Will the next breakthrough in diabetes treatment be "it"?

In the coming decades, the dual prevalence of type 2 diabetes (T2DM) and obesity will continue to be a major global health challenge

Recently, "Nature Reviews Endocrinology" (Nature Reviews Endocrinology) published an annual review of the field of T2DM treatment in 2021, in-depth introduction to the latest clinical research progress in the prevention and treatment of T2DM and obesity, and "incretin" as the field Significant progress brought about

These key breakthroughs include:

The STEP-3 test confirmed that the GLP1 receptor agonist smeglutide (once a week) showed considerable safety and effectiveness in the treatment of obesity, and the average weight of all subjects was reduced by 15%; SURPASS -1 Studies have shown that Tirzepatide (GIP and GLP-1 receptor dual agonist) can reduce the HbA1c level of patients with T2DM by up to 2%, and can bring about a dose-dependent weight loss (7 kg-9 kg); SURPASS-2 The study (head-to-head study) confirmed that Tirzepatide showed unique advantages in reducing HbA1c levels and body weight.

T2DM encounters "double nemesis", "two-pronged approach" for weight loss + hypoglycemia

Incretin, including glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), plays an important role in blood glucose homeostasis and energy balance

GLP1 receptor agonists (GLP1RAs) can bring benefits such as lowering blood sugar, reducing weight, and reducing the risk of cardiovascular events.

It is worth noting that both GLP1 and GIP can inhibit the level of glucagon in the human body under hyperglycemia, and GIP also has the effect of promoting glucagon in hypoglycemia and normal blood sugar

In recent years, incretin has attracted much attention as a new type of hypoglycemic agent

Secretin Secretin 2021 Important Research Summary

GLP1 receptor agonist smeglutide: reduces body weight by 15%

In 2021, the results of the Phase III trial (STEP-3 study) of the GLP1 receptor agonist smeglutide in the treatment of obesity will be published

The inclusion criteria of subjects were: not suffering from T2DM; BMI ≥ 30 kg/m², or BMI ≥ 27 kg/m² but accompanied by at least one weight-related symptom

The results of the study showed that compared with the placebo group, the weight of the patients in the smeglutide group was reduced by 14.

GIP and GLP-1 receptor dual agonist Tirzepatide: 2% lowering blood sugar, weight loss 7 kg-9 kg

Preclinical studies (rodents and monkey animal models) first confirmed that compared with liraglutide, single-molecule GIP and GLP-1 receptor dual agonists can induce dose-dependent weight loss, lower blood sugar, and reduce food intake.

Tirzepatide is a dual agonist of GIP and GLP-1 receptors, and is the first "dual" incretin to carry out a global phase III trial

In addition, the SURPASS clinical project has also reported the efficacy data of Tirzepatide

The results of the study showed that compared with patients in the placebo group, more patients treated with Tirzepatide reached the target of HbA1c<7.

Tirzepatide vs.

SURPASS-2 is a head-to-head comparative study designed to evaluate the difference in efficacy between Tirzepatide and the GLP1 receptor agonist semaglutide in patients with T2DM

The results of the study showed that at week 40, the average HbA1c of patients treated with 5 mg, 10 mg, and 15 mg Tirzepatide decreased by 2.
01%, 2.
24%, and 2.
3%, respectively, while those treated with smeglutide decreased 1.
86%
.
There are statistically significant differences between the two groups, and the results of the study support Tirzepatide treatment
.

In addition, patients treated with 5 mg, 10 mg, and 15 mg Tirzepatide showed a dose-dependent decrease in body weight by 7.
6 kg, 9.
3 kg, and 11.
2 kg, respectively; while patients who received simegliutide treatment decreased by 5.
7 kg (P<0.
001)
.
There is also a statistically significant difference between smeglutide and the lowest dose of Tirzepatide in reducing the weight of patients
.

65%~80% of the patients in the Tirzepatide group and 54% of the patients in the smeglutide group lost at least 5% of their body weight.
At the same time, the incidence of gastrointestinal adverse reactions was similar
.

Tirzepatide vs.
insulin deglu

SURPASS-3 is a randomized, open-label clinical trial
.
A total of 1444 patients were enrolled in the study, and the enrolled patients were treated with Tirzepatide (5 mg, 10 mg, or 15 mg, once a week) or insulin degludec (once a day)
.
The study included patients who received metformin or metformin combined with SGLT-2 inhibitors for poor blood glucose control (baseline HbA1c 8.
17%)
.

The results of the study showed that in the 52nd week of treatment, patients treated with 5 mg, 10 mg, and 15 mg Tirzepatide had a reduction in HbA1c by 1.
93%, 2.
20%, and 2.
37%, respectively, while those receiving deglubber were 1.
34% (P<0.
0001 for all doses of Tirzepatide treatment)
.

Compared with placebo, patients in the Tirzepatide group lost more weight, but at the same time the incidence of gastrointestinal adverse reactions was also higher
.
Severe hypoglycemia or blood glucose level <3 mmol/L occurred in 1%~2% of patients in the Tirzepatide group, compared with 7% in the insulin degludec group
.

summary

In general, GIP and GLP-1 receptor dual agonists have unique advantages in reducing HbA1c and body weight compared with GLP1 receptor agonists, and the gastrointestinal tolerance of the two is similar, and treatment may be stopped due to adverse events.
The sex is low
.

It is worth noting that the current research data for patients of different ethnicities is still relatively limited
.
We know that Asian people can suffer from T2DM at a lower level of BMI.
The role of "dual" incretin in this group of people still needs to be further studied in the future.
In the future, we will also need to pass longer follow-up and phase IV studies.
To identify more safety signals
.

The review finally pointed out that in the future, we need to better position the different therapeutic status of GIP and GLP-1 receptor agonists and GLP1 receptor agonists in the treatment of T2DM, based on different genetic, environmental and clinical factors of patients.
Choose
.

Note: The original text has been deleted

Reference

[1] Chow, E.
, Chan, JCN The emerging role of incretins and twincretins.
Nat Rev Endocrinol (2021).
https://doi.
org/10.
1038/s41574-021-00607-w