<b>Efficacy and safety of mazdutide in Chinese patients with type 2 diabetes: A </b><b>randomized, double-blind, placebo-controlled phase 2 trial</b>
Bo ZhangZhifeng ChengJi ChenXin ZhangDexue LiuHongwei� JiangGuoqing MaXiaoyun WangShenglian GanJuan SunPing JinJianjun YiBimin ShiJianhua MaShandong YeGuixia WangLinong JiXuejiang GuTing YuPei AnHuan DengHaoyu LiLi LiQingyang MaLei QianWenying Yang
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<p dir="ltr">OBJECTIVE We conducted a randomized, double-blind, placebo-controlled phase 2 trial to evaluate the efficacy and safety of mazdutide, a once-weekly GLP-1 and glucagon receptor dual agonist, in Chinese patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Adults with type 2 diabetes inadequately controlled with diet and exercise alone or with stable metformin (glycated haemoglobin A1c [HbA1c] of 7.0%–10.5% [53–91 mmol/mol]) were randomized to receive mazdutide 3 mg (n = 51), mazdutide 4.5 mg (n = 49), mazdutide 6 mg (n = 49), open-label dulaglutide 1.5 mg (n = 50) or placebo (n = 51) subcutaneously for 20 weeks. The primary outcome was change from baseline to week 20 in HbA1c. RESULTS Mean changes in HbA1c from baseline to week 20 ranged from −1.41% to −1.67% with mazdutide (−1.35% with dulaglutide and 0.03% with placebo) (all p<0.0001 versus placebo). Mean percent changes in body weight from baseline to week 20 were dose-dependent and up to −7.1% with mazdutide (−2.7% with dulaglutide and −1.4% with placebo). At week 20, participants with mazdutide were more likely to achieve HbA1c target of <7.0% (53 mmol/mol) and ≤6.5% (48 mmol/mol), and body weight loss from baseline of ≥5% and ≥10%, compared with placebo-treated. The most common adverse events with mazdutide included diarrhoea (36%), decreased appetite (29%), nausea (23%), vomiting (14%) and hypoglycemia (10%; 8% with placebo). CONCLUSIONS In Chinese patients with type 2 diabetes, mazdutide dosed up to 6 mg was generally safe and demonstrated clinically meaningful HbA1c and body weight reduction. Article Highlights l Despite increasing application of GLP-1 receptor agonists in glycemic control, evidence of co-agonism with glucagon receptor in the treatment of type 2 diabetes remains limited. l Does mazdutide, a once-weekly GLP-1 and glucagon receptor dual agonist, reduce HbA1c and body weight in patients with type 2 diabetes? l In this phase 2 study, 20 weeks’ treatment with mazdutide achieved mean HbA1c reductions up to 1.67% and mean body weight reductions up to 7.1%. The most common adverse events with mazdutide were gastrointestinal in nature. l The results supported future development of mazdutide for the treatment of type 2 diabetes.</p>Keywords:
Dulaglutide
Results from cardiovascular outcomes trials (CVOTs) in people with Type 2 diabetes (T2D), such as the Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) study with dulaglutide, have led to a shift toward glucose lowering therapies that provide broad benefits, including cardiovascular (CV) risk reduction and renoprotection. Dulaglutide reduces atherosclerotic CV outcomes (hazard ratio 0.88; 95% CI: 0.79–0.99) and composite kidney outcomes (hazard ratio 0.85; 95% CI: 0.77–0.93) in people with T2D with high risk or established CV disease. The cardiologists' role has now expanded to include not only screening for T2D and treating risk factors, but also recommending or incorporating glucose-lowering agents with proven CV benefit into the care of their patients with T2D.
Dulaglutide
Cardiorenal syndrome
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Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) were introduced for type 2 diabetes therapy nearly 10 years ago, among them short-acting compounds on the basis of the GLP-1-like peptide exendin-4 (exenatide and lixisenatide) and a long-acting GLP-1 RA based on the human GLP-1 sequence (liraglutide). Recently, two novel long-acting GLP-1 RAs on the basis of human GLP-1 sequence, for onceweekly application, have been approved for therapy of type 2 diabetes. Additionally, liraglutide has been approved for treatment of obesity at a higher dose than that used for diabetes therapy. This mini-review gives a short overview of the novel long-acting GLP-1 RAs albiglutide and dulaglutide and also reviews the studies of liraglutide in treatment of obesity leading to its approval for this use. These studies were largely presented at the annual meeting of the European Association for the Study of Diabetes (EASD) in fall 2014.
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Lixisenatide
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Tight glycaemic control is key to reducing the risk of cardiovascular and microvascular complications in people with type 1 diabetes. 1 Standard treatment involves optimising insulin therapy to achieve an HbA 1c level of 48mmol/mol (6.5%) or lower. Although not licensed for use in type 1 diabetes, metformin is included in some clinical guidelines as adjuvant therapy for people with type 1 diabetes who are overweight and wish to improve glycaemic control while minimising the dose of insulin. 1,2 The REMOVAL study is the largest trial to date that has investigated the longer-term effects of metformin in people with type 1 diabetes. 3 Here, we consider the role of metformin in individuals with type 1 diabetes in light of these results and other study findings.
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To evaluate evidence from the medical literature that metformin is effective in preventing type 2 diabetes.Primary literature was accessed via a MEDLINE search (1966-December 2003) using the terms metformin, type 2 diabetes, and prevention.Two studies evaluated metformin's potential to prevent type 2 diabetes, finding that metformin maintained or reduced fasting blood glucose in non-diabetics. Recently, a large study by the Diabetes Prevention Program showed that metformin may reduce the incidence of diabetes. Researchers compared lifestyle changes, metformin therapy, and placebo groups. They found that both lifestyle changes (58%) and metformin therapy (31%) significantly reduced the occurrence of type 2 diabetes versus placebo.These studies provide evidence that metformin may reduce the occurrence of type 2 diabetes. Because long-term efficacy has not been determined, further studies are needed.
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Objective:to observe the curative effect of type 2 diabetes treated with novonorm combined with metformin. Method:34 patients diagnosed with type 2 diabetes on clinic were treated with novonorm combined with metformin for 6 months.Results:the comparison between fasting blood - glucose,postprandial plasma glucose and glycosylated hemoglobin before and after administration indicated significant difference(P0.05).Conclusion:the curative effect of type 2 diabetes treated with novonorm combined with metformin was prominent.
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Lactic acidosis
Gluconeogenesis
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Metformin has been used for the treatment of type 2 diabetes by suppressing hepatic gluconeogenesis. It has been shown that the subclinical inflammatory responses play important roles in the pathogenesis of type 2 diabetes. In the present study, we determined the effects of metformin on the levels of pro-inflammatory cytokines (i.e., IL-6, TNF-α, and MCP-1) and anti-inflammatory mediator IL-10 in blood and urine of patients with type 2 diabetes. There were 210 patients with type 2 diabetes, which were randomized into metformin (n = 112) and non-metformin (gliclazide, acarbose, and repaglinide, n = 98) groups. The levels of cytokines were measured by the ELISA.We found that metformin reduced the levels of IL-6 in blood and MCP-1 in urine, but increased IL-10 levels in blood of patients with type 2 diabetes. There were no significant differences of TNF-α between metformin and non-metformin groups. Furthermore, compared to individual drug treatment, metformin significantly reduced the levels of serum IL-6 and TNF-α, as well as urine MCP-1. When the patients were stratified based on the durations and doses of metformin, we found that there was only change (i.e., increase) in serum IL-10 levels in patients with metformin for more than 1 year compared to treatment for less than 1 year. Metformin (1.5 g) treatment reduced the urinary levels of MCP-1 as compared with dose of 1.0 g in patients with type 2 diabetes.Metformin reduces inflammatory responses without influence on renal function in type 2 diabetic patients.
Gliclazide
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