Management of Post-transplant hyperlipidemia

Management of Post-transplant hyperlipidemia
B. Gisella Carranza Leon, MD Assistant Professor of Medicine Lipid Clinic - Vanderbilt Heart and Vascular Institute Division of Diabetes, Endocrinology and Metabolism Vanderbilt University Medical Center

Disclosures Research support from Amgen

Learning objectives Interpret a lipid profile
Identify mechanisms associated to post transplant dyslipidemia Become familiar with treatment options for different cholesterol disorders in transplant patients

Understanding a Lipid profile

HDL-C (high density lipoprotein) LDL-C* (low density lipoprotein)
Lipid profile Components: Total Cholesterol Triglycerides HDL-C (high density lipoprotein) LDL-C* (low density lipoprotein) * Calculated value. If Tg > 400 mg/dl LDL cannot be calculated and needs to be measured.

Normal Values (adults)
Total cholesterol < 200 mg/dl Triglycerides < 150 mg/dl HDL >40 mg/dl (men) >50 mg/dl (women) LDL < 130 mg/dl Adapted from Journal of Clinical Lipidology, 2014 (8):

Most common dyslipidemias
Hypercholesterolemia Mixed hyperlipidemia Hypertriglyceridemia

Mrs. A TC <200 210 Tg <150 88 HDL >50 49 LDL <130 143
Normal range Patient’s results TC <200 210 Tg <150 88 HDL >50 49 LDL <130 143 Hypercholesterolemia Cholesterol values are in mg/dl.

Ms. C TC <200 302 Tg <150 260 HDL >50 74 LDL <130 176
Normal range Patient’s results TC <200 302 Tg <150 260 HDL >50 74 LDL <130 176 Mixed Hyperlipidemia Cholesterol values are in mg/dl.

Mr. B TC <200 329 Tg <150 1457 HDL >40 36 LDL <130 128
Normal range Patient’s results TC <200 329 Tg <150 1457 HDL >40 36 LDL <130 128 Hypertriglyceridemia Cholesterol values are in mg/dl.

Transplant & hyperlipidemia

Transplant & Hyperlipidemia
Prevalence Cardiovascular disease & Tx Risk factors Immunosuppressive drugs

Prevalence of hyperlipidemia in transplant recipients
World J Transplant 2016;6(1): Ther Adv Endcorinol Metab 2016;7(3) Current pharmaceutical design, 2006 (12): Cardiol Clin 21(2003) Bio Blood Marrow Transplant 2015(21): HCT= allogenic hematopoietic stem cell transplantation

Prevalence of hypercholesterolemia & hypertriglyceridemia in transplant recipients
World J Transplant 2016;6(1): Ther Adv Endcorinol Metab 2016;7(3) Current pharmaceutical design, 2006 (12): Cardiol Clin 21(2003) Bio Blood Marrow Transplant 2015(21): HCT= allogenic hematopoietic stem cell transplantation

Cardiovascular disease (CVD) & transplant
CVD is a common cause of morbidity and mortality among long term transplant survivors 1st cause of death: heart & kidney transplant recipients 2nd cause of death: liver transplant recipients Atherosclerosis  accelerated after transplantation J Heart Lung Transplant 2005:24: Current pharmaceutical design, 2006 (12): World J Transplant 2016;6(1):

Hyperlipidemia & transplant
Incidence ↑ after organ transplantation Risk factor for CVD: Interventions to treat hyperlipidemia: ↓ cardiac deaths and non-fatal MI in clinical trials specific to the transplant population Important for improving outcome after transplant. Lowers cardiovascular risk Risk factor for long-term graft loss: hyperlipidemia is a possible contributor to chronic kidney allograft injury as a non immune risk factor World J Transplant 2016;6(1):

Renal transplant & CV disease risk
National Kidney Foundation Kidney Disease Quality Outcomes Initiative guidelines: Transplanted patients are included in the highest risk category (considered in the highest ASCVD risk group) (2004) Consider renal transplant as a coronary heart disease equivalent risk (2004) Statins should be prescribed adults >30 yrs. of age & s/p kidney transplant regardless of their baseline cholesterol level (2013) Absence of guidelines for other transplant recipients  consider placing these patients in the high risk category ASCVD – atherosclerotic cardiovascular disease KDIGO 2013, Vol 3, issue 3

Hyperlipidemia & heart transplant
Treatment is indicated: Prevent progression of atherosclerosis in native vessels outside the heart Slows the development of transplant vasculopathy

Statins & heart transplant
RCTs have shown that pravastatin & simvastatin Improve survival ↓ incidence of acute rejection ↓ transplant vasculopathy All patients receive a statin after cardiac transplantation regardless of their baseline LDL-C

Non modifiable risk factors
Gender Family history Advancing age Development of diabetes Pre transplant hyperlipidemia Hypothyroidism Proteinuria / kidney dysfunction

Modifiable risk factors
Medications Lifestyle Immunosuppression Weight gain / Diet Excessive alcohol intake Lack of exercise

Immunosuppression & hyperlipidemia
Cyclosporine - ↑ LDL Tacrolimus – ↑ LDL (possibly) Calcineurin inhibitors Azathioprine Mycophenolate sodium Antimetabolites

Immunosuppression & hyperlipidemia
Sirolimus – ↑ LDL & Tg Everolimus – ↑ LDL mTOR Inhibitor ↑ Tg & LDL Corticosteroids

↑ TC, ↑Tg, ↑ VLDL & ↑LDL Cyclosporine & Tacrolimus - Cyclosporine:
Calcineurin inhibitors Cyclosporine & Tacrolimus - Cyclosporine: Binds to the LDL-R  ↑ LDL-C levels ↑ activity of hepatic lipase  LDL ↓ activity of lipoprotein lipase ↓ bile acid synthesis  down regulates LDL-R Highly lipophilic, it is transported in LDL-C particles Effect is dose dependent Tacrolimus: Produces less lipid disturbance ↑ TC, ↑Tg, ↑ VLDL & ↑LDL Ther Adv Endcorinol Metab 2016;7(3)

Conversion from cyclosporine to tacrolimus
124 patients, 1 yr. s/p kidney transplant Randomized: a) cyclosporine b) conversion to tacrolimus At 6 months: Cyclosporine Tacrolimus LDL (mg/dL) 134 120 Tg (mg/dL) 186 152 J Am Soc Nephrol. 2003;14(7):1880

Sirolimus ↑ TC, ↑Tg & ↑LDL Sirolimus: mTOR Inhibitor
Impairs lipoprotein lipase ↑ secretion of VLDL May cause hepatic over production of lipoprotein Dose dependent effect ↑ TC, ↑Tg & ↑LDL Ther Adv Endcorinol Metab 2016;7(3)

↑ ↑ Tg , ↑ TC, ↑ LDL & ↓ HDL Increase: Decrease: Corticosteroids
FFA synthetase lipoprotein lipase activity hepatic synthesis of VLDL synthesis of LDL-R VLDL  LDL HMG-CoA reductase activity ↑ ↑ Tg , ↑ TC, ↑ LDL & ↓ HDL Ther Adv Endcorinol Metab 2016;7(3) Current pharmaceutical design, 2006 (12):

Balancing immunosuppression & hyperlipidemia
Immunosuppressive therapy takes precedence over dyslipidemic therapy Dyslipidemia may be tolerated, even if it cannot be treated optimally Possible changes in immunosuppression: Cyclosporine  tacrolimus Stop sirolimus Lower the steroid dose

Evaluation of dyslipidemia in transplant recipients
Pre / post transplant Fasting lipid panel 3 months follow up Annually

Treatment of post transplant hyperlipidemia

Treatment overview Non-pharmacologic Pharmacologic

Therapeutic lifestyle changes
Diet: Total fat 25-35% of total calories Carbohydrates 50-60% of total calories Fiber g per day Physical Activity: 3-4 times per week minutes Habits: Smoking cessation Alcohol in moderation American Journal of Transplantation 2004 (4) 13-53

Treatment of hypercholesterolemia

Treatment of hypercholesterolemia
LDL % ↓ Statins 18-63 Cholesterol absorption inhibitor 18 Bile acid sequestrants 15-30 Lipid academy 9/2015,

Management of hypercholesterolemia in transplant recipients
Goal: LDL < 100 mg/dl* LDL-C > 100 mg/dl Initiate Therapeutic lifestyle change 3 months + low dose statin Alternative Ezetimibe * If the patient has a history of ASCVD – goal <70 mg/dl American Journal of Transplantation 2012(12): 2012 Practice guideline by AASLD and the American Society of Transplantation

Block cholesterol synthesis
Statins Cholesterol absorption inhibitor Bile acid sequestrants Block cholesterol synthesis Upregulate LDL receptors Modulate inflammatory molecules Clinically proven to ↓mortality & recurrent cardiovascular events

STELLAR Trial Am J Cardiol 2003; 92:

Statins Side effects: Risk of myopathy is greatest … 5-10% myopathy
Cholesterol absorption inhibitor Bile acid sequestrants Side effects: 5-10% myopathy ↑ risk to develop type 2 diabetes mellitus Risk of myopathy is greatest … Elderly GFR < 30 mL/min Maximum statin dose Combination with CYP450 inhibitors

Statins Patient reports myalgias  check a CK
Cholesterol absorption inhibitor Bile acid sequestrants Patient reports myalgias  check a CK 3 to 5 times upper limit of normal  recheck the level weekly > 5 times upper limit of normal  d/c Am Heart J 2004;148: v

Incidence of fatal rhabdomyolysis
Per 1 million prescriptions by drugs is: Fluvastatin 0% Pravastatin 0.04% Atorvastatin Simvastatin 0.12% Am Heart J 2004;148:

Statin drug-drug interaction
Simvastatin and lovastatin Metabolized CYP450- 3A4 Contraindicated with cyclosporine Rosuvastatin Maximum dose is 5 mg /daily when used with cyclosporine Fibrates Gemfibrozil inhibits glucuronidation and uptake of active forms by OATP1B1 transporter by the liver

KDOQI Clinical Practice Guidelines for Managing Dyslipidemias in Chronic Kidney Disease, 2004

Recommended statin doses for adults s/p kidney transplant
mg/d Fluvastatin (40)-80 Atorvastatin (10)-20 Rosuvastatin (5)- 10 Simvastatin / ezetimibe 20/10 Pravastatin (20)-40 Simvastatin (20)- 40 Pitavastatin 2 Doses in ( ) are starting doses and recommended doses when patients are in cyclosporine Lipid abnormalities after renal transplantation uptodate.com KDIGO 2013, Vol 3, issue 3

Cholesterol absorption inhibitor
Statins Cholesterol absorption inhibitor Bile acid sequestrants Binds to cholesterol transporter & blocks its absorption May increase LDL-R Courtesy of MacRae Linton, MD

Statins Cholesterol absorption inhibitor Bile acid sequestrants Ezetimibe 10 mg daily 2nd choice in patients who do not tolerate a statin Used in combination with a statin Smaller dose (5mg/daily?) due to its interaction with cyclosporine which can induce a 2 to 12 fold ↑ in ezetimibe levels

Statins Cholesterol absorption inhibitor Bile acid sequestrants Low risk of serious side effects Reports: Myalgias Rhabdomyolysis Hepatitis Acute pancreatitis Thrombocytopenia

Bile acid sequestrants
Statins Cholesterol absorption inhibitor Bile acid sequestrants ↓ hepatic bile acid pool ↑ hepatic bile acid synthesis from cholesterol ↓ intrahepatic cholesterol pool ↑ LDL receptors ↑ LDL clearance ↓ LDL-C

Statins Cholesterol absorption inhibitor Bile acid sequestrants Colesevelam (welchol): 3 tab bid – take tablets with a meal or liquid Cholestyramine: 8-16 g/day, orally divided into 2 doses Colestipol: 2-16 g/day orally given once of in divided doses

Statins Cholesterol absorption inhibitor Bile acid sequestrants Gastrointestinal side effects – most common Interfere with the absorption of the immunosuppressive drugs (colesevelam usually not a problem) Can raise triglycerides (avoid when Tg > 300 mg/dl) Should be separately administered from them: 1 hour before 4 hours after

What is new in the treatment of hypercholesterolemia?

PCSK-9 inhibitors (Proprotein convertase subtilisin/ kexin type 9)
Alirocumab Evolocumab

Lambert G, et al. “The PCSK9 decade” J Lipid Res 2012; 53:2515-2524

(fully human monoclonal antibodies)
PCSK-9 inhibitors (fully human monoclonal antibodies) Lambert G, et al. “The PCSK9 decade” J Lipid Res 2012; 53:

Summary of Phase 3 Trials – change in LDL
PCSK9 inhibitor Placebo CAD & not at goal Odyssey Combo I - 48 % - 2 % Descartes - 50 % + 8 % FH Rutherford-2 - 60 % - 3 % Odyssey FH I & FH II - 49 % - 9 %

5.15 Comparison of the effect of statins and PCSK9 inhibitors on Serum Lipids Drug class TC LDL HDL TG Statins  15-60% 20-60% 3-15% 10-40% PCSK-9 mAb  38 % 45-70% 7.5 %  16 % Crouse JR III. Hypertriglyceridemia: a contraindication to the use of bile acid binding resins. Am J Med. 1987;83: Knopp RH. Drug treatment of lipid disorders. N Engl J Med. 1999;341: National Cholesterol Education Program. Second Report of the Expert Panel On: Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). Circulation. 1994;89:

FDA approved indications
In addition to diet and maximally tolerated statin therapy … In adults with heterozygous FH* or Clinical atherosclerotic cardiovascular disease who require additional lowering of LDL cholesterol *Evolocumab is also approved for patients with homozygous FH

Dosing : SC injections Alirocumab Evolocumab Initially 75 mg q 2 wks.
Increased 150 mg q 2 wks. 300 mg q 4 weeks Measure LDL-C levels within 4-8 weeks of initiation or titration 140 mg q 2 wks. or 420 mg q 4 wks. To administer the 420 mg dose give three 140 mg injections consecutively within 30 minutes

Side effects Injection site reactions Flu like symptoms Back pain

Objective Population Study design Intervention 1ary end point
N Engl J Med. 2017 May 4;376(18): Clinical efficacy & safety of evolocumab when added to statin therapy Objective Patients with ASCVD & LDL > 70 mg/dl (27,564 pts) Population Double blind, RCT , median follow up was 2.2 yrs. Study design Evolocumab 140 mg q 2 wks. / placebo q 2 wks. Evolocumab 420 mg q 4 wks. / placebo q 4 wks. Intervention Composite of CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization 1ary end point

Objective Population Study design Intervention 1ary end point
Reduce morbidity and mortality on patients with ACS Objective Patients with ACS 1-12 m prior to randomization Population Double blind, RCT , follow up was ≥ 3 yrs. Study design Alirocumab q 2 wks. / placebo q 2 wks. Intervention Composite of CHD death, non fatal MI, fatal or non fatal stroke, unstable angina requiring hospitalization 1ary end point

PCSK9 inhibitors & transplant
Have not been approved to be used in this population

Treatment of hypertriglyceridemia

Hypertriglyceridemia
Indication for pharmacologic treatment: Tg > 500 (1000) mg/dl Goal  prevent pancreatitis (Tg > 1000 mg/dl)

Hypertriglyceridemia cont.
Treat secondary etiology Diseases: Diabetes Nephrotic syndrome Lifestyle: Diet high in simple carbohydrates Alcohol

Hypertriglyceridemia cont.
Drugs: Immunosuppressant agents Estrogen Glucocorticoids Beta blockers Retinoids

Hypertriglyceridemia management
Tg < 500 mg/dl Lifestyle modification Tg > 500 mg/dl Fibrates Fenofibrate Gemfibrozil Omega 3 fatty acids (DHA & EPA) 4 grams daily (2 grs bid)

Treatment of hypertriglyceridemia
Tg % reduction Fibrates 20-50 Omega-3 fatty acids 45 Statins 7-30 Nicotinic acid Lipid academy 9/2015,

Omega 3 fatty acids Fibrates Activate PPAR α
↓ hepatic VLDL cholesterol synthesis ↑ lipoprotein lipase activity KDOQI Clinical Practice Guidelines for Managing Dyslipidemias in Chronic Kidney Disease, 2004 The American Journal of Cardiology, 2007 (99): 3C-18C

Omega 3 fatty acids Fibrates Adverse effects: Contraindications
GI – dyspepsia, diarrhea Increase LFTs May potentiate action of anticoagulation Contraindications Hepatic impairment Pre-existing gallbladder disease

Omega 3 fatty acids Fibrates Fenofibrate: may reversibly ↑ creatinine
Myotoxicity: fenofibrate is preferred over gemfibrozil when added to a statin

Omega 3 fatty acids Fibrates In transplant …
Evidence supporting the safety and efficacy of fibrate use is weak Dose adjusted for kidney function Not recommended Only on Tg >1000 mg/dl KDIGO 2013, Vol 3, issue 3

Omega 3 fatty acids Fibrates Unclear mechanism of action
EPA – eicosapentaenoic acid DHA – docosahexaenoic acid Omega-3: four grams daily (divided doses)

When should you refer a patient to a lipid specialist?
If the patient’s LDL > 190 mg/d or triglycerides >1000 mg/dl The patient has a prior history of intolerance to cholesterol lowering medications If combination therapy is not controlling your patient’s cholesterol level

Lipid Clinic - Vanderbilt Heart and Vascular Institute
Thanks Lipid Clinic - Vanderbilt Heart and Vascular Institute (615)

Management of Post-transplant hyperlipidemia

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