Efficacy and safety of basal-first titration order in individuals with type 2 diabetes receiving short-term intensive insulin therapy: An exploratory analysis of BEYOND V

Aims

To present the results of an exploratory analysis of the BEYOND V study in which Chinese individuals with uncontrolled type 2 diabetes (T2D) received short-term intensive insulin therapy (SIIT) during study run-in (prior to randomization) using a basal-first insulin titration method.

Materials and methods

This was exclusively an exploratory analysis of the 7- to 10-day run-in period of BEYOND V. Participants were hospitalized and had oral therapies withdrawn (except metformin). They received SIIT with once-daily insulin glargine and three-times-daily premeal insulin glulisine, titrated daily from a total starting dose of 0.4 to 0.5 units/kg/d, first adjusting insulin glargine to achieve fasting blood glucose (FBG) of 4.4 to 6.1 mmol/L (79 to 119 mg/dL), then insulin glulisine to achieve pre-meal blood glucose of 4.4 to 6.1 mmol/L. Key outcomes were the proportions of participants achieving FBG and 2-hour postprandial blood glucose (PBG) targets.

Results

Overall, 397 entered the run-in (mean 54.2 years, 235 males [59.2%]). At the end of SIIT, 374/396 participants (94.4%) had both FBG <7.0 mmol/L (<126 mg/dL) and 2-hour PBG <10 mmol/L (<180 mg/dL) and 282/396 (71.2%) had both FBG <6.1 mmol/L (<100 mg/dL) and 2-hour PBG <10 mmol/L. The mean first time taken to achieve FBG <7 mmol/L, 2-hour PBG <10 mmol/L, and both, was 4.35, 3.88, and 5.04 days, respectively. Hypoglycaemia occurred in 99 participants (24.9%). There was no severe hypoglycaemia.

Conclusions

Titrating basal insulin first is an effective and safe method of SIIT in individuals with T2D, rapidly achieving target glucose levels with a relatively low rate of hypoglycaemia.     

Short‐term intensive insulin therapy at diagnosis in type 2 diabetes: plan for filling the gaps

Short‐term intensive insulin therapy is unique amongst therapies for type 2 diabetes because it offers the potential to preserve and improve beta‐cell function without additional pharmacological treatment. On the basis of clinical experience and the promising results of a series of studies in newly diagnosed patients, mostly in Asian populations, an expert workshop was convened to assess the available evidence and the potential application of short‐term intensive insulin therapy should it be advocated for inclusion in clinical practice. Participants included primary care physicians and endocrinologists. We endorse the concept of short‐term intensive insulin therapy as an option for some patients with type 2 diabetes at the time of diagnosis and have identified the following six areas where additional knowledge could help clarify optimal use in clinical practice: (1) generalizability to primary care, (2) target population and biomarkers, (3) follow‐up treatment, (4) education of patients and providers, (5) relevance of ethnicity, and (6) health economics. © 2014 The Authors. Diabetes Metabolism Research and Reviews published by John Wiley & Sons, Ltd.     

不同病程初发2型糖尿病对胰岛素短期强化治疗的反应

目的糖尿病初期胰岛素强化治疗可改善胰岛β细胞功能,但治疗时机尚无一致意见。本研究分析了不同病程初发2型糖尿病患者短期胰岛素强化治疗的胰岛β细胞功能改善程度。方法对2007年2月以来我科诊治的空腹血糖≥11.1mmol/L的初发2型糖尿病患者91例进行胰岛素强化治疗,对糖尿病病程在1周内组(A组,n=41)和12周以上组(B组,n=29)的患者进行分析总结。患者均行口服糖耐量试验测血糖和胰岛素、糖化血红蛋白(HbA1c)、糖化血清蛋白、血脂、尿酸、肝肾功能。每日4次三短一中胰岛素强化治疗4周后复测上述指标。采用稳态模型(HOMA)计算胰岛素抵抗指数(HOMA-IR)和胰岛素分泌指数(HOMA-β)。结果 A组和B组患者治疗后与治疗前相比,空腹血糖、糖化血清蛋白、HbA1c、甘油三酯、胆固醇、低密度脂蛋白胆固醇、收缩压和舒张压均有明显下降(P0.05),尿酸水平有所上升(P0.05),但两组相比无差异。两组患者强化治疗4周后HOMA-IR较治疗前无差异,而HOMA-β较治疗前有明显改善(P0.05),A组HOMA-β改善程度好于B组(P0.05)。以强化4周后HOMA-β为因变量,进行多因素回归分析,影响因素有体重指数、血压、甘油三酯水平、血糖达标时间、治疗前后HbA1c和糖化血清蛋白差值。结论糖尿病病程1周内进行强化治疗,胰岛β细胞功能改善好于病程12周以上,说明病程越短治疗效果越好。     

The effect of short‐term intensive insulin therapy on inflammatory cytokines in patients with newly diagnosed type 2 diabetes

BackgroundDiabetes mellitus was a chronic low‐grade inflammatory disease and had increased circulating inflammatory cytokines and acute phase proteins. We aimed to identify the changes of inflammatory cytokines in newly diagnosed type 2 diabetic patients after short‐term intensive insulin therapy using continuous subcutaneous insulin infusion (CSII).MethodsThirty‐three newly diagnosed type 2 diabetic patients were enrolled between September 2020 to December 2020. Expression of 40 inflammatory cytokines of the patients were tested with RayBiotech antibody array before and after 1 week of intensive insulin therapy of CSII. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was carried out to explore the signaling pathway involved in the therapy.ResultsFive inflammatory cytokines were downregulated significantly after 1 week of CSII therapy. They were interleukin‐6 receptor (IL‐6R), regulated upon activation normal T‐cell expressed and secreted (RANTES), intercellular adhesion molecule‐1 (ICAM‐1), tissue inhibitor of metalloproteinase‐1 (TIMP‐1), and platelet‐derived growth factor type BB (PDGF‐BB) (p < 0.05 and foldchange <0.83). Among patients with baseline glycated hemoglobin (HbA1c) < 10%, three proinflammatory cytokines were decreased significantly after therapy: IL‐6R, RANTES, and ICAM‐1. As for the patients with baseline HbA1c ≥ 10%, eight inflammatory cytokines were inhibited significantly after the treatment, including ICAM‐1, IL‐6R, RANTES, TIMP‐1, TIMP‐2, macrophage inflammatory protein‐1 beta (MIP‐1β), PDGF‐BB, and tumor necrosis factor receptor type II (TNF RII). No matter which subgroup of baseline HbA1c level was considered, the decreased cytokines after CSII therapy were significantly involved in TNF signaling pathway. Nuclear factor‐kappa B (NF‐κB) signaling pathway was mainly enriched in patients with baseline HbA1c ≥ 10%.ConclusionsA panel of 40 inflammatory cytokines, measured by protein microarray, were evaluated for 1 week of CSII treatment in newly diagnosed type 2 diabetic patients. After treatment, many proinflammatory cytokines decreased. In the higher baseline HbA1c subgroup, more proinflammatory cytokines improved. No matter which subgroup of HbA1c level was considered, IL‐6R, RANTES, and ICAM‐1, which were involved in TNF signaling pathway, decreased significantly after CSII therapy. This was the first report showing that the cytokines of IL‐6R, TIMP‐2, PDGF‐BB, and TNF RII decreased after the CSII therapy.     

Continuation versus discontinuation of insulin secretagogues when initiating insulin in type 2 diabetes

We compared the combined use of basal insulin, metformin and insulin secretagogues with a combination of basal insulin and metformin in patients with type 2 diabetes starting basal insulin analogue therapy. This analysis was part of a 24-week trial, in which 964 insulin-naive patients with type 2 diabetes inadequately controlled on oral agents (including metformin) were randomized to insulin glargine or detemir. Secretagogues were stopped or maintained at the site-investigators' discretion. During the study, 57.6% of patients continued their secretagogue treatment. Compared with patients stopping secretagogues, those who continued experienced significantly more hypoglycaemia and weight gain. Insulin doses, however, were significantly lower: 0.6 ± 0.4 versus 0.8 ± 0.4 U/kg/day (p < 0.001). The difference between groups in mean HbA1c reduction was not statistically significant. In conclusion, in type 2 diabetic patients starting basal insulin analogue therapy, continuing both metformin and secretagogues results in more hypoglycaemia and weight gain and lower insulin doses than only maintaining metformin.     

初诊2型糖尿病短期胰岛素强化治疗后胰岛β细胞功能的动态变化

目的观察短期持续胰岛素输注（CSII）对初诊断2型糖尿病（T2DM）患者胰岛β细胞功能的影响,探讨强化治疗的时间。方法对32名FPG≥11mmol/L的初诊断T2DM患者行CSII14d。治疗前、治疗第4天和第15天分别进行OGTT（OGTT组）和精氨酸刺激试验（AST组）,比较两组治疗前后血糖（PG）、稳态模型评估法胰岛素抵抗指数（HOMA-IR）、β细胞功能指数（HOMA-β）、胰岛素分泌指数等指标的变化。结果治疗后两组PG、HOMA-IR降低,HOMA-β增加,14d较3d各指标改善显著;3d后△C30/△G30无升高,△C120/△G120明显升高;14d后两者均升高,差异有统计学意义。治疗3d和14d后精氨酸刺激急性C肽反应无明显变化。结论短期CSII强化治疗FPG明显升高的初诊断T2DM,能显著改善β细胞功能,14d疗效较好。但对非葡萄糖刺激的胰岛素分泌可能无明显影响。     

初诊2型糖尿病患者短期胰岛素强化治疗的临床观察

目的 探讨初诊2型糖尿病(T2DM)患者短期胰岛素强化治疗后获长期缓解的影响因素.方法 42例初诊T2DM患者,经2周胰岛素强化治疗后,先给予饮食及运动干预,若血糖不达标,则加用口服降糖药物.追踪观察至少1年. 结果 (1)与强化治疗前相比,强化治疗后以及1年后随访的FPG、曲线下葡萄糖面积、HOMA-IR明显降低,曲线下胰岛索面积、△I_(30)/△G_(30)明显增加(P<0.05或P<0.01).(2)与需口服降糖药物治疗患者相比,单纯饮食控制患者胰岛素强化治疗后FPG、强化治疗停止时胰岛素用量均明显降低,而△I_(30)/△G_(30).则明显增高(P<0.05). 结论 短期胰岛素强化治疗可改善糖尿病患者病理生理缺陷.以较低的胰岛素用量能良好控制血糖,β细胞功能得到较好恢复的初诊T2DM者将来获得病情缓解的可能性较大.     

胰岛素泵与多次胰岛素皮下注射治疗2型糖尿病疗效对比分析

目的比较短期胰岛素泵(CSII)与多次皮下胰岛素(MSII)注射强化控制2型糖尿病(T2DM)的有效性和安全性。方法对解放军总院内分泌科2006年6月至2007年5月收治住院的96例糖化血红蛋白(HbA1c)>7.5%的T2DM患者随机分为2组,分别给予CSII和MSII进行短期强化达标治疗,比较两组治疗前后的多时点血糖、糖化血清蛋白(GSP)、血糖达标天数、达标时胰岛素总剂量及低血糖事件发生的差异。结果治疗后CSII组与MSII组静脉血空腹血糖(FBG)分别由(13.53±5.01)mmol/L和(12.25±3.49)mmol/L下降到(5.56±0.76)mmol/L和(6.07±0.97)mmol/L,CSII组FBG下降程度更大(P=0.005)。静脉血餐后2h血糖(2hPG)分别由(19.56±5.82)mmol/L和(18.69±3.98)mmol/L下降到(6.93±1.07)mmol/L和(7.28±1.54)mmol/L,两组间比较差异无统计学意义(P>0.05)。两组的7个时点指血血糖均显著降低,两组间差异无统计学意义(P>0.05)。但达标时最高与最低血糖差值CSII组明显小于MSII组(P=0.029),血糖曲线下面积CSII组明显小于MSII组(P=0.017)。CSII组与MSII组GSP分别由(407±79)μmol/L和(410±100)μmol/L下降到(266±74)μmol/L和(297±83)μmol/L,均有显著改善(P均<0.01),两组治疗后绝对下降值CSII组更显著(P<0.05)。CSII组血糖达标时间平均为(3.66±1.41)d,显著短于MSII组的(5.83±1.77)d(P<0.05)。CSII组在达标时和治疗第7天的胰岛素剂量分别是(40.23±7.47)U/d和(36.06±9.71)U/d,均显著少于MSII组的(47.71±17.74)U/d和(45.63±11.91)U/d(P均<0.05)。两组有症状性低血糖事件共35例次,CSII组与MSII组分别有15例次和20例次,其中CSII组血糖≤3.9mmol/L和≤2.8mmol/L的分别为7和0例次,MSII组分别为19和8例次,前者均少于后者。结论两种胰岛素强化治疗均能有效控制尚未胰岛素治疗的T2DM患者的血糖,促进短期血糖达标。但与MSII相比,CSII治疗在降低FBG、缩小血糖波动和整体血糖控制方面更显著,并能够缩短血糖达标时间,减少胰岛素用量和降低低血糖的发生率。     

Predictors of responders to insulin therapy at 1 year among adults with type 2 diabetes

Background: The effectiveness of insulin therapy to lower blood glucose levels in patients with type 2 diabetes (T2D) may depend on a variety of factors. This study aims to determine baseline parameters including body mass index (BMI) threshold that might predict responders to insulin therapy. Methods: This was a retrospective UK population‐based study derived from 358 general practices electronic dataset. We included all patients with T2D, diagnosed at the age of >18 years old and who were initiated on insulin from January 2000 to December 2006. Insulin responders were defined as HbA1c <7.5% and/or HbA1c reduction by >1% at 12 months postinsulin initiation. Results: Results are expressed in mean (s.d.). A total of 6032 patients were identified. Baseline age was 63 years (11.7). In all, 61% of patients (3696) responded to insulin. At 1‐year postinsulin initiation, HbA1c was significantly reduced (9.8 vs. 8.4%, p < 0.001) and weight increased (85.7 vs. 87.9 kg, p < 0.001). Using logistic regression model, older age (p < 0.001), lower BMI (p = 0.046), higher HbA1c (p < 0.001), basal‐bolus insulin therapy and premixed insulin compared to basal insulin alone at baseline were independent predictors of responders to insulin. Gender and social class were not significant predictors of insulin responders. A BMI of <35.3 was derived as a cut‐point for response to insulin (p = 0.038). Conclusion: Overall, insulin therapy confers significant HbA1c reduction and weight increase in patients with T2D. The responsiveness to insulin therapy however appears to depend on baseline age, BMI, HbA1c and insulin regime. Clinicians should take these factors into consideration when making a decision to initiate insulin therapy in patients with T2D.     

Effect of short-term intensive insulin therapy on the incretin response in early type 2 diabetes

AimsShort-term intensive insulin therapy (IIT) and gastric bypass surgery are both interventions that can improve beta-cell function, reduce insulin resistance and induce remission of type 2 diabetes. Whereas gastric bypass yields an enhanced glucagon-like peptide-1 (GLP-1) response that may contribute to its metabolic benefits, the effect of short-term IIT on the incretin response is unclear. Thus, we sought to evaluate the impact of IIT on GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) secretion in early type 2 diabetes.MethodsIn this study, 63 patients (age 59 ± 8.3 years, baseline A1c 6.8 ± 0.7%, diabetes duration 3.0 ± 2.1 years) underwent 4 weeks of IIT (basal insulin detemir and pre-meal insulin aspart). GLP-1, GIP and glucagon responses were assessed by the area-under-the-curve (AUC) of these hormones on oral glucose tolerance tests at baseline and 1-day after the completion of therapy. Beta-cell function was assessed by Insulin Secretion-Sensitivity Index-2 (ISSI-2), with insulin resistance measured by Homeostasis Model Assessment (HOMA-IR).ResultsAs expected, comparing the post-therapy oral glucose tolerance test to that at baseline, IIT increased ISSI-2 (P = 0.02), decreased HOMA-IR (P < 0.001), and reduced AUC_glucagon (P < 0.001). Of note, however, IIT had no significant impact on AUC_GLP-1 (P = 0.24) and reduced AUC_GIP (P = 0.02).ConclusionDespite improving beta-cell function, insulin resistance and glucagonemia, short-term IIT does not change GLP-1 secretion and decreases the GIP response to an oral glucose challenge in early type 2 diabetes. Thus, the beneficial impact of this therapy on glucose homeostasis is not attributable to its effects on incretin secretion.     

短期胰岛素泵强化治疗对新诊断2型糖尿病的临床观察

目的 观察短期应用胰岛素泵强化治疗对新诊断2型糖尿病患者血糖控制的有效性和安全性,及对B细胞功能的影响. 方法 新诊断2型糖尿病79例,随机分为2组,1组用胰岛素泵进行持续皮下胰岛素(诺和锐)输注(CSII组)(40例);另外1组用预混胰岛素(诺和锐30)多次皮下注射(39例)即多次皮下注射胰岛素(MSII组).比较治疗前后血糖、血胰岛素及C肽变化情况及血糖达标时间、胰岛素用量、低血糖事件. 结果 2组均能有效地控制血糖,但CSII组能更快使高血糖状态得以控制,C肽水平较MSII组明显改善(P＜0.05).CSII组较MSII组血糖达标时间更短,胰岛素用量更少,且低血糖事件的发生率显著减少. 结论 短期胰岛素泵强化治疗新诊断的2型糖尿痛患者,具有快速而安全地控制血糖、改善胰岛B细胞功能的优势,是新诊断的2型糖尿病患者一种安全有效的临床治疗方法.     

不同治疗方案对初诊2型糖尿病患者短期胰岛素强化治疗后长期缓解的影响

目的探讨不同治疗方案对初诊2型糖尿病患者短期胰岛素强化治疗后长期缓解的影响。方法84例新诊断的2型糖尿病患者，经过2周的胰岛素强化治疗后，随机分为两组，一组仅予饮食及运动治疗（SDE组），另一组在饮食及运动治疗的基础上加用二甲双胍（MET组），追踪观察至少1年时间，了解两种治疗方案在诱导糖尿病病情缓解作用方面的可能差异。结果（1）随访1年时，SDE组的缓解率为38．1％（16／42），显著低于MET组（缓解率为66．7％，P〈0．01。（2）在1年随访结束时，SDE缓解组中空腹血糖、糖化血红蛋白、曲线下血糖面积（AUCg）、稳态模型胰岛素抵抗指数（HOMA—IR）均高于MET缓解组，曲线下胰岛素面积（AUCi）、▲I30／▲G30以及HOMA—IR、▲I30／▲G30、AUCg、AUCi、BMI的各自变化值（1年随访结束时值-强化治疗结束时值）均低于MET缓解组，差异有统计学意义（P〈0．05—0．01）。结论短期胰岛素强化治疗可使相当多的病例获长期缓解，胰岛素强化治疗后应用二甲双胍治疗可能会增加长期缓解机会。     

The role of insulin pump therapy for type 2 diabetes mellitus

Many patients with type 2 diabetes fail to achieve adequate glucose control despite escalation of treatment and combinations of multiple therapies including insulin. Patients with long‐standing type 2 diabetes often suffer from the combination of severe insulin deficiency in addition to insulin resistance, thereby requiring high doses of insulin delivered in multiple injections to attain adequate glycemic control. Insulin‐pump therapy was first introduced in the 1970s as an approach to mimic physiological insulin delivery and attain normal glucose in patients with type 1 diabetes. The recent years have seen an increase in the use of this technology for patients with type 2 diabetes. This article summarizes the clinical studies evaluating insulin pump use in patients with type 2 diabetes and discusses the benefits and shortcomings of pump therapy in this population. Copyright © 2016 John Wiley & Sons, Ltd.     

Insulin therapy in type 2 diabetes: what is the evidence?

Aim: To systematically review the literature regarding insulin use in patients with type 2 diabetes mellitus Methods: A Medline and Embase search was performed to identify randomized controlled trials (RCT) published in English between 1 January 2000 and 1 April 2008, involving insulin therapy in adults with type 2 diabetes mellitus. The RCTs must comprise at least glycaemic control (glycosylated haemoglobin (HbA1c), postprandial plasma glucose and /or fasting blood glucose (FBG)) and hypoglycaemic events as outcome measurements. Results: The Pubmed search resulted in 943 hits; the Embase search gave 692 hits. A total of 116 RCTs were selected by title or abstract. Eventually 78 trials met the inclusion criteria. The studies were very diverse and of different quality. They comprised all possible insulin regimens with and without combination with oral medication. Continuing metformin and/or sulphonylurea after start of therapy with basal long‐acting insulin results in better glycaemic control with less insulin requirements, less weight gain and less hypoglycaemic events. Long‐acting insulin analogues in combination with oral medication are associated with similar glycaemic control but fewer hypoglycaemic episodes compared with NPH insulin. Most of the trials demonstrated better glycaemic control with premix insulin therapy than with a long‐acting insulin once daily, but premix insulin causes more hypoglycaemic episodes. Analogue premix provides similar HbA1c, but lower postprandial glucose levels compared with human premix, without increase in hypoglycaemic events or weight gain. Drawing conclusions from the limited number of studies concerning basal–bolus regimen seems not possible. Some studies showed that rapid‐acting insulin analogues frequently result in a better HbA1c or postprandial glucose without increase of hypoglycaemia than regular human insulin. Conclusion: A once‐daily basal insulin regimen added to oral medication is an ideal starting point. All next steps, from one to two or even more injections per day should be taken very carefully and in thorough deliberation with the patient, who has to comply with such a regimen for many years.     

胰岛素强化治疗对2型糖尿病患者静息能量消耗的影响

目的观察胰岛素强化治疗对2型糖尿病（T2DM）患者静息能量消耗（REE）的影响。方法对26例T2DM患者经胰岛素强化治疗前后的『临床生化指标、炎症因子及REE进行比较分析。结果胰岛素强化治疗能显著降低REE,用体重（wt）校正后REE／Wt下降约10．4％（P=0．006）。多元回归分析提示REE与FPG、高敏C反应蛋白（hsDRP）、白介素6（IL-6）正相关（P〈0．05）。结论胰岛素强化治疗可降低T2DM患者的REE,REE的降低与血糖下降及炎症反应的改善相关。