Daily preparations and weekly preparations, different GLP-1RAs have their own magical powers to lower blood sugar and protect the heart

*For medical professionals to read for reference, GLP-1RA is in full bloom
.

 Reviewer: Professor Gao Yan The prevalence of diabetes in Peking University First Hospital is increasing year by year, and diabetes can cause a variety of complications
.

Among them, cardiovascular disease is the main cause of disability and death in diabetic patients [1]
.

Studies have shown that 33.
9% of type 2 diabetes (T2DM) patients in China suffer from cardiovascular disease (CVD), of which 94.
9% are atherosclerotic cardiovascular disease (ASCVD) [2]
.

Diabetes is an independent risk factor for cardiovascular disease, and cardiovascular disease is the leading cause of death in diabetes
.

In recent years, new hypoglycemic drugs glucagon-like peptide-1 receptor agonists (GLP-1RA) have attracted more and more attention.
They control blood sugar by regulating insulin and glucagon secretion in a glucose concentration-dependent manner.
, both the effectiveness and safety of hypoglycemic, but also has obvious advantages of weight loss [3], the status of treatment in major guidelines has also been continuously improved
.

The "China Type 2 Diabetes Prevention and Control Guidelines 2020 Edition" (hereinafter referred to as the 2020 "CDS Guidelines") updated the diagnosis and treatment path for T2DM patients, which proposed that for T2DM patients with ASCVD or high cardiovascular risk, regardless of their glycosylated hemoglobin (HbA1c) Whether the target is met, GLP-1RA or sodium-glucose co-transporter-2 (SGLT-2) inhibitors with evidence of ASCVD benefit should be added to metformin as long as there are no contraindications
.

For T2DM patients without ASCVD or cardiovascular risk factors, heart failure, and chronic kidney disease, on the basis of life>
.

The 2020 American Diabetes Association (ADA) Banting Award focuses on islet cell dysfunction and insulin resistance [5], emphasizing that β-cell glucose sensitivity is significantly reduced in T2DM patients, and β-cell glucose sensitivity is closely related to Blood glucose levels are significantly negatively correlated [6-7]; insulin resistance is closely related to the occurrence and development of T2DM disease [8], studies have shown that the insulin resistance index (HOMA-IR) is an independent risk factor for CVD events in T2DM patients [9]
.

Understanding disease pathogenesis is at the core of disease management and treatment, and with the deepening understanding of diabetes
.

The disease management concept of T2DM is also constantly updated
.

New hypoglycemic drugs represented by GLP-1RA bring a new turning point for the treatment of T2DM
.

The weakened effect of incretin is the main factor affecting the decline of β-cell function.
Studies have shown that GLP-1RA treatment can improve the function of β-cells in patients with early T2DM, improve the sensitivity of β-cells to glucose to promote insulin secretion, and significantly reduce the Insulin resistance [10-13]
.

 A large number of studies have confirmed that GLP-1RA has multiple important physiological roles in the human body: GLP-1RA acts on β cells of the pancreas, can induce insulin secretion and synthesis in a glucose concentration-dependent manner, promote cell regeneration, and inhibit cell apoptosis
.

GLP-1RA can also act on α cells to inhibit the secretion of glucagon, effectively reducing blood sugar without increasing the occurrence of hypoglycemia
.

At the same time, GLP-1RA can also act on multiple organs such as the liver, gastrointestinal tract, peripheral muscles, brain, and heart to reduce hepatic glucose output; weaken gastrointestinal motility, delay gastric emptying, reduce appetite, and increase satiety, thereby Reduce energy intake, reduce body weight; also have the role of central protection and cardiac function protection [14]
.

The anti-inflammatory, anti-atherosclerotic effect of GLP-1RA is the primary mechanism of its cardiovascular protection while markedly, durable, and safe in HbA1c reduction and weight loss: GLP-1RA and cardiac GLP-1RA receptor binding can improve Myocardial ischemia and protect myocardial progenitor cells; induce endothelial cell nitric oxide (NO) synthesis to increase coronary blood flow and protect endothelial function; reduce oxidative stress; inhibit the expression of vascular cell adhesion factor in the endothelium; Stiffness, its vasodilator and antioxidant functions can also play an anti-atherosclerotic role [15]
.

Both contribute to the improvement of ASCVD by GLP-1RA
.

Optimizing blood glucose management and improving cardiovascular outcomes Blood glucose control is the primary goal of diabetes management.
Long-term follow-up in the UKPDS study has confirmed that intensive blood glucose control can significantly reduce complications in patients with T2DM, especially microvascular complications
.

For every 1% reduction in HbA1c, the risk of various complications decreased significantly, and the incidence of heart failure and myocardial infarction decreased by 16% and 14%, respectively [16]
.

Therefore, early control of blood sugar and the management of HbA1c reaching the target (HbA1c<7%) are crucial
.

A number of clinical studies including Chinese T2DM patients have confirmed that GLP-1RA can effectively improve fasting and 2h postprandial blood glucose, reduce HbA1c, and reduce body weight [1]
.

 At present, GLP-1RAs listed in China include daily preparations benaglutide, exenatide, lixisenatide, liraglutide and weekly preparations of exenatide, dulaglutide, loxenatide and division Meglutide
.

Taking the GLP-1RA daily preparation liraglutide as an example (Figure 1), it can significantly reduce HbA1c, with a maximum reduction of 1.
6%, and the compliance rate of HbA1c<7% is 66%, which can significantly reduce fasting blood sugar and postprandial blood sugar at the same time.
[17-22]
.

Figure 1 Results of the LEAD series of studies GLP-1RA weekly preparations also achieved outstanding results in effective hypoglycemic
.

For example, semaglutide can significantly reduce HbA1c either as a single drug or in combination with other oral drugs or insulin, with a maximum reduction of 1.
8% [23-32]; for T2DM patients with different baseline HbA1c levels, different doses of dulaglutide (0.
75mg, 1.
5mg) can simultaneously control the fasting blood glucose and postprandial blood glucose of patients to reduce HbA1c[33]
.

 The long-term goal of cardiovascular protection diabetes treatment is to prevent chronic complications, improve patients' quality of life and prolong life through good metabolic control
.

A meta-analysis of 7 large clinical studies including 56,004 patients worldwide showed that GLP-1RA reduced the risk of 3P-MACE (major adverse cardiovascular event: cardiovascular death or non-fatal myocardial infarction or non-fatal stroke composite event) by 12%, 12% reduction in risk of cardiovascular death, 16% reduction in fatal and non-fatal stroke, 9% reduction in fatal or non-fatal myocardial infarction, 12% reduction in risk of all-cause mortality, 9% reduction in hospitalization for heart failure, composite renal endpoint (new onset of massive proteinuria, glomerular filtration rate decreased by 30%, progression to end-stage renal disease or renal disease leading to death) decreased by 17%, and the safety was very good, no severe hypoglycemia, pancreatic cancer and pancreatitis were observed increased risk [1]
.

This has also become an effective and safe clinical treatment plan that takes into account both hypoglycemic and heart protection
.

Represented by liraglutide, semaglutide, and dulaglutide, their cardiovascular benefits have been successively confirmed by LEADER, SUSTAIN 6, and REWIND studies (Figure 2)
.

The LEADER study showed that compared with the placebo control group, liraglutide significantly reduced the risk of MACE by 13%; at the same time significantly reduced the risk of cardiovascular death by 22%; significantly reduced the risk of all-cause mortality by 15%
.

The results of the SUSTAIN 6 study showed that semaglutide significantly reduced the risk of MACE by 26%, mainly by reducing the risk of non-fatal stroke by 39%
.

The results of the REWIND study also showed that in T2DM patients with cardiovascular disease and high risk of cardiovascular disease, dulaglutide can reduce 3P-MACE and reduce the risk of non-fatal stroke [36]
.

At the same time, these studies have shown that such drugs can improve multiple cardiovascular risk factors, including body weight, blood pressure, blood lipids, etc.
[35]
.

 Figure 2 LEADER, SUSTAIN 6 and REWIDN studies confirmed the cardiovascular protective effects of liraglutide, semaglutide, and dulaglutide in daily and weekly preparations.
Flowers bloom to prolong the half-life of GLP-1 and increase its duration of action , Different GLP-1RA also adopted different means
.

For example, the daily preparation liraglutide changes the molecular structure of natural human GLP-1, replaces 34-position lysine with arginine, and adds C16 fatty acid chain at 26-position, significantly prolonging the half-life of natural GLP-1 by 13 hours , can achieve once-daily injection administration
.

The weekly preparation semaglutide is by replacing the 8th and 34th amino acids of GLP-1 molecule, and at the same time connecting the C18 fatty diacid side chain through the spacer at the 26th lysine to further prolong the half-life in vivo.
Weekly injections were achieved for up to 7 days [37-39]
.

Exenatide weekly preparation and dulaglutide are combined with microglobulin technology and macromolecular protein IgG Fc fragment respectively, prolonging their half-life and reducing the number of injections, which greatly facilitates the improvement of patient compliance
.

 Of course, the coexistence of daily preparations and weekly preparations also provides doctors and patients with more choices, which is helpful for the realization of clinically personalized hypoglycemic management programs
.

It is concluded that reaching the blood glucose target in the early stage of T2DM can improve the long-term benefits of patients.
Cardiovascular risk management is an important part of diabetes management
.

With the continuous updating of the concept of diabetes treatment, the center of simple "blood sugar control" has shifted to the center of individualization, with the goal of "improving cardiovascular outcomes"
.

GLP-1RA can control blood sugar, and can improve multiple cardiovascular risk factors such as blood lipids, blood pressure, and body weight.
Some GLP-1RA drugs such as liraglutide, semaglutide, and dulaglutide have been shown in large clinical studies.
Significant cardiovascular benefits have been shown, further meeting the long-term benefit needs of clinical treatment
.

Expert Profile Prof.
Yan Gao ◇ Chief physician, professor and doctoral supervisor of the Department of Endocrinology, Peking University First Hospital As well as clinical research and laboratory research work on thyroid disease and diabetes Editorial board of the journal ◇ Has trained and is cultivating a number of master and doctoral students, many of whom have become academic leaders in the field of endocrinology in China Diabetes Branch of Chinese Medical Association.
Chinese Journal of Diabetes.
2021;13(4):315-408.
[2]Hong Tianpei, et al.
Diabetes Ther, 2022; Mar 21.
[3]Abd El Aziz MS, et al.
Diabetes Obes Metab.
2017;19(2):216-227.
[4]Chinese Journal of Diabetes.
2020;1(12):1-12.
[5]2020 ADA oral presentation: A Journey in Diabetes.
[6]Ele Ferrannini, et al.
JCEM.
2005;90:493-500.
[7]Ele Ferrannini, et al.
Med Clin N Am.
2011;95:327-33.
[8]Ele Ferrannini, et al.
Med Clin N Am.
2011;95:327-339.
[9]Bonora E, et al.
Diabetes care.
2002;25(7):1135-1141.
[10]Retnakaran R et al.
Diabetes Care.
2014 Dec;37(12) :3270-8.
[11]Chang AM, et al.
Diabetes.
2003;52:1786–1791.
[12]Matthews D, et al.
Diabetes.
2010;59(Suppl 1):S1513-P.
[13]Garber A, et al.
Lancet.
2009;373(9662):473–81.
[14]baggio LL, et al.
Gastroenterology.
2007;132(6 ):2131-57.
[15]Lo CWH, et al.
Cardi Fail Rev.
2021 Mar;7:e04.
[16]Stratton IM, et al.
BMJ.
2000;321(7258):405-412.
[17 ]Marre, et al.
Diabet Med.
2009;26:268-278.
[18]Nauck, et al.
Diabetes Care.
2009;32:84-90.
[19]Garber, et al.
Lancet.
2009;373: 473-481.
[20]Zinman, et al.
Diabetes Care.
2009;32:1224-1230.
[21]Russell-Jones, et al.
Diabetologia.
2009;52:2046-2055.
[22]Buse, et al 2009;374:39-47.
[23]Sorli C, et al.
Lancet Diabetes Endocrinol.
2017;5:251-260.
[24]Ahrén B, et al.
Lancet Diabetes Endocrinol.
2017;5:341 -354.
[25]Ahmann AJ, et al.
Diabetes Care.
2018;41:258-266.
[26]Aroda VR, et al.
Lancet Diabetes Endocrinol.
2017;5:355-366.
[27]Rodbard HW, et al.
J Clin Endocrinol Metab.
2018;103:2291-2301.
[28]Pratley RE, et al.
Lancet Diabetes Endocrinol.
2018;6:275-286.
[29]LingvayI, et al.
Lancet Diabetes Endocrinol.
2019;7(11):834-844.
[30]Zinman B, et al.
Lancet Diabetes Endocrinol.
2019; 7:356-367.
[31]Capehorn MS, et al.
Diabetes Metab.
2019 Sep 10.
[32]Linong Ji, et al.
[961-P] Poster presented at: American Diabetes Association 80th Scientific Session; June 12- 16, 2020; Virtual.
[33]Li Q,et al.
Diabetes Ther.
2021 Dec 6.
[34]Marso SP, et al.
N Engl J Med.
2016;375(4):311-322.
[35] Marso SP, et al.
N Engl J Med.
2016;375(19):1834-1844.
[36]Gerstein HC, et al.
Lancet.
2019;394(10193):12130.
[37]Yoshiaki Mu, et al.
.
Chinese Journal of Internal Medicine.
2020;59(11):836-846.
[38]Lau J, et al.
J Med Chem.
2015;58:7370-7380.
[39]Kapitza C, et al.
J Clin Pharmacol.
2015;55:497-504.
For information use only by medical and health professionalsLancet Diabetes Endocrinol.
2019;7:356-367.
[31]Capehorn MS, et al.
Diabetes Metab.
2019 Sep 10.
[32]Linong Ji, et al.
[961-P] Poster presented at: American Diabetes Association 80th Scientific Session; June 12-16, 2020; Virtual.
[33]Li Q,et al.
Diabetes Ther.
2021 Dec 6.
[34]Marso SP, et al.
N Engl J Med.
2016;375(4):311 -322.
[35]Marso SP, et al.
N Engl J Med.
2016;375(19):1834-1844.
[36]Gerstein HC, et al.
Lancet.
2019;394(10193):12130.
[37 ] Yoshiaki Mu, et al.
Chinese Journal of Internal Medicine.
2020;59(11):836-846.
[38]Lau J, et al.
J Med Chem.
2015;58:7370-7380.
[39]Kapitza C, et al al.
J Clin Pharmacol.
2015;55:497-504.
For informational use by healthcare professionals onlyLancet Diabetes Endocrinol.
2019;7:356-367.
[31]Capehorn MS, et al.
Diabetes Metab.
2019 Sep 10.
[32]Linong Ji, et al.
[961-P] Poster presented at: American Diabetes Association 80th Scientific Session; June 12-16, 2020; Virtual.
[33]Li Q,et al.
Diabetes Ther.
2021 Dec 6.
[34]Marso SP, et al.
N Engl J Med.
2016;375(4):311 -322.
[35]Marso SP, et al.
N Engl J Med.
2016;375(19):1834-1844.
[36]Gerstein HC, et al.
Lancet.
2019;394(10193):12130.
[37 ] Yoshiaki Mu, et al.
Chinese Journal of Internal Medicine.
2020;59(11):836-846.
[38]Lau J, et al.
J Med Chem.
2015;58:7370-7380.
[39]Kapitza C, et al al.
J Clin Pharmacol.
2015;55:497-504.
For informational use by healthcare professionals only2021 Dec 6.
[34]Marso SP, et al.
N Engl J Med.
2016;375(4):311-322.
[35]Marso SP, et al.
N Engl J Med.
2016;375(19): 1834-1844.
[36]Gerstein HC, et al.
Lancet.
2019;394(10193):12130.
[37]Yoshiaki Mu, et al.
Chinese Journal of Internal Medicine.
2020;59(11):836-846.
[38 ]Lau J, et al.
J Med Chem.
2015;58:7370-7380.
[39]Kapitza C, et al.
J Clin Pharmacol.
2015;55:497-504.
For informational use by healthcare professionals only2021 Dec 6.
[34]Marso SP, et al.
N Engl J Med.
2016;375(4):311-322.
[35]Marso SP, et al.
N Engl J Med.
2016;375(19): 1834-1844.
[36]Gerstein HC, et al.
Lancet.
2019;394(10193):12130.
[37]Yoshiaki Mu, et al.
Chinese Journal of Internal Medicine.
2020;59(11):836-846.
[38 ]Lau J, et al.
J Med Chem.
2015;58:7370-7380.
[39]Kapitza C, et al.
J Clin Pharmacol.
2015;55:497-504.
For informational use by healthcare professionals only
.

Such information is not intended to replace professional medical advice in any way and should not be considered medical advice
.

If such information is used for purposes other than understanding information, this platform and the author do not assume relevant responsibilities
.

- End - For contributions/reprints/business cooperation, please contact: yxjxxg@yxj.
org.
cn