Intensive Therapy in Early Diabetes
Published: September 23, 2010
STOCKHOLM -- Early treatment of screen-detected type 2 diabetes works regardless of how intensively glucose, lipids, and blood pressure are managed, experts concluded on the basis of a large randomized trial presented here.
The ADDITION trial showed that early intensive therapy was feasible in primary care but failed to reduce the major cardiovascular complications of diabetes, Simon J. Griffin, MD, of the University of Cambridge, England, and colleagues reported here at the European Association for the Study of Diabetes meeting.
Intensive management yielded a nonsignificant 17% lower risk of composite cardiovascular events after five years compared with good routine care (rate 7.2% versus 8.5%, hazard ratio 0.83, P=0.12).
The researchers had hoped to reverse the string of almost universally negative results with intensive management -- notably in ACCORD, ADVANCE, and the VA Diabetes Trial -- by starting earlier in the disease course.
* Note that this study was presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
* Explain to interested patients that a study among primary care practices in several European countries found that early blood glucose detection of type 2 diabetes with initiation of treatment was feasible.
* Note that intensive therapy showed a trend toward improved cardiovascular outcomes but not a significant difference, partially because both standard and intensive treatments yielded similar adherence to guidelines.
But some diabetes specialists weren't ready to write off the strategy.
The "fairer conclusion" is that intensive therapy is effective, just not more so than routine care, when compared with no screening and no diabetes treatment, said study discussant William Herman, MD, MPH, of the University of Michigan in Ann Arbor, at the session.
He showed a risk prediction model projection that if the patients in the trial had gone untreated over the same period, the primary composite endpoint rate would have been twice that of either type of care.
The intensive goals are fine and it's not too hard to achieve them, concluded Peter Gottlieb, MD, of the University of Colorado Denver, who was not involved in the trial.
If anything, "their control group was too good," he commented in an interview. "If you had the original control group that they expected, their results would have been totally statistically significant."
All agreed that the standard of care improved over the course of the study, bringing the routine care group closer to the intervention group for treatment targets.
The trial's 3,057 patients (age 40 to 69) who screened positive for diabetes at primary care practices in Britain, the Netherlands, and Denmark had been randomized to routine care by national guidelines or intensive treatment according to the following protocol:
* Antihypertensive treatment started with an ACE inhibitor at a blood pressure of 120/80 mm Hg or higher, with directions to intensify treatment for blood pressures of 135/85 mm Hg or greater.
* Lipid-lowering medication was to start if lipids were 3.5 mmol/l (135 mg/dL) or higher with intensification for those at or above 4.5 mmol/l (174 mg/dL).
* The treatment target for blood glucose was a hemoglobin A1c of 6.5% or less.
But guidelines for routine care went from a recommendation for antihypertensive treatment at a systolic blood pressure of 140 to 155 mm Hg in 2001 at baseline to 130 to 140 mm Hg at follow-up. For cholesterol, the treatment threshold fell from 5.0 to 6.0 mmol/l at baseline down to 4.5 mmol/l at follow-up.
Diabetes treatment goals remained largely stable, but some countries had adopted a recommendation that included 6.5% in the A1c target range, the researchers noted.
Not surprisingly, the biggest differences were between baseline and follow-up for treatment and risk factor profiles, rather than between the intensive intervention and routine control groups, Herman noted.
The majority of patients in both groups achieved the intensive group treatment targets with differences of only 2.86 mm Hg for systolic blood pressure, 0.27 mmol/l for total cholesterol, and 0.08% for hemoglobin A1c between groups -- though all favored intensive management -- at the average 5.3 years of follow-up.
Not surprisingly, then, the individual components of the primary outcome measure all showed hazard ratios favoring intensive management, with none statistically significant. The results were:
* For cardiovascular death, 0.88 (95% confidence interval 0.51 to 1.51)
* For myocardial infarction, 0.70 (95% CI 0.41 to 1.21)
* For stroke, 0.98 (95% CI 0.57 to 1.71)
* For revascularization, 0.79 (95% CI 0.53 to 1.18)
No amputations occurred in either group.
All-cause mortality, too, favored intensive management but again without a significant impact (HR 0.91, 95% CI 0.69 to 1.21).
Although done under specific systems of care with variation in practice between nations, the results likely generalize to everyday general practice outside the European countries included, Herman pointed out in his presentation.
"This is an important study that I personally never believed would be performed," he told the audience.
Gottlieb noted that standard care may be even poorer in the U.S., which he largely chalked up to less informed primary care physicians taking care of the vast majority of diabetes patients.
The study was supported by many scientific foundations, including the Novo Nordisk Foundation and Wellcome Trust, as well as by unrestricted grants from Novo Nordisk, ASTRA, Pfizer, GlaxoSmithKline, Servier, HemoCue, Bio-Rad, and Merck.
Griffin reported that over the past two years he received honoraria for lecturing from Unilever, GlaxoSmithKline, Novo Nordisk, and Eli Lilly as well as travel support from Eli Lilly.
Herman provided no information on potential conflicts of interest.
Gottlieb reported consulting for sanofi-aventis in other areas of diabetes care.
Primary source: European Association for the Study of Diabetes
Gaede P, et al "EDEG-PCRD Symposium: Benefits of early intensive multifactorial therapy in type 2 diabetes" EASD 2010.