THE METABOLIC MEMORY IN

ACTION UKPDS FOLLOW UP DATA

THE LEGACY EFFECT

THE ORIGINAL UKPDS STUDY

The United Kingdom prospective diabetes Study (UKPDS) was a randomized,

prospective, multicenter trial launched in 1977, enrolling patients until 1991 and

completed by 1997, with final results published in 1998.

Here researchers randomly assigned 4,209 patients to either conventional therapy in
the form of dietary restriction or intensive therapy with sulfonylurea, insulin or, in

overweight patients metformin only,

The study showed a reduced risk of microvascular complications, a nonsignificant
reduction in MI, and no improvement in all-cause mortality with intensive glucose
lowering using a sulfonylurea or insulin, instead of conventional glucose control

through diet.
It is generally said that the Original UKPDS study have formed the "cornerstone" for

diabetes management:
They first about the need for intensive glucose control.

THE 10 YEARS FOLLOW UP DATA

In post-trial monitoring, 3277 patients were asked to attend annual UKPDS clinics for

5 years from 1997.

No attempts were made to maintain their previously assigned therapies.
Annual questionnaires were used to follow patients who were unable to attend the

clinics.
All patients in years 6 to 10(2002 to 2005) were assessed through questionnaires.
Diabetes is a disease for a lifetime.The question was when intervening was stopped,
would the impact of good early control disappear or would there be a continuing
benefit, what is being called

THE LEGACY EFFECT.

RESULTS

Between-group differences in glycemic control were lost in the first year after the trial

closed.
At 10 years, patients assigned to intensive control with sulfonylurea and insulin had
reduced risk for microvascular disease (24%), MI (15%), death from any cause (13%)
and any diabetes-related end point (9%) compared with patients assigned to

conventional therapy.
Patients assigned to metformin experienced significant risk reductions for MI (33%),
death from any cause (27%) and any diabetes-related end point (21%) that
Persisted over time compared with controls.

DISCUSSION

Thus the UKPDS follow up data not only conclusively showed the benefit of intensive
glycemic control in reducing the microvascular complication , but showed benefit in
reducing macrovascular complications like MI , stroke , and reduction of death from

all cause mortality as well.

An important point to consider over here is that since original UKPDS included only
newly detected T2DM patients , all these patients got the intensive therapy right
after diagnosis , which gave them the metabolic memory , resulting in an improved

macrovascular outcome in the long run.

Thus the massage is very clear start intensive treatment right after diagnosis , to
provide patients physiology with the metabolic memory , so that long term

macrovascular complecatiuon can be avoided.

Thus we need to stop the macrovascular complications initially before they set in ,
rather than trying to control them late.

The significance of this early control will be more evident if we consider 3 more landmark
studies presented in 2008.

ACCORD, ADVANCE, VADT TRIALS

ACCORD (Action to Control Cardiovascular Risk in Diabetes, New England

Journal of Medicine, June 2008)

ADVANCE (Action in Diabetes and Vascular Disease: Preterax and

Diamicron Modified Release Controlled Evaluation, New England Journal
of Medicine, June 2008)
VADT (Glucose Control and Vascular Complications in Veterans with Type
2 Diabetes, New England Journal of Medicine, Jan 2009)

DISCUSSION CAN YOU FIND OUT HOW METABOLIC MEMORY HAS PLAYED
ITS PART HERE ?

See none of these 3 trials showed significant reduction in macrovascular outcome why ? All
these trials included patients on whom macrovascular complication would have already set
in to some extent.
THUS YOU CANNOT STOP A MOVING TRAIN, ITS BETTER TO NOT TO LET THE TRAIN START,
Thus , we are seeing a continued benefit of earlier intervention. The message is very clear
early intensive glucose control leads to increased benefits over time, and waiting and
treating later leads to disappointing results. The emphasis has to be on keeping blood
glucose normal from day one, rather than trying to rescue it from some high value later on.

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