Good news! - Latest results from DCCT/EDIC

The EDIC study continued to follow the DCCT patients - for nearly 30 years now. The latest results were reported this weekend.... and the good news is that the dramatic advantages of intensive therapy on reduced complication rates have held up over time....with the majority of the benefit being explained by differences in A1C..... summary below:

ADA: Intensive Tx Yields Long-Term Gain in Type 1 Diabetes
By Kristina Fiore, Staff Writer, MedPage Today
Published: June 23, 2013
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco

Action Points
This study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
Benefits seen with intensive therapy for type 1 diabetes in a large epidemiological study persist through extended follow-up.
Point out that over 18 years, patients who had intensive management -- achieving a glycated hemoglobin (HbA1c) target of 7% -- had a lower risk of retinopathy, a reduced risk of microalbuminuria, and a lower risk of macroalbuminuria.

CHICAGO -- Benefits seen with intensive therapy for type 1 diabetes in a large epidemiological study persist through extended follow-up, according to the latest data from the Diabetes Control and Complications Trial (DCCT) and Epidemiology of Diabetes Interventions and Complications (EDIC) trial.

Over 18 years, patients who had intensive management -- hitting a glycated hemoglobin (HbA1c) target of 7% -- had a 46% lower risk of retinopathy, a 39% reduced risk of microalbuminuria, and a 61% lower risk of macroalbuminuria (P<0.0001 for all), several investigators involved in the trial reported during a special symposium at the American Diabetes Association (ADA) meeting here.
"As we follow this population longer, we've been able to show that early benefits with regard to early complications has extended," study co-chair David Nathan, MD, of Massachusetts General Hospital (MGH) in Boston, told MedPage Today. "We've demonstrated that loss of kidney function is reduced, people develop less severe eye complications, and we see a host of other benefits on long-term severe complications that we didn't see during the initial trial because the patients were too young and had diabetes for a relatively short period of time."

The 10-year DCCT was followed by the ongoing EDIC trial, and has now been running for a total of 30 years.

The DCCT revealed that intensive therapy -- lowering HbA1c to 7% rather than the 9% which was standard practice at the time -- in patients with type 1 diabetes diminished a range of complications about 35% to 75%, establishing intensive therapy as the standard of care.

The trial was extended into EDIC and Judith Fradkin, MD, director of diabetes at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) said during a press briefing that 95% of trial patients who are still alive continue to participate in the trial.

At the meeting, several researchers presented updated data on complications including retinopathy, nephropathy, and musculoskeletal complications.

Lloyd Paul Aiello, MD, PhD, of the Joslin Diabetes Center at Harvard Medical School, reported a 46% reduced risk of retinopathy after 18 years of follow-up in the EDIC study with intensive therapy compared with the standard of care (P<0.0001). He noted that 86.7% of that risk reduction was explained by between-group differences in HbA1c levels.

Aiello also reported a reduction in severe diabetic retinopathy with intensive management, with a 47% reduced risk of proliferative diabetic retinopathy and a 35% reduced risk of clinically significant macular edema (P<0.0001 for both). During the 18 years of EDIC follow-up, the researchers also saw a 39% lower risk of focal laser therapy and a 48% lower risk of any ocular surgery (P<0.0001). "Further EDIC follow-up has demonstrated a consistent beneficial effect on severe eye disease," Aiello said. "Although the risk reduction has decreased with time, the effect is still substantial." Ian de Boer, MD, of the University of Washington in Seattle, reported nephropathy findings that pointed to a "continued separation of microvascular and macrovascular complications" over 18 years of EDIC data. Specifically, the researchers saw a 39% reduced risk of microalbuminuria and a 61% reduced risk of macroalbuminuria with intensive therapy through that time (P<0.0001 for both). Once again, the vast majority of risk reduction -- between 91% and 100% -- was explained differences in HbA1c levels, de Boer said. Earlier analyses that had been previously reported also showed that intensive therapy delayed the development of hypertension and preserved estimated glomerular filtration rate (eGFR), he added. "The kidney findings speak volumes about the long-term benefits of intensive therapy," de Boer said during a press briefing. "It's demonstrated that intensive therapy can have a sustained, long-term impact on mini manifestations of this microvascular and macrovascular disease." The researchers also reported new data on musculoskeletal complications, particularly cheiroarthropathy, which is periarticular skin thickening of the hands and limited joint mobility. It typically results from the accumulation of advanced glycation end-products in collagen, and includes carpal tunnel syndrome, adhesive capsulitis, Dupuytren's contracture, flexor tenosynovitis (or "trigger finger"), and prayer sign (or trouble holding the hands flat when palm-to-palm).

Mary Larkin, RN, of MGH, and colleagues conducted a cross-sectional analysis of EDIC data during years 18 and 19.

They found that a third of of about 1,200 patients (33%) had at least one type of this complication, with the most common being adhesive capsulitis, followed by carpal tunnel and then prayer sign.

Another 20% of patients had at least two complications, and another 10% had at least three, Larkin said. About 3% had four or more complications.

Only 34% were free of these complications, Larkin reported.

Risk factors for these conditions included older age, female gender, longer duration of disease, and higher HbA1c over time. It was also associated with neuropathy and retinopathy, but not with nephropathy, she reported.

"Cheiroarthropathy represents an important constellation of long-term complications worthy of further clinical and research attention," Larkin said. "Surveillance of musculoskeletal disorders should be considered in routine care of patients with type 1 diabetes."

Nathan said these conditions may have been under-recognized in type 1 diabetes in the past.

John Lachin, MD, of George Washington University in Washington, D.C., said longer term EDIC data also show a reduced risk of cardiovascular effects with intensive management, as well as cardiovascular mortality -- a finding that somewhat departs from recent findings in type 2 diabetes.

"This is a little different from type 2 diabetes, where there's been a question as to whether intensive therapy is important or not," Nathan told MedPage Today.

Lachin said the mortality data are in press and therefore embargoed and could not be released at the time of his ADA presentation.

But he noted that, as with other complications, the long-term benefits of intensive therapy on cardiovascular outcomes are largely mediated by HbA1c levels.

The study was supported by the NIDDK.

The researchers reported no conflicts of interest.

Primary source: American Diabetes Association
Source reference:
Nathan DM, et al "DCCT/EDIC 30th anniversary symposium -- contributions and progress" ADA 2013.

HPNpilot - Thanks for posting this good news. When I was diagnosed in 1984, many doctors felt that diabetes was going to run its course, no matter how the patient treated themselves. There were some doctors that speculated and hoped that good control had to matter. The groundbreaking DCCT results in 1993 showed that the more hopeful doctors, to that point, were indeed correct.

Since my diagnosis, I've always sided with the more hopeful perspective that keeping the A1c down would help. I'm now going to follow some of the links and see if they have any data on neuropathy, particularly the autonomic variety. The experience of one of our members, Jen, showed that better control in her case led to big improvements in her kidney eGFR number and is consistent with this announcement. Better is better!

What isn't covered in the news story is the reduction in cardiovascular mortality - the article is in press - but that should be very interesting too, as heart disease is the # 1 killer of diabetics. Demonstrated reduction in heart disease associated with lower A1c will be interesting indeed, as apparently it has not dropped much with A1c in type 2 patients.

Absolutely great news! The drop in risks of complications is astoundingly large.

This is interesting, and I'm glad that they are still following up on people 30 years later. Does anyone know what they consider "intensive therapy"? Just curious . . . thanks!

Here is the original New England Journal of Medicine paper from 1993

They defined "conventional therapy" as

Conventional therapy consisted of one or two daily injections of insulin, including mixed intermediate and rapid-acting insulins, daily self-monitoring of urine or blood glucose, and education about diet and exercise13,25. Conventional therapy did not usually include daily adjustments in the insulin dosage. The goals of conventional therapy included the absence of symptoms attributable to glycosuria or hyperglycemia; the absence of ketonuria; the maintenance of normal growth, development, and ideal body weight; and freedom from severe or frequent hypoglycemia. Women who became pregnant or were planning a pregnancy received intensive therapy until the time of delivery, after which they resumed conventional treatment. Patients in the conventional-therapy group were examined every three months.

Intensive therapy was defined as follows:

Intensive therapy included the administration of insulin three or more times daily by injection or an external pump. The dosage was adjusted according to the results of self-monitoring of blood glucose performed at least four times per day, dietary intake, and anticipated exercise. The goals of intensive therapy included preprandial blood glucose concentrations between 70 and 120 mg per deciliter (3.9 and 6.7 mmol per liter), postprandial concentrations of less than 180 mg per deciliter (10 mmol per liter), a weekly 3-a.m. measurement greater than 65 mg per deciliter (3.6 mmol per liter), and hemoglobin A1c (glycosylated hemoglobin), measured monthly, within the normal range (less than 6.05 percent). The patients initially chose either multiple injections or pump therapy and could subsequently change to the other method if their glycemic goals were not achieved or if such was their preference. The patients in the intensive-therapy group visited their study center each month and were contacted even more frequently by telephone to review and adjust their regimens.

Note that what was intensive therapy in 1993 is now standard practice in the developed countries, and the DCCT study convinced people that intensive therapy worked.

What the new studies show is that the gains are sustained.

Awesome. Thanks!

I think this is important work. It is unlikely we will ever get a trial funded like the DCCT. The scale was very costly and it would never get approved today because we now know that intensive insulin therapy works to reduce complications. But we are now in a quandry. We still have questions about whether "everything" is better with tighter blood sugar control. David Nathan, a well respected researcher, raises questions about whether the results translate to T2. In fact I believe that adverse results in T2 controlled trials were due to really bad choices of therapy (no diet, overuse of known harmful drugs and lack of competent insulin use). So I believe the results do apply to T2. But we have conflicting evidence. And this leaves us in a quandry. Is it ethical to do a trial on T2s in the same way? Would we give intensive insulin therapy to one group of T2s and achieve tight blood sugar control only to watch the other control arm accumulate adverse complications? I don't think we can.

Good point... such a trial would likely be unethical. But a retrospective study
comparing people's A1C history over many years with their current complication rates could probably be done, assuming you could find a large body of fairly continuous patient records to do it on. It would not be as clean as a two armed randomized trial, but would not have the ethical problems of randomizing some people to a treatment arm that has high likelihood of being inferior, given the T1 data.

For those that may have not been paying attention way back in 1993, the results of this landmark study were published earlier than originally planned because the study practitioners felt ethically required to do so. Staying on the original timeline, given the clear and persuasive evidence gathered to date, it would have harmed some study participants by withholding the conclusive results.

I'm basing this on my memory and a quick search did not reveal confirmation. I'm fairly confident that this is what happened but would appreciate comment on this point.

I was diagnosed in 1989 and was lucky to have a pedetrician that was up on research. I remeber him saying that while the DCCT trial have not been finalized it is obvious what the results will be and you need to be intensive insulin therapy. Looking back on it I am very glad to have this man as my doctor.

As much as I criticize the medical community, like you, I am very grateful to the general medical practitioner that correctly diagnosed me as a T1 in 1984 without any antibody tests. Like your doctor, he was up on the medical literature and knew that people like me existed. I started on insulin immediately and didn't suffer the runaround many adult T1s endure simply because they're not juveniles.

But the 6.05 % A1C goal had to be changed due to significant hypoglycemia in the intensive control group. I believe they upped it to either 6.5 or 7%

Thanks for posting this. For any of us who have literally had to fight with our endos and CDE's for the right to maintain a "normal" A1C this is great ammunition.
Meanwhile - did the people who were originally involved in the DCCT and subsequently the EDIC get their pumps/insulin/medical care all covered ? That's better than 30 years of stuff for a very nice price.

If you look at the original 1993 paper, they have a graph that shows the occurrence of hypoglycemia vs. A1C. and they clearly state that hypoglycemia is the main barrier to tight control (Figure 5)....

The actual achieved A1C in the intensive group was 7

Yes I read that the achieved A1C was 7% but if the goal was 6.05% then they fell significantly short of that.