Managing dyslipidemia in solid organ transplant patients

Abstract

Solid organ transplant recipients face an increased risk of dyslipidemia, which contributes to cardiovascular complications. Commonly used drugs such as ciclosporin and tacrolimus can aggravate and cause dyslipidemia. Immunosuppressive drugs particularly ciclosporin and tacrolimus are also known to worsen dyslipidemia in transplant recipients. Mammalian target of rapamycin (mTOR) inhibitors like sirolimus and everolimus also alter lipid metabolism. Lifestyle and dietary modifications should be encouraged. Careful consideration of immunosuppressant choices is also vital to control dyslipidemia. Statins are recommended as first-line agents for lipid-lowering therapy, with consideration for potential drug interactions. Other options, such as ezetimibe and nicotinic acid, may be considered as alternatives. The management of dyslipidemia in renal transplant patients mainly involves statin therapy, although the clinical effectiveness in this population is not well-documented. Lifestyle modifications, careful drug selection, and statin therapy are key components in managing dyslipidemia in solid organ transplant patients.

1. Introduction

Transplantation of organs such as the heart, lung, liver, kidney, or allogenic hematopoietic stem cells has witnessed a significant increase in recent years. However, it is important to recognize that dyslipidemias, characterized by abnormal lipid levels, can predispose transplant patients to an elevated risk of developing atherosclerotic cardiovascular disease (ASCVD) and transplant vasculopathy. This risk is further compounded by immunosuppressant induced dyslipidemia, which is commonly observed in many organ transplant recipients.1, 2, 3, 4, 5 Atherosclerosis appears to be particularly more aggressive in transplant patients and more so in heart transplant recipients. In these patients, a different type of coronary atherosclerosis—cardiac allograft vasculopathy (CAV) is found which is morphologically distinct from the usual atheromatous plaque. It is likely to be triggered by an inflammatory response and dyslipidemia which is common in transplant patients⁵

Managing dyslipidemia in transplant patients requires a comprehensive understanding of the underlying causes of lipid disturbances and careful consideration of potential drug–drug interactions and side effects. The treatment approach aims to reduce the risk of cardiovascular complications while considering the individual patient's medical history and specific transplantation-related factors.

2. Immunosuppresive drugs used in transplantation affecting dyslipidaemias

Immunosuppressive drugs can have varied effects on lipid metabolism and in general, lead to increase in Total Cholestrol, VLDL (Very Low Density cholesterol), and TG (Triglycerides), and in the size and density of LDL (low density cholesterol) particles.6, 7, 8

Dyslipidemia in transplant patients is largely induced by the immunosuppressant therapy, occurs in 27–71 % of organ transplant recipients. Immunosuppressor-mediated dyslipidaemia is characterised by an increase in LDL cholesterol, VLDL cholesterol, and/or an increase in total plasma triglycerides, mainly VLDL triglycerides. 9, 10

Apart from impacting lipids, immunosuppressants also cause hypertension (CsA and tacrolimus) hyperglycaemia and diabetes (corticosteroids, worsened by CsA, tacrolimus). However, as immunosuppressants have significantly improved survival in transplant patients, they are unavoidable and a necessary evil.

The most commonly used drugs of this class are ciclosporine (CsA) and tacrolimus. CsA increases the blood levels of all statins, caution needs to exercised when using this drug specially atorvastatin.

Atorvastatin can have adverse drug interaction with CsA, which is metabolised through CYP3A4, and may increase systemic statin exposure and the risk of myopathy. Pitavastatin and rosuvastatin are metabolised through different CYP enzymes than the others, and have less potential for interaction.¹¹

Tacrolimus is also metabolised by CYP3A4, but has less potential for harmful interaction with statins than CsA. Other drugs that influence CYP3A4 activity should be avoided if possible, and used with extreme caution in patients receiving both calcineurin inhibitors and statins.

Inhibitors of the mammalian target of rapamycin (mTOR), sirolimus, and everolimus, are strongly associated with an alteration in lipid metabolism. It has been demonstrated that patients treated with sirolimus had higher levels of total cholesterol and triglycerides compared to other immunosuppressants.¹¹

3. Management of dyslipidaemia in transplant patients

In renal transplant patients the dyslipidemia management with statins has been extensively studied as the number of renal transplants being all over the world is quite large. Underlying diseases and immunosuppressive drugs can have an effect on patients undergoing renal transplantation.¹⁰ Due to a lack of randomised trials in this population, the clinical effectiveness of statins in renal transplant patients is unknown. A systematic review of the benefits and risks of statins in patients with a functioning kidney transplant included 3465 patients from 22 studies, all of whom were free of CHD. The authors came to the conclusion that statins may reduce CV events. 12

However, in patients with a functioning renal transplant who are at increased risk of CVD, extrapolating from the clear evidence of benefit from statin therapy in people with moderate GFR reductions may be appropriate.¹³

The anti-inflammatory and immunomodulatory properties of statins, as well as their impact on endothelial function, may help with renal haemodynamics. Furthermore, reducing cholesterol levels has been shown to be beneficial in both medium- and high-risk patient populations in a number of big clinical trials.13, 14

As a general principle, statin therapy should be given to all adult kidney transplant recipients. The first dose should be low. Dose titration should be done cautiously due to potential drug–drug interactions, especially in patients on CsA.⁷

4. Recommendations for management of dyslipidemia in the solid organ transplantation

Due to the well known increase in CVD in transplant recipients, the latest ESC guidelines on dyslipidaemia consider these patients as a category in need of special attention.¹⁵

Several common underlying causes of dyslipidemia in these patients include diabetes, obesity, metabolic syndrome, and chronic kidney disease (CKD). Moreover, immunosuppressive drug regimens employed in transplantation have notable adverse effects on lipid metabolism. Glucocorticoid therapy, for instance, contributes to weight gain and worsens insulin resistance, resulting in elevated total cholesterol (TC), very-low-density lipoprotein (VLDL), triglycerides (TG), as well as increased size and density of low-density lipoprotein (LDL) particles.¹⁶

Calcineurin inhibitors, particularly ciclosporin, increase hepatic lipase activity, reduce lipoprotein lipase levels, and bind to the LDL receptor (LDLR), leading to reduced clearance of atherogenic lipoproteins. Tacrolimus, another commonly used calcineurin inhibitor, has a lesser impact on lipid profiles compared to ciclosporin. Sirolimus, a structural analogue of tacrolimus, causes dyslipidemia in nearly half of the patients receiving it.

Furthermore, treating dyslipidemia in transplant recipients reduces not only the incidence of CVD, but also other complications related to increased lipid levels such as chronic allograft nephropathy; in addition, in heart transplant recipients, keeping LDL levels <100 mg/dl has been shown to reduce the risk of developing cardiac allograft vasculopthy.⁵

Lifestyle modifications should be actively promoted as drug-induced dyslipidaemia is worsened by a sedentary lifestyle, obesity and stimulation of appetite with steroids. Consumption of the Mediterranean diet has been shown to have a significant impact on LDL and TGs.¹⁷

Deflazacort which is a commonly used steroid having less effect on insulin resistance, can improve the metabolic parameters in transplant recipients.¹⁸

Consider reducing the dosage of immunosuppressants or replacing drugs with greater hyperlipidemic effect, such as CsA and mTOR inhibitors, which have greater hyperlipidaemic effects. Steroid withdrawal showed a significant reduction in total cholesterol, LDL, and triglycerides. Furthermore, changing the immunosuppressive drug from CsA or sirolimus to tacrolimus also resulted in better control of lipid levels. 19, 20

5. Use of statins in transplant patients

Statins are recommended as the first-line agents for lipid-lowering therapy in transplant patients. Initiation should begin with low doses and careful up-titration, taking into account potential drug–drug interactions. Both Rosuvastatin and atorvastatin are used in India extensively. In cases where statins are not tolerated, ezetimibe can be considered as an alternative for individuals with high LDL cholesterol, while nicotinic acid can be an used for reducing triglycerides and increasing the high-density lipoprotein cholesterol. However, it is important to note that there are no outcome data available for these drugs, and they are generally reserved as second-line drugs only.

Statins are indicated to be used by most of the international guidelines as first-line drugs for dyslipidaemia in transplant recipients.¹⁵ However statins should be used with caution due to potential drug interactions as Calcineurin inhibitors, mainly CsA, and mTOR inhibitors are both metabolised by cytochrome CYP3A4, which is involved in atorvastatin, lovastatin, and simvastatin metabolism. CsA also acts as both an inhibitor and a substrate for permeability glycoprotein (P-gp), which also has as substrates like atorvastatin.

Due to the reasons mentioned above, concentrations of both immunosuppressants and statins can increase the risk of serious side effects of statins such as rhabdomyolysis. Statins that are metabolised from other cytochromes, such as CYP2C9 like rosuvastatin, should be used preferably in these patients.19, 20, 21 Using statins at lower dosage in combination with immunosuppressants like as tacrolimus, sirolimus, or everolimus, is an acceptable strategy to reduce the side effects. 19, 20

6. Using non statin drugs in transplant patients

Non statin drugs such as Ezetimibe is considered to be a second-line drug, used in combination with statins to lower the cholesterol levels. It has also been used as monotherapy for those patients who have statin related adverse events or intolerance in transplant patients.^15,21 However, there is no outcome data available for this drug, which should generally be reserved for second-line use after giving statins. Caution needs to be exercised while using CsA, as it can induce a 2–12-fold increase in the ezetimibe levels ²⁰ Fibrates should be used with caution as they can decrease CsA levels and also have the potential to cause myopathy. There is a need to be cautious when using fibrates, as they can lower ciclosporin levels and potentially cause myopathy. If fibrate therapy is planned in combination with a statin, extreme caution is warranted. Cholestyramine is not very effective as a monotherapy and should be avoided in these patient.¹⁵ The data with use of PCSk-9 inhibitors and bempedoic acid in this group of patients is lacking.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.