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Statins and the Liver. Dr Udaya Kalubowila MBBS, MD Senior Registrar in Gastroenterology/ Medicine University Medical Unit CNTH Ragama . Introduction. Cardiovascular disease are the leading cause of death in many countries.
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Statins and the Liver Dr Udaya Kalubowila MBBS, MD Senior Registrar in Gastroenterology/ Medicine University Medical Unit CNTH Ragama
Introduction • Cardiovascular disease are the leading cause of death in many countries. • Clinical trails have confirmed the advantages of statins in CVD and stroke. • Examples; • ASCOT(Atorvastatin), WOSCOP(Pravastatin), ALLHAT(Pravastatin) SPARCL( statin in stroke prevention) Trails with 4100 patients showed 16% RR reduction for non fatal and 45% RR reduction for fatal strokes.
However hepatotoxic effect of statins had been a major concern since its introduction. • Prevalence of back ground chronic liver disease is rising • prevalence of NAFLD in an urban Sri Lankan population ( based on ultra sound criteria) is 35%. -Ragama Health Study • Prevalence of alcohol consumption above the safe limit which could lead to elevation of transaminases is also high in our country.
Statins • One of the most commonly prescribed medications in the world • Acts by inhibiting the enzyme 3 hydroxy3 methyl glutaryl CoA reductase . • Main benefit of statins is thought to be via reduction of LDL cholesterol levels. • However many other mechanisms also have been implicated. • Statins were first approved for used in 1987. • At least 6 statins are available for use in most countries.
Liver Function test abnormalities from statins • Small percentage of patients experience an increase in both ALT/AST. • Usually seen within the first six months of treatment. • Usually asymptomatic. • Reverse on stopping or with dose reduction. • They may also return to normal with continuation of the treatment. • With the standard doses , no significant elevations of S.Bilirubin, Alkaline phospatase ,Gamma GT are commonly encountered.
The mechanism of elevation of AST/ALT • Unknown. • Asymptomatic elevation in AST/ALT occurs with all lipid lowering agents( Ezetimibe has no direct effect on hepatic cholesterol synthesis or bile acid excretion). • It is thought to be due to a liver response to lipid lowering • Spontaneous fluctuations of transaminases occurring in patients with lipid abnormalities have also been implicated.
Clinically significant Liver Injury • Rare • could be due to idiosyncratic or immunoallergic mechanisms • common for many other drug. • ALL common patterns of liver (hepatocellular, cholestatic, mixed) injury have been reported. • Estimated risk of fulminant liver failure (Merk’s World- wide Adverse Event Database) attributable to lovastatin was 2 in one million.
Statins and Liver Toxicity: A Meta-Analysis: Results • Patients and Trial Characteristics • from A total of 49275 patients 13 trails • The mean age of these patients was 60 years, and 77% were men. • Of these, 27,276 patients were receiving a statin and 21,999 were receiving placebo.
Meta-Analysis • Two of the included trials evaluated fluvastatin(2106 patients),four evaluated lovastatin (16,085), five evaluated pravastatin(26,019), and two evaluated simvastatin (5065). • The average follow-up of these trials was 3.6 years.
Statins and Liver Toxicity: Conclusion • Our results support previous observations that pravastatin, lovastatin, and simvastatin, at low-to-moderate doses, are not associated with a significant risk of LFT abnormalities and that LFT monitoring, other than prior to starting therapy, is not warranted in patients taking a low-to-moderate dose (20- 40 mg/day). • Analysis also says additional data are required to determine whether other statins have a similar safety profile.
Guidelines • Guidelines on managing IHD,CVD recommend on lowering LDL cholesterol below 70mg/dl • To achieve these goals patients may needs to take fairly high dose of statins • However guidelines on managing IHD are not very clear on following issues,
Current issues with statins cont- • Can statins be introduced to a patient with chronic liver disease/elevated liver enzymes. • How to deal with a patient who develops elevated transaminases following introduction of statins
Practical issues • NAFLD is common in patients with hyperlipidemia and type 2 diabetes mellitus therefore IHD. • Presence of fatty liver may itself increases the cardiovascular risk. • These are the very patients who are going to be benefitted by statins.
NAFLD and Statins • Studies are limited. • However existing data provide evidence that, statins can be used safely in NAFLD. • Hyperlipidemic patients with elevated baseline AST/ALT are at not higher risk of hepatatoxicity than hyperlipidemic patients with normal liver enzymes.
Evidence • Incidence of statin hepatatoxicity over a 6 months in 342 hyperlipidemic patients with elevated base line AST/ALT who received statins was compaired to, • 1437 hyperlipidemic patients with normal AST/ALT who received statins, • and 2245 patients with elevated liver enzymes who did not receive statins.
PPP Project(Prospective Pravastatin pooling) • Provides quantitative data on the safety and tolerability of pravastatin administered over a period of 5 years. • 19,592 patients were evaluated. • Of these,319 pravastatin treated patients and 262 placebo treated patients had elevated liver enzymes. • Incidence of elevated ALT at any time during postrandamization was • 5% in the pravastatin group. • 7.3% in the placebo group.
Alcohol and statins • Studies are limited. • However over 2000 participants(11%) of Heart protection study were taking alcohol>21 units a week, found to have no increased risk of having clinically significant liver injury. • Results of few studies of statin therapy in patient with hepatitis C ,cirrhosis and HCC show benefit with out increased risk of adverse effects( Pharmacotherapy 2008 Apri;28(4)522-9).
Are Patients With CLD at a Higher Risk for Rabdomyolysis From Statins? • Important complication of statin therapy. • Risk increases with the increasing dose of statin ( not a liner relationship). • Patients with decompensated cirrhosis have higher serum concentration of statins due to reduced hepatic activity of CYP3A and other metabolizing enzymes.
CLD and Rabdomyolysis • Studies are limited. • The plasma concentration of rosuvastatin is increased in patient with chronic alcoholic liver disease and Child grade A and B cirrhosis compaired to volunteers with normal liver functions. • Data suggest that patients with steatosis and NASH have decreased hepatic CYP3A expression and activity. • Study by Weltman and colleagues • 2003ISSX(International Society for study of Xenobiotics)
Is Current Labeling Clinically Relevant? • Not evidence based and clinically relevant. • The presumed purpose of this recommendation is to identify the patients with liver disease and to monitor for statin hepatotoxicity. • However it is evident that transaminases are insensitive to detect underlying liver diseases(79% patients with documented hepatic steatosis in the Dallas Heart Study had normal aminotransferases) .
Is Current Labeling Clinically Relevant? • No sound rationale why statins should not be used in patients with CLD. • Routine monitoring is not cost effective. • However baseline measurement , may helps to prevent falls attribution of elevated transaminases to statin therapy
Conclusion • Can we introduce statins to a patient with elevated liver enzymes? Yes. However it is safe to withhold statins if there is clinically significant elevation of S. Bilirubin and Alkaline Phospatase. • Can we introduce statins to a patient who consume alcohol above the safe limit? Yes. • Can cirrhotics be treated with statins? Probably can, If their have compensated cirrhosis . • When to stop? When there is a clinically significant liver injury.
Take Home Massages • Available data indicate that the statins are remarkably safe from a liver point of view. • Current recommendation on routine monitoring of liver function test after starting statins are not evidence based (National Lipid association Task Force, USA). • Further studies are necessary to evaluate the safety of statins in patient with advanced cirrhosis.
References • PfefferMA,KeechA,Sacks FM,Cobbe SM,TonkinA,et al, Safety and Tolerability of Pravastatin in long term clinical trails. Circulation 2002105;2341-2346 • Chalsani N,AljadheyH,Kesterson J,Hall SD. Patients with elevated liver enzymes are not at higher risk for statin hepatotoxicity. Gastroenterology 2004;128:1287-1292. • de Denus S,Spinler SA,MillerK,PetersonAM, Statins and Liver toxicity: a meta analysis. Pharmacotherapy 2004;24:584-591 • Sidharth S. Bhardwaj M, Chalasani, N. Lipid Lowering Agents That Cause Drug Induced Hepatotoxicity, Clinics in Liver disease. • Chalasani N, Statins and Hepatotoxicity: Focus on patients with fatty liver. Hepatology 2005:41.690-95 • OnoferiMD,Butler KL,Fuke DL,Miller AB, Pharmacotherapy 2008 Apri,28(4)222-9
Acknowledgement • Professor Janaka de Silva (Senior professor of Medicine) • Dr Anuradha Dassanayake (Consultant Physician) • Dr Arjuna de Silva( Consultant Physician) • And the GI Team CNTH Ragama THANK YOU