Lipids in liver transplant recipients

Table 1 Hypercholesterolemia and its estimated atherogenic potential[25]

LDL-cholesterol (mg/dL)
< 100	Optimal
100-129	Near/above optimal
130-159	Borderline high
160-189	High
≥ 190	Very high

LDL: Low density lipoprotein.

Table 2 Hypertriglyceridemia and its estimated atherogenic potential[25]

Triglycerides (mg/dL)
< 150	Optimal
150-190	Near/above optimal
200-499	High
≥ 500	very high

Table 3 Proposed targeted triglyceride serum concentrations in liver transplant recipients[42]

Triglyceride-targets and -limits
Triglyceride-targeted serum concentrations < 200 mg/dL
Triglycerides < 400 mg/dL with life-style intervention1: tolerable
Triglycerides < 500 mg/dL despite lipid-lowering medication before start of immunosuppression: no initiation of therapy with mTOR-inhibitors
Triglycerides > 500 mg/dL under mTOR-inhibitors: if despite therapy triglycerides < 500 mg/dL, change to different group of immunosuppressant (or reduce doses)

¹Life-style modification/ therapy (lipid-lowering medication): (1) weight loss; (2) increase physical activity; (3) optimize glucose-metabolism; and (4) lipid lowering agents. mTOR: Mammalian target of rapamycin.

Table 4 Serum high density lipoprotein-cholesterol concentrations and predicted atherogenic impact[25]

HDL-cholesterol (mg/dL)
> 60	Optimal
40-60	Near optimal
< 40	Atherogenic

HDL: High density lipoprotein.

Table 5 Criteria of the metabolic syndrome (3 of 5 criteria have to be fulfilled)[25]

Risk factor	Limit value
Abdominal obesity	Abdominal measurement
Men	> 120 cm
Women	> 88 cm
Triglycerides	≥ 150 mg/dL
HDL-cholesterol
Men	< 40 mg/dL
Women	< 50 mg/dL
Blood pressure	≥ 130/≥ 85 mmHg
Fasting blood sugar or insulin-glucose tolerance test after 60, 120 and 180 min	≥ 110 mg/dL

Table 6 Proposed low density lipoprotein-cholesterol-serum concentrations and limits for therapeutic interventions[25]

Risk category	LDL-targeted serum concentration (mg/dL)	Life style modification12 starting at LDL-serum concentrations (mg/dL)	Medical treatment
CHD, PAD, CVD3	< 100	≥ 100	≥ 130
≥ 2 risk factors	< 130	≥ 130	≥ 160
0-1 risk factor	< 160	> 160	> 190

¹Aspects of life style modification: (1) nutrition: (a) saturated fats < 7% of calories, dietary cholesterol < 200 mg/d; (b) increase of soluble fibers (10-25 g/d) and sterols of vegetable origin (2 g/d) as an option of lowering LDL-levels; (2) weight management; and (3) physical activity;

²If LDL-serum concentrations after 3 mo still elevated, consider medical treatment;

³Documented vascular atherosclerosis. CHD: Coronary heart disease; CVD: Cardiovascular disease; LDL: Low density lipoprotein; PAD: Peripheral artery disease.

Table 7 Lipid lowering agents, their impact on lipoprotein metabolism, and potential interaction profiles[49]

Agent (daily dose)	Interactions	Comment
HMG-CoA reductase inhibitors (statins)
Lovastatin (20-80 mg)	Lovastatin, Simvastatin, Atorvastatin are mainly catabolized via hepatic CYP3A4: Caution in case of use of CYP3A4-Inhibitors (e.g., Itraconazole, Ketoconazole, HIV-protease-inhibitors Erythromycin, Clarithromycin, Telithromycin, Nefazodon).	Class of drugs with the highest lipid lowering effect
Pravastatin (20-40 mg)		Contraindications:
Simvastatin (20-80 mg)		(1) advanced liver diseases;
Fluvastatin (20-80 mg)		(2) Rosuvastatin: simultaneous use of Cyclosporine;
Atorvastatin (10-80 mg)	Caution if fibrates or nicotinic acid are simultaneously used: high risk of myopathies.	and (3) Statin intolerance
Rosuvastatin (5-40 mg)		Caution: serious interactions due to competitive inhibition of CYP450 3A4-metabolism cannot be ruled out: Prefer Fluvastatin or Pravastatin for treatment due to absence of CYP450 3A4 metabolisis.
	Simultaneous use of calcineurin-inhibiting agents might reduce the elimination of statins: high risk of myopathies and rhabdomyolysis. Monitoring is necessary and low statin doses at the beginning are recommended.
	Caution with dose escalation. No interactions have been observed between Sirolimus and
	Atorvastatin and between Everolimus and Atorvastatin respectively Pravastatin.
Bile acid binding anion exchange resins
Colestyramine (4-16 g)	Caution: may reduce or retard gastrointestinal absorption of simultaneous orally administered agents.	Lowering of LDL-cholesterol, also used in combination with Statins or Ezetemibe
Colesevelam (2.5-3.75 g)
	If interactions are possible, agents should be taken > 1 before or > 4 h after Colestyramine intake. Colesevelam should be taken 4 h before or after taking other drugs.	Contraindications:
		Ileus or occlusion of bile ducts
	Blood level monitoring is required for agents with a narrow therapeutic window.
	Caution with simultaneous use of immunsuppressants or lipid lowering agents.
	e.g., bioavailability of mycophenolic acid can be reduced due to the simultaneous use of bile acid binding anion exchange resins (40% in case of MMF + Colestyramine). Intervals of medication intake mentioned above are obligatory.
Nicotinic acid
Sustained-release tablets (Niaspan®) (1-2 g)	In some cases simultaneous use of nicotinic acid and HMG-CoA reductase inhibitors was associated with myopathies/rhabdomyolysis: careful assessment of risks and benefits is required. Tredaptive® (according to medicinal product's professional information use was only evaluated in combination with Simvastatin): small increase of AUC and Cmax of Simvastatin (probably without any clinical relevance).	Lowering of LDL and triglyceride serum concentrations
Nicotininc acid/Laropiprant (Tredaptive®) (1-2 g)		Contraindications
		(1) advanced liver diseases;
		(2) acute peptic ulcer;
		and (3) arterial bleeding
	Hot drinks, alcohol and spicy foods may favor flush. Simultaneous use with nicotinic acid should be avoided.
Fibrates
Gemfibrozil (2 × 600 mg)	Caution: Simultaneous treatment with HMG-CoA reductase inhibitors leads to an increased risk for myopathies and rhabdomyolysis. Statin serum concentrations can rise: no combination with statins or monitor patients closely.	Reducing triglycerides. Avoid combination with HMG-CoA reductase inhibitors.
Fenofibrate (200 mg)		Contraindications
Bezafibrate (200-600 mg)		(1) advanced liver dysfunction;
		and (2) severe renal impairment
	Combination with Calcineurin-Inhibitors and mTOR-Inhibitors leads to an increased risk for rhabdomyolysis and other side effects: monitoring is required.
Cholesterol resorption reducing agents
Ezetemibe (Ezetrol®) (10 mg)	Caution: Simultaneous treatment with HMG-CoA reductase inhibitors leads to an increased risk of myopathies and rhabdomyolysis and elevation of liver enzymes: close monitoring of liver function is required.	Lowering of LDL cholesterol:
		(1) advanced liver diseases;
		and (2) persistent elevated liver enzymes
		Rare interactions (no induction of CYP450 enzymes)
	No combination with fibrates: tolerability and effectiveness were not evaluated.
	Combination with Fenofibrate leads to an increased risk for cholelithiasis and gall bladder diseases.
	Caution with the simultaneous use of Cyclosporine: AUC of Ezetemibe rises, no data concerning changes in Cyclosporine-blood levels available. No clinical effects and interactions with other immunosuppressants have been observed to date. Monitoring of immunosuppressive agents is required[50].

AUC: Area under the curve; CYP: Cytochrome P; LDL: Low density lipoprotein; HIV: Human immunodeficiency virus; HMG-CoA: 3-hydroxy-3-methylglutaryl-coenzyme A; MMF: Mycophenolate mofetil; mTOR: Mammalian target of rapamycin.