第二代基礎胰島素類似物效益與安全性比較-回顧現有的資料

2017-11-17 Comparative Efficacy and Safety of Second-generation Basal Insulin
Analogues – a Review of Emerging Comparative Data

第二代胰島素類似物~ 迄今為止的故事
與第一代基礎胰島素類似物 (Gla-100)比較, 對於T2DM, 第二代基礎胰島素類似物 Gla-300 及 IDeg-100 (IDeg-100 或簡稱 IDeg) 有較佳的藥物動力學及藥效學, 能更穩定的控制血糖 (一天之間變動較小), 低血糖機率也降低, 一天僅需注射一次, 注射時間也很彈性
第二代基礎胰島素類似物優於第一代基礎胰島素類似物, 但第二代基礎胰島素之間的互相比較, 資料不多. 
Second-generation basal insulin analogues – the story so far
Compared with first-generation basal insulin analogues, second generation treatments (insulin largine 300 U/mL [Gla-300] and insulin degludec [IDeg]) have demonstrated improved pharmacokinetic (PK) and pharmacodynamic (PD) profiles that provide greater glucose stability (less intra-day variation), together with a lower risk of hypoglycaemia, in patients with type 2 diabetes mellitus (T2DM). As a result, clinicians now have insulin treatment options that provide glycaemic control with the benefit of a stable, ultra-long duration of action that allows once-daily administration with flexibility in daily injection time. However, while the available evidence demonstrates that Gla-300 and IDeg provide similar clinical benefits to first-generation basal insulin analogues (albeit via different mechanisms of action), no direct comparison between the second-generation basal insulin analogues has been presented to date.

第十一屆先進糖尿病技術與治療共識會, 有三篇第二代基礎胰島素類似物的研究
DELIVER-D study
LIGHTNING
the BRIGHT study 是第一篇關於第二代基礎胰島素類似物正面交鋒 (head to head)隨機控制研究(RCT) 

Emerging data from the 11th International Conference on Advanced Technologies & Treatments for Diabetes (ATTD)
Data from three studies of second-generation basal insulin analogues were presented at ATTD (Vienna, Austria) in February 2018. Real-world evidence from the DELIVER-D study  was validated by a second realworld study, LIGHTNING,  which used a similar methodology applied to a larger source dataset of electronic medical records. In addition to the real-world studies, the BRIGHT study provides the first randomised controlled trial (RCT) evidence from a head-to-head comparison of second-generation basal insulin analogues. The most recent data from each of these three studies (DELIVER-D, LIGHTNING, BRIGHT) were presented at the ATTD 2018 meeting and are reviewed here.

當病患的治療從第一代基礎胰島素類似物轉換成第二代基礎胰島素類似物

第二代胰島素類似物 (Gla-300 in EDITION, IDeg in BEGIN) 相較於第一代基礎胰島素類似物 (Gla-100) , 治療效果穩定且安全性提高, 但這些研究中, 低血糖病患常常被排除掉, 此外, 也沒有關於 Gla-300 與 IDeg 兩者的比較 Assessing comparative real-world findings in patients switching from first- to second generation basal insulin analogues DELIVER-D 
Previously published data from the EDITION and BEGIN clinical trials and subsequent meta-analyses have demonstrated consistent efficacy and improved safety profiles for second-generation basal insulin analogues (Gla-300 in EDITION and IDeg in BEGIN), compared with insulin glargine 100 U/mL (Gla-100). However, the extent to which these findings from strictly controlled RCT settings are applicable to real-life practice has yet to be examined. In these initial trials, patients with hypoglycaemia were often excluded. In addition, no direct comparisons between Gla-300 and IDeg have been presented to date. 

DELIVER-D 研究是回溯性觀察性研究, 在美國使用第一代基礎胰島素類似物的病患, 換成第二代基礎胰島素類似物後, 根據電子醫療紀錄評估安全性與效益, 調查第二代基礎胰島素類似物正面交鋒的差異, 這篇研究資料來自 PHIED, 涵蓋 39 個美國健康照護整合網絡, 收集T2DM成人病患從 Gla-100 換成 Gla-300 or IDeg(IDeg-100 or IDeg-200, 台灣好像沒有進 IDeg-200), 病患在過去六個月內至少曾處方一次 Gla-100, 且在此期間沒有使用其他基礎胰島素 DELIVER-D was a retrospective, observational study assessing safety and efficacy outcomes from electronic medical records in patients in the US switching from first-generation Gla-100 to either Gla-300 or IDeg. Head-to-head differences between the two second-generation basal insulin analogues were investigated.8 DELIVER-D assessed data from the Predictive Health Intelligence Environment database, which covers 39 integrated US healthcare networks. Data were gathered for adult patients with T2DM who were switched from Gla-100 to either Gla-300, IDeg 100 U/mL or IDeg 200 U/mL (index date: first prescription date during the period 1st March 2015 to 31st December 2016) and who had at least one Gla-100 prescription within 6 months before the index date (baseline period), but who had not received any other basal insulin prescriptions during this period. 

病患需要有至少先前12個月的電子醫療紀錄才能被收錄, 且收案後需有 6 個月以上的記錄, 且在六個月的基準期至少有一次A1C測量數據, 根據傾向分數隨機配對成 Gla-300 或 IDeg. 
在傾向分數配對後, Gla-300 與 IDeg 兩組, 先前12個月的人口統計與基礎值相似. 
評估病患在6個月追蹤期間, 根據先前基礎值低血糖事件率, 調整後的低血糖 (血糖<70)發生率及事件發生率(每人每年)
In order to be included in the study, patients were required to have electronic medical records for at least 12 months prior to, and at least 6 months following the index date, and to have had at least one glycated haemoglobin (HbA1c) measurement during the 6-month baseline period.8 Patients who switched from Gla-100 to Gla-300 or IDeg were matched in a 1:1 ratio using a propensity score based on: baseline demographics (age, gender, race, insurance type, geographic region); their clinical characteristics 12 months prior to the index date (body mass index, Charlson comorbidity index score, prevalence of comorbidities, concomitant medication use); and their clinical characteristics within the 6-month baseline period (HbA1c, hypoglycaemia incidence, utilisation of all-cause health care). After propensity score matching, the Gla300 (n=810) and IDeg (n=810) cohorts were comparable in terms of demographics and baseline characteristics.8 The DELIVER-D study included endpoints in both the full matched cohorts and in a subgroup of patients with HbA1c measurements at both the 6-month baseline and during 3–6 months of follow-up. In the matched cohorts, both the incidence of hypoglycaemia (identified by International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM]/ International Classification of Diseases, 10th Revision, Clinical Modification [ICD-10-CM]) code and/or plasma glucose level ≤70 mg/dL [3.9 mmol/L]) and the event rate (events per patient per year [PPPY], adjusted for baseline hypoglycaemia event) during the 6-month follow-up period were assessed. 

在subgroup中, 檢視的治療終點是 A1C 下降值, 及達到目標值A1C 的病患比例. 
In the subgroup, the endpoints examined were HbA1c reduction from baseline (closest to index date) at follow-up (latest available value during the follow-up period), and the proportion of patients attaining target HbA1c. 

Gla-300 與IDeg 降低A1C的療效相似 (A1C 降低 0.49% VS 0.48%), 達成目標血糖的病患比例相近 (A1C <7.0% 12.9% VS 15.9%) (A1C<8.0% 44.2% VS 44.6%)
在更換藥物期間, 病患低血糖機率降低, 根據基礎值調整後的低血糖發生率, 兩組沒有明顯差異
兩種第二代基礎胰島素類似物, 低血糖事件減少的機率相近, 降低低血糖急診就診機率與低血糖住院率也相近, 
以上資料顯示, 兩種第二代基礎胰島素類似物療效與安全性都有改善
Both Gla-300 and IDeg provided similar clinically meaningful decreases in HbA1c following switching (0.49% and 0.48% reductions in HbA1c, respectively) and enabled similar proportions of patients to achieve the target HbA1c of either <7.0% or <8.0% (12.9% versus 15.9% and 44.2% versus 44.6%, respectively). Following switching, patients on the second generation treatments experienced a lower incidence of hypoglycaemia versus baseline (Gla-300: 16.5 to 11.9%; IDeg: 15.4 to 12.7%); there was no significant difference between Gla-300 and IDeg when adjusted for baseline hypoglycaemia incidence (Figure 1). Both second-generation treatments provided similar reductions in the average number of hypoglycaemia events per year (least squares mean [LSM] difference in event rate -0.01 events/PPPY, 95% confidence interval [CI] [-0.18, 0.15], p=0.88) and the rate of emergency visits or hospitalisations for hypoglycaemia (LSM difference in event rate -0.01 events/PPPY, 95% CI [-0.12, 0.09], p=0.82). Until RCT data are available to support head-to-head comparisons, these data provide valuable insights into real-world outcomes and demonstrate the improved efficacy and safety profiles of modern second-generation basal insulin analogues in routine clinical practice. 

LIGHTNING 研究, 評估T2DM 從 Gla-100 或 IDet, 轉換成 Gla-300 or IDeg 的效益與安全性, 


Humedica electronic health records- 來自50個美國的健康照護系統, 700 間醫院, 7000 位醫師, 500萬個T2DM病患

資料包括有 77萬9813名使用基礎胰島素類似物治療的患者, 13萬155筆使用基礎胰島素類似物治療符合收案條件, 排除可能是 T1DM 病患, 排除研究期間更換使用基礎胰島素十次以上病患, 

The LIGHTNING study assessed real-world efficacy and safety outcomes in patients with T2DM switching to first- (Gla-100 or insulin detemir [IDet]) or second-generation (Gla-300 or IDeg) basal insulin analogues. Preliminary results of an analysis of Humedica electronic health records – a database capturing data from over 5 million people with diabetes across more than 50 US healthcare systems, 700 hospitals and 7,000 clinics – from 1st April 2015 to 31st December 2016 – are presented here.9 The dataset included 779,813 people with T2DM receiving basal insulin analogues. A total of 130,155 basal insulin analogue treatments complied with the study inclusion criteria (Figure 2), representing patients either initiating a new basal insulin or switching between basal insulins. Patients were excluded from the study if they had a likely predominant diagnosis of type 1 diabetes, or if they had more than 10 basal insulin switches within the study window (as such cases
would likely represent unusual clinical behaviour).9  

使用 patient treatment 做為一個研究單位. 僅計算在每個 patient treatment 治療期間的低血糖事件,
Data presented here focus only on findings in patients switching between basal insulin treatment options. The study approached its assessment using an analysis unit of ‘patient treatment’ – the period of time between treatment index (basal insulin initiation or switching event) and treatment end – and only counted on-treatment hypoglycaemic events during each patient treatment unit. Propensity score matching was used to match cohorts for potentially confounding characteristics, allowing for between treatment comparison. 

關鍵結果包括嚴重低血糖發生率, A1C 與基礎值的變化, 嚴重低血糖定義為血糖 < 70, 需要住院或急診治療, A1C 變化則是計算基礎值與追蹤 76-180 天的變化. 
Key outcomes included the incidence of severe hypoglycaemia and HbA1c change from baseline in a subgroup of patients with HbA1c measurements in both time windows. Severe hypoglycaemia was defined as any hypoglycaemic event (ICD-9 or ICD-10 identified or plasma glucose ≤70 mg/dL [3.9 mmol/L]) related to an inpatient or emergency department encounter. HbA1c change was assessed as change from baseline to 76–180 days’ follow-up.9 

不管先前使用哪一種第一代基礎胰島素類似物, 使用 Gla-300 的病患, 嚴重低血糖機率顯著降低
Switching from any basal insulin, patients who switched to Gla-300 had a significantly lower incidence of severe hypoglycaemia versus patients switched to the first-generation basal insulin analogues Gla-100 and IDet (p=0.009 and p=0.002, respectively). 

第二代基礎胰島素 IDeg 與 Gla-300 比較, 兩組嚴重低血糖降低的機率相似
總體來說, 換成 Gla-100, IDet, Gla-300, A1C 降低幅度相似, 而第二代基礎胰島素之間的結果也相似. 
不管病患之前使用哪一種基礎胰島素, 換成 Gla-100, Gla-300, IDet, IDeg, 在這項大型觀察性研究報告也支持 DELIVER-D 的研究結果, 
第二代基礎胰島素類似物, 相較於第一代基礎胰島素, 改善的效益與安全性相近. 
第二代基礎胰島素治療, 降低嚴重低血糖的機率也相近. 
In the direct comparison between second-generation basal insulins, IDeg and Gla-300 provided similar reductions (p=0.370) in the rate of severe hypoglycaemia (Figure 3).9 Overall, results of the analysis showed that there was a similar reduction in HbA1c for patients switching to Gla-100, IDet and Gla-300, and similarly there was no significant difference between the second-generation treatments (Gla-300 and IDeg; p=0.591; Figure 4).9 Findings from this large, observational study of patients switching from any basal insulin to Gla-100, Gla-300, IDet or IDeg support the conclusions of DELIVER-D: that in real-world populations, second-generation basal insulin analogues provide similar efficacy and improved safety profiles versus first-generation agents. Both second-generation treatments (Gla-300 and IDeg) provided similar reductions in the rate of severe hypoglycaemia during a 6-month follow-up.