Treatment of diabetes mellitus of patients with chronic liver

disease

Ayman Alsebaey, MD. Lecturer of Hepatology,

National Liver Institute.

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The treatment of diabetes mellitus of patients with

chronic liver disease

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This lecture is based on

Garcia-Compean D, Gonzalez-Gonzalez JA, Lavalle-Gonzalez FJ, Gonzalez-Moreno EI, Maldonado-Garza HJ, Villarreal-Perez JZ. The treatment of diabetes mellitus of patients with chronic liver disease. Annals of hepatology 2015; 14: 780-8

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30% of cirrhotic patients have DM.

80% with normal fasting blood glucose

have impaired glucose tolerance (IGT).

DM liver disease [bi-directional].

Hepatogenous diabetes (HD):

Is cirrhosis complicated with DM.

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DM AND CIRRHOSIS

DM increases the risk of: Fibrosis

Decreased response to antivirals e.g. PegINF/RBV

Hepatic encephalopathy

Portal hypertension

Variceal bleeding

Ascites, SBP, HRS.

Hepatocellular carcinoma [HCC]

Mortality

Low survival.

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Treatment of DM in patients with chronic liver disease

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Control of hyperglycemia

Is the aim of the treatment.

Obstacles: Pharmacodynamic studies of antidiabetic drugs have been

conducted irregularly in these patients.

Only few studies have evaluated the rate of control of hyperglycemia

The effectiveness of specific drugs

the impact of treatment on morbidity and mortality

the safety of antidiabetic drugs.

Difficult to achieve: 30% achieve it.

hepatotoxicity, hypoglycemia and lactic acidosis as the drugs are metabolized in the liver.

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Lifestyle and exercise

Not studies well in decompensated patients.

Active exercise is difficult in active liver disease.

Restrictive diet may exaggerate the malnutrition.

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Inhibitors of alpha-glucosidase

α-glucosidases degradate disaccharides in the intestine.

Acarbose decreases absorption of carbohydrates and postprandial hyperglycemia.

Low liver toxicity.

It is associated with significant reduction of

fasting and postprandial hyperglycemia

HbA1c and C-peptide in diabetic patients with compensated cirrhosis.

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Biguanides

Metformin improves insulin sensitivity and lipid metabolism.

Excreted unchanged by the kidney as not metabolized by the liver.

Perils and promise:

As causing lactic acidosis so should not used in decompensated patients.

This is nonsense as being anecdotal and only in alcoholic patients.

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NASH:

metformin is not useful as causes only biochemical

improvement.

HCC:

Reduced risk of HCC in HCV diabetic patients.

PegINF/RBV:

Metformin may improve the response and SVR.

No risk of lactic acidosis:

But caution in decompensated patients with borderline

renal functions.

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Insulin Sensitizers [thiazolidinediones]

TZDs improve the insulin sensitivity.

Conditions of use:

ATs <3ULN. ** Avoid in CTP C patients.

Troglitazone

is associated with hepatotoxicity so halted.

Pioglitazone:

is metabolized by the CYP2C8l and CYP3A4 system.

Associated with increased body weight.

Improved response to PegINF/RBV therapy.

Conflicting results in NASH [no histological effect].

Rosiglitazone:

Slow elimination so be careful when used in cirrhotic patients.

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Insulin Secretagogues

Sulfonylureas

Meglitinides

Incretin-based therapies

SGLT2 inhibitors

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Sulfonylureas

They increase insulin secretion.

They may cause marked hypoglycemia in kidney and cirrhosis patients.

Tolbutamide:

Do not use as its t1/2 increases by 50% in cirrhosis.

Glibenclamide [Daonil], Gliclazide [Diamicron], Glimepiride [Amaryl].

Metabolized by the liver and eliminated through bile and kidney.

Should be avoided in advanced cases as hepatotoxic

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Meglitinides

Repaglinide [Diarol].

Increase insulin secretion.

Metabolized by the liver and eliminated in bile.

Advanced liver disease metabolismtoxicity.

Nateglinide [Starlidine].

Is more safe as is not altered in patients with CLD

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Incretin-based therapies

Safe in liver patients:

Barely metabolized in the liver and are excreted unchanged by the kidney

Injectable glucagon-like peptide-1 (GLP-1) receptor agonists.

Exenatide and liraglutide

They stimulate insulin secretion

Inhibit the release of glucago.

Reduce postprandial plasma glucose levels.

Reduce gastric emptying time and body weight.

Oral inhibitors of dipeptidylpeptidase-4 (DPP-4)(gliptins).

Sitagliptin [Januvia], vildagliptin [Janumet] and linagliptin [Tradjenta]

Increase of incretin and GLP-1 secretion

No hypoglycemia or increasing the body weight

Highly safe in advanced liver disease. 16

Liraglutide [Victoza]

Mild elevation of the liver enzymes.

Long-acting GLP-1 receptor agonists:

Once weekly

Exenatide long-acting release (LAR), albiglutide, dulaglutide and semaglutide.

Safe in patients without cirrhosis.

Not studies in advanced cases

Linagliptin [Tradjenta]:

Excreted in bile (enterohepatic)

Safe in advanced cases.

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SGLT2 inhibitors

Inhibition of glucose reuptake in the kidney

glucosuria and osmotic diuresis

Dapagliflozin, Canaglifozin And Empaglifozin.

Take care in patients with risks of hypovolemia

Older age, cardiovascular diseases

Treatment with diuretics, liver cirrhosis with circulatory dysfunction.

Contraindicated in renal dysfunction.

Side effects:

Renal failure, arterial hypotension

Urinary tract candidiasis

Body weight reduction and hyperkalemia 18

Dapagliflozin [Forxiga]:

Metabolized by the liver [glucuronidation]

Cirrhosis toxicity.

Canagliflozin [Invokana] And Empagliflozin

[Jardiance]

Hepatotoxicity is low in patients with mild and moderate

liver function impairment.

Avoid in CTP C as no studies.

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Insulin

60% of diabetic patients with liver cirrhosis require insulin administration

Insulin requirements: high in patients with compensated cirrhosis.

low in decompensated patients due to a reduction in hepatic clearance and gluconeogenesis close monitoring is needed.

Short-acting insulin analogues insulin lispro, aspart and glulisine are safe.

Insulin degludec: Long acting.

Not affected by cirrhosis.

Can be used without fear of hypoglycemia.

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Liver transplantation

Liver transplantation

It quickly normalizes glucose tolerance and insulin

sensitivity in hepatogenous diabetes:

67% of cases are cured.

33% of cases, diabetes is not cured in cirrhotic patients

due to the persistence of a reduction in the functioning

of beta cells of the pancreas

De nove DM post transplant

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Thanks

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