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

4/12/2018 Diabetes management in liver and kidney disease Epidemiology 1

4/12/2018 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 >200 ≥ 6.5 % DM >126 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 2

4/12/2018 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 3

4/12/2018 Prevalence of diabetes Cirrhosis Hep C Hep C Hep B No viral RNA Abs +ve infection DM 35% +ve IGT 28 % Normal 37 % 18% 15% 11.4% 12.5% glucose tolerance 9932 subjects; FPG > 126 (Taiwan) Huang et al Am J Gastroenterol 2007; 102 :1237 Nishida J Endo Soc 2017; 1: 886 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

4/12/2018 Prevalence NAFLD; NASH (ultrasound & liver biopsy study in middle aged population without known liver disease) Whole Diabetic Non diabetic cohort N= 54 (n=328) NAFLD 156 40 --- (46%) (74%) NASH 40 12 30 (12.2%) (22%) (10.9%) NASH with 9 -- --- stage 2-4 (2.7 %) fibrosis Williams et al Gastroenterol 140: 124 (2011) Age standardized prevalence of obesity, DM, NAFLD in a Chinese population Male Female 2007 2013 P value 2007 2013 P value (n=1719 (n=602 (n=1917 (n=757 Obesity 15.82 19.41 <0.01 13.18 18.77 <0.01 BMI > 28 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 23.48 44.31 <0.01 17.56 43.06 <0.01 (by US) Wu et al Scientific Reports 2017; 7: 41518 5

4/12/2018 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 6

4/12/2018 US 2015 d ata ~ 468,000 have ESRD and ~ 250,000 have diabetes ~ 193,000 have functioning kidney transplant and about 24 % of this population have diabetes Pathophysiology 7

4/12/2018 Peripheral hyperinsulinemia in cirrhosis AUC 0-180 min 76 + 15 vs 22 + 4 pmol/L Letiexhe et al J. Clin End Metab 1993; 77:1263 Liver Tx normalizes insulin resistance 7 6 5 4 3 2 M value mg/[kg.min] 1 0 Perseghin et al. Hepatology 2000; 32:694 8

4/12/2018 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 Post Change in % using % using Change in C Rx hep C HbA1c * insulin Insulin % on HbA1c Rx Before after insulin ** HbA1c treatment treatment Patient 7.27 7.08 -0.19 49.8% 51.0% + 1.2 not cured (n=255) Patient 7.20 6.82 -0.37 41.3 % 38% - 3.3 cured (n=2180) Examined 1 year after Rx * 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 9

4/12/2018 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 10

4/12/2018 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 2 1 hepatorenal syndrome was 38.5 % 1 type 2 – steady or slowly progressive renal failure Planas et al Clin Gastroenterol Hepat 2006;4:1385 11

4/12/2018 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 Metformin More complex + another + 2 others insulin regimens In making therapeutic decision take into account efficacy; hypoglycemia risk; effect on weight; major side effects; cost 12

4/12/2018 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 m 2 – 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 13

4/12/2018 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 14

4/12/2018 Metabolism Duration Duration Recommendation of action of action in CKD Glyburide 1 Liver; active Up to 24 Increased Avoid if GFR <60 metabolites; hrs Avoid in liver failure excreted bile & urine Glipizide Liver 90% 6-12 hrs Unaffected Can be used in CKD (Glucotrol) 10 % excreted in Avoid in liver failure urine Glimepiride 2 Liver but active Up to 24 Increased Reduce dose (1mg) in renal (Amaryl) metabolites hrs failure Avoid in liver failure Repaglinide 3,4 Liver; 3 hrs Unaffected Can be used in CKD (Prandin) metabolites Use cautiously in liver disease excreted in bile Nateglinide 5,6 Liver; 2 hrs Unaffected Can be used in CKD & liver (Starlix) metabolites disease excreted in urine 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 Pioglitazone (Actos) • Reduces microalbuminuria and hyperfiltration • Beneficial effect on NAFLD; NASH • Metabolized by liver; safe in CKD 15

4/12/2018 Pioglitazone or Vitamin E for NASH Placebo Vitamin E Pioglitazone Improvement in 19 % 43 % 34 % NASH (p=0.001) (p=0.04) Total NAFLD -0.5 -1.9 -1.9 activity score (p<0.001) (p<0.001) P values < 0.025 considered statistically significant Sanyal et al N Engl J Med 2010 362: 1675 Adverse effects of pioglitazone • Weight gain • Heart failure • Fracture risk • Macular edema • Bladder cancer 16