EASD 2022: UKPDS 44 Year Follow Up Symposium

The symposium elaborates on the UKPDS trial, the monitoring and intervention phase, the legacy effect of the drugs used, the economic aspects of the trial and dementia outcome of the trial. It highlights certain pointers such as the association between previous randomization to a strategy of intensive glucose control with sulphonylureas or insulin or with metformin compared with a strategy based on diet and the risk of complications over time.

The trial was initiated in 1977 with newly diagnosed Type 2 diabetes patients and it continued for the next 20 years. Upon randomization, there were around 42997 person-years of follow-up. The monitoring phase continued from 1997 to 2007 with 66,792 person-years of follow-up. This was followed by 14 years of NHS administrative data up to 2021.  At present, there are around 78,000 person-years of follow-up with a range of 0 to 42 years; 14 participants from the original randomized cohort have been followed for over 40 years;4209 participants were randomised into intensive group(n=2729) treated with sulfonylurea/insulin, overweight treated with metformin(n=342) and compared to control group with diet restrictions(n=1138).

In the initial findings it was observed that intensive therapy was associated with significant benefits in diabetes related endpoints, especially in microvascular disease.  Intensive blood glucose control by either sulfonylureas or insulin substantially decreases the risk of microvascular complications, all-cause mortality but not macrovascular disease. Intensive metformin treatment in overweight diabetes patients decreased the risk of diabetes related endpointsPost study monitoring from 1997-2007 showed that any diabetes-related endpoint sustained over the course of follow-up. This was deemed a legacy effect. . The legacy effect refers to the impacts the previous conditions have on current processes or properties. The 44-year Kaplan-Meier analysis showed that the patients allocated to sulfonylurea or insulin had a lower risk of any diabetes-related endpoint as compared to the conventional group (Hazard ratio 0.81, P=0.015) indicating that the legacy effect continued. Early intensive blood glucose control with sulfonylurea or insulin led to 11% fewer deaths and 26% fewer microvascular complications, even in the 44-year follow up study. The glycemic difference of metformin in the overweight patients was only two thirds that of the intensive sulfonylurea insulin group, 0.6% compared with 0.9%. The metformin treatment group had a hazard ratio of 0.81 (P=0.015) indicating a legacy effect of metformin. Intensive blood glucose control with metformin demonstrated 31% fewer heart attacks and 25% fewer deaths, in the long-term follow up study.

With respect to economics, the UKPDS was the first large scale trial where the economics was integrated at a very early stage. The economic data such as the cost and resource-use data associated with patients, the use of drugs during hospital care was collated while collecting data for the clinical trial. Data regarding the quality of life of patients too was collected. The data from the cost-effectiveness of major therapies showed that metformin, a relatively economic drug, had a very large effect in reducing complications which further reduced the overall costs. It was also observed that intensive blood glucose control increased life expectancy and quality-adjusted life years. 

A systematic review of 20 studies has shown that men and women with diabetes have a 60% greater risk of developing dementia and the risk is greater for vascular dementia as opposed to non-vascular causes. Several Mendelian randomisation analyses suggest that antidiabetes treatments such as insulin, sulfonylurea or GLP1 agonists may reduce the risk of dementia. From the UKPDS trial data, around 12% patients in the conventional group and 13% patients in the sulfonylurea/insulin group (hazard ratio 0.86) developed dementia. Overall, with sulfonylurea or insulin treatment for 10 years, the incidence of dementia reduces from 29% to an increase of 4%; with Metformin there is a reduction of 49% to an increase of 18%. 

In summary, the UKPDS trial has emphasized that intensive therapy causes a considerable diabetes-related risk reduction with subsequent economic benefits and an improved quality of life. There is also an added benefit of the reduction in the risk of dementia with this intervention.