ueda2016 diabetes&liver - ashraf talaat

Prof. Ashraf Talaat ,MD.Internal Medicine Departement

Endocrinology,Diabetes&Metabolism UnitChief of Nephrology&Renal Dialysis Units

Banha Faculty of MedicineBanha University

Egypt

Diabetes & The Liver from old concepts to new evidence

UEDA,2016 ,Aswan

“ DDA”

Delta Diabetes Association

Pharos civilization in Ancient Egypt … on The Nile River...made the first lesson to the whole world …which is….!!!???

2/17/2016

Agenda

Magnitude of the problem.

Effect of CLD on diabetes.

Effect of diabetes on CLD.

Anti-diabetic agents and the normal liver.

Management of hyperglycemia in CLD:

o In patients with compensated CLD.

o In patients with decompensated CLD.

Agenda

Magnitude of the problem.

Prevalence of diabetes in adults(20-79 years)

387 million people have diabetes in the world and more than 37 million people in the Middle East and North Africa (MENA)Region, by 2035 this will rise to 68 million.

The Middle East and North Africa (MENA)Region,

1 in 10 adults have diabetes; the Region has the highest

prevalence of diabetes.

in Egypt in 2014 , There were over 7.5 million cases of diabetes

International Diabetes Federation. IDF Diabetes Atlas, 6th edition. Brussels.

The rates of diabetes in Egypt has significantlyincreased exceeding international rates, (IDF,2016).

Egypt is now ranked eighth highest in the worldin terms of the disease.

Diabetes and CLD are commonconditions in Egypt.

The 2 conditions often coexist.

DM CLD

Tolman et al. Diabetes Care. 2007 Mar;30:734-43.

Agenda

Magnitude of the problem.

Effect of CLD on diabetes.

Fix the Defect

Diabetes & Liver diseases

Both problems have an important interaction considering etiology & the presence of any

problem of each affect the management of the other.

Liver is the main organ concerned with glucose homeostasis through:

1)Glycogenesis :In the postprandial state (under effect of insulin)

2) Glycogenolysis & Gluconeogenesis :

In the fasting state (mainly under effect of glucagon)

??????????

What is the relationship

between liver diseases &

abnormalities of glucose

homeostasis

???????

Classified into 3 cateogries:

Liver diseases as a consequence of IR/ DM

Abnormalities of glucose metabolism as aconsequence of liver diseases

Diseases causes liver diseases & abnormalities ofglucose metabolism

Facing the Problem..

0 20 40 60

NASH

Chronic active hepatitis

50 %

33 %

30 %Cirrhosis 60 %

Prevalence of diabetes

DM CLD

Tolman et al. Diabetes Care. 2007 Mar;30:734-43.

NAFLDInsulin

Resistance

HCV

Cirrhosis

Hepatogenous

diabetes ?!!

Abnormalities of glucose metabolism as a consequence of liver diseases :

I) Hypoglycemia : Is rare in liver diseases, however it may occur in:

-Acute liver cell failure and terminal cirrhosis-Hepatocellular carcinoma

II) Impaired glucose tolerance & DM: -Hepatogenous DM-Post-Liver Transplantation-HCC

Hepatogenous DM

(Association of cirrhosis with impaired glucose metabolism)

60% of cirrhotic patients have IGT

20% of cirrhotic patients have DM

This is different from T2DM because it occurs in absence of risk factors e.g. age,BMI or family history.

The mechanism underlying hepatogenous DM is:“ insulin resistance”,

may be due to:

1. Hyperinsulinemia

2. Elevated level of FFA.

3. Chronic inflammation (through effect of inflammatory cytokines e.g. IL1,IL6 andTNF-alpha).

Diseases causes liver diseases & abnormalities of glucose metabolism

Metabolic diseases causing hypoglycemia

Glycogen storage (type I, III).

Hereditary fructose intolerance

Tyrosinemia

Diseases causing DM

Hemochromatosis

Chronic hepatitis C

Autoimmune liver diseases

Cystic Fibrosis

Mechanisms of IGT/DM in CHC infection

A) Insulin Resistance .

B) Defective Insulin Secrection:-Direct autoimmune damage of B-cells by the virus.

- InterferonThe incidence of new onset DM in CHC patients who achievedSVR after IFN therapy is lower than the incidence in who failedtherapy.

Adverse impact of IR/T2DM on outcome in CHC

Natural History:The association between IR/T2DM and CHC leads to more progression to liver

cirrhosis.

Response to therapy:IR/T2DM patients are associated with reduced rates of RVR as well as SVR in CHC

treated patients.

Improvement of insulin sensitivity by life style modification and drugs(metformin OR TZD) has improved the responsiveness of standardantiviral therapy in non-diabetic patients especially in genotype 4 .

.

Be Positive…..always..!!!!!!!

Agenda

Magnitude of the problem.

Effect of CLD on diabetes.

Effect of diabetes on CLD.

Anti-diabetic agents and the normal liver.

Management of hyperglycemia in CLD:

o In patients with compensated CLD.

o In patients with decompensated CLD.

Khan et al. Postgrad Med. 2012 Jul;124:130-7.

↑ fibrogenesis & progression

to cirrhosis

↑ risk of liver failure

↑ risk of HCC

↑ premature mortality.↓ response to antiviral ₨

CLD

Agenda

Magnitude of the problem.

Effect of CLD on diabetes.

Effect of diabetes on CLD.

Anti-diabetic agents and the normal liver.

Management of hyperglycemia in CLD:

o In patients with compensated CLD.

o In patients with decompensated CLD.

Kindly think

When start, start right

AgentHepatic

metabolismRisk of

hepatotoxicity

Metformin

2nd generation SUs

Repaglinide

Pioglitazone

Acarbose

NO

YES

NO

NO

YES

YES

LOW

LOW

NO

LOW

AgentHepatic

metabolismRisk of

hepatotoxicity

Sitagliptin

Saxagliptin

Vildagliptin

NO

YES

NO

YES LOW

NO

Insulin:

Insulin is metabolized by insulinase in

the liver and kidney.

About 50% of insulin is removed, by

‘first-pass’ hepatic extraction.

Tolman et al. Diabetes Care. 2007 Mar;30:734-43.

Statins:

May cause elevation in liver enzymes:

o Minor: rarely exceeds 3 times ULN.

o Transient without long-term effects.

o Severe liver damage is very rare.

Tolman et al. Diabetes Care. 2007 Mar;30:734-43.

Agenda

Magnitude of the problem.

Effect of CLD on Diabetes.

Effect of diabetes on CLD.

Anti-diabetic agents and the normal liver.

Management of diabetes in CLD:

o In patients with compensated CLD.

o In patients with decompensated CLD.

Management of DM in Liver diseases It depends on:

1)Severity of liver disease:

Assessed by

Child-Pugh Classification

Model for End-stage Liver Disease (MELD)

2) Activity of liver disease:

Assessed by the liver of transaminases (markers of liver cell injury).

The injury is considered significant if the level of ALT is 2.5 fold than normal.

3)Type and cause of diabetes.

4)Other factors :

e.g. age of patient, severity of diabetes, occupation, socioeconomic state,presence of other diabetic complications

Glycemic target:

Individualized

Moscatiello et al. Nutrition, Metabolism & Cardiovascular Diseases (2007) 17, 63-70

Compensated CLDwith good life expectancy

Decompensated CLD with poor life expectancy

More aggressive target Non-aggressive target

What are the signs of decompensation?

Ascites.

Coagulopathy.

Encephalopathy.

Moscatiello et al. Nutrition, Metabolism & Cardiovascular Diseases (2007) 17, 63-70

Agenda

Magnitude of the problem.

Effect of CLD on diabetes.

Effect of diabetes on CLD.

Anti-diabetic agents and the normal liver.

Management of diabetes in CLD:

o In patients with compensated CLD.

o In patients with decompensated CLD.

In patients with compensated CLD:

Lifestyle modification:

Mediterranean diet:

o High complex CHO.

o High monounsaturated fats.

o Low amounts of red meat.

Weight loss: in patients with NAFLD.

In patients with compensated CLD:

Pharmacologic therapy:

The same as that without CLD … Why?

o Drug metabolism is altered (only

altered in patients with liver failure).

at higher risk for hepatotoxicity.

Tolman et al. Diabetes Care. 2007 Mar;30:734-43.

In patients with compensated CLD:

Metformin:

First-line therapy in most patients.

Stop:

o If liver or renal functions deteriorated.

o In the setting of acute illness.

Tolman et al. Diabetes Care. 2007 Mar;30:734-43.

Can we use metformin incompensated patients with HCV?

Nkontchou et al. J Clin Endocrinol Metab, August 2011, 96(8):2601–2608

?Conclusions: use of metformin was associated

with reduced incidence of HCC & mortality.

In another study adding metformin to

interferon & ribavirin was associated with a

better response to anti-viral therapy.

Can we use metformin incompensated patients with NAFLD?

Yes.

It is safe and may be even beneficial.

Romero-Gómez et al. Hepatology 2009; 50: 1702-1708.

In patients with compensated CLD:

Sulfonylureas:

Safe to use.

The main side effect is hypoglycemia.

SUs with a short half-life such as glipizide

are preferred.

Tolman et al. Diabetes Care. 2007 Mar;30:734-43.

In patients with compensated CLD:

Repaglinide:

Safe to use.

Less hypoglycemia than SUs.

Tolman et al. Diabetes Care. 2007 Mar;30:734-43.

In patients with compensated CLD:

Pioglitazone:

In patients with NAFLD may lead to

improvement in ALT and liver histology.

Do Not use if ALT ≥ 3 times ULN.

Tolman et al. Diabetes Care. 2007 Mar;30:734-43.

In patients with compensated CLD:

DPP-4 inhibitors:

Sitagliptin & saxagliptin can be safely

used without dose adjustment.

Vildagliptin is not approved in patients

with hepatic insufficiency.

Khan et al. Postgrad Med. 2012 Jul;124:130-7.

Sodium-glucose transporter 2 inhibitors (sglt2i)

(GLIFLOZINS)

Sglt2 i

• Sodium-glucose co-transporter 2 (SGLT2)

• inhibitors work by blocking the reabsorption

of filtered glucose in the kidneys.

.This leads to glucosuria and improved

glycemic control.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors

Clinical trials showed an in incidence of liver damage and breast and bladder cancers amongst those taking the drug but not to a high enough degree to indicate a clear increase in risk.

Sodium/glucose co-transporter 2 inhibitors as highly suitable for the inhibition of progression of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic fatty liver disease, diabetic fatty liver .

In patients with compensated CLD:

Insulin:

Higher doses may be needed due to

insulin resistance.

Tolman et al. Diabetes Care. 2007 Mar;30:734-43.

In patients with compensated CLD:

Statins:

Safe in patients with compensated CLD.

Especially helpful in patients with NAFLD.

May be hepato-protective in patients

with HCV.

Tolman et al. Diabetes Care. 2007 Mar;30:734-43.

In patients with compensated CLD:

Aspirin:

Safe to use.

The cardio-protective dose (75-150 mg)

is not Hepatotoxic.

Tolman et al. Diabetes Care. 2007 Mar;30:734-43.

Agenda

Magnitude of the problem.

Effect of CLD on diabetes.

Effect of diabetes on CLD.

Anti-diabetic agents and the normal liver.

Management of hyperglycemia in CLD:

o In patients with compensated CLD.

o In patients with decompensated CLD.

Glycemic target in decompensated CLD:

The objective is just to ↓ the osmotic

symptoms related to diabetes .. Why?

• Prognosis depends on the complications

of the primary hepatic disease, rather

than diabetes complications.

Moscatiello et al. Nutrition, Metabolism & Cardiovascular Diseases (2007) 17, 63-70

In patients with decompensated CLD:

Lifestyle modification:

> 50% of patients are malnourished.

Avoid dietary restriction as it may result in:

o Hypo-albuminemia.

o Coagulopathy due to ↓ vitamin K intake.

o Worsen overall prognosis.

In patients with decompensated CLD:

Tolman et al. Diabetes Care. 2007 Mar;30:734-43.

Metformin

SU & Repaglinide

Pioglitazone

DPP-4 inhibitors

Aspirin & statins

Fear of lactic acidosis

Fear of hypoglycemia

Fear of hepatotoxicity

Limited experience

No prognostic benefit

Insulin

In patients with decompensated CLD:

Insulin:

The safest and most effective therapy.

The main risk is severe hypoglycemia.

Careful glucose monitoring is needed.

Dose may be decreased due to reducedhepatic breakdown of insulin.

Tolman et al. Diabetes Care. 2007 Mar;30:734-43.

In patients with decompensated CLD:

Insulin Regimen

Meal-related insulin administration

00.00 08.00 12.00 18.00 24.00

RegularLisproAspartGlulisine

Why we don’t usually need basal insulin

in patients with decompensated CLD?

Tolman et al. Diabetes Care. 2007 Mar;30:734-43.

Glycemic profile is characterized by

low fasting plasma glucose due to

↓ hepatic glucose production.

In patients with decompensated CLD:

Follow up of glycemic control:

o SMBG is preferred over HbA1c …. WHY?

Cirrhosis (± hypersplenism) reduces

RCSs life-span false low HbA1c.

Summary

Type 2 diabetes is associated with a large number of liver disorders including elevated liver enzymes, fatty liver disease, cirrhosis, hepatocellular carcinoma. In addition, there is an unexplained association with HCV.

The presence of liver disease (unless decompensated) has little implication for the specific treatment of diabetes, and the presence of diabetes has little implication for the specific treatment of liver disease.

Patients with decompensated liver disease are more susceptible to hypoglycemia and require careful monitoring.

There continues to be a need for long-term placebo controlled trials for the treatment of NAFLD and for the treatment of diabetes in patients with liver disease.

CONCLUSIONS

CompensatedCLD

DecompensatedCLD

Glycemictarget

Follow up

Lifestyle modification

More aggressive Non aggressive

Dietary modification

Avoid dietary restriction

HbA1C SMBG

Metformin

SU & Repaglinide

Pioglitazone

DPP-4 inhibitors

Insulin

In patients with compensated CLD

Stop if liver or renal function deteriorated.

Be aware of hypoglycemia

Avoid if ALT level ≥ 3 ULN

Avoid vildagliptin

High dose may be needed

In patients with decompensated CLD

Insulin in the best line of therapy

2/17/2016

,

.DCDC I7th,6-8 April,2016,Ras Elbarr,Domyat

2/17/20

16

Doctor

PHARMACYDISPENSE

patientsFamily

Position Statement of the American Diabetes Association

(ADA) & the European Association for the Study of

Diabetes (EASD)

Hypoglycaemia in type 2 diabetes was long thought to be a trivial issue , as it occurs less commonly than in type 1 diabetes. However, there is emerging concern based mainly on the results of recent clinical trials and some cross-sectional evidence of increased risk of brain dysfunction in those with repeated episodes

93Diabetes Care, Diabetologia. 19 April 2012