several other type 2 diabetes pharmacologic prevention trials are currently being conducted (NAVIGATOR - nateglinide and valsartan, DREAM -ramipril and rosiglitazone, ACT NOW - pioglitazone and ORIGIN - insulin glargine) and their outcome is awaited with interest.
Thus, it has been conclusively shown that lifestyle modification and drug therapy can delay the onset of type 2 diabetes. Whether there has been true 'prevention' in those subjects who did not develop diabetes is a different matter. Cost-effective analyses have not been conducted, although individual health benefit is likely to ensue.
The American Diabetes Association Working Group on the Prevention of Diabetes recommends a lifestyle intervention strategy for patients with IFG (impaired fasting glucose) or IGT but does not recommend routine prescription of drug therapy until more is known about the cost-effectiveness of such a policy.
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