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Diabetes management in liver and kidney disease

Epidemiology

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Clinical case

A 59 year old man with alcoholic cirrhosis; portal hypertension; mild encephalopathy

Fasting plasma glucose - 103, March 2016; 101, July 2017

HbA1c 5.4 % Feb 2017

Random plasma glucose - 212, March 2017; 220, September 2016

Questions

Does he have diabetes?

Should he take metformin?

Category FPG 2hPG HbA1c

Normal <100 <140 <5.7

IFG 100-125 --- ---

IGT --- 140-199 ---

High risk ---- ---- 5.7 – 6.5

DM >126 >200 ≥6.5 %

A diagnosis of diabetes needs to be confirmed on a separate day

WHO cutoff for normal fasting plasma glucose is 110 mg/dl (6.1 mmol/l);

& lower cutoff of 6% for HbA1c

No need to test if hyperglycemic crisis or symptoms of hyperglycemia

and glucose > 200 mg/dL

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HbA1c levels may be lower in cirrhosis because of increased red cell turnover due to hypersplenism

HbA1c levels may lower in ESRD due to anemia & Erythropoietin therapy

Kanda et al J Jpn Diabetes Soc 1993:36:847

56 patients with cirrhosis were screened for diabetes with75g OGTT; WHO criteria

22 (39%) – normal (FPG < 110; 2hr glucose < 140)

13 (23 %) – impaired glucose tolerance (140-199) ; impairedfasting glucose (110-125)

13 (23 %) – FPG < 110; but 2hr glucose > 200

8 (14 %) - FPG > 126 and 2hr glucose > 200

Nishida et al Am J Gastroenterol 2006: 101:70

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Cirrhosis

DM 35%

IGT 28 %

Normalglucose tolerance

37 %

Nishida J Endo Soc 2017; 1: 886

Hep C RNA +ve

Hep CAbs +ve

Hep B No viralinfection

18% 15% 11.4% 12.5%

9932 subjects; FPG > 126 (Taiwan)

Huang et al Am J Gastroenterol 2007; 102 :1237

Prevalence of diabetes

Nonalcoholic fatty liver disease (NAFLD)

• Hepatic steatosis

• Non alcoholic steatohepatitis (NASH) - hepatic steatosis with hepatocyte injury (ballooning) & inflammation

• NASH cirrhosis - cirrhosis due to steatohepatitis

Chalasani et al Hepatology 2012 55:2005 (Guideline)

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Whole cohort(n=328)

DiabeticN= 54

Non diabetic

NAFLD 156 (46%)

40(74%)

---

NASH 40(12.2%)

12(22%)

30(10.9%)

NASH with stage 2-4 fibrosis

9(2.7 %)

-- ---

Prevalence NAFLD; NASH (ultrasound & liver biopsy study in middle aged population without known liver disease)

Williams et al Gastroenterol 140: 124 (2011)

Male Female

2007 (n=1719

2013(n=602

P value 2007(n=1917

2013(n=757

P value

ObesityBMI > 28

15.82 19.41 <0.01 13.18 18.77 <0.01

Diab 6.37 9.23 <0.01 4.41 8.48 <0.01

HTN 38.1 38.6 >0.05 33.04 33.01 <0.05

Dyslipid 53.46 65.5 <0.01 41.96 54.7 <0.01

NAFLD (by US)

23.48 44.31 <0.01 17.56 43.06 <0.01

Age standardized prevalence of obesity, DM, NAFLD in a Chinese population

Wu et al Scientific Reports 2017; 7: 41518

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Summary - liver disease and diabetes(hepatogenous diabetes)

• Up to 35 % of patients with cirrhosis have diabetes

• Up to 18 % of patients with hepatitis C infection have diabetes

• Obesity increases the risk of diabetes and NAFLD.

• Extrapolation of NHANES data suggests that ~ 400,000 people in US have NASH cirrhosis and ~ 4 million have NAFLD associated advanced fibrosis 1

1 Kabbany et al Am J Gastroenterol 2017; 112: 581

2007 - 2012 NHANES data; single sample marker CKD

13.6 % of pop (~ 30 million) CKD; 3.9 % of pop CKD + DM (~ 8 million)

https://www.niddk.nih.gov/health-information/health-statistics/kidney-disease

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US 2015 data

~ 468,000 have ESRD and ~ 250,000 have diabetes

~ 193,000 have functioning kidney transplant andabout 24 % of this population have diabetes

Pathophysiology

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AUC 0-180 min

76 + 15 vs 22 + 4 pmol/L

Peripheral hyperinsulinemiain cirrhosis

Letiexhe et al J. Clin End Metab 1993; 77:1263

0

1

2

3

4

5

6

7

M valuemg/[kg.min]

Liver Tx normalizes insulin resistance

Perseghin et al. Hepatology 2000; 32:694

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Hepatitis C infection increases peripheral insulin resistance(minimal fibrosis - score <F2; BMI 25.7 + 3.3; Caucasian men)

Milner et al Gastroenterology 2010; 138:932

Successful Rx of Hepatitis C can improve glucose control in T2D

Pre hep C RxHbA1c

Posthep C RxHbA1c

Change in HbA1c *

% usinginsulin Before treatment

% using Insulin after treatment

Change in% on insulin **

Patientnot cured (n=255)

7.27 7.08 -0.19 49.8% 51.0% + 1.2

Patientcured(n=2180)

7.20 6.82 -0.37 41.3 % 38% - 3.3

* Mean difference HbA1c drop cured vs not cured – 0.18; p=0.03** Mean difference in % on insulin cured vs not cure -4.5 %; p= 0.04

Hum et al. Diabetes Care 2017 40: 1173

Examined 1 year after Rx

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Summary

• Insulin resistance occurs in cirrhosis and in hepatitis C patients without cirrhosis

• In cirrhotic patients, liver transplant will improve resistance &those with sufficient beta cell reserve will be cured of their diabetes

• Treating hepatitis C successfully may improve glucose control

Treating hyperglycemia in liver and kidney disease

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Grade A – 5 to 6

Grade B – 7 to 9

Grade C -10 to 15

Pugh et al Brit J Surg 1973;60:646

http://kdigo.org/wp-

content/uploads/2017/02/KDIGO_2

012_CKD_GL.pdf

Hepatorenal syndrome

Functional renal failure due to effective hypovolemia & intrarenal vasoconstriction

263 cirrhotic patients with moderate or tense ascites followedfor 40.9 + 2.6 months

5 year probability of hepatorenal syndrome was 11.4 %

1 year survival of type 21 hepatorenal syndrome was 38.5 %

1type 2 – steady or slowly progressive renal failure

Planas et al Clin Gastroenterol Hepat 2006;4:1385

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Hypoglycemia in liver disease

Cirrhosis – 156 patients : 6 patients had glucose levels <60; 2 patients < 50

Zimmerman et al Arch Int Med 1953; 91:577

ADA/EASD algorithm 2015

6 classes of drugs:

MetforminGLP1 receptor agonists/DPP 4 inhibitorsSulfonylureas (+other secretagogues)PioglitazoneSGLT2 inhibitorsInsulin

Metformin Metformin + another

Metformin + 2 others

More complexinsulin regimens

In making therapeutic decision take into account efficacy; hypoglycemia risk; effect on weight; major side effects; cost

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Contraindications can damage your health—is metformin a case in point?

• Pooled data- 206 comparative trials – no cases of fatal or nonfatal lactic acidosis in 47,846 patient years of metformin use, or in 38,221 patient years of non-metformin use

• Old age is not an absolute contraindication

• May be safe at estimated GFR as low as 40ml/min

• Stable heart failure (NYHA 1 & II) not a contraindication

• Metformin is cleared by the kidney and half life is less than 5 hours

Cochrane review: Diabetologia 2005; 48:2454

2016 FDA recommendations

eGFR > 60 ml/min/1.73 m2 – no metformin dose adjustment

45 to 60 - more frequent monitoring

30 to 45 – not recommended but can continue if taking. Consider50% dose reduction with renal monitoring every 3 months

<30 – do not use

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Metformin use improves survival in cirrhosis

Retrospective study 250 patients -172 continued metformin and 78 discontinuedafter diagnosis of cirrhosis

Median survival 11.8 vs 5.6 yrs

Subgroup analysis – benefit withNASH induced cirrhosis

No cases of lactic acidosis

Zhang et al Hepatology 2014;60:2008

Metformin use in T2D patients with HCV cirrhosis reduces risk of hepatocellular carcinoma and liver-related death and transplant

5yr incidenceHCC

5.9 % vs 17.4%

No Met - treated with diet, secretagogues; insulin

Nkontchou et al JCEM 2011; 96:2601

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Metabolism Duration of action

Durationof action in CKD

Recommendation

Glyburide 1 Liver; active metabolites; excreted bile & urine

Up to 24 hrs

Increased Avoid if GFR <60Avoid in liver failure

Glipizide(Glucotrol)

Liver 90%10 % excreted in urine

6-12 hrs Unaffected Can be used in CKDAvoid in liver failure

Glimepiride 2

(Amaryl)Liver but active metabolites

Up to 24 hrs

Increased Reduce dose (1mg) in renal failureAvoid in liver failure

Repaglinide 3,4

(Prandin)Liver;metabolites excreted in bile

3 hrs Unaffected Can be used in CKDUse cautiously in liver disease

Nateglinide 5,6

(Starlix)Liver; metabolites excreted in urine

2 hrs Unaffected Can be used in CKD & liverdisease

1.Jonsson et al. Eur J Clin pharmacol 1998 53: 429. 2 Rosenkranz et al Diabetologia 1996 39: 1617

3. Marbury et al. Clin pharmacol ther 2000 67:7. 4. Hatorp et al J Clin Pharmcol 2000;40:142

5. Devineni et al J Clin Pharmacol 2003; 43:163 6. Gangopadyay et a. Ind J End Metab 2017; 21:341

• Reduces microalbuminuria and hyperfiltration

• Beneficial effect on NAFLD; NASH

• Metabolized by liver; safe in CKD

Pioglitazone (Actos)

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Placebo Vitamin E Pioglitazone

Improvement in NASH

19 % 43 %(p=0.001)

34 %(p=0.04)

Total NAFLD activity score

-0.5 -1.9(p<0.001)

-1.9(p<0.001)

P values < 0.025 considered statistically significant

Sanyal et al N Engl J Med 2010 362: 1675

Pioglitazone or Vitamin E for NASH

Adverse effects of pioglitazone

• Weight gain

• Heart failure

• Fracture risk

• Macular edema

• Bladder cancer

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GLP-1 receptor agonists

Metabolism Recommendation

Exenatide (Byetta)

Renal excretion Reduce dose to 5 mcg BID stage 3 CKD. Do not use for GFR < 30

Liraglutide(Victoza)

Proteolysis No dose change

Albiglutide (Tanzeum)

Proteolysis No dose change

Dulaglutide(Trulicity)

Proteolysis No dose change

Lixisenatide (Adlyxin)

Renal excretion No dose change for eGFR >30

Liraglutide reduce progression from microalbuminuriato macroalbuminuria

Mann et al N Engl J Med 2017;377:839 (Leader trial)

161 vs 215

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Liraglutide1.8 mg(n=26)

Placebo(n=26)

P value

Resolutionof NASH (biopsy)

9/23(39 %)

2/22 (9%) 0.019

Progressionof fibrosis

2/23(9%)

8/22(36 %)

0.04

30% had diabetes; liraglutide improved glucose levels & promoted weight loss

Effect of liraglutide on NASH after 48 week Rx

James Armstrong et al Lancet 2016;387:679

FDA report of acute kidney injury with exenatide and liraglutide

- thought to be due to vomiting, diarrhea & dehydration

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DPP 4 inhibitors

Metabolism Recommendation

Sitagliptin (Januvia)

80% renal clearance 100 mg usual dose. 50 mg for GFR 30-50; 25 mg for < 30

Saxagliptin (Onglyza)

CYP3A4/5 metabolism; active metabolite; 24 % renal excretion

5 mg daily usual dose. 2.5 mg if GFR< 50 or if taking strong CYP/3A4 inhibitors

Linagliptin(Tradjenta)

80 % eliminated via bile and gut; 5 % renal clearance

No dose change in renal disease or liver disease

Alogliptin (Nesina)

> 70% renal clearance 25 mg daily usual dose. 12.5 mg for GFR 30-60; 6.25 mg for < 30

Sitagliptin did not alter CKD outcomes (TECOS)

Saxagliptin improved albumin creatinine ratio but not eGFR (SAVOR –TIMI)

Cornel et al. Diab. Care Oct 2016Mosenzon et al Diab Care Oct 2016

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SGLT2 inhibitors

Metabolism Recommendation

Canagliflozin (Invokana)

Liver; 33 % renal clearance

Lower efficacy CKD 3Do not use if GFR < 45

Dapagliflozin(Farxiga)

Liver & kidney metabolism

10 mg daily usual dose. Use 5 mg if liver disease. Do not use GFR <60

Empagliflozin(Jardiance)

Liver and kidney

Do not use if GFR < 45

Empagliflozin reduces albuminuria

Cherney et al Lancet Diab Endocrinol 2017 5:610

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Explanation of benefit of empagliflozin

• Improved glucose• Improved BP• Reduced weight• Improved intrarenal hemodynamics – supported by

observation that benefit lost when drug stopped.• Animal data that drug may reduce glomerulosclerosis and

tubulointersitial fibrosis.

Drug Kidney disease

Liver disease

Metformin Safe to use eGFR greater than30 ml/min/1.73 m2

Beneficial in NASH related

cirrhosis; hepatitis C cirrhosis;

may reduce risk for hepatocellular

CA. No evidence that there is an

increased risk of lactic acidosis.

Stop in decompensated liver

failure

Pioglitazone Safe Beneficial NAFLD; NASH; OK in class A cirrhosis; not recommended LFTs >3 times ULN

Oral secretagogues

Use glipizide, repaglinide, nateglinide. Lower dose glimepiride.

NateglinideRepaglinide (cautiously)

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Drug Kidney disease Liver disease

GLP1 receptoragonists

Liraglutide; albiglutide;dulaglutide. Cautiously –acute kidney injury in setting of vomiting & dehydration

Beneficial NAFLD;NASHOK in class A cirrhosis

DPP4 inhibitors Linagliptin no dose adjustment; others renaldosing. Safe to use

Safe to use. OK in class A; cautious class B; avoid class C cirrhosis

SGLT2 inhibitors Avoid in CKD 3 to 5 OK in class A;cautious class B; avoid class C cirrhosis

Insulin Safe Safe

Alpha glucosidase inhibitors

Avoid acarbose in CKD 4Miglitol cleared by kidney -do not use

OK in class A, B. Avoid class C

Urine protein<0.16mg/mg creat

Urine albumin<30mg/g creat

Hb12-15.5

Homeglucose levels

mg/dL

HbA1c Fructosamine

190-270 umol/L

59 year woman with renal transplant

10.88 7874 12.3 200s 8.3% 267

52 year woman with alcoholic cirrhosis and DM

-- <5 11.9 Am 157-277Lunch 168-177Dinner 121-282

7 % 364

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Renal failure

Increased red cell turnover and erythropoietin treatment can falsely lower HbA1c by as much as 1.5%

Liver failure

Decreased red cell survival time due to hypersplenism can falsely lower HbA1c by 0.5 to 2.2 % (mean 1.7)

In these cases fructosamine may be a better estimate of glucose control

Inaba et al J Am Soc Nephrol 2007; 18:896Little et al Clin chim Acta 2013; 418:73Kanda et al J Jpn Diabetes Soc 1993:36:847