sirolimus and Dyslipidemias

Inhibitors of the mechanistic target of rapamycin (mTOR) have unique antiatherosclerotic effects, such as depletion of plaque macrophages, induction of autophagy, and activation of cholesterol efflux. However, a common side effect of their use is dyslipidemia, a well-known risk factor for atherosclerosis. Indeed, mTOR inhibitors prevent lipid storage, increase low-density lipoprotein cholesterol levels, and activate lipolysis. Although the net effect of mTOR inhibition seems favorable, the use of cholesterol lowering drugs to manage dyslipidemia remains the most recommended strategy.

Topics: Atherosclerosis; Dyslipidemias; Everolimus; Humans; Protein Kinase Inhibitors; Sirolimus; TOR Serine-Threonine Kinases

mTOR inhibitors are now approved by regulatory agencies for the treatment of a variety of malignancies. The risk of metabolic complications with these agents is not well characterized.. PubMed was searched for articles published from 2001 until 2011. Eligible studies included prospective randomized trials evaluating temsirolimus, everolimus, and ridaforolimus in patients with all solid tumor malignancies. Sixteen eligible phase II clinical trials and 8 randomized controlled clinical trials were included in a systematic review and meta-analysis and the number of metabolic related AEs (hyperglycemia, hypercholesterolemia, and hypertriglyceridemia) was extracted. Incidence rates and incident rate ratios were calculated.. Twenty-four trials, including 4261 patients, were included in the calculation of the incidence rate. The average incidence rate of all grade metabolic related events was 0.70 (95% CI, 0.47, 0.93). The average incidence rate of serious (grade 3 and 4) metabolic related adverse events was 0.11 (95% CI, 0.08, 0.15). The incidence rate ratio (IRR) of a metabolic adverse event with mTOR inhibitor therapy compared with control was 2.93 (95% CI, 2.33, 3.70) and of serious grade 3 and 4 metabolic adverse events was 4.58 (95% CI, 2.86, 7.34). The IRR of all grade hyperglycemia was 2.95 (95% CI, 2.14, 4.05) and of grade 3-4 hyperglycemia was 5.25 (95% CI, 3.07, 9.00). The IRR of all grade hypertriglyceridemia was 2.49 (95% CI, 1.76, 3.52) and of grade 3-4 hypertriglyceridemia was 2.01 (95% CI, 0.65, 6.27). The IRR of all grade hypercholesterolemia was 3.35 (95% CI, 2.17, 5.18) and of grade 3-4 hypercholesterolemia was 6.51 (95% CI, 1.48, 28.59). These findings suggest a statistically significant increase in the risk of hyperglycemia, hypercholesterolemia (all grades and grade 3 and 4), and all grade hypertriglyceridemia associated with mTOR therapy when compared with control.. The risk of all grade and grade 3-4, hyperglycemia, hypercholesterolemia, and hypertriglyceridemia, are increase in patients treated with mTOR inhibitors compared with control.

Topics: Antibiotics, Antineoplastic; Dyslipidemias; Everolimus; Humans; Hyperglycemia; Incidence; Neoplasms; Randomized Controlled Trials as Topic; Sirolimus; TOR Serine-Threonine Kinases

Statins are currently able to stabilize atherosclerotic plaques by lowering plasma cholesterol and pleiotropic effects, but a residual risk for atherosclerotic disease remains. Therefore, effective prevention of atherosclerosis and treatment of its complications is still a major clinical challenge. A large body of evidence indicates that mammalian target of rapamycin (mTOR) inhibitors such as rapamycin or everolimus have pleiotropic anti-atherosclerotic effects so that these drugs can be used as add-on therapy to prevent or delay the pathogenesis of atherosclerosis. Moreover, bioresorbable scaffolds eluting everolimus trigger a healing process in the vessel wall, both in pigs and humans, that results in late lumen enlargement and plaque regression. At present, this phenomenon of atheroregression is poorly understood. However, given that mTOR inhibitors suppress cell proliferation and trigger autophagy, a cellular survival pathway and a process linked to cholesterol efflux, we hypothesize that these compounds can inhibit (or reverse) the basic mechanisms that control plaque growth and destabilization. Unfortunately, adverse effects associated with mTOR inhibitors such as dyslipidemia and hyperglycemia have recently been identified. Dyslipidemia is manageable via statin treatment, while the anti-diabetic drug metformin would prevent hyperglycemia. Because metformin has beneficial macrovascular effects, this drug in combination with an mTOR inhibitor might have significant promise to treat patients with unstable plaques. Moreover, both statins and metformin are known to inhibit mTOR via AMPK activation so that they would fully exploit the beneficial effects of mTOR inhibition in atherosclerosis.

Topics: Absorbable Implants; AMP-Activated Protein Kinases; Animals; Apolipoproteins E; Cholesterol; Clinical Trials as Topic; Coronary Artery Disease; Drug Evaluation, Preclinical; Drug Interactions; Drug Therapy, Combination; Drug-Eluting Stents; Dyslipidemias; Everolimus; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperglycemia; Macrophages; Metformin; Mice; Mice, Knockout; Plaque, Atherosclerotic; Rabbits; Receptors, LDL; Rupture, Spontaneous; Sirolimus; Swine; Tissue Scaffolds; TOR Serine-Threonine Kinases; Triglycerides

Medical management of pancreatic neuroendocrine tumors has recently been improved by new molecules of which the mTOR inhibitor everolimus. If digestive neuroendocrine tumors are rare, the incidence is in constant increase and the prevalence in digestive cancers put them right behind colorectal cancers. Everolimus has demonstrated efficacy in unresectable and progressive pancreatic neuroendocrine tumors, by doubling the median progression free survival (11 versus 4.6 months), with a median time of exposure to everolimus of nine months. Everolimus is generally maintained until progression or intolerance and some patients are treated during several years. Potential metabolic disorders induced by everolimus (dyslipidemia, hyperglycemia) in patients with life expectancy of several years, justify monitoring of these parameters and accurate treatment management algorithm. These will avoid worsening patient's prognostic, but also prematurely discontinue potentially effective treatment or contraindicate other therapeutic weapons, in a pathology in which there are multiple therapeutic options in metastatic phase. We propose a standard practice in terms of initial assessment, monitoring, care threshold, and therapeutic objectives to manage metabolic disorders, fitted to our patients with advanced pancreatic neuroendocrine tumors.

Topics: Dyslipidemias; Everolimus; Humans; Hyperglycemia; Neuroendocrine Tumors; Pancreatic Neoplasms; Sirolimus

The mTOR (mechanistic target of rapamycin, formerly known as mammalian target of rapamycin) kinase is centrally involved in the regulation of cell growth and metabolism in response to intra- and extracellular energetic stimuli and growth factors. The importance of mTOR in health and diseases has fueled the development of molecules that inhibit mTOR signaling, including rapalogs (sirolimus, temsirolimus, everolimus and deforolimus), which complex with FK506-binding protein 12 (FK-BP12) to inhibit mTOR complex 1 (MTORC1) activity in an allosteric manner, or the more recent ATP-competitive mTOR inhibitors (mTORi), which target the catalytic site of the enzyme. However, clinical development of these mTORi has revealed that these drugs produced numerous side effects that could be serious and/or debilitating. Despite pharmacological efforts to develop drugs with an improved safety profile, these side effects are often unpredictable and may frequently preclude the efficiency of mTORi.. The objective of this review is to perform a comprehensive survey of the safety profiles of various rapalog-based therapies from the available clinical literature. The authors will discuss the potential mechanisms of these therapies, taking into account the knowledge of the biological pathways regulated by mTOR.. A better prevention and management of mTORi-related side effects requires the identification of alterations in related biological pathways that will help to delineate therapeutic targets.

Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Dyslipidemias; Everolimus; Humans; Immunosuppressive Agents; Protein Kinase Inhibitors; Sirolimus; TOR Serine-Threonine Kinases

Calcineurin inhibitor drugs (CNI) are the mainstay of modern immunosuppression in renal transplantation. However, they contribute significantly to the chronic loss of renal grafts and the high morbidity and mortality in this population due to their deleterious effects on the renal graft, cardiovascular profile and tumour pathology. Anti-mTOR drugs, sirolimus (SRL) and everolimus (EVE) are potent immunosuppressants with antiproliferative and anti-migratory capacities. These properties mean that they have a potential protective role in graft dysfunction, in renal function optimisation and the appearance of malignant tumours. Indeed, clinical trials and observational studies have demonstrated that conversion from CNI to anti-mTOR-based maintenance therapy has beneficial effects on transplant outcomes in terms of renal function, without significant increase in acute rejection rates. This review article examines the evidence of the use of anti-mTOR in the following clinical situations following renal transplantation: 1) prevention of immune dysfunction and renal function preservation in de novo renal transplantation and after early or late CNI withdrawal; 2) chronic dysfunction of the renal graft; 3) cardiovascular effects; 4) de novo post-transplant diabetes, and 5) de novo tumour pathology.

Topics: Animals; Calcineurin Inhibitors; Diabetes Mellitus, Type 2; Dyslipidemias; Everolimus; Evidence-Based Medicine; Graft Rejection; Graft vs Host Disease; Humans; Hypertrophy, Left Ventricular; Immunosuppressive Agents; Kidney; Kidney Transplantation; Models, Animal; Multicenter Studies as Topic; Neoplasms; Postoperative Complications; Randomized Controlled Trials as Topic; Sirolimus; TOR Serine-Threonine Kinases

Prognosis after cardiac transplantation continues to improve with long-term outcomes limited by malignancy and coronary allograft vasculopathy (CAV). Everolimus may potentially reduce these late term complications, while maintaining the low cellular rejection rates seen with standard therapy.. Multiple studies have demonstrated the efficacy of everolimus in reducing acute rejection in heart transplant patients, progression and development of CAV, and the prevention and treatment of common malignancies, including skin cancer and Kaposi sarcoma. This review re-examines these studies with a focus on patient tolerability and safety.. Tolerability and safety of everolimus remain a concern with pneumonitis, effusions, mouth ulcers, edema and impaired wound healing associated with morbidity and mortality. Studies have repeatedly demonstrated renal function deterioration with concomitant everolimus and a standard dose calcineurin inhibitor (CNI). This impact can be partly reduced with CNI dose reduction without an increase in the rate of rejection.. If future studies confirm reduced CAV and malignancy rates, everolimus will become an important agent in de novo and maintenance immunotherapy in cardiac transplantation. Patient centered immunotherapy is preferred to protocol-based immunotherapy as it allows tailoring of immune therapy to each individual patient's rejection risk and side profile.

Topics: Animals; Disease Susceptibility; Dyslipidemias; Everolimus; Graft Rejection; Heart Transplantation; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Diseases; Lung Diseases; Mice; Multicenter Studies as Topic; Neoplasms; Postoperative Complications; Randomized Controlled Trials as Topic; Sirolimus; TOR Serine-Threonine Kinases; Vascular Diseases; Wound Healing

The incidence, pathogenesis, consequences and treatment of mammalian target of rapamycin (mTOR) inhibitor dyslipidemia are not well described. We conducted a systematic review of randomized controlled trials reporting cholesterol and triglycerides in mTOR versus non-mTOR inhibitor immunosuppressive treatment regimens in kidney transplant recipients. All but one of 17 trials reported higher levels of cholesterol and triglycerides, or an increased prevalence of treatment with lipid-lowering agents. Approximately 60% of mTOR inhibitor-treated patients received lipid-lowering agents (2-fold higher than controls). There appeared to be little difference between dyslipidemias caused by sirolimus (14 trials) versus everolimus (3 trials). It was difficult to determine the extent to which declines in lipids over time posttransplant were due to lipid-lowering therapy, changes in doses and/or discontinuations of mTOR inhibitors. From the four trials that measured lipoproteins, it appeared that at least some of the increase in total cholesterol with mTOR inhibitors was due to increased low-density lipoprotein cholesterol. What direct or indirect effects mTOR inhibitors have on atherosclerotic cardiovascular disease in kidney transplant patients are unknown. However, in the absence of the necessary clinical trials, dyslipidemia should be managed, as it would be in nontransplant patients at high risk for cardiovascular disease.

Topics: Cholesterol; Dyslipidemias; Everolimus; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Protein Kinases; Randomized Controlled Trials as Topic; Risk Factors; Sirolimus; TOR Serine-Threonine Kinases; Triglycerides

Dyslipidemia is a risk factor for premature cardiovascular morbidity and mortality in renal transplant recipients (RTRs). Pharmacotherapy with mTOR inhibitors aggravates dyslipidemia, thus necessitating lipid-lowering therapy with fluvastatin, pravastatin, or atorvastatin. These agents may not sufficiently lower lipid levels, and therefore, a more potent agent like rosuvastatin maybe needed.. We have aimed to assess the lipid-lowering effect of rosuvastatin as compared with fluvastatin in RTR receiving everolimus. Safety was assessed as the pharmacokinetic (PK) interaction potential of a rosuvastatin/everolimus combination in RTR. A 12-hour everolimus PK investigation was performed in 12 stable RTR receiving everolimus and fluvastatin (80 mg/d). Patients were then switched to rosuvastatin (20 mg/d), and a follow-up 12/24-hour PK investigation of everolimus/rosuvastatin was performed after 1 month. All other drugs were kept unchanged.. In RTR already receiving fluvastatin, switching to rosuvastatin further decreased LDL cholesterol and total cholesterol by 30.2±12.2% (P<0.01) and 18.2±9.6% (P<0.01), respectively. Everolimus AUC0-12 was not affected by concomitant rosuvastatin treatment, 80.3±21.3 μg*h/L before and 78.5±21.9 μg*h/L after, respectively (P=0.61). Mean rosuvastatin AUC0-24 was 157±61.7 ng*h/mL, approximately threefold higher than reported in the literature for nontransplants. There were no adverse events, and none of the patients had or developed proteinuria.. Rosuvastatin showed a superior lipid-lowering effect compared to fluvastatin in stable RTR receiving everolimus. The combination of everolimus/rosuvastatin seems to be as safe as the everolimus/fluvastatin combination.

Topics: Aged; Biomarkers; Cytochrome P-450 CYP3A; Drug Interactions; Drug Substitution; Dyslipidemias; Everolimus; Fatty Acids, Monounsaturated; Female; Fluorobenzenes; Fluvastatin; Genotype; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunosuppressive Agents; Indoles; Kidney Transplantation; Lipids; Male; Middle Aged; Norway; Phenotype; Prospective Studies; Pyrimidines; Rosuvastatin Calcium; Sirolimus; Sulfonamides; Treatment Outcome

The optimal long-term regimen for immunosuppression for kidney transplant recipients is unknown. We conducted a randomized trial involving 150 kidney transplant recipients to compare tacrolimus/sirolimus, tacrolimus/mycophenolate mofetil (MMF), and cyclosporine/sirolimus. All patients received daclizumab induction and maintenance corticosteroids. Median follow-up was 8 yr post-transplant. Acute rejection (AR) occurred significantly less often among those treated with tacrolimus/MMF (12%) than among those treated with tacrolimus/sirolimus (30%) or cyclosporine/sirolimus (28%). Mean estimated GFR was consistently higher in the tacrolimus/MMF arm, especially after controlling for donor age in a multivariable model during the first 36 mo (P ≤ 0.008). The rate of dying with a functioning graft was significantly higher among those treated with tacrolimus/sirolimus (26%) than among those treated with tacrolimus/MMF (12%) or cyclosporine/sirolimus (4%). We did not observe significant differences in actuarial graft survival at 8 yr post-transplant between the groups. Patient noncompliance seemed responsible for 45% (13/29) of observed graft failures, with 11 of these occurring after 36 mo. Significantly more viral infections, protocol violations, and need for antilipid therapy occurred among patients receiving sirolimus, but we did not observe differences between the groups with regard to infections requiring hospitalization or new-onset diabetes. Taken together, these results suggest that maintenance therapy with tacrolimus/MMF is more favorable than either tacrolimus/sirolimus or cyclosporine/sirolimus.

Topics: Adolescent; Adult; Aged; Cyclosporine; Diabetes Mellitus; Drug Therapy, Combination; Dyslipidemias; Female; Florida; Graft Rejection; Guideline Adherence; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Infections; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Sirolimus; Young Adult

We designed a randomized trial to assess whether the early withdrawal of cyclosporine (CsA) followed by the initiation of everolimus (Evr) monotherapy in de novo liver transplantation (LT) patients would result in superior renal function compared to a CsA-based immunosuppression protocol. All patients were treated with CsA for the first 10 days and then randomized to receive Evr in combination with CsA up to day 30, then either continued on Evr monotherapy (Evr group) or maintained on CsA with/without mycophenolate mofetil (CsA group) in case of chronic kidney disease (CKD). Seventy-eight patients were randomized (Evr n = 52; CsA n = 26). The 1-year freedom from efficacy failure in Evr group was 75% versus 69.2% in CsA group, p = 0.36. There was no statistically significant difference in patient survival between the two groups. Mean modification of diet in renal disease (MDRD) was significantly better in the Evr group at 12 months (87.7 ± 26.1 vs. 59.9 ± 12.6 mL/min; p < 0.001). The incidence of CKD stage ≥ 3 (estimated glomerular filtration rate < 60 mL/min) was higher in the CsA group at 1 year (52.2% vs. 15.4%, p = 0.005). The results indicate that early withdrawal of CsA followed by Evr monotherapy in de novo LT patients is associated with an improvement in renal function, with a similar incidence of rejection and major complications.

Topics: Adult; Calcineurin Inhibitors; Cyclosporine; Dyslipidemias; Everolimus; Female; Humans; Immunosuppressive Agents; Kidney Function Tests; Liver Transplantation; Male; Middle Aged; Renal Insufficiency; Sirolimus

We report three-year (interim) effects of combining sirolimus (Siro) vs. mycophenolate mofetil (MMF) as adjunctive therapy with calcineurin inhibitors (CI) in renal transplantation in the three different CI-based regimens.. Between May 2000 and December 2001, 150 recipients of deceased donor (DD) and living donor (LD) kidney transplants were randomized into three groups (n=50/group): Group A (Tacro/Siro), Group B (Tacro/MMF) and Group C (CsA/Siro). This report details drug dosing and monitoring, protocol discontinuance, biopsy-proven rejection, graft failure, other adverse events, and death at 36 months postoperatively.. Actual patient and graft survival respectively in Group A was 90% and 82%, in Group B was 92% and 88%, and in Group C was 96% and 88% (not significant). Biopsy-confirmed acute rejection incidents showed a trend in favor of Group B (10%) vs. Group A (26%) and Group C (20%) combined (P=0.07). The geometric mean */SE serum creatinine concentration and arithmetic mean +/- SE Cockroft-Gault creatinine clearance calculations, respectively, were 1.39*/1.1 and 72.8+/-4.3 for Group A, 1.36*/1.1 and 72.1+/-4.1 for Group B, and 1.60*/1.1 and 61.8+/-3.8 for Group C, a statistically favorable difference for Group B over Group C (P=0.04). There was also less de novo development of posttransplant diabetes mellitus and lipid disorders in Group B vs. A and C (P<0.04).. This three-year (interim) analysis has indicated a trend towards better graft function, fewer endocrine disorders, and fewer acute rejection episodes comparing adjunctive MMF and Tacro vs. Siro and Tacro or Siro and CsA, in the dosages used.

Topics: Adolescent; Adult; Aged; Blood Pressure; Cross-Over Studies; Diabetes Mellitus; Dyslipidemias; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Kidney; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Sirolimus; Tacrolimus

Long-time use of pharmacological immunosuppressive agents frequently leads to metabolic disorders. Most studies have focused on islet toxicity leading to posttransplantation diabetes mellitus. In contrast, the link between intestinal dysbiosis and immunosuppressive drug-induced metabolic disorders remains unclear.. We established a mouse model of metabolic abnormality via sirolimus treatment. Fecal microbiota was examined using 16S rRNA gene MiSeq sequencing. Intestinal barrier function was assessed using fluorescein isothiocyanate-dextran assay and mucus immunostaining. Systemic inflammation was determined using a multiplexed fluorescent bead-based immunoassay.. Sirolimus induced dyslipidemia and glucose intolerance in mice in a dose-dependent manner. Interestingly, the clinical-mimicking dose of sirolimus altered the intestinal microbiota community, which was characterized by the enrichment of Proteobacteria, depletion of Akkermansia, and potential function shifts to those involved in lipid metabolism and the immune system. In addition, the clinical-mimicking dose of sirolimus reduced the thickness of the intestinal mucosal layer, increased the intestinal permeability, and enriched the circulating pro-inflammatory factors, including interleukin (IL)-12, IL-6, monocyte chemotactic protein 1, granulocyte-macrophage colony stimulating factor, and IL-1β. Our results showed a close association between intestinal dysbiosis, intestinal barrier failure, systemic inflammation, and metabolic disorders. Furthermore, we demonstrated that oral intervention in the gut microbiota by Lactobacillus rhamnosus HN001 protected against intestinal dysbiosis, especially by depleting the lipopolysaccharide-producing Proteobacteria, and attenuated the sirolimus-induced systemic inflammation, dyslipidemia, and insulin resistance.. Our study demonstrated a potentially causative role of intestinal dysbiosis in sirolimus-induced metabolic disorders, which will provide a novel therapeutic target for transplant recipients.

Topics: Animals; Bacteria; Cytokines; Disease Models, Animal; Dysbiosis; Dyslipidemias; Feces; Gastrointestinal Microbiome; Inflammation Mediators; Insulin Resistance; Intestinal Mucosa; Lacticaseibacillus rhamnosus; Male; Metabolic Syndrome; Mice, Inbred C57BL; Probiotics; Sirolimus

There are limited data comparing the clinical outcomes among new-generation drug-eluting stents (DES) in acute myocardial infarction (AMI) patients with dyslipidemia after percutaneous coronary intervention (PCI). We thought to investigate 2-year clinical outcomes among durable-polymer (DP)-coated stents [zotarolimus eluting (ZES) and everolimus eluting (EES)] and biodegradable-polymer (BP)-coated biolimus-eluting stent (BES) in dyslipidemic AMI patients after PCI. Finally, a total 2403 enrolled patients were divided into ZES (n = 953), EES (n = 1145) or BES (n = 305) group. The primary endpoint was major adverse cardiac events (MACE) defined as total death (TD), cardiac death (CD), myocardial infarction (MI), target lesion revascularization (TLR), target vessel revascularization (TVR) and non-TVR. The secondary endpoint was the incidence of definite or probable stent thrombosis (ST). The 2-year adjusted hazard ratio (HR) of MACE for ZES vs. EES [HR, 1.066; 95% confidence interval (CI) 0.752-1.511; p = 0.720], ZES vs. BES (HR 0.933; 95% CI 0.565-1.541; p = 0.786), EES vs. BES (HR 1.876; 95% CI 0.535-1.436; p = 0.600) and ZES/EES vs. BES (HR 0.929; 95% CI 0.591-1.462; p = 0.751) was similar. The cumulative incidences of ST were comparable (ZES vs. EES vs. BES = 1.1% vs. 0.9% vs. 1.1%, p = 0.675) and adjusted HR was not different. In addition, the 2-year adjusted HR of TD, CD, MI, TLR, TVR, and non-TVR was similar. The AMI patients with dyslipidemia receiving ZES, EES, or BES after PCI showed comparable safety and efficacy during 2-year follow-up periods. Therefore, DP-DES or BP-DES is equally acceptable in dyslipidemic AMI patients during PCI.

Topics: Absorbable Implants; Drug-Eluting Stents; Dyslipidemias; Everolimus; Female; Follow-Up Studies; Humans; Male; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Polymers; Prospective Studies; Prosthesis Design; Sirolimus; Time Factors; Treatment Outcome

In transplant patients receiving de novo anticalcineurin-free sirolimus (SRL)-based immunosuppression, we determined the influence of cytochrome P450 3A5 (CYP3A5) and ATP-binding cassette, sub-family B (MDR/TAP), member (ABCB1) genotypes on SRL blood levels and medium-term relevant clinical outcomes, in order to improve effectiveness of immunosuppression strategies when anti-mammalian target of rapamycin (anti-mTOR) inhibitor is indicated for clinical reasons.. Forty-eight renal transplant recipients (suffered 48% diabetes mellitus, 91% hypertension, and 47% dyslipidemia) were genotyped for CYP3A5 (6986A>G) and ABCB1 (3435C>T) polymorphisms by polymerase chain reaction-restriction fragment length polymorphism. Sirolimus blood levels were determined using microparticle enzyme immunoassay technique. Relationships between genotypes and pharmacokinetics, graft function, and patient-graft survival were determined by univariate analysis.. CYP3A5*1/*3 showed lower SRL levels than CYP3A5*3/*3 (4.13±1.54 vs. 8.49±4.18 ng/mL; p=0.003) and level/dose ratio (LDR) (92.74±37.47 vs. 178.62±116.45; p=0.019) in early post-transplant period. In ABCB1 polymorphisms, CT genotypes showed higher SRL levels than CC and TT (8.93±2.22 vs. 7.28±2.47 vs. 7.35±1.15 ng/mL; p=0.038) in the late period; LDR in CC and CT were 171.29±36.24 vs. 335.66±138.71 (p=0.003), despite receiving lower doses (p=0.018). Acute rejection rate was 14% vs. 42% for *3/*3 and 14% (TT), 48% (CT), and 31% (CC). Median patient survival was 45 months, significantly lower than that of *3/*3 patients (69 months). Death-censored graft survival during 5-year follow-up was similar for both CYP3A5 genotypes and significantly lower in TT than CT and CC groups, without survival differences.. CYP3A5 and ABCB1 polymorphisms influenced SRL levels; preliminary data suggest this may affect patient and graft survival. Genotyping renal transplant patients could help select candidates for SRL (genotype*3/*3 for CYP3A5 and CT for ABCB1), when anti-mTOR immunosuppression is indicated.

Topics: ATP Binding Cassette Transporter, Subfamily B; Cytochrome P-450 CYP3A; Diabetes Mellitus; Dyslipidemias; Female; Graft Survival; Humans; Hypertension; Kidney Transplantation; Male; Middle Aged; Polymorphism, Single Nucleotide; Sirolimus; Treatment Outcome

It has not been established whether the achievement of optimal medical therapy (OMT) before implantation of a drug-eluting stent has a clinical benefit for patients with stable coronary artery disease (CAD). This study included 3,004 patients with CAD treated with drug-eluting stent from 123 Japanese participating centers. The achievement of OMT was defined as control of blood pressure <130/80 mm Hg, hemoglobin A1c <7.0%, and low-density lipoprotein cholesterol <100 mg/dl. The primary end point was target vessel failure, a composite of death related to the target vessel, myocardial infarction, or clinically driven revascularization at 24 months after stent implantation. Immediately before the procedure, only 548 patients (18.2%) had achieved all 3 target criteria (the achieved OMT group), whereas the remaining 2,456 patients failed to achieve one or more criteria (the non-OMT group). At 24 months, the incidence of target vessel failure was 7.0% in the achieved OMT group versus 10.0% in the non-OMT group (hazard ratio 0.68, 95% CI 0.48 to 0.96, p = 0.03). The incidence of non-Q-wave myocardial infarction was also lower in the achieved OMT group than in the non-OMT group (0.5% vs 1.5%, p = 0.08). Multivariate logistic regression analysis identified that hemoglobin A1c <7.0% was the only protective predictor of 24-month target vessel failure (odds ratio 0.56, 95% CI 0.43 to 0.73, p <0.01). In conclusion, this study demonstrated that in patients with stable CAD scheduled for stent implantation, achievement of OMT before percutaneous coronary intervention significantly reduced subsequent cardiac events. Achievement of OMT is still insufficient in modern clinical practice.

Topics: Adrenergic beta-Antagonists; Aged; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antibiotics, Antineoplastic; Antineoplastic Agents, Phytogenic; Blood Pressure; Cholesterol, LDL; Coronary Angiography; Coronary Artery Disease; Diabetes Mellitus; Drug-Eluting Stents; Dyslipidemias; Female; Glycated Hemoglobin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Hypoglycemic Agents; Japan; Male; Middle Aged; Paclitaxel; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Proportional Hazards Models; Prospective Studies; Randomized Controlled Trials as Topic; Risk Reduction Behavior; Sirolimus

Cardiovascular disease is the most common cause of sickness and death for long-term kidney transplant recipients, and dyslipidemia is an important risk factor for developing cardiovascular disease. Lipid-lowering strategies, with the use of statins, have been shown to reduce the cardiovascular risks related to dyslipidemia, but concomitant use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors and immunosuppressive agents may increase the risk of rhabdomyolysis owing to a drug-drug interaction. We report a case of simvastatin-induced rhabdomyolysis and acute kidney injury triggered by addition of sirolimus and cisplatin-based chemotherapy to a kidney transplant recipient who had previously tolerated chronic statin therapy.

Topics: Acute Kidney Injury; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Drug Interactions; Dyslipidemias; Fatal Outcome; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunosuppressive Agents; Kidney Transplantation; Lung Neoplasms; Middle Aged; Renal Dialysis; Rhabdomyolysis; Risk Factors; Severity of Illness Index; Simvastatin; Sirolimus; Time Factors; Treatment Outcome

The optimal medication therapies are recommended in patients with coronary artery disease even after the coronary revascularization. However, the information of optimal medical therapy in dialysis population is scant. We assessed the efficacy of statin on the clinical outcomes after Sirolimus-eluting stent (SES) implantation in patients with and without dialysis.. We analyzed date from 843 consecutive patients who successfully treated with SES in our institution between August 2004 and November 2006. Among patients, 96 patients (11.4%) were undergoing dialysis. In non-dialysis patients, 405 patients (54%) were treated with statin at hospital discharge. In dialysis patients, only 16 patients (17%) were treated with statin. In non-dialysis patients, mortality rate was significantly lower in patients treated with statin than those without statin (4.4% vs. 13.9%, p<0.0001). While in dialysis patients, mortality rate was similar between patients treated with and without statin (56.3% vs. 57.6%, p=0.86). After adjusting for confounders, the hazard ratios for mortality were 0.39 (95% confidence interval (CI), 0.14-0.99; p=0.047) in non-dialysis patients and 1.79 (95% CI, 0.39-7.86; 0.45) for dialysis patients. The interaction probability between statin use and dialysis for mortality was 0.016.. The use of statin may have beneficial effect on reducing mortality rate in patients after SES implantation in non-dialysis patients. However, such favorable effect was not observed in dialysis population.

Topics: Aged; Biomarkers; Cause of Death; Comorbidity; Coronary Disease; Drug-Eluting Stents; Dyslipidemias; Female; Follow-Up Studies; Heart Failure; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kaplan-Meier Estimate; Kidney Failure, Chronic; Male; Middle Aged; Myocardial Revascularization; Proportional Hazards Models; Renal Dialysis; Retrospective Studies; Sirolimus; Treatment Outcome

New-onset diabetes after transplantation is associated with an increase in risk of graft failure, cardiovascular disease, and mortality. Therefore, it compromises the overall beneficial outcome of organ transplantation.. A patient with new-onset diabetes after renal transplantation showed glucose and lipid metabolism improvements after switching immunosuppressant from everolimus to cyclosporin A. A subcutaneous adipose tissue biopsy displayed changes in gene and protein expression that could contribute to the clinical improvement of hyperglycemia and dyslipidemia.

Topics: Adipose Tissue; Aged; Cyclosporine; Diabetes Mellitus; Dyslipidemias; Everolimus; Female; Glucose; Humans; Immunosuppressive Agents; Kidney Transplantation; Sirolimus; TOR Serine-Threonine Kinases

Hyperlipidemia is a common adverse effect of sirolimus (SRL). We previously showed significant associations of ABCB1 3435C>T and IL-10 -1082G>A with log-transformed SRL dose-adjusted weighted-normalized trough. We further examined to see whether these polymorphisms were also associated with SRL-induced dyslipidemia.. Genotyping was performed for ABCB1 1236C>T, 2677 G>T/A, and 3435C>T; CYP3A4 -392A>G; CYP3A5 6986A>G and 14690G>A; IL-10 -1082G>A; TNF -308G>A; and ApoE ε2, ε3, and ε4 alleles. The longitudinal changes of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels after SRL treatment before statin therapy were analyzed by a linear mixed-effects model, with adjustments for selected covariates for each lipid.. Under the dominant genetic model, ABCB1 3435C>T was associated with TC (P=0.0001) and LDL-C (P<0.0001) values after SRL administration. Mean TC and LDL-C levels were 26.9 and 24.9 mg/dL higher, respectively, in ABCB1 3435T carriers than 3435CC homozygotes at an average SRL trough concentration of 4 ng/mL without concomitant medication. ABCB1 1236C>T under the recessive model and IL-10 -1082G>A under the dominant model were associated with log-transformed TG values (P=0.0051 and 0.0436, respectively). Mean TG value was 25.1% higher in ABCB1 1236TT homozygotes compared with ABCB1 1236C carriers and was 12.4% higher in IL-10 -1082AA homozygotes than -1082G carriers.. ABCB1 polymorphisms were found to be associated with lipid responses to SRL treatment, confirming the role of ABCB1 gene in SRL pharmacokinetics and pharmacodynamics. Further studies are necessary to define the role of ABCB1 and IL-10 polymorphisms on SRL-induced dyslipidemia in renal transplantation.

Topics: Adult; Aged; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cholesterol, LDL; Dose-Response Relationship, Drug; Dyslipidemias; Female; Genotype; Graft Rejection; Humans; Immunosuppressive Agents; Interleukin-10; Kidney Transplantation; Linear Models; Longitudinal Studies; Male; Middle Aged; Pharmacogenetics; Polymorphism, Single Nucleotide; Retrospective Studies; Sirolimus; Triglycerides

This study analyzed the incidence, time course, and risk factors associated with dyslipidemia during the first year after kidney transplantation among patients receiving various immunosuppressive regimens.. The analysis included 474 kidney transplant recipients receiving cyclosporine (CSA) combined with sirolimus (SRL; n=137) or mycophenolate (MMF, n=58) or everolimus (EVR, n=47); or SRL combined with MMF (n=32); or tacrolimus (TAC) combined with SRL (n=86) or MMF (n=114). All patients received prednisone. We evaluated the influence of demographic features, clinical outcomes, and statin use on lipid profiles during the first year after transplantation. total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (hdl-C), low-density lipoprotein cholesterol (ldl-C), non-HDL-C, TC:HDL-C, LDL-C:HDL-C, TG:HDL-C.. Lipid profiles were within the recommended ranges in 28% of patients pretransplantation and in 10% at 1 year; 27% of them received statins. At 1 year, LDL-C<100 mg/dL was observed in 31.8% of patients but more than 35% of these patients still showed other lipid fractions or ratios outside recommended target concentrations. Among all patients with LDL-C>100 mg/dL, almost 70% to 80% had other lipid fractions or ratios within target ranges. A logistic regression analysis showed age, gender, time on dialysis, diabetes, type of calcineurin inhibitor (CSA vs TAC), adjunctive therapy (SRL/EVR vs MMF) and prednisone dose to be associated with dyslipidemia.. Dyslipidemia is frequent at 1 year after transplantation. The lack of agreement among changes observed in lipid fractions and ratios suggests that more studies are necessary to guide therapy besides targeting LDL-C concentrations as recommended by current guidelines.

Topics: Adult; Analysis of Variance; Biomarkers; Brazil; Chi-Square Distribution; Cyclosporine; Drug Therapy, Combination; Dyslipidemias; Everolimus; Female; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Lipids; Logistic Models; Male; Middle Aged; Mycophenolic Acid; Odds Ratio; Prednisone; Retrospective Studies; Risk Assessment; Risk Factors; Sirolimus; Tacrolimus; Time Factors; Treatment Outcome

Topics: Adaptor Proteins, Signal Transducing; Dyslipidemias; Hypercholesterolemia; Protein Kinase Inhibitors; Protein Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Sirolimus is a potent immunosuppressive drug that has been shown to decrease the incidence of rejection post renal transplantation. Dyslipidemia is a well recognized side effect of sirolimus therapy, which may have an impact on patient survival and post-transplant cardiac morbidity and mortality. It is unknown whether sirolimus-induced dyslipidemia is aggravated by concomitant use of tacrolimus which may also affect lipid profile. To compare sirolimus induced dyslipidemia in tacrolimus based vs. tacrolimus free regimens in renal transplant recipients.. Patients who received sirolimus post kidney transplantation for at least nine sequential months were included in our retrospective study. Forty-eight renal transplant recipients were divided into 2 groups based on the immunosuppressive regimen; Group 1 received prednisone, sirolimus and mycophenolate mofetil, while Group 2 received prednisone, sirolimus, mycophanolate mofetil and tacrolimus. Lipid profile was assessed pre-transplantation and at one, three, six and nine months post sirolimus therapy.. Both groups showed significant but comparable elevation in total cholesterol, LDL-C and triglycerides with sirolimus therapy. The elevation was evident starting from the first month of sirolimus administration and remained to the ninth month at the end of the follow up period. At first month, mean triglycerides was 2.68 and 2.6 mmol/L (P>0.1) and mean total cholesterol was 6.3 and 5.7 mmol/L in group 1 and 2 (P>0.1); respectively. By the ninth month, triglycerides level was 2.6 and 3.9 mmol/L (P>0.1) while mean total cholesterol level was 6.2 and 6.1 mmol/L (P>0.1) in group 1 and 2 respectively. Lipid-lowering agents and total steroids dose were similar in both groups.. Hypercholesterolemia and hypertriglyceridemia secondary to sirolimus therapy is independent from concomitant tacrolimus use. Lipid-profile should be monitored in all renal transplant recipients receiving sirolimus as early as first month regardless of the immunosuppressive regimen used.

Topics: Adult; Cohort Studies; Drug Therapy, Combination; Dyslipidemias; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Male; Renal Insufficiency; Retrospective Studies; Sirolimus; Tacrolimus

Statins are an established therapy after cardiac transplantation. Sirolimus (Srl) has been used successfully in cardiac transplant patients. However, potential side effects are hyperlipidemia and interactions with statins. The aim of the study was to evaluate the safety and efficacy of statin therapy after switch to a Srl-based immunosuppression.. Ninety-eight long-term patients were switched from Cyclosporine A to Srl. Also all patients received mycophenolate mofetil alone or mycophenolate mofetil plus steroid therapy. Reasons for switch were renal dysfunction, graftvasculopathy, or skin cancer. Patients were switched 7.8+/-4.7 years after transplant. Total observation period was 12 months before and after switch, respectively. Safety evaluation consisted of regular measurements of CPK and liver enzymes to evaluate the incidence myopathy and hepatoxicity. Efficacy analysis was performed by serial blood lipid assessments (low-density lipoprotein, high-density lipoprotein, total cholesterol, and triglycerides).. Forty-three percentage of patients received atorvastatin, 38% pravastatin, and 18% other drugs or therapy changes. Most lipid blood levels increased significantly after switch (cholesterol: 192.9+/-38.6 mg/dL vs. 221.8+/-49.2 mg/dL, P<0.0001; low-density lipoprotein: 108.0+/-35.6 mg/dL vs. 123.8+/-37.9 mg/dL, P<0.0001; and triglycerides: 178.3+/-88.2 mg/dL vs. 225.5+/-139.1 mg/dL, P<0.0001). Blood lipid levels after switch were not associated with statin type. Overall safety was acceptable, although incidence of myopathy doubled after switch (n=20 vs. 40; P<0.01). However, most cases were asymptomatic CPK elevations in the pravastatin group. Hepatotoxicity rate was 4% and only temporary.. Statin therapy after switch from cyclosporine A to Srl in long-term cardiac transplant patients is safe. However, regular testing of blood lipids and CPK should be mandatory.

Topics: Adrenal Cortex Hormones; Aged; Atorvastatin; Cholesterol; Cyclosporine; Dyslipidemias; Female; Heart Transplantation; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipoproteins, LDL; Male; Middle Aged; Postoperative Complications; Pravastatin; Pyrroles; Safety; Sirolimus; Treatment Outcome; Triglycerides

Sirolimus is a potent immunosuppressive agent, which is associated with dyslipidemia in clinical transplantation. The present study was undertaken to investigate the potential hepatocyte mechanisms by which sirolimus causes dyslipidemia.. Using both a quantitative assay of intracellular cholesterol and an [3H]-labeled cholesterol efflux assay, we studied the effect of sirolimus on cholesterol accumulation and cholesterol efflux in HepG2 cells in the absence or presence of inflammatory stress induced by interleukin-1beta. The gene and protein expression of molecules involved in cholesterol homeostasis were examined by real-time reverse-transcription polymerase chain reaction and Western blotting.. Sirolimus inhibited low-density lipoprotein (LDL) receptor (LDLr)-mediated cholesterol ester accumulation induced by interleukin-1beta in HepG2 cells. This inhibitory effect was mediated by down-regulation of sterol regulatory element-binding proteins (SREBP) cleavage activating protein (SCAP) and SREBP-2 mRNA expression. Using confocal microscopy, we demonstrated that sirolimus reduced translocation of SCAP-SREBP2 complex from endoplasmic reticulum to Golgi for activation, thereby inhibiting LDLr gene transcription. Reduction of LDLr in the liver may result in a delay of LDL-cholesterol clearance from circulation causing an increase of plasma cholesterol concentration. Furthermore, sirolimus increased cholesterol efflux mediated by adenosine triphosphate-binding cassette transporter A1 gene expression by increasing peroxisome proliferator-activated receptor-alpha and liver X receptor-alpha gene and protein expression. Increased cholesterol efflux from HepG2 cells may increase high-density lipoprotein cholesterol level and also contribute to apolipoprotein B lipoprotein formation by enhancing transfer of high-density lipoprotein cholesterol to apolipoprotein B lipoproteins.. This study demonstrates that the increase of LDL cholesterol by sirolimus is partly due to the reduction of LDLr on hepatocytes.

Topics: Cell Line; Cholesterol, LDL; Dyslipidemias; Endoplasmic Reticulum; Golgi Apparatus; Hepatocytes; Homeostasis; Humans; Immunosuppressive Agents; Intracellular Signaling Peptides and Proteins; Membrane Proteins; Protein Transport; Receptors, LDL; RNA, Messenger; Sirolimus; Sterol Regulatory Element Binding Protein 2

Chronic allograft nephropathy (CAN), cardiovascular mortality, and posttransplant malignancy are complications of conventional immunosuppression after kidney transplantation. The aim was to study feasibility of sirolimus (SRL) maintenance monotherapy in a pilot experience. All patients with SRL monotherapy of at least 6 months follow-up were included. In 19 patients, age 58 (34-74) years, SRL monotherapy was introduced 98.1 (49-193) months after transplantation by withdrawing concomitant immunosuppressants from protocols already including SRL or introducing SRL and withdrawing other immunosuppressants. Follow-up is 20.0 (6-41) months. One patient died from hepatocellular carcinoma, diagnosed before SRL monotherapy, with functioning graft. No rejections occurred. SRL trough concentration was 10.7 (4.6-16.1) microg/L. Creatinine (1.77 [1.0-2.9] mg/dL vs. 1.68 [0.8-3.3] mg/dL after 6 months, 1.97 [0.8-4.6] mg/dL at last follow-up; P=NS). Proteinuria increased tendentially (333 [67-893] vs. 890 [46-4011] mg/day). No significant changes of hemoglobin, triglycerides, or cholesterol occurred. SRL monotherapy late after kidney transplantation is feasible in selected patients.

Topics: Adult; Aged; Calcineurin Inhibitors; Creatinine; Drug Administration Schedule; Dyslipidemias; Feasibility Studies; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Pilot Projects; Proteinuria; Sirolimus