THE VALIDITY OF GENERALIZING THE DCCT RESULTS

TO PATIENTS WITH INSULIN-DEPENDENT DIABETES MELLITUS IN THE GENERAL POPULATION WAS CONFIRMED

The DCCT cohort was generally similar to IDDM patients in the WESDR in terms of demography, rates of progression in the conventionally treated group, and association between HbA1c levels and progression of retinopathy [49].

WHAT ARE THE LONG-TERM EFFECTS OF INTENSIVE INSULIN THERAPY ON MICROAND MACROVASCULAR DISEASE?

The Epidemiology of Diabetes Interventions and Complications (EDIC) study was a multicenter, longitudinal, observational study designed to use the well-characterized DCCT cohort of >1,400 patients to determine the long-term effects of former separation of glycemic levels on microand macrovascular outcomes [30]. At the end of the DCCT, patients in the conventional treatment group were offered intensive therapy, and the care of all patients was transferred to their own physicians. To assess whether the benefits of intensive therapy persist, the EDIC study compared the effects of former intensive and conventional therapy on the occurrence and severity of retinopathy, nephropathy, neuropathy, and cardiovascular disease after the end of the DCCT. Retinopathy was evaluated on the basis of centrally graded fundus photographs in 1,208 subjects during the fourth year after the DCCT ended [50] and 1,211 subjects at year 10 [51].

EFFECTS OF IMPROVED CONTROL ON RETINOPATHY WERE SUSTAINED IN THE LONG-TERM

The proportion of patients who had worsening of retinopathy including PDR, macular edema, and the need for laser treatment was lower in the intensive therapy group than in the conventional therapy group in the 10 years following DCCT closeout [51]. At entry to the DCCT, the mean HbA1c level in each treatment group was 9.0%. Following 6.5 years of DCCT follow-up, the mean HbA1c levels were 7.3 and 9.0% in the intensive and conventional therapy groups, respectively. One year after the DCCT closeout, the HbA1c values had converged. Over 10 years in the EDIC study, the mean HbA1c levels in the two groups were almost the same (8.0% in the conventional therapy group vs. 7.98% in the intensive therapy group). Despite similar HbA1c levels over the period of observation following the DCCT closeout, the ongoing risk of worsening of retinopathy remained significantly reduced in the intensive compared with the conventional group (“metabolic memory”). The decrease in HbA1c from approximately 9% to about 8% resulted in only small reductions in the progression of retinopathy in the conventional group. After 4 years of follow-up in the EDIC study, 49% of the patients in the conventional treatment group had progression of retinopathy of three or more steps from the DCCT baseline as compared with 18% of the patients in the intensive therapy group [50]. After 10 years, 60.6% in the conventional group had progressed vs. 35.8% in the intensive therapy group. An important benefit was the continued significant reductions at 4 and 10 years of the EDIC follow-up in the adjusted odds of severe NPDR or worse, clinically significant macular edema, and photocoagulation. However, the difference in retinopathy between

the two groups was becoming less. The odds reductions at 10 years were less than that observed at 4 years, except for those for photocoagulation. Metabolic memory waned faster in patients with more severe retinopathy than in those with milder retinopathy. As the severity of retinopathy increased at the DCCT closeout, the relative benefits of intensive therapy decreased. The risk of further progression of diabetic retinopathy increased significantly with higher HbA1c levels at DCCT baseline (19% increase in risk per 1% increase in HbA1c level), higher mean blood pressure at DCCT closeout (11% increase in risk per 5 mm increase in mean BP), and hyperlipidemia at DCCT closeout (70% increase in risk for those with hyperlipidemia vs. those without). Eighty-nine percent of the prolonged effect of DCCT intensive therapy treatment on further retinopathy progression was explained by the differences in the DCCT mean HbA1c levels, whereas the EDIC mean HbA1c levels explained only 1.6% of the prolonged intensive effect.

INTENSIVE DIABETES THERAPY HAS LONG-TERM BENEFICIAL EFFECTS ON THE RISK OF CARDIOVASCULAR DISEASE

AND MORTALITY

A statistically significant benefit of intensive insulin therapy on cardiovascular disease in the DCCT/EDIC study was observed at year 11 of the EDIC study beyond the end of the DCCT. Patients who had been randomized to the intensive arm had a 42% reduction in any cardiovascular disease outcomes and a 57% reduction in the risk of nonfatal myocardial infarction, stroke, and cardiovascular death compared with those who had received conventional treatment [52]. As is the case with microvascular complications, it may be that a period of intensive diabetes management plays a greater role in lessening cardiovascular risk before atherosclerosis is well developed.

QUALITY OF LIFE MEASURE

The Diabetes Quality of Life Measure (DQOL) was designed to evaluate the relative burden of an intensive regimen among patients with type 1 diabetes enrolled in the DCCT [53]. During the DCCT, DQOL scores, functional health status, and psychological distress were similar between treatment groups. However, among intensively treated patients, symptoms of psychiatric distress rose with the frequency of hypoglycemic episodes [54]. Following islet cell transplantation, the risk of short-term clinical consequences found with intensive or conventional insulin therapy (DKA, hypoglycemia, poor glycemic control) is abolished. Quality of life appears to improve initially after islet cell transplantation due primarily to a reduced fear of hypoglycemia but declines with the loss of insulin independence [55].

“METABOLIC MEMORY”: A PHENOMENON PRODUCING A LONG-TERM BENEFICIAL INFLUENCE OF EARLY METABOLIC CONTROL ON CLINICAL OUTCOMES

In the DCCT/EDIC studies, “metabolic memory” was used to describe the persistent benefit of reduced progression of retinopathy which outlasted by at least 10 years the period of good control of blood glucose on DCCT intensive insulin therapy [50].

An early glycemic environment is remembered in the target organs prone to hyperglycemic damage. The benefit is an apparent discrepancy between the level of hyperglycemia and the incidence and severity of diabetic complications. The duration of the metabolic memory can be determined by quantifying the continuing differences in the long-term clinical effects between the original treatment groups. It is not known how long the risk of progression will be delayed by the memory effect. AGE (Advanced Glycation End Products) is implicated in diabetic complications and metabolic memory [56, 57]. In the DCCT/EDIC studies, AGE formation measured in skin biopsy 1 year before DCCT closeout and 10 years later, was significantly lower in the intensive therapy subjects compared with conventional therapy subjects [58], and levels of AGEs were significantly associated with the 10-year incidence or progression of retinopathy [59].

The induction, maintenance, and “switching off” of the “metabolic memory” (a term coined by Cahill [60]) were recently reviewed by Ceriello et al. [61]. with evidence gathered in part from reviews on the pathobiology [62], reactive species [63], mitochondrial DNA mutators [64], endothelial dysfunction [65], and AGE [66]. In the hypothesis, intracellular hyperglycemia induces overproduction of superoxide, a ROS, at the mitochondrial level as a possible cause of the metabolic memory of hyperglycemic stress after glucose normalization. Overproduction of ROS is the first and key event in the activation of all other pathways involved in the pathogenesis of diabetic complications, such as the polyol pathway flux, increased AGE formation, activation of protein kinase C, and increased hexosamine pathway flux. Mitochondrial proteins are glycated in hyperglycemia, and this effect induces mitochondria to overproduce superoxide anion, a condition that does not depend on glycemic levels. Superoxide and similar reactive species target nucleic acid, proteins, and lipids/lipoproteins with a long half-life over a prolonged time. Binding of AGEs to the receptor for AGE called “RAGE” results in intracellular ROS generation, which promotes the expression of RAGE themselves. Mitochondrial DNA may influence gene expression and, at the same time, may contribute to an overgeneration of free radicals at the mitochondrial level. These self-maintaining conditions, leading to a persistent oxidative stress generation independent of the actual glycemic levels, may contribute to the appearance of the metabolic memory. It was shown in endothelial cells that reducing intracellular production of free radicals, particularly at the mitochondrial level, was capable of “switching off” the metabolic memory [67]. Additional explanations such as genetic factors may be needed to explain susceptibility to severe complications [68].

RECENT DECREASE OF ANNUAL INCIDENCE

AND PREVALENCE OF RETINOPATHY

Several recent cohort studies report decreases in the cumulative incidence of progression of retinopathy [14], proliferative retinopathy [14, 69, 70], macular edema [10, 70], and new blindness in a diabetic population [71] with increasing calendar year of diagnosis. A meta-analysis, which reviewed rates of progression of diabetic retinopathy to proliferative retinopathy and/or severe visual loss in a combined population of persons with type 1 and type 2 diabetes, concluded that rates of these outcomes were lower since 1985 [72]. Estimates of the annual rates of progression of diabetic retinopathy,

incidence of PDR, improvement of retinopathy, and incidence of macular edema and clinically significant macular edema for the four periods of the WESDR 25-year incidence study reveal that in contrast to the first 10 years of follow-up when incidence rates were constant, annualized incidence and progression rates decreased over the past 10–15 years [14]. Also, there was a lower prevalence and incidence of PDR in persons who were more recently diagnosed with diabetes. Coincident with these declines, there was gradual improvement in glycemic control. This data suggested the efficacy of improved glycemic control in reducing the complications of diabetic retinopathy, or else the reason for the decline in prevalence was explained by death, leading to survival of the healthiest. Also, there have been recent reports of lower prevalence of diabetic retinopathy [73], and proliferative retinopathy [74], compared with previous reports of prevalences in the WESDR baseline. However, a lower cumulative incidence of proliferative retinopathy was not found in the Pittsburgh Study [75]. The environment of the population could have changed because of an upward trend in the initiation of intensive blood glucose control by physicians as well as improved adherence to treatment by patients because of translation of the results of the DCCT. A greater percentage of people than before are monitoring blood glucose four times per day and injecting insulin three or more times daily. Also taking place is the aggressive management of both renal and cardiovascular disease with improved control of blood pressure and lipids and use of renin-angiotensin system blockers. Early blockade of the renin-angiotensin system with either an angi- otensin-converting enzyme (ACE) inhibitor or an angiotensin system blocker (ARB) did not slow nephropathy progression but slowed the progression of retinopathy independently of changes in blood pressure [76].

NEED FOR A MORE PHYSIOLOGIC GLYCEMIC CONTROL REGIMEN

Does it matter by what means a reduction in glycemia is obtained? Risk gradients for progression of diabetic retinopathy as a function of mean HbA1c are similar for both intensive therapy and conventional therapy, which suggests that a similar benefit in the reduction of complications could be obtained with another less intensive, more effective regimen [34]. Diabetes management is an integral part of daily living and requires extensive education and lifestyle changes. It is difficult to sustain near-normal blood glucose continuously even with frequent corrective adjustments of insulin dosage. Intensive therapy regimen is extremely demanding and requires substantial effort and resources by the patients and the healthcare team to try to reach their goal of normal glycemia. People with type 1 diabetes have the burden of hypoglycemia, ketoacidosis, injections three to four times per day, insulin pump manipulations, self-monitoring blood glucose four times per day, adjusting insulin dose based on glucose level, meal size and composition, and activity level. In the EDIC 4-year follow-up examination, less than half of the patients in each group were performing self-monitoring of blood glucose four or more times per day [50]. It is the increased likelihood of severe hypoglycemia that reduces the capacity to increase administration of insulin to reach glycemic targets [77]. Both hypoglycemia and weight gain deter many patients and physicians from aiming at stringent control [78]. Insulin underuse may be adopted by patients attempting to limit weight gain [79, 80], as well as for manipulation, or because of recklessness, error,

or fatigue in the day-to-day effort of managing diabetes. Failure to adhere to insulin treatment, expressed as a prescribed vs. dispensed index, was shown to occur in 28% of a cohort of adolescents and young adults with type 1 diabetes attending a teaching clinic and was directly associated with failure to take insulin, poor glycemic control, and acute hospital admissions for DKA [81]. Suboptimal adherence with diabetes treatment increases healthcare costs [82]. The UK Hypoglycemic Study Group [83] reported an incidence of severe hypoglycemia of 110 episodes per 100 patient years in patients with type 1 diabetes who were necessarily treated with insulin for <5 years and an incidence of 320 episodes per 100 patient years in those with type 1 diabetes for >15 years. The prospective population-based study of Donnelly et al. [84]. indicated that the incidence of any and of severe hypoglycemia was about 4,300 and 115 per 100 patient years, respectively in type 1 diabetes.

Insulin analogues (Insulin Lispro, Aspart, Glulisine, Glargine, and Detemir) were developed to provide greater efficacy, safety, and convenience compared with conventional human insulin [85]. These are synthetic insulins which have undergone small changes in amino acid sequence relative to human insulin with more rapid absorption resulting in pharmacokinetic and pharmacodynamic profiles that mimic the action of endogenous insulin more closely. Their effect, to reduce postprandial hyperglycemia, and frequency of nocturnal hypoglycemia help improve adherence with therapy in type 1 diabetes. Detemir has ability to limit weight gain [86]. The combination of both longand short-acting insulin analogues leads to significant minor reductions in both HbA1c and nocturnal hypoglycemia in adults compared with NPH insulin and unmodified human insulin managed with a multiple injection regimen [87].

The limitations of long-acting insulin has driven the popularity of CSII but with the drawback of subcutaneous administration, carbohydrate counting, and the continued need for frequent adjustments of infusion rates based on intermittent self-monitoring of blood glucose and training in the management. Trials of modern insulin pumps report decreases of HbA1c 0.6–0.4% compared with multiple daily insulin injections with no increase in hypoglycemia [88].

Continuous glucose monitoring devices which measure interstitial glucose every 5 min for 72 h show glycemic excursions, permit immediate adjustment of insulin, and are able to alert patients to a falling glucose level. Alarm system specificity may not yet be sufficient for reliable use [89]. A meta-analysis of clinical trials comparing continuous glucose monitoring system with self-blood glucose monitoring in type 1 diabetes showed that the use of continuous monitoring did not significantly reduce HbA1c levels [90].

In the DCCT in which subjects were carefully selected for adherence with care, and received management from experts with access to full resources, 44% of patients in the intensive therapy group achieved HbA1c less than or equal to 6.05 mol/L on one or more occasions during the study. Fewer than 5% in the intensively treated group was able to maintain their HbA1c level at less than or equal to 6.05% over the course of the study [29]. At the upper limit of the nondiabetic range of 6.0%, it is estimated that there is still some risk of retinopathy progression (risk 0.52/100 patient years) [34]. Over a lifetime, even a small increment or decrement of mean HbA1c could substantially increase or decrease, respectively, the risk of progression to more severe complications.