The new hypoglycemic rookie debuted in EASD, and the strength interpreted the role of islet β cell function improvement

Tirzepatide is a glucose-dependent insulin-stimulating polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) receptor agonist in type 2 diabetes mellitus (T2DM) as a novel diabetes treatment Research on blood sugar reduction and weight loss in patients is endless
.
In September 2022, at the annual meeting of the European Association for the Study of Diabetes (EASD), a large number of recent research progress on Tirzepatide was announced, among which Tirzepatide's research on the improvement of islet β cell function [1] was eye-catching
.
Based on this research, "Medical Community" invited Professor Hong Tianbei of Peking University Third Hospital to give further interpretation and sharing, in order to give advice and inspiration
to the majority of endocrinology medical workers on the platform.

Exploring the cause and improving the function of islet β cells is the fundamental of T2DM treatment

Islet β cell dysfunction and insulin resistance are considered to be the most basic pathophysiological features of T2DM [2], and islet β cell dysfunction has a complex pathogenesis, which is generally believed to be mainly caused
by genetic and environmental factors 。 "Genetic factors can explain part of the islet β cell dysfunction, but other non-genetic factors also play a very important role in islet β cell dysfunction in T2DM patients, such as glucose toxicity and lipidtoxicity often adversely affect
islet β cell function, blood sugar control and disease prognosis in T2DM patients.
" Professor Hong Tianpi analyzed, "Pathophysiological changes such as chronic non-specific inflammatory response, oxidative stress, endoplasmic reticulum stress, mitochondrial dysfunction caused by factors such as glycolipid toxicity, blood sugar fluctuations, and environmental endocrine disruptors are the key factors leading to a decrease in the number of islet β cells and a decrease in insulin secretion capacity [3,4]
.
"

Professor Hong Tianpei continued to analyze the mechanism of T2DM: "When the body has insulin resistance, in order to cope with the increase in metabolic demand, islet cell plasticity can be manifested as an increase in the compensatory nature of islet β cells, and its source α cell to β cell transdifferentiation and pancreatic endocrine precursor cells (or stem cell) derived β cell proliferation includes islet β cell proliferation, etc.
, if the body cannot achieve this compensatory response to the increased metabolic demand, it means that hyperglycemia occurs
.
In general, the occurrence and progression of diabetes is closely related to the inability to achieve compensatory enhancement of islet β cell function.

”

For how to improve the functional status of islet β cells, the Clinical Expert Consensus on the Evaluation and Protection of T2DM Islet β Cell Function [2] clearly points out that important strategies for protecting islet β cells include active weight loss, early intervention and durable and stable blood glucose control
.
Professor Hong Tianpei said: "On the one hand, weight loss can be achieved through intensive lifestyle interventions (dieting, moderate-intensity exercise), weight-loss drugs, metabolic surgery and other measures to reduce ectopic fat deposition in the liver, muscles and pancreas, improve insulin resistance, reduce metabolic stress, and thus improve the function
of islets β cells 。 On the other hand, since high glycemic toxicity and blood glucose fluctuations are important reasons for the damage of islet β cell function, intensive insulin therapy or timely and reasonable combination of hypoglycemic drugs with different mechanisms of action is the key to maintaining long-term stable control of blood sugar, and it is also an important measure to
improve the function of islet β cells.
”

Referring to the drug selection of islet β cell protection, Professor Hong Tianbei pointed out that the protective effect of glucagon-like peptide-1 receptor agonists (GLP-1RA) on islet β cells has been fully confirmed in animal experiments, and there is also some evidence
in human studies.
Strategies for cell protection β islets include weight loss, blood sugar control, etc.
, and some new drugs currently under development, such as Tirzepatide, are also worth paying attention
to.

The original and bright research provides evidence that new drugs can improve the function of pancreatic islet β cells in multiple dimensions

A randomized, double-blind parallel-controlled clinical trial of the effect of Tirzepatide on islet β cell function was published at EASD this year, and Professor Tianpei Hong further analyzed the design ideas of the new study, which included a total of 117 patients (aged 20-74 years, with a duration of T2DM for at least 6 months, and 3 months before entering the study, patients were receiving lifestyle interventions and stable doses of metformin, with or without another stable dose of oral hypoglycemic agents), randomized (3:3:2) to subcutaneous injection of Tirzepatide 15 mg, semeglutide 1 mg, or placebo once
a week.
The effects of 15 mg Tirzepatide, 1 mg semeglutide, and placebo on islet β cell function were investigated using glucose clamps and mixed meal tolerance test (MMTT), and study endpoint measures were assessed
at baseline and during the last week of treatment (week 28).

For the results of the study disclosed on EASD, Professor Hong Tianbei also interpreted:

• During hyperinsulin-normoglycemic clamps (EGC) and hyperglycemic clamps (HGC): HGC and EGC assessments showed significant improvements
  in Tirzepatide insulin secretion response and disposal index in both the first and second phases.
  Tirzepatide significantly improved insulin sensitivity (M value), insulin secretion rate (ISR), and islet β cell glucose sensitivity (i.
  e.
  , the ratio of ISR to glucose increase)
  than semeglutide and placebo.
  

• Tirzepatide improved islet β cellular glucose sensitivity in HGC assessment: islet β cellular glucose sensitivity was significantly improved in both the Tirzepatide and semeglutide groups compared with baseline; Compared with the semeglutide group, the islet β cell glucose sensitivity was significantly further improved
  in the Tirzepatide group.
  

• During the MMTT evaluation: a greater reduction in fasting blood glucose and area under the blood glucose curve (AUC) in the Tirzepatide group compared with the semeglutide group or placebo group; Compared with placebo, Tirzepatide and semeglutide reduced incremental glucose AUC similarly; However, compared with placebo or semeglutide, total and incremental insulin AUC were significantly reduced in the Tirzepatide group, and the reduction was greater
  than in the semeglutide group.
  

• Tirzepatide improved the functional evaluation results of MMTT-derived islet β cells: the ISR of Tirzepatide and semeglutide was significantly higher than the baseline level at a glucose concentration of 7.
  2 mmol/L.
  The increase in ISR at 7.
  2 mmol/L glucose was significantly greater in the Tirzepatide group than in the placebo and semeglutide groups
  .
  

a: Tirzepatide vs placebo; b: semeglutide versus placebo; c: Tirzepatide vs semeglutide
.
P<0.
05

"Overall, the study yields very clear evidence that Tirzepatide improves islet β cell function not only from data from the gold standard analytical method for assessing islet β cell function and glucose sensitivity.

In addition, MMTT, commonly used in clinical practice, has also shown that the drug can significantly improve islet β cell function and insulin resistance
.
And Tirzepatide's data were not only better than placebo, but also better than the weekly subcutaneous semeglutide data, which was very surprising
.
Professor Hong Tianpei concluded
.

It is worth looking forward to the advantages of reducing blood sugar and weight loss to bring more benefits to patients

Tirzepatide is a GIP/GLP-1 receptor agonist, and both GIP and GLP-1 receptors are expressed
in islet β cells.
Previous studies have shown that Due to high glycemic toxicity, patients with T2DM may cause the expression of these incretinin receptors, including GLP-1 receptors and GIP receptors, to be downregulated in islet β cells [5], but the insulin release effect is still present, which means that the incretin effect is still present
.
Professor Hong Tianpei said: "The key to this study is to explore the potential mechanism by
which Tirzepatide exerts its advantages in hypoglycemic and weight-reducing metabolism.
There is no doubt that Tirzepatide can improve the pathophysiological defects of T2DM by improving multiple dimensions of islet β cell function (including islet β cell sensitivity to glucose, insulin secretion ability, etc.
) and reducing insulin resistance, which is very closely related
to the hypoglycemic effect of the drug 。 The new study, published in EASD, largely explains why
Tirzepatide exerts a significant advantage in glycemic control in T2DM patients.
”

Tirzepatide's SURPASS series of clinical trials [6-10] evaluated its efficacy and safety
as monotherapy and in combination with a representative class of hypoglycemic drugs in patients with T2DM.
Overall, SURPASS-1 (versus placebo), SURPASS-2 (versus weekly subcutaneous semeglutide), SURPASS-3 (insulin de gludec), Data from five global registration clinical trials, including SURPASS-4 (versus insulin glargine) and SURPASS-5 (versus placebo), showed three dose groups for Tirzepatide for T2DM subjects with different diabetic courses and backgrounds (5 mg, 10 mg, and 15 mg) all significantly reduced glycated hemoglobin (HbA_1c) and body weight
.

Professor Hong Tianpei pointed out: "GLP-1RA has been widely used in daily clinical practice, and has been recommended as the preferred drug for T2DM patients in major guidelines at home and abroad [11-12].

Tirzepatide, as a GIP/GLP-1 receptor agonist, has been shown to be superior to the GLP-1RA weekly formulation semeglutide in phase 3 clinical trials
.
In this newly announced clinical study, Tirzepatide explains why it has better metabolic benefits from improving islet β cell function and insulin resistance, and these research data make us very much look forward to the early approval of Tirzepatide for clinical application in China, and hope that this innovative drug can bring more benefits to T2DM patients
。 ”

summary

Tirzepatide can lead to long-term stable control
of blood glucose levels in T2DM patients by significantly improving islet β cell function and insulin resistance.
With the continuous deepening of Tirzepatide's clinical research, the accumulation of a large amount of evidence-based medical evidence has helped to promote its status in the treatment of T2DM, the 2022 edition of the American Diabetes Association (ADA)/EASD: T2DM Hyperglycemic Management Consensus [13].
The updated T2DM management drug pathway adds the GIP/GLP-1 receptor agonist Tirzepatide, and recommends its hypoglycemic efficacy as "very high", hypoglycemic risk as "none", and weight loss effect as "very efficient", which provides a good basis
for the clinical application of the drug.