were performed monthly [27]. It was determined that hemoglobin A1c (HbA1c) could be used as a surrogate marker for glycemia [28]. The targets’ were preprandial blood glucose 3.9–6.7 mmol/L and postprandial blood glucose level lower than 10 mmol/L, weekly blood glucose 3 a.m. measurement higher than 3.6 mmol/L, and HbA1c values within the nondiabetic range (<6.05%) [29]. The most important primary outcome measures in the primary prevention cohort were persistent development of any retinopathy (at least one microaneurysm in either eye) at two consecutive visits scheduled at 6-month intervals, and in the secondary prevention cohort, sustained (at least two consecutive 6-month visits) three-step progression of diabetic retinopathy based on scores in both eyes.

At enrolment, the primary prevention group had no photographic evidence of retinopathy, visual acuity of 20/25 or better in each eye, and urinary albumin excretion less than 40 mg/24 h. The secondary prevention group had presence of very mild to moderate nonproliferative diabetic retinopathy (NPDR) in at least one eye and visual acuity of 20/32 or better in each eye [5].

Stereoscopic color fundus photographs of the seven-standard fields were taken every 6 months and graded in masked fashion at the University of Wisconsin Fundus Photograph Reading Center using the protocol of the ETDRS. Grades of the various lesions were used to construct an interim ETDRS score and a final score [15, 16]. Observations were performed for a mean of 6.5 years (range 3–9 years) after randomization. The study was completed by 99% of patients, and the assigned treatment was received 97% of the time [30].

Over the 9-year period of the study of both the primary and secondary prevention groups, the average difference in HbA1c between the two groups was statistically different, nearly 2% [29]. The average within-subject mean HbA1c was 9.1% in the conventional group vs. 7.2% in the intensive group. With regard to the distribution of HbA1c, 31% had a mean HbA1c between 8.5 and 9.49% in the conventional group vs. 5% of the intensive group. Conversely, among those in the intensive group, 50% had a mean HbA1c between 6.5 and 7.49% vs. 8% of the conventional group. Almost exactly 23% of intensive and conventional group subjects had a mean HbA1c between 7.5 and 8.49%.

ON AVERAGE, 3 YEARS WAS REQUIRED TO DEMONSTRATE THE BENEFICIAL EFFECT OF INTENSIVE TREATMENT

There was initial (“early”) worsening of retinopathy (13.1% of subjects in the intensive insulin group and 7.6% in the conventional treatment group) in the first year of treatment [31] (except in the group with no retinopathy) similar to reports in the early feasibility studies [20–24]; then after 3 years, the rate of sustained progression was lower and the beneficial effects of intensive therapy increased over time for all retinopathy groups except moderate NPDR (43/<43), which took longer to demonstrate a beneficial effect. After 3 years, the magnitude of progression was also less as measured by the number of steps on the severity scale. These differences increased with longer follow-up and were associated with higher rates of recovery from progression of three or more steps on the scale compared to conventional therapy [32].

THE EARLIER IN THE COURSE OF DIABETES THAT INTENSIVE THERAPY IS INITIATED, EVEN BEFORE THE ONSET OF RETINOPATHY, THE GREATER THE LONG-TERM BENEFITS

In the primary prevention group on intensive insulin therapy, the 9-year cumulative incidence of developing at least one microaneurysm in persons with no diabetic retinopathy at baseline was 70% in persons with 2.5 or fewer years of duration of diabetes and 62% in persons with more than 2.5 years duration of diabetes at baseline. The 9-year cumulative incidence of sustained three-step progression in persons with diabetes duration of 2.5 years or less without retinopathy at baseline was 7% compared with 20% when the duration of diabetes was greater than 2.5 years. In the secondary prevention group on intensive insulin therapy, the 9-year cumulative incidence of sustained threestep progression in eyes with baseline level of severity 20/<20 to 35/<35 was lower compared to eyes with retinopathy severity level 43/<43 (11.5–18.2 vs. 43.8%) [33].

RISK REDUCTION IN THE PRIMARY PREVENTION COHORT

The incidence of diabetic retinopathy was reduced by 27% by intensive treatment over 9 years [33]. The adjusted mean risk of retinopathy sustained progression by three or more steps was reduced by 76% [29].

RISK REDUCTION IN THE SECONDARY PREVENTION COHORT

Intensive therapy reduced the mean risk of sustained progression by three or more steps by 65% during the entire study. Progression to severe NPDR or worse was reduced by 47%. The need for laser treatment of macular edema or proliferative retinopathy was reduced by 59%. The incidence of clinically significant macular edema in the intensive therapy group decreased but not statistically significantly [33].

THERE WAS NO GLYCEMIC THRESHOLD REGARDING PROGRESSION OF RETINOPATHY

There was significant reduction in the risk of retinopathy in an exponential relationship along the entire range of HbA1c in the study [34]. Although the magnitude of the absolute risk reduction declined with continuing proportional reductions in HbA1c, there were still meaningful further reductions in risk as HbA1c was reduced toward the normal range [35]. Each 10% reduction in HbA1c resulted in (a) 35% risk reduction in sustained onset, (b) 39% reduction in progression of three or more steps of severity, and

(c) 37% reduction for development of severe NPDR or proliferative diabetic retinopathy (PDR) [34]. A simple exponential regression model showed that, in the combined groups, small differences in any given value of the HbA1c (assumed held constant over time) correspond to large differences in the cumulative incidence of sustained retinopathy progression over a period of many years [35]. The short-term (within-day) variability in blood glucose around a patient’s mean value had no influence (independent of conventional therapy or intensive therapy) on the development or the progression of

retinopathy [36]. However, glucose variability should be reduced as much as possible to limit hypoglycemia unawareness and severe hypoglycemia and maintain quality of life. Another study using DCCT data found that glycemic instability (SD of glucose profile set samples for each visit) had little influence on the HbA1c value of a patient [37]. Longer-term variability in HbA1c adds to the mean value in predicting microvascular complications. A 1% absolute increase in HbA1c SD results in at least a doubling in retinopathy [38].

A re-examination of previously presented DCCT findings [34] and additional analysis of DCCT data [39] show that virtually all (96%) of the beneficial effect of intensive vs. conventional therapy on progression of retinopathy and other outcomes is explained by the reductions in the mean HbA1c levels. The total glycemic exposure (HbA1c and duration of diabetes) explains only ~11% of the variation in retinopathy risk in the complete cohort. Subjects within the intensive and conventional treatment groups with similar HbA1c level over time have similar risks of retinopathy progression especially after adjusting for factors in which they differ [39].

THE RISK OF HYPOGLYCEMIA INCREASED CONTINUOUSLY

BUT NOT PROPORTIONALLY AS THE GOAL OF NORMOGLYCEMIA WAS APPROACHED

Severe hypoglycemia was three times more common in the intensive therapy group compared with the conventional therapy group [29]. The rate of severe hypoglycemic episodes requiring treatment was 62/100 patients years in the intensive insulin treatment group compared with 19/100 patients years in the conventional arm of the study [40, 41]. This risk persisted over the duration of the study and was inversely correlated with the HbA1c. The risk of severe hypoglycemia within the intensive group increased exponentially as the HbA1c was reduced. Although the risk of severe hypoglycemia continues to increase at lower HbA1c values with intensive therapy, the risk gradient flattens substantially [29]. Among all risk factors for hypoglycemia, the dominant predictor was history of prior episodes of hypoglycemia [40, 42]. Among patients with HbA1c 6.0%, 21.3 events were predicted per 100 patient years.

DIABETIC KETOACIDOSIS (DKA)

In the DCCT, the risk of diabetic ketoacidosis (DKA) was similar between intensive and conventional treatment groups (1.8–2/100 patient years), despite lower HbA1c levels achieved in the intensive group [41]. Among the intensive treatment group, rates were higher for patients using CSII compared with those on multiple injections (3.09 vs. 1.39 per 100 patient years) [41]. In a meta-analysis evaluating the effect of intensive treatment on the risk of DKA using data from 14 randomized trials, the overall risk of DKA was greater for patients treated with intensive vs. conventional therapy largely due to the effect of CSII [43]. In the EURODIAB study, 8.6% of type 1 diabetes participants had been admitted to hospital for treatment of DKA in the previous 12 months [44].

EFFORTS TO NORMALIZE BLOOD GLUCOSE ARE ASSOCIATED WITH WEIGHT GAIN IN PEOPLE WITH TYPE 1 DIABETES

In the DCCT, the incidence of becoming overweight, defined as body mass index (BMI) ³27.8 kg/m2 for men and BMI ³27.3 kg/m2 for women during the median 6.5 years of follow-up was 41.5% in the intensive therapy group compared to only 26.9% in the conventional therapy group [41]. The rate of weight gain decreases with time up to 9 years [45]. Weight gain includes an increase in fat mass. The strongest predictors of weight gain were higher baseline HbA1c concentration and larger decrements in HbA1c during intensive therapy from baseline to 1 year. After adjusting for baseline HbA1c, weight, insulin dose (U/kg), and stimulated C-peptide, weight gain of experimental subjects still remained significantly greater than that of standard subjects [46]. The greater weight gain in people with severe hypoglycemia suggests that overeating is a causal factor. Insulin-induced weight gain and heightened risk of obesity, if undesirable, could diminish long-term compliance with intensive therapy and, if continued, could become a risk factor for cardiovascular disease.

CONNECTING PEPTIDE (C-PEPTIDE) RESPONDERS HAVE LESS RISK OF PROGRESSION OF RETINOPATHY

In the DCCT, 303 of 855 patients with type 1 diabetes of duration 1–5 years were C-peptide responders (C-peptide levels 0.20–0.50 pmol/mL) after ingestion of a mixed meal [47]. They were randomly assigned to receive either intensive or conventional treatment. Responders with C-peptide levels >0.50 pmol/mL were excluded from enrollment. Responders receiving intensive therapy maintained a higher stimulated C-peptide level and a lower likelihood of becoming nonresponders than did responders receiving conventional therapy. Among intensive therapy patients, responders had a lower HbA1c value, reduced risk for retinopathy progression, and a lower risk for severe hypoglycemia compared with nonresponders [47, 48]. The risk of losing C-peptide responses to stimulation was reduced by 57% by intensive treatment. The characteristic decline in b cell function was prolonged to the sixth year after initiation of intensive therapy, about 2 years beyond conventional therapy. Interestingly, no difference in the development of complications was seen between the previous responders and nonresponders in the conventional treatment group. Intensively treated nonresponders had the highest rate of severe hypoglycemia (17.3 episodes per 100 patient years). In the intensive therapy group, the adjusted odds for retinopathy were 3.2-fold higher for those with undetectable C-peptide than for those in the sustained C-peptide group. In those receiving conventional treatment, the odds of retinopathy were no different among C-peptide groups [48]. These findings support early introduction of intensive therapy to sustain endogenous insulin secretion which, in turn, is associated with better metabolic control and lower risk for hypoglycemia and progression of retinopathy. The weaker benefit of sustained C-peptide secretion in the conventional group compared with the intensive therapy group on microvascular complications suggests that glycemic control is potentially a more important factor in imparting the benefit of continuing b cell function than the direct effect of C-peptide secretion itself.