diabetes management in liver and kidney disease · summary - liver disease and diabetes...
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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
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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