Intensive therapy dramatically reduces CVD risk in type 1 diabetes

Caroline Cassels

December 22, 2005

Boston, MA - Achieving near-normoglycemic levels in type 1 diabetes reduces the risk of nonfatal myocardial infarction, stroke, or death from cardiovascular disease by 57%[1].

The Epidemiology of Diabetes Interventions and Complications (EDIC) study, a long-term follow-up study of the landmark Diabetes Control and Complications Trial (DCCT), compared cardiovascular risk in patients who achieved near-normal blood glucose levels through intensive management with those using a conventional blood-glucose-management approach and found a dramatically decreased risk of CVD.

The findings are reported in the December 22, 2005 issue of the New England Journal of Medicine.

"The magnitude of the reduction in cardiovascular risk was really quite surprising. We expected to see a reduction somewhere in the area of about 25%, which is a good result, and what you'd expect to see from blood-pressure- or cholesterol-lowering-treatment strategies in this patient population," principal investigator Dr David Nathan (Massachusetts General Hospital) told heart wire . "This is the first study to demonstrate that intensive therapy does decrease heart disease and stroke [in type 1 diabetes], and by a whopping 57%."

Launched in 1983, the DCCT followed 1441 patients with type 1 diabetes, aged 13 to 39, who were randomized to intensive or conventional blood-glucose-lowering treatments and compared the effects of the two on diabetic complications.

Intensive therapy consisted of three or more daily injections of insulin or treatment with an external insulin pump with dose adjustments based on at least four self-monitored glucose measurements per day. Daily glucose goals were 70 to 120 mg/dL before meals and peak levels of less than 180 mg/dL after meals. Glycosylated hemoglobin was less than 6.05%.

In contrast, conventional therapy had no glucose goals beyond those needed to prevent symptoms of hyper- and hypoglycemia and consisted of one or two daily injections of insulin.

Determining CVD benefit

Published in 1993, the study found intensive blood-glucose-lowering therapy reduced retinopathy, nephropathy, and neuropathy by up to 76%. As a result, intensive therapy is now the standard of care in type 1 diabetes. However, because of the study's relatively short follow-up time, researchers were unable to determine the impact of tight glucose control on cardiovascular risk.

"We couldn't answer the CVD question because at that time our study population was quite young and generally healthy. What we wanted to do was to determine whether longer-term follow-up would, in fact, reveal a benefit of that original intensive therapy. So we followed them for an additional 12 years."

Of the 1441 original randomized patients who began the trial in 1983, 1422 completed the DCCT. Of the surviving cohort, 1397 (97%) agreed to participate in the long-term DCCT/EDIC follow-up study, and of these, 1340 ultimately remained in the study. The DCCT/EDIC study reports follow-up data from 1994 to February 2005.

During an average of 17 years of follow-up, the number of CVD events in the conventional group was more than double that of intensive-therapy subjects. The upshot was that intensive therapy reduced the risk of any CVD event by 42% and the risk of nonfatal MI, stroke, or death by 57%.

CVD events in intensive treatment vs conventional treatment in type 1 diabetes

Group CVD events Patients, n
Intensive treatment 46 31
Conventional treatment 98 52

Methods used in the DCCT study included quarterly measurement of glycosylated hemoglobin values and annual measurement of fasting lipid levels, serum creatinine, and other CVD risk factors. Microalbuminuria and albuminuria were defined by urinary albumin excretion of 40 mg in a 24-hour period and at least 300 mg in a 24-hour period, respectively.

Renal disease was defined by the development of serum creatinine level of at least 2 mg/dL or the need for dialysis or kidney transplantation. Annual electrocardiograms were obtained and interpreted by practitioners who were blinded to the patients' treatment protocols.

During the DCCT/EDIC follow-up study, methodology remained the same, but glycosylated hemoglobin was measured annually and fasting lipid levels and renal function were assessed every other year.

The authors report that the absolute difference between groups in the mean glycosylated hemoglobin value at the end of the mean 6.5 years of the DCCT was approximately 2%—7% in the intensively treated group vs 9% in the conventional-therapy group.

Sustained cardioprotective benefit

At the end of DCCT, those in the conventional-therapy group were offered intensive treatment and all participants were returned to the care of their own healthcare provider for diabetes treatment. As time went on, said Nathan, the gap between the glycosylated hemoglobin values narrowed to 8.0% for the intensive-treatment group and 8.2% for the original conventional-treatment group. Nevertheless, he said, the intensive-treatment group demonstrated a sustained cardioprotective benefit of this early, intensive therapy.

"The message we've had for over a decade now is that, with pretty rare exceptions, all patients with type 1 diabetes should practice intensive therapy. It appears from his study that the earlier you introduce this therapy, the greater its impact."

While intensive therapy can be onerous for patients, said Nathan, they should be counseled on the magnitude of the benefits of achieving rigorous glucose control.

"We've shown them through clinical trials, specifically the DCCT and now through the EDIC follow-up study, that they can delay and even prevent serious complications, but it's a road they have to travel, to a large extent, by themselves. The good news is that the more they practice it, the more they will succeed, and the more likely they are to remain untouched by the ravages of diabetes," he said.

Whether these results apply to type 2 diabetes remains to be seen, Nathan said, but it is expected that the Action to Control Cardiovascular Disease Risk in Diabetes (ACCORD) trial, which will report results in 2009, will help answer this question.

Turning theory into practice

In an accompanying editorial, Dr William Cefalu (University of Vermont College of Medicine, Burlington) questioned whether, in light of the DCCT/EDIC trial results, the glycosylated hemoglobin value of 7.0% suggested by the American Diabetes Association should be reassessed[2]. "These clinical guidelines were suggested on the basis of cutoff points that were relevant for the prevention of microvascular complications, not for cardiovascular disease."

Furthermore, he pointed out, current recommended glycosylated hemoglobin values are even higher for children and adolescents—"the population most likely to benefit" from the study's findings.

However, he acknowledged that achieving current target levels for children and adolescents is difficult "for even the most skilled providers" and may prevent translation of the findings of the EDIC study in this clinical population.

"The medical community needs better means, different strategies, and a different mind-set if we hope to improve and maintain glycemic control in patients with type 1 diabetes and minimize side effects. Until the latter issue is addressed by the availability of new therapies and innovative approaches, the translation of research findings from a landmark study such as the DCCT/EDIC trial may not alter clinical practice for many years. Given the complications and mortality attributed to cardiovascular disease among patients with type 1 diabetes, this delay would be most unfortunate," he writes.

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