A fundamental controversy regarding whether diabetic microangiopathy is related exclusively to the existence and duration of hyperglycemia or whether it reflects a separate genetic disorder have been resolved by the findings of the DCCT and of the United Kingdom Prospective Diabetes Study (UKPDS), which confirmed the beneficial effects of improved glycemic control in both type 1 and type 2 diabetes, respectively. In addition, with increased understanding of the pathophysiology of both type 1 and type 2 diabetes, large prospective studies have been initiated in attempts to prevent onset of these disorders. Investigators with the Diabetes Prevention Trial 1 (DPT-1) and the Diabetes Prevention Program (DPP) have recently reported their findings.
A. CLINICAL TRIALS IN TYPE 1 DIABETES
1. Diabetes Prevention Trial-1 - This multicenter study sponsored by the National Institutes of Health was designed to determine whether the development of type 1 diabetes mellitus could be prevented or delayed by immune intervention therapy. Daily low-dose insulin injections were administered for up to 8 years in first-degree relatives of type 1 diabetic patients who were selected as being at high risk for development of type 1 diabetes because of detectable islet cell antibodies and reduced early-insulin release. Unfortunately, this immune intervention failed to affect the onset of type 1 diabetes compared with a randomized untreated group. A related study using oral insulin in lower risk first-degree relatives who have islet cell antibodies but whose early insulin release remains intact also failed to show an effect on the onset of type 1 diabetes. After an average of 4.3 years of observation, type 1 diabetes developed in about 35% of persons in both the oral insulin and the placebo groups.
2. The Diabetes Control and Complications Trial - A long-term therapeutic study involving 1441 patients with type 1 diabetes mellitus reported that “near” normalization of blood glucose resulted in a delay in the onset and a major slowing of the progression of established microvascular and neuropathic complications of diabetes during a follow-up period of up to 10 years. Multiple insulin injections (66%) or insulin pumps (34%) were used in the intensively treated group, who were trained to modify their therapy in response to frequent glucose monitoring. The conventionally treated groups used no more than two insulin injections, and clinical well-being was the goal with no attempt to modify management based on HbA1c determinations or the glucose results.
In half of the patients, a mean hemoglobin A1c of 7.2% (normal: < 6%) and a mean blood glucose of 155 mg/dL were achieved using intensive therapy, while in the conventionally treated group HbA1c averaged 8.9% with an average blood glucose of 225 mg/dL. Over the study period, which averaged 7 years, there was an approximately 60% reduction in risk between the two groups in regard to diabetic retinopathy, nephropathy, and neuropathy. Intensively treated patients had a threefold greater risk of serious hypoglycemia as well as a greater tendency toward weight gain. However, there were no deaths definitely attributable to hypoglycemia in any persons in the DCCT study, and no evidence of posthypoglycemic cognitive damage was detected.
The general consensus of the ADA is that intensive insulin therapy associated with comprehensive self-management training should become standard therapy in patients with type 1 diabetes mellitus after the age of puberty. Exceptions include those with advanced renal disease and the elderly, since in these groups the detrimental risks of hypoglycemia outweigh the benefits of tight glycemic control.
3. Immune Intervention Trials in New-Onset Type 1 Diabetes - At the time of diagnosis of type 1 diabetes, patients still have significant B cell function. This explains why soon after diagnosis patients go into a partial clinical remission (“honeymoon”) requiring little or no insulin. This clinical remission is short-lived, however, and eventually patients lose all B cell function and have more labile glucose control. Attempts have been made to prolong this partial clinical remission using drugs such as cyclosporine, azathioprine, prednisone, and antithymocyte globulin. These drugs have had limited efficacy, and there are concerns about toxicity and the need for continuous treatment.
Newer agents that may induce immune tolerance and appear to have few side effects have been used in new-onset type 1 patients. Three small studies, one with a heat shock protein peptide (DiaPep277) and two with anti-CD3 antibodies, have demonstrated that these agents can preserve endogenous insulin production. Larger phase 2 clinical trials are currently in progress.