1 / 28

Statins and the Liver

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.

dwight
Download Presentation

Statins and the Liver

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Statins and the Liver Dr Udaya Kalubowila MBBS, MD Senior Registrar in Gastroenterology/ Medicine University Medical Unit CNTH Ragama

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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,

  12. 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

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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).

  18. 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.

  19. 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)

  20. 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) .

  21. 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

  22. 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.

  23. 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.

  24. 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

  25. 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

More Related