糖尿病藥物的肝毒性

https://www.uspharmacist.com/article/hepatotoxicity-of-antidiabetic-drugs

曾被報告有高毒性的抗糖尿病藥物有: SU磺醯尿素, AGI, 雙胍類, TZD

Hypoglycemic Agents in the Treatment of Diabetes
Many therapeutic drugs target both fasting and postprandial hyperglycemia and other metabolic parameters involved in the diabetes-associated complications. These drugs are directed towards increasing insulin secretion, decreasing insulin resistance, and increasing insulin penetration into the cells. Antidiabetic drugs with reported cases of hepatotoxicity include sulfonylureas, alpha-glucosidase inhibitors, biguanides, and thiazolidinediones (Table 1).

SU磺醯尿素類
第一代 SU: 目前很少使用
tolbutamide (Orinase), 有肝毒性
tolazamide (Tolinase) 僅三例肝毒性報告
chlorpropamide (Diabinese) 有肝毒性
第二代SU, 肝毒性不常見
glipizide (Glucotrol),
glyburide (DiaBeta,
Micronase, Glynase)
glimepiride (Amaryl) 沒有英文文獻的肝毒性報告, 但有法文文獻的肝毒性案例

Sulfonylureas
Sulfonylureas have been used as first-line oral antihyperglycemic agents for type 2 diabetes since 1954. First-generation sulfonylureas include tolbutamide (Orinase), tolazamide (Tolinase), and chlorpropamide (Diabinese). Chlorpropamide and tolbutamide are well recognized as causes of hepatotoxicity.7 However, there have been only three reported cases of hepatic injury caused by a third oral hypoglycemic agent, tolazamide.7 With the arrival of second-generation sulfonylureas, first-generation sulfonylureas are rarely used. Second-generation sulfonylureas include glipizide (Glucotrol), glyburide (DiaBeta, Micronase, Glynase), and glimepiride (Amaryl). Drug-induced hepatotoxicity has been reported infrequently with second-generation sulfonylureas. For glimepiride, a second-generation sulfonylurea, there have been no reports of hepatotoxicity in English literature; however, hepatotoxicity has been reported in French literature.


AGI 是第二型糖尿病的輔助治療藥物, 此類藥物的原型藥是 acarbose, 因 acarbose 服用之後僅非常少量被吸收進入體內, 理論上是很安全的藥物, 常見的副作用是脹氣, 但也有一些嚴重肝毒性的案例報告, 儘管acarbose造成的肝毒性不常見, 服用此藥仍需監控肝功能
Alpha-Glucosidase Inhibitors
The glucosidase inhibitors are useful adjunctive therapies for type 2 diabetes. The prototype of this class is acarbose (Precose). Because acarbose is minimally absorbed in unchanged form after oral administration, the drug is widely believed to be safe, with only flatulence as a commonly reported complaint. However, cases of severe hepatotoxicity have been reported.10-12 Although acarbose-induced hepatotoxicity appears to be uncommon, diabetic patients receiving long-term acarbose therapy should be closely monitored for this adverse effect.
雙胍類, metformin 廣泛用於治療第二型糖尿病, 罕見但嚴重的副作用是乳酸中毒, 成因是metformin 會干擾粒線體的氧化過程, Metformin的肝毒性很罕見, 僅有兩例急性肝炎, 以及一例膽汁鬱積,還有一例急性肝炎案例是metformin及其代謝物引起的特異性不良反應,


Biguanides
Metformin 的肝臟毒性很罕見.
Metformin hydrochloride is widely used for the treatment of type 2 diabetes. A serious but rare side effect, lactic acidosis, is caused because of its interference with mitochondrial oxidative processes.13 Metformin (Fortamet, Glucophage, Riomet) hepatotoxicity has rarely been reported, with two cases of acute hepatitis and one of bland cholestasis.13-15 A well-documented case of acute hepatitis caused by an idiosyncratic adverse reaction to metformin or to one of its metabolites, has also been reported. 13

TZD 胰島素增敏劑, glitazones, 臨床上使用的有三種, troglitazone, pioglitazone, and rosiglitazone.
Troglitazone (Rezulin) 1997年上市, 上市一年後出現肝損傷及肝衰竭的案例, 因證據明顯, 於2000年下架
pioglitazone (Actos) 達到肝毒性的安全劑量較高, 肝毒性罕見, 通常輕微且可逆, 極少數案例顯示與肝毒性有關連, 有一例服用 Pioglitazone 六個月後發生膽汁鬱積性肝炎, 停藥六周之後肝指數回到正常
rosiglitazone (Avandia) 達到肝毒性的安全劑量較高, 肝毒性罕見, 通常輕微且可逆
有一個案例是 56歲女性, 曾服用 troglitazone, 後來改成 rosiglitazone, 之後發生嚴重的膽汁鬱積性肝炎, 顯示服用 troglitazone 引起肝損傷的病患,  rosiglitazone 並非安全替代物

Thiazolidinediones 胰島素增敏劑, 用於臨床的有三種.
Thiazolidinediones (TZDs, also known as glitazones) are insulin sensitizers now widely used for the treatment of type 2 diabetes. Three TZDs have been used in clinical practice: troglitazone, pioglitazone, and rosiglitazone.

1997年上市, 上市一年內出現肝臟損傷及肝衰竭的案例, 再經過一年, troglitazone 肝毒性證據明確 2000 年被下架.
Troglitazone: Troglitazone (Rezulin), a peroxisome proliferators–activated receptor gamma agonist that enhances insulin sensitivity, was approved for the treatment of type 2 diabetes in 1997.16 It was an effective antidiabetic drug with a fundamentally new mechanism of action. However, within a year after its widespread use, individual cases of liver injury and failure were reported.16-19 The mounting evidence for the idiosyncratic hepatotoxicity of troglitazone in the following years led to its withdrawal from the market in 2000.

之後做了大量努力以闡明 troglitazone 肝毒性的原因. 學者提出一些假說, 包括毒性代謝物的產生與蓄積, 粒線體功能不良, 氧化壓力, 膽鹽運輸被抑制, 膽鹽毒性. 以及細胞凋零.
Since then, a considerable effort has been made to elucidate the mechanism of troglitazone-induced hepatotoxicity. A number of hypotheses were brought forward to explain troglitazone-induced cell injury, including the formation and accumulation of toxic metabolites, mitochondrial dysfunction and oxidant stress, inhibition of the bile salt transporter and bile acid toxicity, and the induction of apoptosis.17

troglitazone下架後, 只剩兩種 TZD. 幸運的是這兩種藥物的肝毒性安全劑量很高, 肝毒性案例非常罕見, 通常是輕微且可逆, 非常少數報告認為 TZD 與肝細胞損傷及肉芽腫性肝炎有關聯,
Pioglitazone and Rosiglitazone: After the withdrawal of troglitazone due to hepatotoxicity, only pioglitazone (Actos) and rosiglitazone (Avandia) can be used for the treatment of patients with type 2 diabetes. Fortunately, these two newer drugs in the TZD class have a much larger margin of safety for liver toxicity. Very rare reports of liver toxicity, usually milder and reversible, have been seen with these drugs. Very few case reports have implicated it as a cause of hepatocellular injury and granulomatous hepatitis.

曾有報告說, Rosiglitazone 8mg/d 造成膽汁鬱積的肝炎, 這表示對於使用 troglitazone 造成肝損傷的病患, 使用 rosiglitazone 不總是安全,
Severe cholestatic hepatitis caused by rosiglitazone (8 mg/day) was reported in a 56-year-old female patient who had a history of receiving troglitazone treatment; it is indicated that rosiglitazone is not always a safe alternative in patients who had liver injury due to troglitazone.23 Pioglitazone-induced hepatocellular-cholestatic liver injury in a 49-year-old patient with diabetes who was on this drug for six months. Liver enzyme values returned to normal six weeks after the patient discontinued pioglitazone therapy.
結論, TZD雖然要考慮其肝毒性警示, 但對於肝臟還算是相當安全的藥物. 有一些研究指出, TZD可以減少一些非酒精性脂肪性肝炎的肝臟脂肪, 可能對於此類病患的不良代謝後果起到保護的作用, 也許最後能避免脂肪肝病患進展成肝硬化.
In conclusion, while pharmacovigilance for hepatotoxicity is probably still warranted, the practitioner and patient can be fairly confident that these drugs are safe from a liver standpoint. Finally, recent work would suggest that these agents may prove useful to reduce hepatic fat in patients with nonalcoholic steatohepatitis and may possibly protect against adverse metabolic consequences and the ultimate development of cirrhosis in patients with fatty livers.

Pioglitazone and rosiglitazone 可作為糖尿病單一治療藥物, 也可以與 metformin 結合使用,
TZD + insulin 可減少每天需要的胰島素劑量, 需要根據每天的治療結果調整胰島素劑量以免發生低血糖, 根據一項前瞻性開放標籤非隨機研究, 評估 TZD + insulin 對於治療血糖控制不良病患的安全性與效益, 結論是兩者結合安全有效
Pioglitazone and rosiglitazone are used either as monotherapy or in combination with metformin, sulfonylureas, or glinides. The combination of TZDs with insulin is also appealing, as it allows improvement of glycemic control while decreasing the daily insulin requirement. Insulin dosage has to be adjusted regularly to avoid hypoglycemic episodes. Recently, a prospective, open-labeled, nonrandomized study was conducted to assess safety and efficacy of rosiglitazone and insulin treatment in combination with poorly controlled insulin-treated patients with type 2 diabetes.25 It was concluded that the rosiglitazone plus insulin combination is safe and effective in this population. However, further studies are warranted.

使用兩種以上藥物組合控制血糖

先看A1C 是否超過 8.5, 如果小於 8.5., 使用 metformin 治療, 但如果有高血糖症狀則建議打胰島素
A1C 如果在 8.5% 以上, 建議使用 Metformin 加上其他藥物 Metformin 可以與所有其他藥物組合

SGLT2i 可減重, 美國臨床內分泌學會推薦的Metformin 組合

SU和 Glinide 不建議並用
DPP4i 與 GLP1RA 不建議並用
Combination therapy of oral hypoglycemic agents in patients with type 2 diabetes mellitus

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5668409/

這篇是韓國內科醫學雜誌的文章. 

美國糖尿病學會沒有特定推薦哪一種藥物搭配metformin作為第二種組合藥物

美國臨床內分泌學會則推薦, 先選 SGLT2i, 因為有減重效果. 

There are six major classes of antidiabetic agents that can be combined with metformin. They are sulfonylurea (SU), thiazolidinediones (TZDs), dipeptidyl peptidase-4 inhibitors (DPP4i), sodium-glucose cotransporter-2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists, and insulin. The American Diabetes Association does not prioritize any specific medication and recommends physicians to choose one based on their efficacy, hypoglycemic risk, weight effects, side-effects, and cost [4]. However, the American Association of Clinical Endocrinologists recommended the SGLT2i first, followed by DPP4i, TZD, α-glucosidase inhibitors, and SU among the OHAs, mainly based on the weight-reducing effect [5]. In this paper, we provide a comparative review among the OHAs based on meta-analyses and suggest a guide to select one as a first-combination medication with metformin.