HCV and Diabetes. Francesco Negro. University Hospital of Geneva, Switzerland HepDART, Tuesday, December 10 th, 2013, Big Island, HI

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1 HCV and Diabetes Francesco Negro University Hospital of Geneva, Switzerland HepDART, Tuesday, December 10 th, 2013, Big Island, HI

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4 Host genes Sedentary lifestyle HCV Drugs Environmental toxins (bisphenol A, phthlates?) Type 2 Diabetes Diet Smoking Excess alcohol consumption Adipocytokines Low-grade inflammation

5 HCV infection and risk of diabetes A systematic review and meta-analysis Estimate risk of type 2 or adult-onset diabetes Case-control, cross-sectional, cohort studies Clinic-based and general population-based Minimal sample size = 200 Excluded patients who were children, transplant recipients, pregnant, or who were undergoing dialysis, or who had thalassemia, cancer 34 unique studies from 32 eligible reports, spanning the period from 1997 to 2008 WHITE et al, J Hepatol 2008;49:831-44

6 HCV infection and risk of diabetes A systematic review and meta-analysis Studies OR 95% CI Unadjusted, retrospective Adjusted, retrospective Unadjusted, longitudinal Adjusted, longitudinal Adjusted, retrospective, HCV vs HBV Unadjusted, monoinfected vs HIV coinfected WHITE et al, J Hepatol 2008;49:831-44

7 HCV is associated with an increased prevalence of T2D in persons >40 yrs The Third NHANES Survey, Cross-sectional national survey Representative sample of the general adult population in the US 9841 persons >20 years of age 8.4% had T2D, and 2.1% were anti-hcv+ Anti-HCV+ persons aged 40 or older: Adjusted OR for diabetes 3.77 (95% CI: ) Independent of BMI, age, sex, race, family history of diabetes MEHTA et al, Ann Intern Med 2000;133:

8 Prevalence of type 2 diabetes in HCV+ vs. HCVaccording to different classes of age (The Third NHANES Survey, ) VHC+ VHC- MEHTA et al, Ann Intern Med 2000;133:

9 HCV increases the incidence of T2D in high-risk patients (>60 years, BMI >35) The Atherosclerosis Risk in Communities Study (ARIC) Prospective, community-based, case-cohort study 1084 T2D-free persons aged years (HCV 0.8%) 548 developed T2D over 9 years of FU Risk Group HCV n Incident T2D cases HR (95% CI) Low Low ( ) High High ( ) HCV precedes diabetes! MEHTA et al, Hepatology 2003;38:50-56

10 Incidence of T2D in transplant recipients After liver transplantation: New onset diabetes occurs more commonly in HCV+ than HCV- recipients [OR = 1.39; 95%CI ] CHEN et al, Transpl Int 2009;22: Elevated HOMA-IR and post-lt diabetes accelerate fibrosis progression (especially in case of older donors) FOXTON et al, Am J Transplant 2006;6: VELDT et al, Am J Transplant 2009;22: After kidney transplantation: Post-transplant diabetes occurs more often in HCV+ than HCV- recipients [pooled RR = 1.36; 95% CI ] FABRIZI et al, Int J Artif Organs 2008;31:675-82

11 HCV patients without diabetes are more insulin resistant than controls HCV (n=121) Controls (n=137) P Age 37.9 ± ± 12.7 NS Males 74 (61%) 74 (54%) NS BMI 26.5 ± ± 4.6 NS Waist-to-hip ratio 0.89 ± ± 0.1 NS C-peptide 826 ± ± 298 <.001 HOMA-IR 2.4 ± ± HUI et al, Gastroenterology 2003;125:

12 Insulin resistance is higher in chronic hepatitis C than in matched chronic hepatitis B patients CHC (n=240) CHB (n=80) Male sex (%) 166 (69.0) 61 (76.2) NS Age 41.2 ± ± 12.4 NS BMI 23.8 ± ± 3.1 NS WC 88.7 ± ± 9.0 NS F3-F4 (%) 51 (21.2) 16 (20.0) NS HOMA-IR 2.8 ± ± 1.1 <.001 C-peptide (pg/ml) 2.6 ± ± 0.6 <.001 MOUCARI et al, Gastroenterology 2008;134: p

13 Insulin-Stimulated Akt Phosphorylation (Fold Increase From Baseline) HCV Impairs Insulin-Stimulated PKB/Akt Phosphorylation in the Liver Leading to Insulin Resistance P= Non HCV HCV AYTUG et al, Hepatology 2003;38:

14 Mechanisms of HCV-induced hepatic IR

15 HCV Hepatic Insulin Resistance (post-insulin receptor interactions) Extrahepatic Insulin Resistance (mediated by soluble factors) 20-34% 66-80% Whole body insulin resistance VANNI et al, Hepatology 2009 MILNER et al, Gastroenterology 2010

16 Endogenous glucose production (EGP) and glucose disposal in hepatitis C without MS (euglycemic hyperinsulinemic clamp + tracers infusion + indirect calorimetry, n=14) 3 non-3 VANNI et al, Hepatology 2009;50:

17 Insulin-stimulated glucose uptake by adipocytes Lipolysis (adipocytes) (secretion of glycerol stimulated by isoproterenol) Endocrine effects of HCV on adipocytes: 1 - Insulin-stimulated glucose uptake is suppressed 2 - Isoproterenol-stimulated lipolysis is inhibited by insulin * Isoproterenol Insulin Huh Control HCV-1b KADDAI et al, International Meeting on HCV, Venice 2012

18 TNFa IL-8 IL-18 Hepatoadipokines? Cytokines? Lipids? Skeletal muscle Role of immune cells in HCV-induced IR? Adipokines? Cytokines? Lipids? HCV-infected liver Adipokines? Cytokines? Adipose tissue KADDAI & NEGRO, Exp Rev Gastroenterol Hepatol 2011

19 Clinical impact of HCV-associated glucose metabolism disturbances Steatosis? Accelerated fibrosis progression? Hepatocellular carcinoma? Cardiovascular/renal morbidity?

20 Mechanisms of liver steatosis induced by insulin resistance ~15% dietary fat ~26% ~59% BROWNING & HORTON, J Clin Invest 2004;114:147 DONNELLY et al, J Clin Invest 2005;115:

21 Plasma levels of non-esterified fatty acids are not increased in HCV infection without the metabolic syndrome In the pre-diabetic stage, NEFA levels are similar to controls and equally suppressed by insulin, arguing against a role of HCV-induced IR in the pathogenesis of HCV-associated steatosis VANNI et al, Hepatology 2009; 50:

22 Insulin resistance accelerates fibrosis progression 260 chronic hepatitis C patients Subgroup of 121 patients with F0-F1 matched to 137 healthy volunteers by sex, BMI, waist-to-hip ratio Independent predictors of HOMA-IR: BMI (P<.001), prior antiviral therapy failure (P<.001), portal inflammation (P<.001) and HCV-3 (P=.01) By MV, the HOMA-IR score (but not steatosis) was independently associated with fibrosis score (P<0.001) and progression rate (P=0.03) HUI et al, Gastroenterology 2003;125:

23 mrna Fold Increase mrna Fold Increase Insulin is Pro-Fibrogenic Insulin and glucose stimulate production of CTGF in hepatic stellate cells Glucose Insulin * * 0 5 mm 30 mm * * * 6 4 * 0 20 UI/mL * * 2 * h 6 h 24 h 96 h 0 2 h 6 h 16 h 24 h PARADIS et al, Hepatology 2001;34:

24 Diabets increases the risk of HCC in chronic hepatitis C with advanced fibrosis 541 chronic hepatitis C patients, Ishak scores (16%) had diabetes Median FU 4.0 years (range ) 5-year occurrence of HCC: 11.4% (95% CI ) if diabetes 5.0% (95% CI ) (P=0.013) if no diabetes MV Cox regression: diabetes is independently associated with HCC in patients with Ishak 6 (HR 3.28, 95% CI , P=.009) VELDT et al, Hepatology 2008;47:

25 HCV increases the risk of HCC in diabetic patients A population-based cohort study from Taiwan (n = 19,349 DM vs. 77,396 controls) Variable Crude HR (95% CI) Adjusted HR (95% CI) Sex Women Reference Reference Men 2.27 ( ) 2.32 ( ) Age group (years) Reference Reference ( ) 4.26 ( ) ( ) 8.78 ( ) Diabetes mellitus No Reference Reference Yes 2.03 ( ) 1.73 ( ) Comorbidity (yes vs. no) Obesity 0.36 ( ) Cirrhosis 19.2 ( ) 8.65 ( ) Alcoholic liver damage 5.00 ( ) 1.36 ( ) Nonalcoholic fatty liver disease 1.58 ( ) Hepatitis B 6.63 ( ) 2.52 ( ) Hepatitis C 16.2 ( ) 5.61 ( ) LAI et al, Am J Gastroenterol 2012;107:46-52

26 Excess extrahepatic mortality associated with HCV The REVEAL HCV Cohort Study 19,636 HBsAg-seronegative adults, aged yrs 1,095 anti-hcv+ [5.6%] 2,394 deaths after an average FU of 16.2 years Causes of death Multivariate-adjusted HR (95% CI) All causes 1.89 ( ) All liver-related ( ) HCC ( ) All extrahepatic diseases 1.35 ( ) All cancers, except HCC 1.32 ( ) Diabetes 1.49 ( ) Cardiovascular diseases 1.50 ( ) Nephritis/nephrosis 2.77 ( ) LEE et al, J Infect Dis 2012;206:469-77

27 Association between HCV and cardiovascular disorders 19,741 patients enrolled in NHANES 173 anti-hcv+ (0.88%) HCV infection was independently associated with arterial hypertension and cardiac failure (OR 2.49, 95% CI, ) after adjustment for age, obesity and smoking Potential pathogenetic role of HCV-induced lipid and glucose metabolism alterations YOUNOSSI et al, Aliment Pharmacol Ther 2013;37:647-52

28 The treatment of glucose metabolism disorders due to HCV is......the treatment of HCV!

29 SVR is associated with a two-thirds reduction in the risk of developing diabetes 2842 Japanese non-diabetic patients with chronic hepatitis C IFN-a ± ribavirin 143 patients developed diabetes after a mean FU of 6.4 years: 26/1175 SVR (2.2%) vs 117/1667 non-svr (7%) Factors independently associated with T2D development: Factor HR 95% CI p Advanced fibrosis Lack of SVR Pre-diabetes Age 50 years ARASE et al, Hepatology 2009;49:

30 Cumulative incidence of type 2 diabetes in chronic hepatitis C: SVR vs non-svr years years years Age >50 years Cirrhosis Pre-diabetes ARASE et al, Hepatology 2009;49:

31 SVR reduces the risk of developing impaired fasting glucose or T2D 734 Spanish patients with chronic hepatitis C, no IFG, no T2D (Peg)-IFN-a + ribavirin Average FU: 27 ± 17 months (from treatment start) Abnormal glucose concentrations reported in 49/430 (11.4%) SVR vs. 74/304 (24.3%) non-svr Factor Adjusted HR 95% CI p Fibrosis stage SVR ROMERO-GOMEZ et al, J Hepatol 2008;48:721-7

32 SVR reduces the risk of developing impaired fasting glucose or T2D Factors not associated with a reduced risk: age, sex, BMI, family history of T2D, HCV RNA load and genotype, liver steatosis, AST, lipid profile ROMERO-GOMEZ et al, J Hepatol 2008;48:721-7

33 SVR prevents the development of insulin resistance in hepatitis C 431 HCV+ patients, 12% insulin resistant (HOMA-IR>2) Baseline HOMA-IR associated with with steatosis, fibrosis stage, HCV RNA, and body weight, but did not affect response to therapy During FU, de novo insulin resistance occurred less frequently in SVR than in non-svr (17% vs. 7%, p=.007) Post-therapy insulin resistance was associated with treatment failure and 10% increase body weight AGHEMO et al, Hepatology 2012;56:1681-7

34 Excess mortality associated with cardiovascular and renal diseases in anti-hcv+ patients Role of viremia LEE et al, J Infect Dis 2012;206:469-77

35 3,113 anti-hcv+ (208 treated) 12,452 uninfected controls from the Taiwan National Health Insurance Program Database HCV infection was associated with a 23% increase of the risk of stroke (after correction for risk factors) Antiviral treatment decreased this risk by ~60% HSU et al, Aliment Pharmacol Ther 2013;38:415-23

36 Antiviral therapy reduces the complications of diabetes in chronic hepatitis C 9,572 diabetic patients (Taiwan National Health Insurance Research Database): 1,411 HCV+ treated with peg-ifn-a/ribavirine 1,411 HCV+ untreated controls 5,644 uninfected controls Antiviral treatment was associated with a decreased incidence of: End-stage nephropathy (HR 0.16, 95% CI ) Ischemic stroke (HR 0.53, 95% CI ) HSU et al, Hepatology 2013 (in press)

37 CAVEAT IR is associated with a decreased virologic response to IFN-a

38 SVR (%) Insulin resistance decreases SVR in chronic hepatitis C treated with IFN-a HCV-1 = OR 2.43; 95% CI, ; p= HCV-2 / HCV-3 = , p< HOMA-IR <2 HOMA-IR 2-4 HOMA-IR >4 ROMERO-GOMEZ et al, Gastroenterology 2005;128:636 POUSTCHI et al, J Hepatol 2008;48:28-34

39 Insulin sensitizers in chronic hepatitis C Effects on response to therapy with PEG-IFN-a and RBV Overbeck 2008 Elgouhari 2008 n Drug RVR SVR 5 NR 30 naive G-1 (20 obese) Conjeevaram naive G-1 Romero-Gomez naive G-1 Khattab 2010 Harrison naive G-4 (HOMA-IR >2) 150 naive G-1 (HOMA-IR >2) PIO, 15 mg qd during SOC PIO, 30 mg qd 4 wks before SOC + 4 wks during SOC PIO, 30 mg qd during SOC Metformin 425 mg tid 4 wks mg tid 44 wks during SOC PIO, 30 mg qd during SOC PIO 30 mg qd 4 wks + PIO 45 mg qd 4 wks before; then PIO 45 mg qd during and 24 wks after SOC NO 50% lean 60% obese 20% placebo EOTR 80% vs. 50% in placebo 28% in MET vs. 6.3% in placebo 27.1% in PIO 6.1% in controls 6.5% in PIO 16.4% in controls NA NA NO 52.5% vs. 42.2% 60.4% vs. 38.7% 26% vs. 38.4%

40 Will baseline IR be associated with a lower virologic response to DAA???

41 HCV RNA and HOMA-IR decline during danoprevir monotherapy HCV RNA decline predicted by baseline HCV RNA, but not by HOMA-IR, nor sex, age, BMI, ALT or triglycerides MOUCARI et al, Gut 2010;59:1694-8

42 HOMA-IR may no longer predict virological response to telaprevir-containing regimens (n=161, naive, G-1 from study C208) SERFATY et al, Gut 2012;61:

43 HCV causes IR HCV and diabetes In persons at risk, HCV-induced IR may lead to type 2 diabetes Diabetic HCV+ patients have increased liver and extrahepatic morbidity and mortality Cure of HCV may reduce the burden of diabetesrelated morbidity and mortality

44 Should we extend the indications for treatment of HCV to reduce mortality in those at risk of extrahepatic disorders, independently of the severity of hepatitis C? Male, 61 years, F1, obese...? Female, 64 years, F1, type 2 diabetes...?