EASD 2022: UKPDS 44-year follow-up results found that the timing of T2DM initiation of insulin therapy from the metabolic memory effect!

At the 58th European Association for the Study of Diabetes (EASD) Annual Meeting (EASD), the latest data from the UKPDS Prospective Diabetes Study (UKPDS) for 44 years of follow-up was announced, UKPDS is a study that included 5102 patients with type 2 diabetes (T2DM) in 23 clinical centres in the UK, mainly observing the impact of different treatment models on clinical outcomes.

UKPDS follow-up for 44 years: metabolic memory effects persist

Residual effects are defined as phenomena
in which intensive glycemic control persists to have a beneficial effect on disease outcomes or complications even after prolonged cessation of intervention.
Metabolic memory refers to the long-term harm to microvascular and macrovascular complications resulting from the initial hyperglycemic state
.
"Metabolic memory" and "legacy effects" are similar concepts used to describe the long-term beneficial effects
of early intensive glycemic control on diabetic microvascular and macrovascular complications.

The latest UKPDS data [1-3] show that, after 44 years of follow-up, participants receiving intensive sulfonylurea/insulin therapy had a 10% reduction in the incidence of any diabetes-related endpoint event, a 15% lower risk of myocardial infarction, a 26% lower risk of microvascular complications, and an 11% lower risk of all-cause mortality compared with usual care (see Table 1 for details).

This study fully confirms the long-term microvascular and macrovascular benefits of early good glycemic control in T2DM patients, suggesting the persistence of metabolic memory effects, and clinical hypoglycemic therapy should be initiated
as soon as possible in T2DM patients.

Table 1 UKPDS follow-up data results RRR: associated risk reduction

From the mechanism of metabolic memory effect, the necessity of achieving blood glucose standards at an early stage is seen

The mechanism of metabolic memory effect is related to epigenetics, oxidative stress and inflammation [4-6], in terms of epigenetics, long-term hyperglycemia can epigenetic modification endothelial cells on the one hand, causing continuous changes in microvessels and macrovessels, and on the other hand, the expression of pro-inflammatory genes will also be enhanced; In terms of oxidative stress, hyperglycemia can cause mitochondria to produce too much superoxide anion and reactive oxygen species (ROS), increase cellular oxidative stress, and induce endothelial dysfunction
.
The overproduction of superoxide anions continues even after the later normalization of blood glucose levels, which explains the emergence of diabetic complications in diabetic patients even after good glycemic control in the
later stages.

In addition, AGEs (advanced glycation end products) promote oxidative stress, increased vascular permeability, pathological angiogenesis, thrombosis, and further promote endothelial dysfunction
.
From the perspective of the mechanism of metabolic memory effect, the timing of early realization of blood sugar control is very important, and timely blocking the "metabolic memory" effect of hyperglycemia before the irreversible damage caused by hyperglycemia can become a powerful weapon
to reduce long-term complications in diabetic patients.

Insulin intensive therapy achieves diabetes remission and blocks metabolic memory effects

In recent years, some studies have shown that in newly diagnosed patients with T2DM, early insulin intensive therapy can reverse β cell function in T2DM patients, delay the progression of the disease, and achieve diabetes remission [7-8]; In another study [9], short-term intensive insulin therapy with newly diagnosed T2DM was shown to be superior
to intensive treatment with oral hypoglycemic drugs.

Therefore, the Chinese Guidelines for the Prevention and Treatment of Type 2 Diabetes (2020 Edition)[11] recommend intensive insulin therapy
when newly diagnosed T2DM patients have HbA1c ≥ 9.
0% or fasting blood glucose ≥ 11.
1 mmol/L with significant hyperglycemia symptoms.

After the failure of oral drugs, insulin therapy is started in time to relieve the metabolic memory effect of hyperglycemia

Clinically, most T2DM patients will first choose lifestyle modification combined with oral hypoglycemic drugs treatment plan, some patients may not be able to achieve blood glucose standards, from the metabolic memory effect it is not difficult to see that the state of long-term hyperglycemia will lead to irreversible pathophysiological changes, for these patients as soon as possible and timely release of the hyperglycemic metabolic memory effect is particularly important, then in this part of the patients immediate start of insulin therapy means that blood sugar control is easier to achieve, the delay of complications even does not appear [10
。

Therefore, the Chinese Guidelines for the Prevention and Treatment of Type 2 Diabetes (2020 Edition)[11] recommend that intensive insulin therapy be selected for T2DM patients with T2DM who have failed oral hypoglycemic drugs after 3 months of treatment with lifestyle and oral hypoglycemic drugs, emphasizing the necessity of
immediate initiation of insulin therapy.

In summary, the data of UKPDS follow-up for 44 years suggest that the metabolic memory effect of hyperglycemia persists, and poor glycemic control will lead to irreversible pathophysiological changes, so the timing of early glycemic control is very important, and early insulin intensive therapy in some newly diagnosed T2DM patients can achieve diabetes remission; For patients with T2DM after oral drug failure, immediate initiation of insulin therapy can relieve the metabolic memory effect of hyperglycemia, so early and timely initiation of insulin therapy can block the "metabolic memory" effect of hyperglycemia, which is a powerful weapon to reduce long-term complications in diabetic patients!