DM CKD 腎功能不良之抗糖尿病藥物OAD選擇 renal insufficiency and choice of anti-diabetic drugs

#DM #CKD
Diabetes medication in CKD
2015台灣慢性腎臟病臨床診療指引
慢性腎臟病預防與治療-藥物篇
第二型糖尿病合併慢性腎臟疾病之口服降血糖藥物治療
2018 年美國糖尿病學會針對糖尿病腎病變之標準治療建議

CKD慢性腎病定義
如果沒有蛋白尿. eGFR 60 以上, 還不算 CKD.
如果有蛋白尿, eGFR 即使超過 90 也算CKD

台灣慢性腎臟病臨床診療指引第八章慢性腎臟病藥物治療

TZD 用於腎衰竭不需調整劑量, 但會造成體液滯留, 心衰竭, 水腫. 如果腎衰竭病患排鹽排水能力下降, 不建議使用. 

DPP4i 僅 linagliptin(Trajenta) 在腎衰竭不用調整劑量

2019台灣糖尿病腎臟疾病臨床照護指引

根據下表, 透析患者, 禁用藥物包括以下五類

Metformin

SU

AGI

SGLT2i

GLP1RA 的 exenatide 及 lixisenatide 

下面這兩張是一樣的. 不過一張沒有標示 GFR. 下面有標示 GFR

看上面英文說明. 應該是 Trajenta 公司出的廣告單 DPP4i 之中. 只有 Trajenta 不需要根據腎功能調整劑量. 比較方便.

有些腎功能不良需調整OAD劑量

Diabetes treatment in patients with renal disease: Is the landscape clear enough?

有微白蛋白尿的糖尿病患者, 相較於沒有微白蛋白尿的糖尿病, 心血管疾病增加兩倍
Diabetic subjects with microalbuminuria have increased risk (2x) of cardiovascular disease than those with normoalbuminuria.

多數CKD stage 3 的糖尿病患者, 在腎臟尚未失去功能之前, 可以會先死於心血管疾病.
Most diabetic patients with CKD stage 3 will suffer a serious cardiovascular event, possibly fatal before their chronic kidney disease progress to end stage kidney failure.

有心衰竭或是慢性腎病變時，SGLT2抑制劑優於GLP1受體促效劑。

2018 糖尿病臨床照護指引 DAROC Clinical Practice Guidelines for Diabetes Care 2018

抗糖尿病藥物與腎功能考量
Metformin eGFR < 30 禁用
SGLT2i 需根據腎功能調整劑量
GLP1RA 需根據腎功能調整劑量, 開始服用或增加劑量要小心, 可能造成腎損傷
DPP4i 根據腎功能調整劑量, 但 linagliptin 在腎衰竭不用減量
TZD 有可能造成體液滯留, 所以通常不建議使用於腎衰竭病患
SU: 不建議使用 glyburide, 可使用glipizide 及 glimepiride , 要保守, 避免低血糖
胰島素: 不管是人類胰島素或胰島素類似物, 需根據腎功能減低劑量, 根據每次的治療反應調整劑量.

glimepiride (Amaryl) 腎功能不良建議謹慎使用. 起始劑量 1mg (半顆) QD

SULFONYLUREAS

磺醯尿素類在世界上廣泛使用, 可促進胰島素分泌, 會增加低血糖風險, 低血糖風險是這個藥物在慢性腎衰竭病患主要考量. 

Sulfonylureas are old drugs widely used worldwide. These drugs ease the secretion of insulin and are related with increased risk of hypoglycemia, which is a major issue for CKD patients.

Glibenclamide (eGFR < 60 mL/min 不建議使用)

Glibenclamide (glyburide) is metabolized in the liver and excreted by the kidneys equally and intestine. Some metabolites are active and can accumulate in CKD despite the fact that biliary removal partially counteracts the limited renal excretion.

Hypoglycemia may be serious and lasting more than 24 h in CKD.

The use of glibenclamide in subjects with moderate CKD (eGFR 60-90 mL/min) should be limited (reduced dose, frequent monitoring due to increased risk of hypoglycemia). The drug and is contraindicated in stage ≥ 3 CKD (eGFR < 60 mL/min)[17].

Glimepiride= GFR 30-60 需減量. <30不要用

Glimepiride is metabolized by the liver to two major metabolites each of which has hypoglycemic activity. In renal disease these metabolites summed. Although the half-life is 5-7 h, the drug can cause severe hypoglycemia that lasts more than 24 h. Its use is safe in GFR > 60 mL/min and with a reduced dose of up to 30 mL/min. In CKD stage 4 or 5 the use of glimepiride is dangerous[18].

Gliclazide= 嚴重腎衰竭沒有資料可參考, 但根據藥性可以使用

Gliclazide is metabolized by the liver to inactive metabolites that are eliminated in the urine. Thus, gliclazide causes less hypoglycemia than other sulfonylureas. In CKD sage 1, 2, 3 (eGFR > 30 mL/min) gliclazide can be used. There are no data in patients with severe CKD but according to its metabolism the use (in reduced dose) of gliclazide is also permitted in these subjects[19].

Glipizide (Minidiab) 嚴重腎衰竭不需調整劑量 

Glipizide (Minidiab) also does not need dose adjustment in severe and moderate renal disease and can be used safely. (The only caution remains the risk of hypoglycemia).

第二代 Sulfonylureas 包含 glipizide、gliclazide 、glyburide、glimepiride，其 中，glipizide 與 gliclazide 較適用於 CKD 病人。 Glipizide 的半衰期及清除率不受 eGFR 降低影響，雖然它數個不具活性的代 謝物會因此累積，但不會對血糖造成影響；所以 CKD 病人使用不需調整劑量。 Gliclazide 代謝物不具活性，輕度、中度腎功能不良不需調整劑量，嚴重腎功能 不良則不建議使用。Glyburide（glibenclamide）的部分代謝物具有活性，會有 造成低血糖風險，第 1-2 期 CKD 病人需減低劑量，第 3-5 期病人應避免使用。 Glimepiride 活性代謝物的排除會因 eGFR 降低而累積，以致延長 glimepiride 作用， CKD 第 3-4 期病人需從低劑量開始使用。

Meglinitides 類： 本類藥品與 sulfonylureas 一樣會促進胰島素分泌，但開始作用時間較快，作 用時間較短。 雖然 repaglinide 濃度、半衰期及曲線下面積（area under curve，AUC）會 因 eGFR 降低而增加，但不需調整劑量。Nateglinide 的活性代謝物會因 eGFR 降 低造成累積，CKD 病人使用需非常小心。

腎衰竭使用促胰島素分泌劑型. 可以用 Rapaglinide (Novonorm) 

GLINIDES 短效. 所以低血糖風險較SU低 . 

Glinides, repaglinide and nateglinide, are short acting secretagogues. The short duration of their action means reduced risk of hypoglycemia compared to sulfonylureas. This is an advantage for diabetic subjects with CKD because they belong in the high risk for hypoglycemia group as already mentioned. 

Repaglinie 腸胃道吸收. 肝代謝. 代謝物不具降血糖活性, 腎衰竭可用

Repaglinide is absorbed from the gastrointestinal tract and metabolized in the liver by oxidation and conjugation with glucuronic acid. The major metabolites of repaglinide are M1, M2 and M4. These metabolites are excreted via the bile into the feces and have no hypoglycemic activity[20].

Repaglinide can be used even in CKD stages 4 and 5 without dose reduction.

Nateglinide 腎衰竭第五級不建議使用

Nateglinide is also rapidly absorbed from the gastrointestinal tract and metabolized in liver to 9 main metabolites (M1-M9). These metabolites have much weaker hypoglycemic activity than the parent compound. The only metabolite that retains high activity is the metabolite M7. The concentration of this metabolite however is low (< 7%), resulting in a hypoglycemic effect, which is attributed mainly to intact nateglinide. The excretion of the drug in urine is unchanged form at 16% and by 84% in the form of metabolites.

In CKD stage 5 we avoid nateglinide, and in stage 4 we adjust the dose (60 mg × 3)[21].

另外. 抗糖尿病藥物與腎臟功能的關係

SGLT2i 及 GLP1 RA 可以減少CKD的發生及惡化.

SGLT2i 三種藥物, 嚴重腎衰竭不建議使用.
dapagliflozin (Forxia) 在 eGFR < 60 不建議使用.
Canagliflozin 和 Empagliflozin 在 eGFR < 45 不建議使用.

GLP1RA  不可以與DPP4i 或 SGLT2i 併用
Liraglutide(victoza) 腎衰竭不用調整劑量, 在體內可被完全分解, 目前沒有使用在 eGFR < 60 的紀錄
Exenatide (Byetta® 降爾糖；Bydureon® 穩爾糖)腎衰竭 eGFR<30不要用., eGFR 30-60 劑量減半
dulaglutide(如 Trulicity) 腎衰竭不用調整劑量