Rational therapy for diabetes: early recognition of adverse effects and avoidance of disruptive false alarms

Corresponding to the uncontrolled diabetes pandemic, significant effort has been invested in developing new therapeutic options. Nevertheless, all medicines have possible adverse effects. Recently, a trend of 'scrutinizing' novel hypoglycaemic drug side effects based on scant scientific data has emerged. With recent publications highlighting possible dangers of rosiglitazone, insulin glargine, sitagliptin, exenatide and, most recently, pioglitazone, it seems that all means are valid and that every database is suitable, even if specifically defined as inadequate for the purpose of data analysis. The use of such data may lead authors to draw erroneous conclusions that may be granted unwarranted impact upon publication in leading scientific journals and eventually lead patients and misinformed physicians to wrongly change beneficial medication regimes. Adherence to strict scientific methodology, ongoing large clinical trials and creating adjudicated patient databases may facilitate early recognition of adverse effects while avoiding disruptive false alarms.     

利拉鲁肽对高脂饮食喂养大鼠的血脂谱的调节作用

目的研究利拉鲁肽对高脂饮食喂养SD大鼠脂肪代谢的影响。方法将48只雄性SD大鼠随机分为四组,分别予以普通饮食（ND）、高脂饮食（HFD）、高脂饮食加小剂量利拉鲁肽腹腔注射（HFD＋SGLP-1）、高脂饮食加大剂量利拉鲁肽腹腔注射（HFD＋LGLP-1）。喂养8周后检测大鼠血脂、血糖、体重,并检测大鼠肝脏ApoE蛋白表达水平的变化。结果与ND组比较,HFD组大鼠体重、血脂及血糖水平显著升高,肝脏ApoE蛋白水平显著降低（P〈0．05）。而与HFD组比较,HFD＋SGLP-1组和HFD＋LGLP-1组大鼠体重、血脂及血糖水平明显降低,ApoE蛋白水平明显增高（P〈0．05）,但以HFD＋LGLP-1组效果最为显著。结论利拉鲁肽能够显著抑制高脂饮食喂养导致的体重增加,降低血糖及血脂水平,并调节血脂谱。利拉鲁肽改变血脂谱的作用可能与其增加肝脏ApoE蛋白的表达有关。     

2 型 糖尿病患者对利拉鲁肽的治疗满意度调查及使用评 价简

目的评价2型糖尿病患者对利拉鲁肽使用的治疗满意度,为临床用药提供参考。方法对2011年10月～2013年4月于辽宁中医药大学附属医院住院期间使用利拉鲁肽的115例2型糖尿病患者采用随机抽样方法抽取37例患者为调查对象,对利拉鲁肽使用前和使用后进行治疗满意度的问卷调查,采用SPSS17．0统计软件对数据进行分析。结果使用利拉鲁肽后糖尿病治疗的总体质量满意度由68．75％提高至96．88％,其中低血糖发生比率由原来25．00％偶尔发生降至9．38％偶尔发生,高血糖比率由62．50％降至15．63％,认为利拉鲁肽可以增加糖尿病治疗信心的患者占93．75％．95．74％患者认为利拉鲁肽在操作技术层面简单方便,28例（87．50％）患者认为医疗费用较原方案有所增加,使用初期有5例患者出现一过性恶心反应,1例患者出现一过性腹泻,其中有1例患者伴有一过性呕吐,此不良反应均在使用利拉鲁肽3～4d后明显减轻或消失。结论利拉鲁肽作为新型的肠促胰岛素类似物治疗2型糖尿病整体治疗满意度提高。但会产生短暂的胃肠道反应,且治疗费用有所提高,但对治疗满意度无太大影响。     

利拉鲁肽联合强化降糖序贯方案对初诊2型糖尿病患者血糖控制效果及胰岛素第一时相分泌的影响

目的研究利拉鲁肽联合强化降糖序贯方案对初诊2型糖尿病患者血糖控制效果及胰岛素第一时相分泌的影响。方法前瞻性选择2017年1月至2018年9月上海市杨浦区中心医院收治的68例T2DM患者,采用随机数字表法将患者分为对照组(n=34)和观察组(n=34)。完成胰岛素强化治疗后,对照组患者给予二甲双胍治疗,观察组患者在对照组的基础上加用利拉鲁肽治疗。比较两组患者的血糖指标、胰岛功能、胰岛素第一时相分泌情况、血清炎症因子水平和血管内皮功能。结果治疗前,两组患者的血糖指标相近,差异无统计学意义(P> 0. 05);治疗后,观察组患者的空腹血糖(FPG)、餐后2 h血糖(2 h PG)和糖化血红蛋白(HbAlc)水平分别为(6. 42±0. 85) mmol/L、(8. 27±1. 15) mmol/L和(5. 82±0. 95)%,低于对照组,空腹C肽(FCP)水平为(779. 62±73. 17) pmol/L,高于对照组,差异均具有统计学意义(P <0. 05)。治疗前,两组患者的胰岛功能指标相近,差异无统计学意义(P> 0. 05);治疗后,观察组的胰岛β细胞功能指数(HOMA-β)水平为(43. 64±9. 63)%,高于对照组,胰岛素抵抗指数(HOMA-IR)水平为(1. 48±0. 94),低于对照组,差异均具有统计学意义(P <0. 05)。治疗前,两组患者的AUCIns和AUCC-P相近,差异无统计学意义(P>0. 05);治疗后,观察组的AUCIns和AUCC-P水平分别为(758. 49±55. 28) mU·min/L和(37. 21±6. 29) ng·min/m L,高于对照组,差异均具有统计学意义(P <0. 05)。治疗前,两组患者的血清炎症因子水平和血管内皮功能相近,差异无统计学意义(P>0. 05);治疗后,观察组患者的白细胞介素-6(IL-6)、肿瘤坏死因子-α(TNF-α)和内皮素-1(ET-1)水平分别为(10. 86±2. 91) ng/L、(6. 25±2. 34) ng/L和(51. 26±5. 29) ng/L,低于对照组,一氧化氮(NO)水平为(42. 37±5. 42)μmol/L,高于对照组,差异均具有统计学意义(P <0. 05)。结论与单纯强化降糖序贯方案相比,利拉鲁肽联合强化降糖序贯方案可以明显改善初诊T2DM患者的血管内皮功能和胰岛素第一时相分泌,改善糖代谢和胰岛功能,减轻患者的炎症状态。     

Liraglutide for Weight Management in the Real World: Significant Weight Loss Even if the Maximal Daily Dose Is Not Achieved

IntroductionObesity is a global health challenge, and pharmacologic options are emerging. Once daily subcutaneous administration of 3 mg liraglutide, a glucagon like peptide-1 analogue, has been shown to induce weight loss in clinical trials, but real-world effectiveness data are scarce.MethodsIt is a single-centre retrospective cohort study of patients who were prescribed liraglutide on top of lifestyle adaptations after multidisciplinary evaluation. In Belgium, liraglutide is only indicated for weight management if the BMI is >30 kg/m² or ≥27 kg/m² with comorbidities such as dysglycaemia, dyslipidaemia, hypertension, or obstructive sleep apnoea. No indication is covered by the compulsory health care insurance. Liraglutide was started at 0.6 mg/day and uptitrated weekly until 3 mg/day or the maximum tolerated dose. Treatment status and body weight were evaluated at the 4-month routine visit.ResultsBetween June 2016 and January 2020, liraglutide was prescribed to 115 patients (77% female), with a median age of 47 (IQR 37.7–54.0) years, a median body weight of 98.4 (IQR 90.0–112.2) kg, a BMI of 34.8 (IQR 32.2–37.4) kg/m², and an HbA1c level of 5.6%. Five (4%) patients did not actually initiate treatment, 9 (8%) stopped treatment, and 8 (7%) were lost to follow-up. At the 4-month visit, the median body weight had decreased significantly by 9.2% to 90.8 (IQR 82.0–103.5) kg (p < 0.001). Patients using 3.0 mg/day (n = 60) had lost 8.0 (IQR 5.8–10.4) kg. The weight loss was similar (p = 0.9622) in patients that used a lower daily dose because of intolerance: 7.4 (IQR 6.2–9.6) kg for 1.2 mg (n = 3), 7.8 (IQR 4.1–7.8) kg for 1.8 mg (n = 16), and 9.0 (IQR 4.8–10.7) kg for 2.4 mg/day (n = 14). Weight loss was minimal if liraglutide treatment was not started or stopped prematurely (median 3.0 [IQR 0.3–4.8] kg, p < 0.001, vs. on treatment). Further analysis showed an additional weight reduction of 1.8 kg in the patients that had started metformin <3 months before the start of liraglutide (p < 0.001). The main reasons for liraglutide discontinuation were gastrointestinal complaints (n = 5/9) and drug cost (n = 2/9).ConclusionIn this selected group of patients, the majority complied with liraglutide treatment over the initial 4-month period and achieved a significant weight loss, irrespective of the maximally tolerated maintenance dose. Addition of metformin induced a small but significant additional weight loss.     

Extrinsic compression of pancreactic duct by intragastric balloon treatment and its potential to cause acute pancreatitis: two case reports and clinical discussion

We describe two cases of increased pancreatic enzyme levels after intragastric balloon (IGB) placement possibly related to extrinsic pancreatic duct compression, followed by a short review of the literature.Case 1 is the first, to our knowledge, of a patient with asymptomatic increase of pancreatic enzymes due to pancreatic duct compression, with unknown clinical significance. We hypothesize that this finding maybe can be relatively common in IGB users and almost certainly an important risk factor for the development of acute pancreatitis (AP). On the other hand, case 2 reports an AP that occurred one day after IGB placement, presented with nausea and vomiting, making AP a differential diagnosis of initial IGB intolerance.     

利拉鲁肽对肥胖大鼠脂肪组织内质网应激的影响

目的:研究利拉鲁肽对肥胖大鼠脂肪组织内质网应激的影响。方法:取大鼠分别用基础饲料和高脂饲料喂养8周后,分为正常对照组、肥胖组、肥胖-利拉鲁肽组,前2组大鼠腹腔注射0.9%氯化钠注射液,肥胖-利拉鲁肽组大鼠腹腔注射利拉鲁肽100μg/kg,每日2次,连续8周。末次给药后隔夜禁食处死大鼠,称体质量,取肾周及睾周脂肪组织,计算脂体比,检测脂肪组织中类蛋白质激酶激活的双链RNA的内质网激酶(PERK)、肌醇需求激酶1-α(IRE1-α)、C/EBP同源蛋白(CHOP)mRNA的表达和葡萄糖转运蛋白78(GRP78)的表达。结果:与正常对照组比较,肥胖组大鼠体质量、脂体比和脂肪组织中PERK、IRE1-α、CHOP mRNA及GRP78蛋白表达均明显升高(P<0.01);与肥胖组比较,肥胖-利拉鲁肽组大鼠上述指标均明显降低(P<0.01)。结论:利拉鲁肽可显著减轻肥胖大鼠体质量及内脏脂肪组织过度累积,并可缓解脂肪组织内质网应激。     

利拉鲁肽对肥胖大鼠体质量、血脂水平和下丘脑炎症通路的影响研究

目的:研究利拉鲁肽对肥胖大鼠体质量和血清中总胆固醇(TC)、甘油三酯(TG)水平及下丘脑炎症通路的影响。方法:取大鼠分别用基础饲料和高脂饲料喂养8周后,分为正常对照组、肥胖组、肥胖-利拉鲁肽组。正常对照组和肥胖组大鼠腹腔注射0.9%氯化钠注射液,肥胖-利拉鲁肽组大鼠腹腔注射利拉鲁肽100μg/kg,每日2次,连续8周。末次给药后隔夜禁食处死大鼠,称体质量,检测各组大鼠给药前和末次给药后血清中TC、TG水平和下丘脑细胞核因子κB(NF-κB)mRNA及细胞因子信号转导抑制因子3(SOCS-3)蛋白的表达。结果:与正常对照组比较,肥胖组大鼠体质量和血清中TC、TG水平及下丘脑NF-κB mRNA、SOCS-3蛋白表达水平均明显升高(P<0.01);与肥胖组比较,肥胖-利拉鲁肽组大鼠体质量和血清中TC、TG水平及下丘脑NF-κB mRNA、SOCS-3蛋白表达水平均较明显降低(P<0.01)。结论:利拉鲁肽能显著改善高脂诱导肥胖大鼠的体质量增加、血脂紊乱,其机制可能涉及下丘脑炎症调节通路的改善。     

Insulin degludec + liraglutide: a complementary combination

ABSTRACT

Introduction: The treatment of patients with type 2 diabetes mellitus remains challenging, as it goes beyond adequate glycemic control, in particular addressing weight, blood pressure and other contributors to cardiovascular disease. In addition, the progressive nature of type 2 diabetes mellitus demands the intensification and combination of glucose lowering therapies. In many patients, there is a clinical inertia for the initiation of insulin therapy, leading to failure in reaching glycemic targets in many patients.

Areas covered: Recently a fixed-ratio combination therapy of the basal insulin degludec and the glucagon-like peptide-1 analogue liraglutide has been developed and approved by the EMA. The rationale for this combination, as well as an overview of the published phase III clinical trials (DUAL I,II,V), are covered, highlighting the most important conclusions.

Expert opinion: The combination therapy of insulin degludec and liraglutide is an attractive therapeutic strategy in patients with type 2 diabetes mellitus as it gives a robust glycemic control with a low risk for hypoglycemia and less weight gain or even weight loss. The fixed-ratio combination of insulin degludec and liraglutide offers a smart therapeutic strategy in patients with type 2 diabetes mellitus where basal insulin needs to be initiated or intensified.