The latest results of 44 years of UKPDS research are announced: blood glucose legacy effects remain

The 58th European Association for the Study of Diabetes (EASD) Annual Meeting 2022 was held
in Stockholm, Sweden on September 20~23, 2022.

At the meeting, Professor Rury R.
Holman from the United Kingdom presented the latest results of 44 years of UKPDS research, which answer the question
of whether the residual effect after intensive glycemic control or metformin treatment still exists.

UKPDS Research Profile

The UKPDS study began in 1977 and included 5102 patients with newly diagnosed type 2 diabetes, with the main purpose of the study to explore the impact of
intensive blood glucose and blood pressure control on the development of chronic complications in patients with type 2 diabetes.
The randomised controlled trial component of the study was from 1977 to 1997, the post-trial observation component from 1997 to 2007, and the follow-up component
under the supervision of the National Health Service (NHS) in the United Kingdom from 2007 to 2021.
As of 2021, the overall mortality rate of the population in the UKPDS study was 84.
4%.

Fig.
1 UKPDS 44 years study subjects

Analysis of residual effects after intensive glycaemic control

The study found that participants receiving sulfonylurea/insulin intensive therapy had a significantly lower proportion of any diabetes-related endpoint events (hazard ratio 0.
90, 95% confidence interval 0.
83 to 0.
98, P = 0.
016) and a significantly lower risk of myocardial infarction (hazard ratio 0.
85, P = 0.
0074) compared with usual care, The risk of microvascular complications was significantly reduced (hazard ratio 0.
74, P<0.
0001) and the risk of all-cause mortality was significantly reduced (hazard ratio 0.
89, P=0.
0093).
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Figure 2 Kaplan-Meier plot of any diabetes-related endpoint event in the sulfonylurea/insulin intensive treatment group versus usual care group

Table 1 Effects of sulfonylurea/insulin intensive therapy on diabetes complications and outcomes

Fig.
3 Cumulative risk ratio of sulfonylurea/insulin intensive therapy versus usual care for all-cause mortality

Analysis of residual effects of metformin treatment

The results of the 44-year study of UKPDS showed that participants treated with metformin had a significantly lower proportion of any diabetes-related endpoint events (hazard ratio 0.
81, 95% confidence interval 0.
68 to 0.
96, P = 0.
015), a significantly lower risk of myocardial infarction (hazard ratio 0.
69, P = 0.
0037), and a significantly lower risk of all-cause mortality (hazard ratio 0.
75, P = 0.
002) compared with usual care.
However, there was no significant difference in the risk of microvascular complications between the two groups (hazard ratio 0.
90, P = 0.
49).

Figure 4 Kaplan-Meier plot of any diabetes-related endpoint event in metformin-treated versus usual treatment group

Fig.
5 Cumulative risk ratio of metformin intensive therapy versus conventional treatment for all-cause death

Table 2.
Effects of metformin treatment on diabetes complications and outcomes

Why do hypoglycemic treatments have residual effects? Professor Rury R.
Holman pointed out that the relevant mechanism of blood glucose legacy effects is not fully understood, and the lifelong effects of hyperglycemic status are possible mechanisms, which may be mediated by oxidative stress, glycosylation end products, and epigenetic changes
.

brief summary

Professor Rury R.
Holman summarized the findings as follows:

1.
The glycemic legacy effect first identified in the results of the 30-year follow-up of the UKPDS study persisted at 44 years of follow-up: early use of sulfonylureas or insulin intensive glycemic control reduced the risk of death by 11% while reducing microvascular complications
by 26%.

2.
The metformin legacy effect, first identified in the results of the 30-year follow-up of the UKPDS study, persisted at follow-up to 44 years: intensive glycemic control with early metformin reduced the risk of heart disease by 31% and the risk
of death by 25%.

3.
These landmark results suggest that early detection and intensive treatment of type 2 diabetes have great clinical significance
.