Craig Blackwell, MD
Ophthalmology

Santa Cruz, CA
Diplomate: American Board of Ophthalmology
Fellow: American Academy of Ophthalmology

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Diabetes 2- DCCT

Diabetes Control and Complications Trial

There have been a number of studies that have looked at level of blood sugar control and frequency of complications. Probably the largest and most important is the Diabetes Control and Complications Trial (DCCT).

The beneficial effects of improved glucose control were so pronounced that the study was stopped early. The conventional treatment group was advised to change to intensive control. As part one of the study was closed a long term follow-on study was instituted to monitor long term complications. Following is a description of DCCT part one.

Video Presentation of Diabetes Control and Complications

Study Design

Recruiting for patients with insulin dependent diabetes began in 1983 and closed in 1989, with 1441 participants. Patients and treatments were divided as follows:

  • Patients were divided into two groups depending on whether there were any signs of diabetic damage at entry, indicated by Diabetic Retinopathy (DR) and Nephropathy (DN).

1. Primary Prevention: no damage present at entry.

2. Secondary Intervention: damage already present.

  • Two treatment strategies were used, Conventional treatment and Intensive treatment.
  1. Conventional. 1-2 insulin injections per day and home urine testing, later self blood glucose test once daily.
  2. Intensive. 3-4 insulin injections or pump, and 4 self blood glucose tests daily.

DCCT

Primary Prevention

Secondary Intervention

Retinopathy Nephropathy

None at Entry

Present at Entry

Diabetes Duration

2.6 yrs.

8.75 yrs.

A1c (%)

8.8

8.95

Treatment

Conventional

Intensive

Conventional

Intensive

Table 1. DCCT. Study design and patient characteristics at entry into the study.

Results

Average follow-up in the study was 6.5 years.

The study was stopped prematurely at 6.5 years by the data safety monitoring committee, because the benefits of intensive control became “incontrovertible… and highly unlikely to be reversed with time.”

Average A1c Result for Conventional and Intensive Treatment

  • Conventional treatment : A1c = 9.1%
  • Intensive treatment: A1c = 7.3%

Effect on Complications

Figure 1. Graphs comparing complication rates, as measured by Retinopathy and Nephropathy.  Comparison of conventional and intensive treatment regimens show a clear advantage with intensive treatment. From JAMA 2002;287:2564.

Diabetic Retinopathy: Graph A shows the progression of Retinopathy over a nine year period, comparing conventional and intensive treatment. Up to year 2.5 progression rate was similar, but after that the paths diverged significantly.

  • Comparing Conventional versus Intensive treatment, progression of Retinopathy was reduced 76% in the Primary Prevention group and 54% in the Secondary Intervention Group.
  • There was a very strong relationship between Retinopathy and A1c level. For every 10% decrease in A1c there was a 39% decrease in Retinopathy.

Nephropathy. As the Kidneys are damaged they allow more proteins to leak from the bloodstream into the urine. Therefore kidney damage can be measured by the level of the protein albumin in the urine. Graph B shows the effect of glucose control on Nephropathy is similar to the effect on Retinopathy.

  • For every 10% decrease in A1c there was a 25% decrease in risk of Nephropathy (as measured by albuminuria).

Neuropathy. Damage to the nervous system was measured by a standardized clinical examination by a neurologist, nerve conduction or nerve function testing.

  • Comparing Conventional versus Intensive groups at the five year point, Neuropathy was reduced by 69% in the Primary prevention group and 57% in the Secondary group.

First Conclusion from DCCT

Clearly, the effort involved in maintaining stricter blood sugar control is rewarded by significant reduction in the rate of complications.

That is the first major point to be taken from the study. But there are more chapters to this story. Phase two, described below, showed a persistent benefit from early intensive therapy. Further studies will show the importance of controlling blood pressure.

Phase Two, EDIC

Following the randomized part of the trial (DCCT), phase two involved monitoring the same patients for another seven years under the name of Epidemiology of Diabetes Interventions and Complications (EDIC). 95% of patients from the DCCT participated in this follow-up study.

At the close of the DCCT, patients in the Conventional care group were counseled to switch to the intensive plan. By year seven 83% had done so, reflected in improvement in their A1c scores. At the end of seven years the average A1c scores:

  • Former Conventional Treatment Group: A1c = 8.3%
  • Former Intensive Treatment Group: A1c = 8.1%

Results at 4 Years After DCCT

Conventional Therapy

Intensive Therapy

P Value

Retinopathy: 3 Step Progress

16%

6%

0.006

Retinopathy Proliferative

9%

2%

<0.001

Microalbuminuria

11%

5%

0.002

Table 2. Complication rates for patients followed for 4 years after close of DCCT. Retina damage is quantified on a scale developed in an earlier study of diabetic Retinopathy (ETDRS). An increase of three steps is considered a significant worsening. Advancing to proliferative Retinopathy represents an order of magnitude worsening with much greater threat to vision. Remember, albuminuria is a measure of Nephropathy.

Results at 7 years After DCCT

Figure 2. Incidence of Retinopathy for seven years after close of DCCT. (Technically, 3-step progression on ETDRS scale.) From JAMA 2002;287:2564.

Second Conclusion, from EDIC

The results of EDIC follow-up, Table 2 and Figure 2, show that patients who started out in the Intensive treatment group continue to do better than the Conventional treatment group regarding retinopathy and nephropathy.

This result is unaffected by the increase in A1c, from 7.3 to 8.1 in the former Intensive group, or the decrease in A1c from 9.1 to 8.3 in the former Conventional group.

Summary Conclusions

  • Hyperglycemia does long term damage to small blood vessels.
  • When the effort is made to improve blood sugar control it takes time to reverse the damage done by previous hyperglycemia.
  • Once the effect of improved blood sugar control is able to reduce microvascular complications the beneficial effect is long lasting.

The degree of biologic damage, eg. Retinopathy and Nephropathy, is determined by total glycemic exposure. As damage increases over time there seems to be a buildup of momentum to the process which takes time to reverse even after changes in blood sugar control. Note the trajectory of complications continued to show a long term benefit to those in the Intensive group, extending years after the switch from DCCT to EDIC. The authors expect that even though A1c values reach the same average and the complication rates will converge over time, there will continue to be an advantage for the early intensive treatment.

There may be another advantage to early intensive treatment. The authors theorize that intensive treatment, reducing A1c to 7% or less, early in the process may have “disrupted the pathogenic process … for enough time to slow the rate of progression indefinitely, compared with that of individuals in whom a greater momentum of microvascular complications was maintained by a mean A1c level of 9.0% over the same DCCT time period.”

The risk of tighter blood sugar control is the increased occurrence of hypoglycemia, and excess weight gain.

“The more time patients are exposed to chronically elevated plasma glucose levels, reflected in elevated A1c, the greater their risk of microvascular complications.”

References

The DCCT Research Group. The Effect of Intensive Therapy on the Microvascular Complications of Type 1 Diabetes Mellitus. JAMA. 2002;287:2563-2569

American Diabetes Association. Implications of the Diabetes Control and Complications Trial. Diabetes Care. 2003; 26 (Suppl.1): S25-S27.

The information contained here is for educational purposes and is not a replacement for the individual care of your physician.

C Blackwell, MD Dec 2008