Diabetes management in liver and kidney disease Epidemiology 1 - - PDF document

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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 with 75g OGTT; WHO criteria

22 (39%) – normal (FPG < 110; 2hr glucose < 140) 13 (23 %) – impaired glucose tolerance (140-199) ; impaired fasting 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

4/12/2018 4 Cirrhosis DM 35% IGT 28 % Normal glucose tolerance 37 %

Nishida J Endo Soc 2017; 1: 886

Hep C RNA +ve Hep C Abs +ve Hep B No viral infection 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)

4/12/2018 5 Whole cohort (n=328) Diabetic N= 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 Obesity BMI > 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 and about 24 % of this population have diabetes

Pathophysiology

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AUC 0-180 min 76 + 15 vs 22 + 4 pmol/L

Peripheral hyperinsulinemia in cirrhosis

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

1 2 3 4 5 6 7 M value mg/[kg.min]

Liver Tx normalizes insulin resistance

Perseghin et al. Hepatology 2000; 32:694

4/12/2018 9 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 Rx HbA1c Post hep C Rx HbA1c Change in HbA1c * % using insulin Before treatment % using Insulin after treatment Change in % on insulin ** Patient not cured (n=255) 7.27 7.08

• 0.19

49.8% 51.0% + 1.2 Patient cured (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 followed for 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

4/12/2018 12 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: Metformin GLP1 receptor agonists/DPP 4 inhibitors Sulfonylureas (+other secretagogues) Pioglitazone SGLT2 inhibitors Insulin Metformin Metformin + another Metformin + 2 others More complex insulin regimens In making therapeutic decision take into account efficacy; hypoglycemia risk; effect on weight; major side effects; cost

4/12/2018 13 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. Consider 50% dose reduction with renal monitoring every 3 months <30 – do not use

4/12/2018 14 Metformin use improves survival in cirrhosis

Retrospective study 250 patients -172 continued metformin and 78 discontinued after diagnosis of cirrhosis Median survival 11.8 vs 5.6 yrs Subgroup analysis – benefit with NASH 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 incidence HCC 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

• f action

Duration

• f action

in CKD Recommendation

Glyburide 1 Liver; active metabolites; excreted bile & urine Up to 24 hrs Increased Avoid if GFR <60 Avoid in liver failure Glipizide (Glucotrol) Liver 90% 10 % excreted in urine 6-12 hrs Unaffected Can be used in CKD Avoid in liver failure Glimepiride 2 (Amaryl) Liver but active metabolites Up to 24 hrs Increased Reduce dose (1mg) in renal failure Avoid in liver failure Repaglinide 3,4 (Prandin) Liver; metabolites excreted in bile 3 hrs Unaffected Can be used in CKD Use cautiously in liver disease Nateglinide 5,6 (Starlix) Liver; metabolites excreted in urine 2 hrs Unaffected Can be used in CKD & liver disease

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)

4/12/2018 16 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 microalbuminuria to macroalbuminuria

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

161 vs 215

4/12/2018 18 Liraglutide 1.8 mg (n=26) Placebo (n=26) P value Resolution

• f NASH

(biopsy) 9/23 (39 %) 2/22 (9%) 0.019 Progression

• f 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

• r 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 2016 Mosenzon et al Diab Care Oct 2016

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SGLT2 inhibitors

Metabolism Recommendation

Canagliflozin (Invokana) Liver; 33 % renal clearance Lower efficacy CKD 3 Do 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
• bservation 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 than 30 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. Nateglinide Repaglinide (cautiously)

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Drug Kidney disease Liver disease GLP1 receptor agonists Liraglutide; albiglutide;

• dulaglutide. Cautiously –

acute kidney injury in setting

• f vomiting & dehydration

Beneficial NAFLD; NASH OK in class A cirrhosis DPP4 inhibitors Linagliptin no dose adjustment; others renal

• dosing. 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 4 Miglitol cleared by kidney - do not use OK in class A, B. Avoid class C Urine protein <0.16 mg/mg creat Urine albumin <30 mg/g creat Hb 12-15.5 Home glucose 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- 277 Lunch 168-177 Dinner 121-282 7 % 364

4/12/2018 23 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; 18:896 Little et al Clin chim Acta 2013; 418:73 Kanda et al J Jpn Diabetes Soc 1993:36:847