Diabetes management in liver and kidney disease

Transcription

1 Diabetes management in liver and kidney disease Epidemiology 1

2 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 IGT High risk 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

3 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: 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 ( ) ; impaired fasting glucose ( ) 13 (23 %) FPG < 110; but 2hr glucose > (14 %) - FPG > 126 and 2hr glucose > 200 Nishida et al Am J Gastroenterol 2006: 101:70 3

4 Prevalence of diabetes DM 35% Cirrhosis 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 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 :2005 (Guideline) 4

5 Prevalence NAFLD; NASH (ultrasound & liver biopsy study in middle aged population without known liver disease) Whole cohort (n=328) NAFLD 156 (46%) NASH 40 (12.2%) NASH with stage 2-4 fibrosis 9 (2.7 %) Diabetic N= (74%) 12 (22%) Non diabetic (10.9%) Williams et al Gastroenterol 140: 124 (2011) Age standardized prevalence of obesity, DM, NAFLD in a Chinese population Male Female 2007 (n= (n=602 P value 2007 (n= (n=757 P value Obesity BMI > < <0.01 Diab < <0.01 HTN > <0.05 Dyslipid < <0.01 NAFLD (by US) < <0.01 Wu et al Scientific Reports 2017; 7:

6 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: NHANES data; single sample marker CKD 13.6 % of pop (~ 30 million) CKD; 3.9 % of pop CKD + DM (~ 8 million) 6

7 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 7

8 Peripheral hyperinsulinemia in cirrhosis AUC min vs pmol/l Letiexhe et al J. Clin End Metab 1993; 77:1263 Liver Tx normalizes insulin resistance M value mg/[kg.min] Perseghin et al. Hepatology 2000; 32:694 8

9 Hepatitis C infection increases peripheral insulin resistance (minimal fibrosis - score <F2; BMI ; 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) Patient cured (n=2180) % 51.0% % 38% 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 :

10 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

11 Grade A 5 to 6 Grade B 7 to 9 Grade C -10 to 15 Pugh et al Brit J Surg 1973;60: _CKD_GL.pdf Hepatorenal syndrome Functional renal failure due to effective hypovolemia & intrarenal vasoconstriction 263 cirrhotic patients with moderate or tense ascites followed for 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:

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 6 classes of drugs: ADA/EASD algorithm 2015 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 12

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: 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

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:

15 Metabolism Duration of action Duration of action in CKD Recommendation Glyburide 1 Glipizide (Glucotrol) Glimepiride 2 (Amaryl) Repaglinide 3,4 (Prandin) Nateglinide 5,6 (Starlix) Liver; active metabolites; excreted bile & urine Liver 90% 10 % excreted in urine Liver but active metabolites Liver; metabolites excreted in bile Liver; metabolites excreted in urine Up to 24 hrs Increased Avoid if GFR <60 Avoid in liver failure 6-12 hrs Unaffected Can be used in CKD Avoid in liver failure Up to 24 hrs Increased Reduce dose (1mg) in renal failure Avoid in liver failure 3 hrs Unaffected Can be used in CKD Use cautiously in liver disease 2 hrs Unaffected Can be used in CKD & liver disease 1.Jonsson et al. Eur J Clin pharmacol : Rosenkranz et al Diabetologia : Marbury et al. Clin pharmacol ther :7. 4. Hatorp et al J Clin Pharmcol 2000;40: Devineni et al J Clin Pharmacol 2003; 43: 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

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

17 GLP-1 receptor agonists Metabolism Recommendation Exenatide (Byetta) Liraglutide (Victoza) Albiglutide (Tanzeum) Dulaglutide (Trulicity) Lixisenatide (Adlyxin) Renal excretion Proteolysis Proteolysis Proteolysis Renal excretion Reduce dose to 5 mcg BID stage 3 CKD. Do not use for GFR < 30 No dose change No dose change No dose change No dose change for egfr >30 Liraglutide reduce progression from microalbuminuria to macroalbuminuria 161 vs 215 Mann et al N Engl J Med 2017;377:839 (Leader trial) 17

18 Effect of liraglutide on NASH after 48 week Rx Resolution of NASH (biopsy) Progression of fibrosis Liraglutide 1.8 mg (n=26) 9/23 (39 %) 2/23 (9%) Placebo (n=26) P value 2/22 (9%) /22 (36 %) % had diabetes; liraglutide improved glucose levels & promoted weight loss 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 18

19 DPP 4 inhibitors Sitagliptin (Januvia) Saxagliptin (Onglyza) Linagliptin (Tradjenta) Alogliptin (Nesina) Metabolism Recommendation 80% renal clearance 100 mg usual dose. 50 mg for GFR 30-50; 25 mg for < 30 CYP3A4/5 metabolism; active metabolite; 24 % renal excretion 80 % eliminated via bile and gut; 5 % renal clearance 5 mg daily usual dose. 2.5 mg if GFR< 50 or if taking strong CYP/3A4 inhibitors No dose change in renal disease or liver disease > 70% renal clearance 25 mg daily usual dose 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

20 SGLT2 inhibitors Metabolism Recommendation Canagliflozin (Invokana) Liver; 33 % renal clearance Lower efficacy CKD 3 Do not use if GFR < 45 Dapagliflozin (Farxiga) Empagliflozin (Jardiance) Liver & kidney metabolism Liver and kidney 10 mg daily usual dose. Use 5 mg if liver disease. Do not use GFR <60 Do not use if GFR < 45 Empagliflozin reduces albuminuria Cherney et al Lancet Diab Endocrinol :610 20

21 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 Metformin Kidney disease Safe to use egfr greater than 30 ml/min/1.73 m 2 Liver disease 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) 21

22 Drug Kidney disease Liver disease GLP1 receptor agonists Liraglutide; albiglutide; dulaglutide. Cautiously acute kidney injury in setting of 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 59 year woman with renal transplant 52 year woman with alcoholic cirrhosis and DM Urine protein <0.16 mg/mg creat Urine albumin <30 mg/g creat Hb Home glucose levels mg/dl HbA1c s 8.3% < Am Lunch Dinner Fructosamine umol/l 7 %

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 23