基礎胰島素 NPH 與 基礎宜島素類似物 basal insulin analogue

口服藥治療無法達標時，GLP1受體促效劑優於胰島素使用

名詞定義: 

2001年，研究者提出了「 臨床惰性（clinical inertia）」的概念, 意思是發現問題之後沒有做改善. 

treatment inertia 治療慣性, 治療惰性, A1C 未達治療目標, 卻不改變治療策略, 醫病雙方沒有積極使用胰島素

Therapeutic Inertia 同上。

參考資料: Differentiating Basal Insulin Preparations: Understanding How They Work Explains Why They Are Different

用來作為基礎胰島素的有中效胰島素NPH insulin與長效型胰島素類似物

長效胰島素類似物包括: insulin glargine (Lantus®)及insulin detemir(Levemir®)

NPH 在1940年代開始使用

第一代基礎胰島素於 2000年上市

第二代基礎胰島素於 2015年上市

Human Basal Insulin: NPH Insulin

First-Generation Basal Insulin Analogs: Insulin Glargine 100 Units/mL(簡稱Gla-100) and Insulin Detemir *(簡稱IDet)

Second-Generation Basal Insulin Analogs: Insulin Glargine 300 Units/mL (簡稱 Gla-300) and Insulin Degludec 100 Units/mL  (IDeg-100)  and 200 Units/mL *(台灣沒有 IDeg-200)

新一代的胰島素筆, 可以一次施打 160u 的 Gla-300 or IDeg-200. 好處是可以減少施打次數, 可以降低胰島素筆的數量 (台灣只有 IDeg-100)
a once-daily dose can be administered using a pen device that can deliver up to 160 units of Gla-300 or IDeg-200. This larger delivery dose reduces the number of injections and the number of pens required.

New insulin glargine 300 Units · mL-1 provides a more even activity profile and prolonged glycemic control at steady state compared with insulin glargine 100 Units · mL-1.
Gla-100 第一代基礎胰島素類似物
IDet 第一代基礎胰島素類似物
Gla-300 第二代基礎胰島素類似物
 (IDeg-100) 第二第基礎胰島素類似物

Gla-300 相較於 Gla-100, 降血糖效果較穩定, 血中藥物濃度較穩定 (distributed PK/PD profiles), 濃度減低的時間較長 (50% of the area under the serum insulin)
使用連續性血糖監測, glycemic excursions Gla-300 早上或晚上施打結果相似, 但早上施打 Gla-100 會有較高的血糖上升
Gla-300 相較於 Gla-100, 血糖控制效果相近, 但嚴重低血糖及夜間低血糖機率較低
不過也有研究顯示, Gla-300 與 Gla-100 的低血糖機率差異不大. 

RESULTS:
At steady state, insulin concentration (INS) and glucose infusion rate (GIR) profiles of Gla-300 were more constant and more evenly distributed over 24 h compared with those of Gla-100 and lasted longer, as supported by the later time (∼ 3 h) to 50% of the area under the serum INS and GIR time curves from time zero to 36 h post dosing. Tight blood glucose control (≤ 105 mg · dL(-1)) was maintained for approximately 5 h longer (median of 30 h) with Gla-300 compared with Gla-100.
另一篇研究發現,  第一型糖尿病患, 發生低血糖的事件, Gla-100組每人每年 9次, Gla-300 每人每年 4次.
A randomized controlled study in people with T1D using continuous glucose monitoring also found that nocturnal confirmed and severe hypoglycemia rates were lower with Gla-300 than with Gla-100 (4.0 versus 9.0 events per participant-year) 

(下面是第一代與第二代比較)  IDeg-100 相較於 Gla-100, 低血糖機率降低 21%, 夜間低血糖機率降低 52%, 
另一篇研究發現, IDeg-100 相較於 Gla-100 可將低血糖機率降低 11%-30%. 
DEVOTE研究: 第二型糖尿病患使用 IDeg-100 可顯著降低嚴重低血糖發生率(4.9% vs 6.6%)
In the SWITCH 1 and 2 clinical trials, people with T1D or type 2 diabetes (T2D) treated with IDeg had reduced rates of overall symptomatic hypoglycemia compared with those treated with Gla-100 (SWITCH 1, risk ratio 0.89; SWITCH 2, risk ratio 0.70) [35, 36]. In the DEVOTE study, participants with T2D receiving IDeg had significantly lower rates of severe hypoglycemia compared with those receiving Gla-100 (4.9% vs. 6.6%, respectively; rate ratio 0.60)

研究發現, 使用 Gla-300 發生低血糖的機率較 Gla-100 或 IDet 低 (相較機率 0.75  及 0.43) 
 In the DELIVER 2 and 3 studies, significantly fewer patients treated with Gla-300 experienced hypoglycemia compared with Gla-100 or IDet (adjusted odds ratio 0.75 and 0.43, respectively).

Gla-300 用量比 Gla-100 需增加 10-20%, 使用 Gla-100 的病患如果要改用 Gla-300 需注意換算劑量. 不過這種換算比例並非絕對, 也可能與病患本身有關. 
使用Gla-300與其他基礎胰島素比較, 在相近的劑量下, Gla-300血糖控制( glycated hemoglobin targets )較好, 且低血糖機率較低. 

參考資料 內科學誌 2010 長效型胰島素類似物在第2型糖尿病人的應用(馬偕內分泌暨新陳代謝科)

基礎胰島素使用時機: 第二型糖尿病, 若使用 一種或兩種口服降血糖藥物治療後，而 A1C 仍≧7%，就應考慮加上基礎胰島素

基礎胰島素使用方式: 

~ 睡前打一次insulin glargine或insulin detemir 或是NPH

~ insulin glargine或insulin detemir也可以選擇早上注射。

起始劑量: (口服抗糖尿病藥物續用)

每天 10u, 或每公斤 0.2u. 

如果病患血糖很高, 起始劑量可以提高到每天 20u. 

每天測血糖, 如果血糖仍未到達目標, 每三天增加 2u. 

如果血糖超過 180 可以加大增幅, 例如每三天增加 4u. 

空腹血糖目標範圍(70-130 mg/dL) 新的文章說 80-130 mg/dL

ADA與EASD建議患者注射基礎胰島素後空腹血糖的目標訂為≦130 mg/dL

但很多研究則將目標訂在 120 甚至 100 以下

若患者低血糖風險低, 建議將目標訂嚴格一點 (100 或 120 以下)
飯後血糖標準 (80-160) 較寬鬆一點. 

如果空腹血糖達標, 但 A1C 仍高, 需測量每餐之前的血糖及睡前血糖

飯前血糖最高的那一次, 可餐前追加第二次注射速效胰島素, 

追加注射速效胰島素的起始劑量 4u. 之後每三天可增加2u. 直到血糖達標

如果再追蹤三個月 A1C 仍高. 可以追加第三次餐前速效胰島素注射. 

如果再追蹤三個月 A1C 仍未達標, 可測量飯後血糖, 依照飯後血糖調整餐前速效胰島素注射量. 

biphasic insulin/prandial insulin 

有一篇研究, 比較加上每日兩次biphasic insulin (insulin aspart 30 短效)、每日三次prandial insulin (insulin aspart 短效) 及每日一次或兩次basal insulin (insulin detemir長效)的效果。

治療一年後糖化血色素分別下降1.3%、1.4%與0.8%，糖化血色素≦6.5%的比率分別為17.0%、23.9%與8.1%，統計上biphasic insulin與 prandial insulin兩組沒有差別但皆比basal insulin組要好。

第一年糖化血色素連續兩次≧8.0%或第二年糖化血色素仍＞6.5%的患者，則停用sulfonylurea加上第二種胰島素

biphasic insulin組~~ 中餐多注射prandial insulin一次

prandial insulin組~~  睡前加上basal insulin

basal insulin組~~      三餐分別加上prandial insulin

治療三年後biphasic insulin組、prandial insulin組與basal insulin組分別有67.7%、73.6%及81.6%的患者使用第二種胰島素，糖化血色素比尚未使用胰島素前分別下降1.3%、1.4%與1.2%，統計上三組間沒有差異。

糖化血色素≦6.5%的比率在prandial insulin組(44.79%)與basal insulin組(43.2%)皆比biphasic insulin組(31.9%)要高

發生低血糖的中位數以prandial insulin組(5.7/patient/year)最高、biphasic insulin組(3.0/patient/year)次之，basal insulin組(1.7/patient/year)最低。

體重增加方面，basal insulin組(3.6 kg)比prandial insulin組(6.4 kg)及biphasic insulin組(5.7 kg)都要少。

糖化血色素的控制以口服降血糖藥物加上prandial insulin或basal insulin為基礎的治療皆比以 biphasic insulin為基礎的治療要好。
其中以basal insulin為基礎的治療，發生低血糖的機會與體重的增加都最低

biphasic, 糖化血色素≦6.5%比率(勝), 低血糖機率(中), 體重增加 (中)

臨床上使用基礎胰島素, 加上速效胰島素的方式

-- 主要一餐前, 打速效胰島素

-- 使用預混型胰島素(如NovoMix® 30, (lispromix 50/50), 早晚各打一次

-- 三餐前打速效胰島素, 降血糖效果比預混BID好. 

參考資料 injected insulin 

基礎胰島素 basal insulin 一天注射一至兩次, 維持整天的穩定胰島素濃度, 讓血糖保持在穩定值, 但僅使用 basal insulin 無法涵蓋用餐後的血糖上升. 

餐後血糖 prandial insulins 在用餐之後使用, 作用快速, 降低餐後血糖

Basal vs. Prandial: Insulins can be divided into two categories based on function: basal (long-acting insulin) and prandial (rapid-acting or “mealtime” insulin). Basal insulin is designed to be injected once or twice daily to provide a constant level of insulin action throughout the day. Basal insulin helps keep blood sugars at a consistent level when you are not eating, but it is not enough to cover glucose spikes after mealtime. Prandial insulins, on the other hand, are taken at mealtime and act rapidly on the body, serving to bring down the high sugar levels following meals.

胰島素的結構可分兩類, 人類胰島素及胰島素類似物. 胰島素類似物的價格較高, 但能避免低血糖與體重增加. 整體醫療費用(低血糖掛急診,住院)也許可以降低

Analog vs. Human Insulin: There are also two types of insulin structures: human insulin and analog insulin. Human insulins were developed first and are essentially identical in structure to the insulin produced in the body. Analog insulins are similar in structure but have minor biological modifications to give them desirable properties. While analog insulins cost more, they generally lead to less hypoglycemia and weight gain. Prandial (mealtime) insulin analogs tend to act faster than human insulin.

參考資料  First Online: 30 March 2019

Differentiating Basal Insulin Preparations: Understanding How They Work Explains Why They Are Different

prandial insulins 作用快, 降低餐後血糖

basal insulins 作用時間長, 改善 24 小時血糖控制

clinical action profiles 臨床作用輪廓

研究證實, 第二代基礎胰島素類似物,  insulin glargine U300 及 insulin degludec U100 U200, 一天施打一次, 能提供穩定的血糖控制, 且可降低低血糖機率 (相較於第一代的 insulin glargine U100 及 insulin detemir), 所以可以減少病患整體醫療花費(去醫院的機率)

Since the introduction of insulin as a life-saving agent for patients with type 1 diabetes, insulin preparations have evolved to approximate physiologic insulin delivery profiles to meet prandial and basal insulin needs. While prandial insulins are designed to have quick time–action profiles that minimize postprandial glucose excursions, basal insulins are designed to have a protracted time–action profile to facilitate basal glucose control over 24 h. Given that all insulins have the same mechanism of action at the target tissue level, the differences in time–action profiles are achieved through different mechanisms of protraction, resulting in different behaviors in the subcutaneous space and different rates of absorption into the circulation. Herein, we evaluate the differences in basal insulin preparations based on their differential mechanisms of protraction, and the resulting clinical action profiles. Multiple randomized control trials and real-world evidence studies have demonstrated that the newer second-generation basal insulin analogs, insulin glargine 300 units/mL and insulin degludec 100 or 200 units/mL, provide stable glycemic control with once-daily dosing and are associated with a reduced risk of hypoglycemia compared with previous-generation basal insulin analogs insulin glargine 100 units/mL and insulin detemir. These advantages can lead to decreased healthcare resource utilization and cost. With this collective knowledge, healthcare providers and payers can make educated and well-informed decisions when determining which treatment regimen best meets the needs of each individual patient.

Insulin glargine 及 insulin detemir 與 NPH的比較
NPH造成夜間低血糖的機率較高(半夜三點測血糖)
注射insulin detemir比注射insulin glargine的患者體重增加較少

參考資料~糖尿病筆記

基礎胰島素包括了

舊的人類胰島素（NPH）

長效胰島素類似物（Insulin Glargine U-100以及Insulin Levemir）

更長效胰島素類似物（Insulin Glargine U-300以及Insulin Degludec）

台灣目前核准使用的基礎胰島素

第二代基礎胰島素: Insulin glargine U-300 及 Insulin Degludec Detemir，Insulin Glargine U-100

GLP1RA 健保給付規定: 

Liraglutide(如 Victoza): 當患者已接受口服降血糖藥物，及/或基礎胰島素治療仍未達理想血糖控制時，與口服降血糖藥物及/或基礎胰島素併用。本藥品不得與 DPP-4抑制劑、SGLT-2抑制劑併用。

而 Exenatide(如 Byetta)、dulaglutide(如 Trulicity) 仍規定不可以與基礎胰島素併用

基礎胰島素與GLP1RA合併的藥物：

Xultophy, 組成每1毫升（mL）含有 100單位的 Degludec 與 3.6mg 的 Liraglutide

隨餐胰島素  aspart 三餐給予, 起始劑量, 0.1U/公斤

https://www.dm-note.com/2020-ada-guideline-pharmacologic/

使用基礎胰島素達到空腹血糖穩定或是每日每公斤0.5單位以上, 但 HbA1C 糖化血色素尚未達標，考慮合併注射治療

-- 基礎胰島素加上GLP1受體促效劑 (較不會低血糖也比較不會體重增加。)

-- 一天多次胰島素注射。

使用胰島素治療後

-- 病患需自己監控血糖

-- 可維持使用Metformin。

-- SU和DPP4抑制劑考慮停用

-- 如果使用到大劑量胰島素，可考慮續用TZD或是SGLT2抑制劑來降低胰島素劑量

下面這張圖是延續前面的. 原圖太大分兩張. 

from uptodate Choice of basal insulin 基礎胰島素的選擇

insulin NPH or detemir given at bedtime

insulin glargine or degludec given in the morning or bedtime

每天注射一次胰島素, 可選擇睡前打 NPH or Detemir , 或者每天早上/睡前, 打一次 insulin glargine or degludec.

有些國家的 NPL 製作成單一劑型, 但在美國, NPL 僅有與速效胰島素 lispro 搭配的組合劑型.

A single daily dose of either insulin NPH or detemir given at bedtime or insulin glargine or degludec given in the morning or at bedtime is a reasonable initial regimen (table 1). In practice, payer coverage is often an important consideration in the selection of basal insulin. In some countries, NPL is available as a separate insulin analog for basal coverage [22,23]. In the United States, NPL is only available in combination with rapid-acting lispro (insulin lispro protamine-insulin lispro).

不同的基礎胰島素對於血糖控制差異不大, 在胰島素類似物中, insulin glargine, Detemir, degludec 這三種藥物比起 NPH, 較少造成夜間低血糖, 但缺點是價格較貴. 使用這些藥物造成低血糖需住院或需掛急診的機率並無差異

The basal insulin preparations do not differ significantly in glycemic efficacy [24,25]. Among basal insulin preparations, insulin glargine, detemir, and degludec may have less nocturnal hypoglycemia (but not always total hypoglycemia) compared with NPH, with the important disadvantage of high cost. There does not appear to be any difference in hypoglycemia-related hospital admissions or emergency department visits. As examples:

將研究資料做統合分析, 比較每天打一次 insulin glargine or detemir, 與每天 1-2 次打 NPH, 所有基礎胰島素改善A1c的結果相似, 但有些統合分析發現, 使用 insulin glargine or detemir 的這組, 有症狀及夜間低血糖的機率比使用NPH的這組低, 不過基礎胰島素造成低血糖的機率原本就不是很高. 

●In meta-analyses of trials comparing once-daily insulin glargine or detemir with once-daily or twice-daily NPH insulin, there were similar improvements in A1C with all types of basal insulin [25-28]. However, in some of the meta-analyses, the rates of overall symptomatic and nocturnal hypoglycemia (while relatively infrequent with either basal insulin) were lower in patients treated with either insulin glargine or detemir compared with NPH [25-27].

一篇回溯性觀察性研究發現, 使用 insulin analogs 與 NPH比較, 並不會降低掛急診或住院的低血糖事件, 但NPH這組的血糖控制稍微好些(8.2 VS 7.9 )

●In a retrospective observational study using data from a large health care delivery system (>25,000 patients initiating basal insulin), there was no benefit of insulin analogs compared with NPH in reducing emergency department or hospital admissions for hypoglycemia (11.9 versus 8.8 events per 1000 person-years, respectively) despite slightly better glycemic control in the NPH group (achieved A1C 8.2 versus 7.9 percent with NPH, suggesting they were not treated with less aggressive doses) [29].

Insulin degludec (IDeg-100) 降血糖效果與 insulin glargine (Gla-100)相似, 有些研究發現 insulin degludec (IDeg-100)  的低血糖機率較低, 尤其是對於採嚴格血糖控制的病患在一個雙盲世代研究, 經 65周的追蹤, 共收錄第二型糖尿病患者 721 位, 平均A1C 7.6, 且病患至少有一個低血糖的危險因子, 隨機分配至 一天打一次 insulin degludec (IDeg-100)  或 insulin glargine(Gla-100) , 治療 32 周後, 換成其他替代胰島素, 再繼續治療 32 周, 所有低血糖及夜間低血糖事件, 在 degludec 這組較低, 但發生嚴重低血糖的機率則無差異. 兩組的血糖控制相似

基礎胰島素IDeg-100與Gla-100低血糖機率比較

Insulin degludec appears to have similar glycemic efficacy as that of insulin glargine and, in some trials, a lower rate of hypoglycemia, especially if aiming for more stringent glycemic targets [17,30-33]. As an example, in a 65-week, double-blind, crossover trial, 721 adults with type 2 diabetes (mean A1C 7.6 percent) and at least one risk factor for hypoglycemia were randomly assigned to receive once-daily insulin degludec or insulin glargine for 32 weeks and then crossed over to the alternate insulin treatment for the next 32 weeks [34]. The rate of overall (185.6 versus 265.4 episodes per 100 patient-years of exposure) and nocturnal (55.2 versus 93.6 episodes) symptomatic hypoglycemia was lower with degludec (rate ratios 0.70, 95% CI 0.61-0.80 and 0.58, 95% CI 0.46-0.74, respectively). There was no difference in relatively rare severe hypoglycemia (nonsignificant reduction of 0.62 episodes per 100 patient-years with degludec). Overall glycemic control was similar (A1C 7 to 7.1 percent).

雖然 degludec  (IDeg-100) 顯著降低整體低血糖與夜間低血糖機率(平均每五年減少一次事件), 但還要考量最大效益與花費是否值得, 而 insulin degludec  (IDeg-100) 長期的安全性尚未得知

Although degludec significantly reduced overall and nocturnal hypoglycemia, the modest benefit (on average, one episode less every five years) must be balanced against its relatively higher cost. In addition, the long-term safety profile of insulin degludec is unknown [35].

濃縮胰島素比較~ 彰基藥訊