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Antidiabetic drugs in Patient with Liver Impairments

The choice of antidiabetic drugs (OADs) for patients with Liver Impairments requires special attention by clinicians because many OADs are contraindicated or have adverse effects on the condition.

Antidiabetic drugs in Patient with Liver Impairments
Source Picture: https://www.diabetes.co.uk/diabetes-medication/biguanides.html

This article reviews antidiabetic drug choices in patients with type 2 diabetes mellitus who experience liver impairment, such as liver cirrhosis, fatty liver, non-alcoholic fatty liver, hepatitis B, and hepatitis C.

The liver is an organ that metabolizes most antidiabetic drugs. When liver impairment occurs, especially in chronic liver diseases, the metabolism of antidiabetic medicines is significantly affected. Serious comorbidities often occur in severe liver disorders, such as hypoalbuminemia and acute kidney failure. These comorbidities increase the free fraction of antidiabetic drugs in blood plasma due to decreased metabolism in the liver and excretion in the kidneys, thereby increasing the risk of toxicity or the duration of the drug's effects.

Impaired liver measurement is based on the Child-Pugh score classification, which includes:
  • assessment of total bilirubin levels,
  • serum albumin concentration,
  • prothrombin or international normalized ratio (INR) value,
  • the presence or absence of ascites,
  • and hepatic encephalopathy.


The degree of impaired liver function is adjusted as a category of class A / mild (score 5-6 points), class B / moderate (7-9 points), and class C / severe (score> 10).

A. Metformin
Metformin is a biguanide class of drugs. Metformin can cause lactic acidosis in patients with impaired liver, kidney, and heart function.

The incidence of lactic acidosis is 0.03-0.5 cases per 1000 patients treated with metformin per year. Nonetheless, there are some limited studies that state that metformin is associated with a decreased incidence of liver cancer and liver-related death/transplantation in type 2 DM patients with liver cirrhosis caused by hepatitis C virus.

The American Diabetes Association (ADA) guidelines recommend avoiding metformin therapy in all patients with severe liver disorders (Child-Pugh C).

B. Sulfonylureas
The liver is the main site for sulfonylureas biotransformation. Sulfonylureas, such as glibenclamide and glimepiride, are metabolized to active and inactive metabolites in the liver through liver oxidative enzymes (CYP P450s), then bind extensively to serum proteins and subsequently excreted through the kidneys.

Patients with chronic liver disease are prone to hypoalbuminemia, so they are also prone to increased drug levels in plasma. Thus increasing the risk of hypoglycemia.

ADA and European Association for the Study of Diabetes (EASD) guidelines suggest that sulfonylureas should be avoided in patients with severe liver dysfunction because they increase the risk of hypoglycemia. Some sulfonylureas such as glimepiride and gliclazide are still allowed in patients with mild and moderate liver function with dose adjustments.

C. Meglitinide (Glinid)
Glinides (nateglinide and repaglinide) have shorter half-lives than sulfonylureas, and they are not significantly excreted in the kidneys. Repaglinide clearance is mainly affected by liver function, whereas nateglinide pharmacokinetics is not. Therefore, repaglinide is contraindicated in impaired liver function, whereas nateglinide is not.

A single-dose, open-label parallel-group study conducted by Choudhury S et al. gave 120 mg of nateglinide in cirrhosis patients compared with healthy patients. It showed no statistical difference in pharmacokinetic parameters for either the hepatic cirrhosis group of patients or healthy patients.

There is no need to adjust the dose of nateglinide in patients with mild and moderate hepatic impairment. There are no clinical data available for patients with severe liver function, so nateglinide is not recommended for patients with severe liver diseases.

D. Alpha-glucosidase Inhibitors (Acarbose)
Acarbose has pharmacokinetic characteristics. The character is minimal absorption in the digestive tract and liver metabolism. This character makes acarbose a safe choice for patients with chronic liver disease.

The effects of acarbose on hepatic encephalopathy were studied in 107 patients DM with hepatic cirrhosis. Acarbose therapy was related to a decrease in blood ammonia levels. Also, there were no changes in the biochemical parameters of liver function at the end of the study period.

The ADA guidelines state that acarbose is safe, beneficial, and well-tolerated in patients with impaired liver function, including chronic liver disease.

E. Pioglitazone
Pioglitazone is the only thiazolidinedione class of drugs after rosiglitazone is withdrawn. Pioglitazone is extensively metabolized by CYP2C8 and is excreted as a metabolite and its conjugate in bile and feces.

The safety aspect of pioglitazone has been evaluated in some studies in patients with type 2 diabetes mellitus. Tolman et al. conducted a study by comparing the effectiveness of pioglitazone and glibenclamide against type 2 DM patients for 3 years.

This study found that the hepatocellular injury incidence was 0 cases in the pioglitazone group and 4 cases (0.38%) in the glibenclamide group. There was no liver dysfunction or liver failure in the pioglitazone group.

However, case series studies conducted by Floyd et al. found that the case fatality rate of liver failure was 81% on the use of rosiglitazone or pioglitazone, and only 14% experienced spontaneous improvement.

According to ADA guidelines, should avoid pioglitazone for patients with liver cirrhosis or an increase in serum alanine transferase (ALT)> 2.5 times the upper limit of normal. Pioglitazone can still be used in patients with mild liver dysfunction but is contraindicated in moderate and severe impaired liver function.

F. Dipeptidyl peptidase-4 (DPP-4) inhibitors
DPP-4 inhibitors (sitagliptin, vildagliptin, saxagliptin, alogliptin, linagliptin) are included in incretin-based glucose-lowering agents. Sitagliptin is mainly excreted by the kidneys, and only a small percentage of drugs undergo metabolism in the liver. Vildagliptin is metabolized by hydrolysis, and inactive metabolites are excreted through the kidneys. Saxagliptin is metabolized by CYP3A4 and CYP315 and eliminated through the kidneys and liver.
Alogliptin is metabolized into M-I (N-demethylated active metabolite) via CYP2D6, and M-II (inactive metabolites) and excreted mostly in the kidneys. In contrast to other inhibitors, about 80% of linagliptin is eliminated via the enterohepatic pathway.

The safety of DPP-4 inhibitors in patients with type 2 DM has been reported in some studies.

A meta-analysis of 67 randomized controlled studies (4 alogliptin, 8 linagliptin, 8 saxagliptin, 20 sitagliptin, and 27 vildagliptin) found that adverse events using DPP-4 inhibitors were comparable to placebo. However, there were case reports that report a gradual increase in serum aminotransferase levels in the use of saxagliptin in type 2 DM patients who have no previous history of liver disease.

The findings of this case report contradict the results found in the SAVOR-TIMI 53 trial. Savor-TIMI 53 trial found no liver toxicity in the use of saxagliptin. Pooled analysis of 38 studies conducted by Schweizer et al. reported that long-term use of vildagliptin (> 2 years) did not cause a significant increase in liver enzymes.

The same thing was reported by Schrenthaner et al. in a pooled analysis of 8 randomized controlled trials that found that the use of linagliptin was well tolerated even without significant adverse events in type 2 DM patients with mild and moderate liver disorders. Other results sourced from the EXAMINE study found that no hepatotoxicity was found in the use of alogliptin.

Summary of products from sitagliptin, saxagliptin, linagliptin do not recommend dosage adjustments in patients with chronic liver disease. Vildagliptin is not recommended for patients with elevated alanine or aspartate aminotransferase> 3 times the upper limit of normal.

Based on available data, DPP-4 inhibitors can still be used in patients with mild liver disorders and be used cautiously in disorders of moderate liver function. Whereas in patients with severely impaired liver function, the use of DPP-4 inhibitors is not recommended.

G. Glucagon-like Peptide-1 (GLP-1RA) Receptor Agonist
Exenatide, liraglutide, lixisenatide, and dulaglutide are included in the GLP-1RA group or incretin-based glucose lowering-agents for the management of DMT2. Excretion through the kidneys is the main route of elimination for exenatide. Liraglutide and dulaglutide are metabolized into amino acid components through the catabolic protein pathway.

Clinical data examining the safety of GLP-1RA in patients with chronic liver disease are still limited. However, no severe hepatotoxic effects have been reported so far because most are excreted through the kidneys.

Because clinical data are still limited, GLP-1RA can even be given to patients with mild liver disorders and avoided in patients with moderate and severe liver disorders.

H. Sodium-glucose-co-transporter-2 (SGLT2) inhibitor
Canagliflozin, dapagliflozin, and empagliflozin are drugs that belong to the Sodium-Glucose Cotransporter 2 (SGLT2) inhibitor class. The SGLT2 inhibitors undergo hepatic metabolism by glucuronidation, and only a small portion is eliminated via the kidney route.

Existing clinical data do not find a significant effect between the pharmacokinetics of empagliflozin as well as canagliflozin and liver disorders. However, the results of studies show different things to dapagliflozin. Clinical data examining the impact of using SGLT2 inhibitors in patients with type 2 diabetes with severe liver function disorders are not yet available.

Therefore, it is recommended that SGLT2 inhibitors can still be used in patients with mild liver disorders, used cautiously in moderate liver disorders, and not recommended in severe liver disorders.

I. Insulin
Most of the insulin produced by the pancreas is metabolized in the liver. Hyperinsulinemia is often found in T2DM patients with liver cirrhosis due to reduced hepatic clearance. Insulin is the safest therapy for patients with liver disorders, including chronic liver disease.

However, the ADA guidelines underline the need to adjust insulin doses and monitor blood sugar levels closely in patients with chronic liver disease because of the increased risk of hypoglycemia due to worsening liver function.

Conclusion
Management of type 2 diabetes in patients with impaired liver function, especially chronic liver disease, remains a challenge for clinicians. Antidiabetic drugs such as acarbose, nateglinide, glimepiride, gliclazide, pioglitazone, DPP-4 inhibitors, GLP-1RA, and SGLT2 inhibitors may still be used in patients DM with mild liver dysfunction (Child-Pugh Class A) even though some of them require dose adjustment. 

Insulin therapy is the safest choice for all patients with impaired liver function (Child-Pugh classes A, B, and C). However, it is still advisable to adjust the dose because of the risk of hypoglycemia. 

Avoid sulfonylureas, thiazolidinedione groups, and GLP-1RA groups, for patient DM with severe liver function disorders.


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