Effect of once-weekly dulaglutide versus insulin glargine in people with type 2 diabetes and different baseline glycaemic patterns: A post hoc analysis of the AWARD-2 clinical trial

The long-acting glucagon-like peptide-1 receptor agonist dulaglutide acts by stimulating insulin secretion and reducing glucagon levels in a glucose-dependent manner both in the fasting and postprandial states, resulting in reductions of both fasting glucose (FG) and postprandial glucose (PPG). In contrast, the main mechanism of action of basal insulin is to reduce elevated FG by inhibiting hepatic glucose production. The aim of the present post hoc analysis of the phase 3 AWARD-2 trial was to investigate whether specific baseline glycaemic patterns respond differentially to dulaglutide compared to insulin glargine (glargine). We categorized participants into four subgroups based on prespecified glucose thresholds and their baseline FG and daily 2-hour mean PPG: low FG/low PPG; low FG/high PPG; high FG/low PPG; and high FG/high PPG. Changes in glycaemic measures in response to treatment with dulaglutide or glargine were evaluated in each subgroup. At 52 weeks, significant reductions from baseline in glycated haemoglobin (HbA1c) were observed in all subgroups with dulaglutide 1.5 mg and with glargine (all P < .05), except in patients with low FG/low PPG who received glargine. Greater HbA1c reductions were observed with dulaglutide 1.5 mg compared to glargine in all subgroups (all P ≤ .05), except in the low FG/high PPG subgroup.     

Glycaemic efficacy of an expanded dose range of dulaglutide according to baseline glycated haemoglobin (HbA1c) subgroup: Post hoc analysis of AWARD-11

The AWARD-11 trial demonstrated the safety and efficacy of dulaglutide 3.0 and 4.5 mg compared to dulaglutide 1.5 mg in patients with type 2 diabetes inadequately controlled with metformin. This post hoc analysis examined the change from baseline in glycated haemoglobin (HbA1c) and proportions of patients achieving HbA1c <7% at weeks 36 and 52 with dulaglutide 1.5 mg, 3.0 mg or 4.5 mg across clinically relevant baseline HbA1c subgroups (<8%; 8.0% to < 9.0%; 9.0% to < 10%; and ≥ 10%). Mean reductions in HbA1c were observed across all baseline HbA1c subgroups at 36 weeks (range of HbA1c change: 1.5 mg: −1.0% to −2.2%; 3.0 mg: −1.2% to −2.5%; and 4.5 mg: −1.2% to −3.2%). More patients randomized to 3.0 mg or 4.5 mg (vs. 1.5 mg) achieved HbA1c <7% at 36 weeks regardless of baseline HbA1c; the difference in proportions was greater at higher baseline HbA1c (P-interaction = 0.096). Similar patterns in glycaemic improvement and proportions achieving HbA1c <7% were observed at 52 weeks. Hypoglycaemia and gastrointestinal adverse events were similar among the HbA1c subgroups. Glycaemic control was improved with dulaglutide dose escalation from 1.5 mg to 3.0 mg or 4.5 mg across baseline HbA1c subgroups (<8%; 8.0% to < 9.0%; 9.0% to < 10%; and ≥ 10%).     

Effects of oral semaglutide on cardiovascular outcomes in individuals with type 2 diabetes and established atherosclerotic cardiovascular disease and/or chronic kidney disease: Design and baseline characteristics of SOUL,a randomized trial

Aim

To describe the design of the SOUL trial (Semaglutide cardiOvascular oUtcomes triaL) and the baseline clinical data of its participants.

Materials and methods

In SOUL, the effects of oral semaglutide, the first oral glucagon-like peptide-1 receptor agonist, on the risk of cardiovascular (CV) events in individuals with type 2 diabetes and established atherosclerotic CV disease (ASCVD) and/or chronic kidney disease (CKD) will be assessed. SOUL is a randomized, double-blind, parallel-group, placebo-controlled CV outcomes trial comparing oral semaglutide (14 mg once daily) with placebo, both in addition to standard of care, in individuals aged ≥50 years with type 2 diabetes and evidence of ASCVD (coronary artery disease [CAD], cerebrovascular disease, symptomatic peripheral arterial disease [PAD]) and/or CKD (estimated glomerular filtration rate <60 mL/min/1.73 m²). The primary outcome is time from randomization to first occurrence of a major adverse CV event (MACE; a composite of CV death, nonfatal myocardial infarction or nonfatal stroke). This event-driven trial will continue until 1225 first adjudication-confirmed MACEs have occurred. Enrolment has been completed.

Results

Overall, 9650 participants were enrolled between June 17, 2019 and March 24, 2021 (men 71.1%, White ethnicity 68.9%, mean age 66.1 years, diabetes duration 15.4 years, body mass index 31.1 kg/m², glycated haemoglobin 63.5 mmol/mol [8.0%]). The most frequently used antihyperglycaemic medications at baseline were metformin (75.7%), insulin and insulin analogues (50.5%), sulphonylureas (29.1%), sodium-glucose cotransporter-2 inhibitors (26.7%) and dipeptidyl peptidase-4 inhibitors (23.0%). At randomization, 70.7% of participants had CAD, 42.3% had CKD, 21.1% had cerebrovascular disease and 15.7% had symptomatic PAD (categories not mutually exclusive). Prevalent heart failure was reported in 23.0% of participants.

Conclusion

SOUL will provide evidence regarding the CV effects of oral semaglutide in individuals with type 2 diabetes and established ASCVD and/or CKD.     

Efficacy and safety of adding once-weekly dulaglutide to basal insulin for inadequately controlled type 2 diabetes in Chinese patients (AWARD-CHN3): A randomized,double-blind,placebo-controlled,phase III trial

Aim

To determine the efficacy and safety of once-weekly dulaglutide added to basal insulin in Chinese patients with type 2 diabetes mellitus (T2DM) with inadequate glycaemic control.

Materials and Methods

In the phase III, double-blind AWARD-CHN3 study, Chinese patients with T2DM (N = 291) and glycated haemoglobin (HbA1c) ≥7.0% and ≤11.0% receiving stable doses of basal insulin glargine with metformin and/or acarbose were randomized (1:1) to receive add-on dulaglutide 1.5 mg once weekly or placebo once weekly. The primary endpoint was the superiority of dulaglutide/glargine to placebo/glargine for change from baseline in HbA1c at Week 28.

Results

The least squares (LS) mean ± standard error change in HbA1c from baseline to Week 28 was −2.0 ± 0.08% with dulaglutide/glargine and −1.1 ± 0.07% with placebo/glargine (LS mean difference: −1.0%, 95% confidence interval [CI] –1.1 to −0.8; P < 0.001), and more patients receiving dulaglutide/glargine achieved HbA1c levels <7.0% (75.9% vs. 33.8%; P < 0.001 vs. placebo/glargine). Body weight decreased with dulaglutide/glargine and increased with placebo/glargine (LS mean difference: −1.2 kg, 95% CI –1.8 to – 0.6; P < 0.001). Reductions in fasting serum glucose were greater with dulaglutide/glargine than with placebo/glargine (LS mean difference: −0.8 mmol/L, 95% CI –1.1 to – 0.5; P < 0.001). The incidence of hypoglycaemia was similar with dulaglutide/glargine and placebo/glargine (29.2% vs. 31.3%; P = 0.704); no patient in either group had severe hypoglycaemia. The most common treatment-emergent adverse events with dulaglutide/glargine were decreased appetite (22.2%), diarrhoea (13.2%) and nausea (10.4%).

Conclusions

Dulaglutide added to basal insulin was efficacious and well tolerated in Chinese patients with T2DM.     

前列地尔治疗老年糖尿病合并慢性肾脏病患者的效果分析

目的探讨前列地尔联合常规治疗对老年2型糖尿病(T2DM)合并慢性肾脏病(CKD)患者的治疗效果。方法人选2014年2月至2016年2月在攀枝花市中心医院内分泌科治疗的90例老年T2DM合并CKD患者,采用数字表法随机分为前列地尔组和对照组,每组45例。对照组给予常规治疗,前列地尔组在常规治疗基础上加用前列地尔10μg/d,静脉推注,1次/d,2周为1个疗程,共治疗3个疗程。比较两组患者血脂、血糖、肝功能、肾功能等指标。所有数据采用SPSS 16.0软件进行统计学分析。计量资料用均数±标准差(±s)表示,两组比较采用t检验。计数资料用百分率表示,组间比较用χ~2检验。结果两组患者治疗前空腹血糖(FPG)、糖化血红蛋白(HbAlc)、甘油三酯(TG)、总胆固醇(TC)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)、同型半胱氨酸(Hcy)、血β2微球蛋白(β2-MG)、尿白蛋白排泄率(UAER)、血肌酐(SCr)、估算肾小球滤过率(eGFR)差异均无统计学意义(P0.05)。治疗后,前列地尔组患者的TG、TC、LDL-C、Hcy、β2-MG、UAER显著低于对照组,差异具有统计学意义(P0.05)。两组患者治疗前后的凝血酶原时间(PT)、血小板(PLT)、活化部分凝血活酶时间(APTT)差异无统计学意义(P0.05)。两组不良反应发生率差异无统计学意义(χ~2=0.212,P=0.645)。结论前列地尔联合常规治疗能显著降低老年T2DM合并CKD患者尿蛋白水平,对患者的肾功能具有一定的保护作用。     

Baseline factors associated with glycaemic response to treatment with once‐weekly dulaglutide in patients with type 2 diabetes

Dulaglutide glycaemic efficacy has been demonstrated in the AWARD clinical trial programme. The objective of the present analysis was to determine the major baseline factors associated with the reduction in glycated haemoglobin (HbA1c) in response to dulaglutide. Baseline covariates from patients receiving dulaglutide in six phase III studies (n = 2806) were analysed using a gradient‐boosting method to assess their relative influence on the change in HbA1c after 26 weeks of treatment. Influential variables (relative influence >5%) were further evaluated in univariate and multivariable modelling. The gradient‐boosting analysis showed that the top influential baseline factors associated with HbA1c reduction were: HbA1c (48.8%), age (9.1%), fasting serum glucose (FSG; 8.2%), fasting serum insulin (FSI; 6.7%) and estimated glomerular filtration rate (eGFR; 5.4%). Multivariable regression showed that higher baseline HbA1c was the major factor associated with greater HbA1c reduction [coefficient estimates: ?0.6% (?6.6 mmol/mol); p < 0.0001]. Age ≤65 years, lower FSG level, FSI level ≤55 pmol/L and eGFR ≤100 mL/min/1.73 m² were associated with greater decreases in HbA1c, but the effect was very small [coefficient estimates: ?0.05% to ?0.2% (?0.6 to ?2.2 mmol/mol)]. These data indicate that higher baseline HbA1c, reflecting poor glycaemic status, is the major factor associated with greater reduction in HbA1c in response to dulaglutide treatment.     

Exenatide: its position in the treatment of type 2 diabetes

Type 2 diabetic patients who have not achieved adequate glucose control at the maximum tolerated doses of their oral therapies currently have no alternative other than insulin. A new approach has been developed, using the glucoregulatory properties of the intestinal incretin hormone glucagon-like peptide-1 (GLP-1). This has resulted in the development of a new therapeutic class, the incretin mimetics, of which exenatide is the first to have been approved. Exenatide can bind to the endogenous receptors of GLP-1 and mimic its glucoregulatory actions. It improves glycemic control by acting on the key organs involved in glucose homeostasis: it stimulates insulin secretion and suppresses glucagon secretion in a glucose-dependent way, slows gastric emptying and reduces food intake. It consequently produces significant reductions in fasting and postprandial hyperglycemia. Various clinical studies, both versus placebo and versus insulin, have shown a significant decrease in HbA1c levels (of about 1%), accompanied by weight loss, in patients treated with exenatide. Exenatide efficacy is sustained and all the studies have shown a comparable tolerance profile. The most frequently reported adverse effects were nausea and hypoglycemia when the patient received concomitant sulfonylurea therapy. The aim of this article is to summarize main clinical data on exenatide and to discuss its position in current therapeutic strategy.