Liraglutide for type 2 diabetes mellitus

Introduction: Prevalence of type 2 diabetes mellitus (T2DM) is increasing. Management of this condition and minimizing the cardiovascular risks associated with it poses a significant burden on healthcare resources across the world. Currently available therapeutic agents are effective in glycemic management; however, the majority of these are associated with undesirable effects such as hypoglycemia and weight gain. Incretin-based therapies have been introduced over the last few years and are associated with less risk of hypoglycemia and weight gain.

Areas covered: This review includes current challenges in the management of T2DM, and an overview of glucagon-like peptide-1 (GLP-1)-based therapies, in particular the results of Phase III clinical studies of recently approved liraglutide. Apart from glycemic control, multifactorial interventions are needed to minimize the cardiovascular risks associated with T2DM. Liraglutide is effective in improving glycemic control measured by HbA1c and it is also shown to improve weight. Recently, the National Institute of Health and Clinical Excellence in the UK has approved liraglutide 1.2 mg dose in dual and triple therapy for T2DM.

Expert opinion: Liraglutide, a once-daily GLP-1 analog, has a definite role in selected patients with T2DM and the long-term cardiovascular safety is currently being ascertained in ongoing trials.     

Cardiovascular protection in type 2 diabetes: Insights from recent outcome trials

This review examines recent randomized controlled cardiovascular (CV) outcome trials of glucose-lowering therapies in type 2 diabetes and their impact on the treatment of patients with type 2 diabetes. The trials were designed to comply with regulatory requirements to confirm that major adverse cardiac events (MACE) are not detrimentally affected by such therapies. Trials involving dipeptidyl peptidase-4 (DPP-4) inhibitors did not alter a composite MACE outcome comprising CV deaths, non-fatal myocardial infarction and non-fatal stroke; however, the possibility that some members of this class might incur a small increased risk or worsening of heart failure cannot be excluded. Some studies on glucagon-like peptide-1 receptor agonists (liraglutide: LEADER trial; semaglutide: SUSTAIN-6 trial) found significant benefits for MACE, while treatment with sodium-glucose co-transporter-2 inhibitors (empagliflozin: EMPA-REG OUTCOME trial; canagliflozin: CANVAS trial) also significantly reduced MACE and reduced hospitalization for heart failure. Comparisons among trials are complicated by variance in the populations recruited, particularly CV status at randomization, and differences in trial design, data collection and analyses. A large proportion of patients recruited into these trials have previously experienced adverse CV events; thus, the therapies are mostly assessing secondary prevention of a further event. This contrasts with the overall type 2 diabetes population receiving glucose-lowering therapies, of whom the majority will not have had MACE and will be regarded as primary prevention. Overall, the trials provide reassuring evidence that new glucose-lowering medications do not adversely affect CV events and some of these agents may offer CV protection.     

Pleiotropic effects of liraglutide in patients with type 2 diabetes and moderate renal impairment: Individual effects of treatment

Liraglutide has pleiotropic effects favouring cardiovascular and renal risks. We investigated individual responses to liraglutide in six cardio-renal risk factors to examine whether responses in one risk factor are associated with changes in other risk factors (cross-dependency). We performed secondary analysis of the LIRA-RENAL trial (n = 279) in type 2 diabetes. HbA1c, body weight, systolic blood pressure (SBP)_, low density lipoprotein (LDL)-cholesterol, urine albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) were measured at baseline and after 26 weeks of liraglutide/placebo treatment: “Good responders” had a change within the best quartile. In the liraglutide-treated group, good HbA1c responders showed similar changes in other risk factors analysed to low responders (P ≥ 0.17). Good body weight responders had a larger reduction in HbA1c than low body weight responders (−1.6 ± 0.94 vs. –1.0 ± 0.82%; P = 0.003), but similar changes in the other risk factors (P ≥ 0.11). Good and low responders in SBP, UACR, LDL-cholesterol or eGFR showed similar changes in other risk factors (P ≥ 0.07). Treatment response to liraglutide is largely individual; aside from an association between body weight and HbA1c reduction, there are no obvious cross-dependencies in risk factor response.     

The effects of glucagon-like peptide-1 on the beta cell

Type 2 diabetes is a progressive disease characterized by insulin resistance and impaired beta-cell function. Treatments that prevent further beta-cell decline are therefore essential for the management of type 2 diabetes. Glucagon-like peptide-1 (GLP-1) is an incretin hormone that is known to stimulate glucose-dependent insulin secretion. Furthermore, GLP-1 appears to have multiple positive effects on beta cells. However, GLP-1 is rapidly degraded by dipeptidyl peptidase-4 (DPP-4), which limits the clinical relevance of GLP-1 for the treatment of type 2 diabetes. Two main classes of GLP-1-based therapies have now been developed: DPP-4 inhibitors and GLP-1 receptor agonists. Liraglutide and exenatide are examples of GLP-1 receptor agonists that have been developed to mimic the insulinotropic characteristics of endogenous GLP-1. Both have demonstrated improved beta-cell function in patients with type 2 diabetes, as assessed by homoeostasis model assessment-B analysis and proinsulin : insulin ratio. Additionally, liraglutide and exenatide are able to enhance first- and second-phase insulin secretion and are able to restore beta-cell sensitivity to glucose. Preclinical studies have shown that both liraglutide and exenatide treatment can increase beta-cell mass, stimulate beta-cell proliferation, increase beta-cell neogenesis and inhibit beta-cell apoptosis. Clinical studies are needed to confirm these findings in humans. Replication of these data in humans could have important clinical implications for the treatment of type 2 diabetes.     

脂联素45 T/G基因多态性对利拉鲁肽治疗2型糖尿病患者的临床疗效

目的:研究脂联素45(APM1-45)T/G基因遗传变异对利拉鲁肽治疗2型糖尿病(T2DM)患者的临床疗效以及对T2DM易感性的影响。方法:选取2017年7月至2019年11月期间海口市第三人民医院收治的T2DM患者共95例作为研究对象,均给予利拉鲁肽进行为期14周的治疗,记录不同基因型患者治疗前后的血糖水平、BMI指数和mRNA相对表达等指标变化,统计不良反应的发生情况。结果:APM1-45(rs2241766)位点在研究人群中的基因分布频率为:TT型46例(48.42%),TG型43例(45.26%),GG型6例(6.32%),三种基因型分布频率符合哈迪温伯格平衡(P=0.328)。治疗后,各组患者的餐后2小时血糖(2h PG)、糖化血红蛋白(HbA1c)、空腹血糖(FPG)和BMI相关指标相比治疗前均下降明显,且存在统计学差异(P<0.05);TT基因型患者的各项指标与TG/GG基因型患者相比,下降更多,但二者相比不存在统计学差异(P>0.05)。mRNA相对表达方面,相对于TG/GG基因型患者,TT基因型患者的mRNA的相对表达明显偏低,二者差异具有统计学意义(P<0.05)。患者整体不良反应发生情况较少,各组之间无统计学差异。结论:对2型糖尿病患者,利拉鲁肽进行治疗具有明显效果,在显著降低血糖水平、控制体质量的同时,不良反应发生率较低,G等位基因与T2DM易感性存在一定的相关性,而T等位基因携带者对利拉鲁肽的治疗表现出更优的效果。     

二甲双胍联合利拉鲁肽对多囊卵巢大鼠炎性因子及性激素水平的影响

 目的 研究二甲双胍联合利拉鲁肽对经脱氢表雄酮诱导的多囊卵巢(PCOS)大鼠外周血清炎性因子及性激素水平的影响。方法 将80只PCOS(经脱氢表雄酮诱导)大鼠随机分为对照组(n=40)和干预组(n=40)。对照组大鼠每天给予二甲双胍(270 mg/kg·d)灌胃,干预组大鼠每天给予二甲双胍(270 mg/kg·d)灌胃+利拉鲁肽(5 μg/kg·d)皮下注射, 连续治疗28 d。治疗结束后测定两组大鼠外周血清炎性因子[白细胞介素-6(IL-6)、肿瘤坏死因子-α(TNF-α)、C反应蛋白(CRP)]、激素水平[卵泡雌激素(FSH)、黄体生成素(LH)、雌激素(E₂)、睾酮(T)]。结果 治疗后两组大鼠外周血清IL-6(23.88±7.32)pg/ml、TNF-α(13.24±2.23)ng/L、CRP(1.10±0.19)mg/L、LH(6.57±1.37)mIU/ml、LH/FSH(1.17±0.28)、E₂(1.11±0.18)pg/ml、T(12.21±1.32)ng/dL均较治疗前有所降低且差异有统计学意义(P<0.05),干预组低于对照组,差异有统计学意义(P<0.05);治疗后两组大鼠FSH (5.63±0.77) mIU/ml较治疗前升高,差异有统计学意义(P<0.05),干预组高于对照组,差异有统计学意义(P<0.05)。结论 二甲双胍联合利拉鲁肽能很好的降低PCOS大鼠外周血清炎性因子浓度,改善激素水平,为临床实践提供一定的指导。     

Cardiovascular safety of liraglutide for the treatment of type 2 diabetes

Introduction: Liraglutide is a GLP-1 RA that is an option for treatment of T2DM. Typical of all new glucose-lowering agents, its CV safety profile is of great interest.

Areas covered: This article outlines the efficacy of the GLP-1 RA liraglutide from RCTs, moving through the pivotal phase 3 LEAD trials, and subsequent meta-analyses to assess CV safety. This review describes evolution of regulatory requirements to obtain safety information through dedicated CVOTs.

Expert opinion: Since the FDA mandated that CV outcomes for new diabetes therapies should be assessed via a dedicated CVOT, opinion of their utility in T2DM evolved from cynicism through to enthusiasm. In LEADER, liraglutide became the second modern glucose-lowering agent to demonstrate significant CV benefit. CVOTs are now providing important answers, highlighting the CV benefits of modern glucose-lowering agents, but also raising several questions, notably whether the effects seen with liraglutide and empagliflozin are class-effects or are unique to these molecules. Furthermore it is unknown if these results in patients with high CV risk are applicable to all patients with T2DM, and should be incorporated into new treatment guidelines. In our view it’s prudent to suggest that CVOT findings cannot currently be extrapolated to the whole T2DM population.