"More" benefits from sugar control | The guide tells you that GLP-1RA is preferred in these situations

*Only for medical professionals to read for reference.
Come and get a more ideal combination of metformin! The prevalence of diabetes is increasing year by year.
According to the latest epidemiological survey, the total prevalence of diabetes in my country has reached 12.
8%, and the total number of diabetic patients in mainland China is about 130 million [1].

It is still an important task for endocrinologists to strengthen the management of patients' blood sugar and increase the rate of patient compliance.

 Early intensive treatment with combination medication can help improve the compliance rate of glycosylated hemoglobin (HbA1c) in patients with type 2 diabetes (T2DM).

A study of 5870 patients with T2DM who were treated with metformin as a single agent (HbA1c≥7.
5%) found that the early initiation of the dual-drug combination (≤3 months) patients reached the standard rate of 47.
23%, while the late initiation The compliance rate of patients with dual-drug therapy (10-15 months) is 41.
65%, suggesting that patients who do not meet the standard of metformin single-drug treatment should be intensively treated as soon as possible to increase the rate of compliance [2].

So, how to choose a combination drug? GLP-1RA combined with metformin reduces blood sugar, weight loss, and low risk of hypoglycemia.
In recent years, a new type of hypoglycemic drug glucagon-like peptide-1 receptor agonist (GLP-1RA) has received more and more attention.
Glucose concentration depends on the way to control blood sugar, has both the effectiveness and safety of lowering blood sugar, and also has the advantage of weight loss [3], and the treatment status is also continuously improved in major guidelines.

 In 2020, the Chinese Type 2 Diabetes Prevention and Control Guidelines (hereinafter referred to as the CDS Guidelines) issued at the 24th National Academic Conference (CDS) of the Diabetes Branch of the Chinese Medical Association updated the diagnosis and treatment pathways for T2DM patients.
T2DM patients with atherosclerotic cardiovascular disease (ASCVD) or high-risk factors, heart failure, chronic kidney disease (CKD), regardless of whether their HbA1c meets the standard, it is recommended to add to the first-line treatment with clear evidence of cardiovascular benefit GLP-1RA or sodium-glucose cotransporter 2 (SGLT-2) inhibitor.For T2DM patients without ASCVD or high-risk factors, heart failure, or CKD, when lifestyle intervention and metformin treatment of HbA1c fail to meet the standard, GLP-1RA can be used for treatment (Figure 1) [4].

 Figure 1.
The LEAD series of studies on the treatment path of T2DM patients in the CDS guidelines is a global phase 3 clinical study of the classic GLP-1RA drug liraglutide, which verifies the effectiveness and safety of liraglutide in the treatment of T2DM[5-8] .

Among them, LEAD-2, a 26-week randomized controlled, double-blind double-simulation study, included 1091 T2DM patients with poorly controlled oral hypoglycemic agents, and were randomly assigned to receive metformin + placebo, metformin + liraglutide (0.
6 mg/day, 1.
2mg/day, or 1.
8mg/day), or metformin + glimepiride (4mg/day).

The results of the study showed that after 26 weeks of treatment, the 1.
2mg, 1.
8mg liraglutide group and the glimepiride group had similar blood glucose improvement, but the blood sugar lowering effect was better than that of the placebo group (that is, metformin monotherapy).

And under these two doses, the difference in HbA1c reduction between the liraglutide group and the placebo group can reach 1.
1%, and there are 35.
3% (1.
2mg liraglutide group) and 42.
4% (1.
8mg liraglutide group) respectively.
Group) patients reached the goal of HbA1c<7%.

 The study also found that compared with the glimepiride group (1kg weight gain), different doses of liraglutide can significantly reduce the weight of patients (P<0.
0001), and the average weight loss of patients in the 1.
8 mg liraglutide group was 2.
8 kg[8].

In terms of safety, compared with glimepiride, patients in the liraglutide group at different doses had a lower incidence of mild hypoglycemia (P<0.
001) [8].

 Instead of DPP-4i in combination with metformin, HbA1c, FPG, and weight are further reduced.
The dipeptidyl peptidase-4 inhibitor (DPP-4i), which is also a secretin drug, can also be used in combination with metformin, but compared with Next, GLP-1RA combined with metformin is a more ideal choice for diabetes patients to control sugar. And for patients with poor treatment of metformin combined with DPP-4i, replacing DPP-4i with liraglutide will help patients strengthen blood glucose management.

 LIRA-DPP-4 is a 26-week randomized controlled open study, followed by a 52-week extended study, for a total of 78 weeks.
658 patients who were included in 158 research centers in 13 countries were still not up to the standard after metformin treatment.
Of T2DM patients.

During the complete trial, the patients received liraglutide 1.
2 mg, 1.
8 mg, or sitagliptin 100 mg daily for 52 weeks, and then the sitagliptin group was switched to the liraglutide regimen to continue treatment 26 weeks [9-11].

 The study found that compared with sitagliptin, patients in the liraglutide group had a higher reduction in HbA1c (P<0.
0001) (Figure 2).
After 52 weeks of treatment, patients treated with liraglutide 1.
8 mg/day had 63.
3% achieved the goal of HbA1c<7%, which was significantly better than 27.
1% in the sitagliptin group (P<0.
0001).

More importantly, half of the patients treated with liraglutide 1.
8 mg/day reached the composite endpoint of HbA1c<7% + no weight gain + no hypoglycemia, and only 18.
6% in the sitagliptin group (P<0.
0001 ).

 Figure 2.
Changes in HbA1c of the three groups of patients from baseline to 52 weeks The study also found that the higher the baseline HbA1c of patients in the liraglutide group, the greater the reduction in HbA1c after medication (Figure 3).

 Figure 3.
The higher the baseline HbA1c, the greater the decrease in HbA1c of patients after liraglutide treatment.
In addition, patients treated with sitagliptin were transferred to liraglutide 1.
2mg and 1.
8mg groups, and after 26 weeks of continued treatment, the two groups The patient's HbA1c was further reduced by 0.
24% and 0.
45%, fasting blood glucose (FPG) was further reduced by 0.
84mmol/L and 1.
42mmol/L, and the body weight was further reduced by 1.
64kg and 2.
48kg [11].

 Later, a trial completely conducted in the Chinese population-LIRA-DPP-4 CHINA once again confirmed that the HbA1c, FPG and weight loss of patients treated with liraglutide were significantly better than those in the sitagliptin group (P<0.
0001 ) [12].  Another randomized double-blind study in 86 centers in North America, Europe, and Asia divided sitagliptin combined with metformin in the treatment of patients with poor blood glucose control (HbA1c 7.
5-9.
5%) into two groups randomly, and one group was converted to liraglutide combined The metformin regimen, the other group continued the original regimen.
After 26 weeks of treatment, the results showed that the liraglutide group had better HbA1c control and weight loss effects (P<0.
0001), the HbA1c reduction was 0.
61% higher than the original regimen group, and the weight loss The height is 1.
67 kg, which also suggests that replacing sitagliptin with liraglutide can provide patients with a better blood glucose management plan when dual-administration is used [13].

 In addition to sitagliptin, a random, open-label, parallel clinical study in China found that after 24 weeks of treatment, the hypoglycemic effect of liraglutide in T2DM patients was significantly better than that of saxagliptin and vildagliptin[ 14].

 Therefore, in patients with T2DM whose blood glucose control is not satisfactory after metformin combined with DPP-4i, replacing DPP-4i with liraglutide will help patients better achieve blood glucose standards.

 Summary In order to help more diabetic patients better manage blood sugar, the combination of drugs should be used as soon as possible when the effect of metformin monotherapy is not good, and blood sugar management should be strengthened.

For patients whose HbA1c is not up to standard for lifestyle intervention and metformin treatment, or for patients whose HbA1c is not up to standard with metformin combined with DPP-4i treatment, they can use the hypoglycemic regimen of metformin combined with GLP-1RA, which not only has the effect of reducing blood sugar and Safety can also reduce the weight of patients and help T2DM patients achieve high-quality standards.

 References: [1]Yongze Li, et al.
BMJ.
2020;369:m997.
[2]Rajpathak SN, et al.
J Diabetes Complications.
2014;28(6):831-5.
[3]Abd El Aziz MS, et al.
Diabetes Obes Metab.
2017;19(2):216-227.
[4] Zhu Dalong.
Oral report of the 24th National Academic Conference of Diabetes Branch of Chinese Medical Association.
2020.
[5]Buse, et al.
Lancet.
2009;374:39–47.
[6]Russell-Jones, et al.
Diabetologia.
2009;52:2046–2055.
[7]Marre M, et al.
Diabet Med.
2009;26:268– 278.
[8] Chinese Medical Association Endocrinology Branch, et al.
Chinese Journal of Internal Medicine.
2020;11:836-846.
[9]Pratley RE, et al.
Lancet.
2010;375(9724):1447-56.
[10 ]Pratley RE, et al.
Int J Clin Pract.
2011;65(4):397-407.
[11]Pratley RE, et al.
Diabetes Care.
2012;35(10):1986-93.
[12] Zang L, et al.
Diabetes Obes Metab.
2016;18(8):803-11.
[13]Bailey TS, et al.
Diabetes Obes Metab.
2016;18(12):1191-1198.
[14] Li CJ, et al.
Exp Clin Endocrinol Diabetes.
2014;122(8):469-76.
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