Early and intensive glycaemic control continues to reduce risks of mortality, MI, and microvascular complications even at 44 years after the UKPDS study’s initiation, according to follow-up data presented at the EMW Symposium 2024.

As the biggest trial reported in diabetes to date, the 20-year UKPDS trial, which ran from 1977 to 1997, investigated whether complications of type 2 diabetes (T2D), previously often regarded as inevitable, could be reduced by improving glycaemic control. [Lancet 2024;404:100-102]

“Ten years of post-trial follow-up [from 1997 to 2007] revealed enduring and emerging glycaemic legacy effect and metformin legacy effect,” noted UKPDS’ lead investigator, Professor Rury Holman of the University of Oxford, Oxford, UK. “We aimed to determine whether these effects would wane by extending follow-up for another 14 years [from 2007 to 2021].” [Lancet 2024;404:145-155]

[ Prof Rury Holman ]

“For up to 24 years after the trial ended, the glycaemic and metformin legacy effects showed no sign of waning,” reported Holman.

Early intensive therapy with sulfonylurea or insulin continued to significantly reduce risks of microvascular complications by 26 percent (p<0.0001) vs conventional glycaemic control. “The hazard ratio has not changed [much] over 24 years. It is rock solid,” commented Holman. [Lancet 2024;404:145-155]

At the end of the original trial, there was no statistically significant difference in MI or all-cause mortality between groups. However, after 24 years of follow-up, early intensive therapy with sulfonylurea or insulin significantly reduced risks of MI by 15 percent (p=0.002) and all-cause mortality by 11 percent (p=0.015).

Similarly, early intensive therapy with metformin significantly reduced risks of MI by 31 percent (p=0.003), all-cause mortality by 20 percent (p=0.010), and diabetes-related deaths by 25 percent (p=0.016) after 24 years.

“Early inadequate control of hyperglycaemia appears to induce irreversible pathophysiological changes, thereby increasing the risks of diabetic complications and premature death,” explained Holman.

“Metformin appears to have additional benefits beyond its glucose-lowering effect, with no tachyphylaxis,” he added. “These benefits may include β-cell preservation, reduction in insulin resistance, anti-inflammatory effects, cardioprotective effects, activation of the AMPK pathway, epigenetic modifications, and alteration of gut microbiota.”

An analysis of UKPDS showed that lowering HbA_1c by 1 percent immediately after T2D diagnosis was associated with a 7-fold risk reduction in all-cause mortality (18.8 vs 2.7 percent) and a 3-fold risk reduction in MI (19.7 vs 6.5 percent) compared with delaying the 1 percent HbA_1c lowering until 10 years after diagnosis. Historical HbA_1c values have a greater impact than recent values on clinical outcomes. [Diabetes Care 2021;44:2231-2237]

“Establishing and maintaining near-normal glycaemia from day 1 can minimize the risks of complications and prolong life,” Holman stressed. “For those of you who are treating T2D, start early, treat well, and keep treating.”

“We now have newer therapies [to better control T2D],” suggested Holman. “[Importantly,] therapeutic inertia must be avoided by proactively increasing or adding glucose-lowering therapies whenever blood glucose levels rise.”