Rury R. Holman, MB ChB; Mark Harmel, MPH, CDCES

- I'm pleased to give an update on the UK Prospective Diabetes Study (UKPDS). This is the longest-running follow-up of a randomized controlled trial in type 2 diabetes.

• Those familiar with it may remember that the 20-year trial randomized patients to intensive blood glucose control with sulfonylurea/insulin, or in overweight patients, to metformin, compared with a conventional (primarily diet) policy.

- The end of that trial showed unequivocally that better glucose control could reduce complications — that is, microvascular complications — but did not impact macrovascular complications.

• Once the trial finished, we embarked on a 10-year post-trial monitoring study in which all patients who had survived continue to be followed by the UKPDS team.

- The results from the end of that 10-year period showed that not only was the microvascular protection maintained, but we saw emerging statistically significant risk reductions both for myocardial infarction and for all-cause mortality.

- This emerging risk and continued risk protection, we term the "legacy effect" — that is, a continuing benefit from early intensive glucose control.

• Today, I want to bring you new results because we have a further 14 years of data to add, it will be total 44  years study, historically all time unique follow-up

- In this third phase of the UKPDS, we have engaged with the NHS (National Health Service), which is countrywide in the UK and free at the point of delivery.

- This allows us to collect administrative data — that is, hospital episode statistics and death registry data.

By combining this with the clinical trial data and the post-trial monitoring, we have been able to extend the follow-up to 44 years. We have asked the same questions again:

- If you treat early and intensively with sulfonylurea or insulin, do you see continuing benefit? The answer is, unequivocally, yes.

We see

• 11% fewer deaths and

• 25% fewer microvascular events — that's kidney disease and loss of vision, which are the things which scare our patients so much.

- This is a legacy effect which appears to be enduring, and I'll come back to that.

We also have the trial comparing metformin.

- In the metformin trial in overweight patients, the legacy effect for metformin also continues. We see

• a 31% reduction in heart attacks and

• a 25% reduction in all-cause mortality. That's a one-quarter reduction. These are amazing figures with absolutely stable legacy effects.

The question that we have to address is, why is this continuing benefit seen?

- My view is that what we are looking at is a hyperglycemic legacy effect. I believe that early hyperglycemia really does set the pattern for the rest of a patient's life.

- We're seeing irreversible pathophysiologic changes occurring either through oxidative reactions, inflammatory promotion of the pathways, or epigenetic changes, which seem to set people on a permanent path to be at increased risk.

- Improving their control at a later time certainly reduces their risk, but it never gets them back to the minimal risk that's possible if you treat early and treat well.

I think there are big clinical messages here.

- Metformin clearly has an advantage. It's now used in nonoverweight patients as well as overweight patients. It's extremely inexpensive, and our health economic analyses show that it is not only cost-effective, it's cost-saving.

- The health economic analyses that we've conducted in parallel also show that these intensive therapies extend life, on the order of a year extra and with metformin, 2.7 years extra.

- That might not seem much, but in terms of clinical trial data, this is almost identical to what is seen with a lifetime simulation for the heart protection study with simvastatin, where they saw extensions of life between 1 and 2 years.

I think we have a clear message:

• If you identify and treat people with type 2 diabetes early and if you can avoid hyperglycemia, you can avoid putting them on a high-risk trajectory for complications.

• This doesn't preclude the use of other drugs.

• We're not saying that metformin are necessarily first-line drug, but metformin is up there with the other drugs as potential complementary agents, certainly in people who don't yet have complications.

I think it's cementing metformin´s place for many years into the future. Thank you.




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