Introduction
Dyslipidaemia as a cardiovascular and renal risk factor in CKD
Abnormalities of lipid profile in CKD
Consensus statement 1 | |
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Global CV risk management is a priority in CKD patients at all stages. CKD is acknowledged as a coronary artery disease (CAD) risk equivalent and complete assessment of lipid status (including total and HDL-cholesterol, triglycerides and LDL estimation) is mandatory to devise optimal therapeutic strategy |
Lipid lowering therapeutic strategies
Diet and lifestyle modifications
Statins
Target/mechanism of action | Inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase | ||
Therapeutic target | LDL-cholesterol < 70 mg/dL in patients at high CV risk and < 55 mg/dL in patients at very high CV risk [55] | ||
Potential pleiotropic effects | Pro-inflammatory cytokines and CRP reduction, increased eNOS expression and activity, ROS reduction, atherosclerotic plaque stabilization, platelet aggregation inhibition, fibrosis and left ventricular hypertrophy decrease, reduction in migration and proliferation of vascular smooth muscle cells, nephroprotection, antitumor activity, immunomodulation [56, 57] | ||
Main adverse events | Myopathy (including myositis), rhabdomyolysis with or without AKI, myalgia, muscle cramps, asthenia, hepatitis/jaundice, increased blood levels of liver enzymes, alkaline phosphatase, CPK, HbA1c, and fasting glucose | ||
CKD under conservative therapy | Haemodialysis and Peritoneal dialysis patients | Renal transplantation | |
Indications according to guidelines KDIGO [37] Joint British Societies for the prevention of CV disease [58] NICE [59] Canadian CV Society [60] ESC/EAS [55] | Estimation of CV risk not required if GFR < 60 ml/min/1.73 m2 or if albuminuria is present Indications: Adults ≥ 50 yrs with GFR < 60 ml/min/1.73 m2: statin or statin/ezetimibe therapy recommended Adults ≥ 50 yrs with CKD and GFR ≥ 60 ml/min/1.73 m2: statin therapy recommended Adults 18–49 yrs: statin therapy suggested in the presence of one or more of the following: DM, known coronary disease, estimated 10-year incidence of non-fatal MI or coronary death > 10%, previous ischaemic stroke | It is suggested not to start statin or statin/ezetimi-be therapy It is suggested to continue treatment in patients already on statin or statin/ezetimi-be therapy at the time of dialysis initiation | Statin therapy suggested |
Molecules and dosages resulted effective in clinical studies | Lovastatin (20 mg/day) [61] | ||
Simvastatin-Ezetimibe (SHARP trial) [33] | |||
Fluvastatin (10–30 mg/day) [77] | Rosuvastatin (10 mg/day) [99] | ||
Ezetimibe
EZETIMIBE | ||||
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Target/mechanism of action | ||||
Therapeutic targets in CKD | LDL-cholesterol < 70 mg/dL in patients at high CV risk and < 55 mg/dL in patients at very high CV risk [55] | |||
Potential pleiotropic effects | Enhancement of plaque regression through: inhibition of intestinal absorption of plant sterols (associated with early atherosclerosis in some studies); modulation of genes involved in inflammation and/or oxidative stress, inhibition of the differentiation of monocytes and/or macrophages, inhibition of proliferation of smooth muscle cells; inhibition of platelet aggregation and activation; modulation of atherosclerotic plaque composition [117‐123] | |||
Main adverse effects | Asthenia, myalgia, arthralgia, increased levels of liver enzymes and creatine phosphokinase, diarrhoea, dyspepsia, gastritis, headache | |||
CKD on conservative therapy | Extracorporeal dialysis | Peritoneal dialysis | Renal transplantation | |
Dosages tested in clinical studies and indications according to guidelines KDIGO [37] Joint British Societies for the prevention of CV disease [56] NICE [57] Canadian CV Society [58] ESC/EAS [55] | Ezetimibe monotherapy not recommended Adults ≥ 50 yrs with GFR < 60 ml/min/1.73 m2: statin or statin/ezetimibe therapy recommended | It is suggested not to start statin or statin/ezetimi-be therapy It is suggested to continue treatment in patients already on statin or statin/ezetimi-be therapy at the time of dialysis initiation | Ezetimibe 10 mg + simvastatin 10 or 20 mg/day [33] | No specific indication for ezetimibe therapy |
Fibrates
FIBRATES | |
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Target/mechanism of action | Fibrates interact with the liver peroxisome proliferator activated receptors (PPARs isotype-α), increasing the lipoprotein lipase activity and decreasing the synthesis and serum levels of triglycerides |
Targets in other diseases | Reduction of triglycerides by 35–50%, increase in HDL-cholesterol by 5 (mono-therapy) to 20% (patients with triglycerides > 500 mg/dl) |
Potential pleiotropic effects | The fibric acid derivatives may lower serum fibrinogen levels. Fenofibrate reduces serum uric acid levels. |
Main adverse effects | Fairly well tolerated. Rare gastrointestinal symptoms, urticaria, myalgias (mainly in combination with statins); transaminases and alkaline phosphatase minor increase; increase in bile lithogenicity Fibrates have been linked to creatinine increase but these changes may be related to a class effect of other PPARs isotype- α agonists |
Drug interaction | Possible enhancement of oral anticoagulant effects (warfarin) Fenofibrate may increase the clearance of cyclosporine and reduces serum cyclosporine levels (in heart transplant patients) |
Recommendations | Fibrates may be second-line agents to reduce triglycerides in nephrotic syndrome The combination of fibrate and statin should be avoided (myositis) Bezafibrate is primarily excreted by the kidney and should be avoided in CKD A close monitoring of serum creatinine is mandatory during fenofibrate treatment, mainly in elderly, diabetic, high-risk patients and discontinuation of the drug should be suggested for a creatinine increase > 30%. Fenofibrate should be used with caution in renal transplant recipients on cyclosporine whose levels have to be regularly monitored Fibrates are contraindicated in patients with GFR < 15 mL/min/1.73 m2) |
Bile acid sequestrants
Bile acid sequestrants | |
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Target/mechanism of action | They bind the bile acids in the intestine, reducing the lipids solubilisation and the absorption of cholesterol. They reduce the reabsorption of bile acids, increasing their liver synthesis and reducing the LDL-cholesterol. The increase in bile-acid production causes the increase of triglyceride synthesis in the liver |
Targets in other diseases | Reduction of LDL-cholesterol by 10–15% (25% at maximum dosage, but with low gastrointestinal tolerance). One report focusing on colestipol described a decrease of LDL-cholesterol up to 30% in patients with nephrotic syndrome |
Main adverse effects | Bloating and constipation at the maximal dosage (low compliance). Increased serum triglyceride levels (transiently when triglycerides are at normal levels; contraindicated with triglycerides > 250 mg/dl). These drugs are chloride salts and hyperchloremic acidosis may be possible (rarely); volume depletion, renal failure and use of spironolactone may increase this risk |
Drug interaction | These drugs may interfere with the absorption of many other drugs (i.e. thiazides, furosemide, propranolol, thyroxine, digoxin, warfarin, etc.); Colesevelam seems to interfere less than other drugs of the same class with the pharmacokinetics of other medications |
Recommendations | In CKD every stage the bile acid sequestrants may be proposed as second-line agents in association with other lipid-lowering drugs in patients with incompletely controlled LDL-cholesterol levels and normal triglycerides It is recommended to assume other medications 1 h before or 3–4 h after bile acids sequestrants |
Omega-3 fatty acids
PCSK-9 inhibitors
Consensus statement 2 | |
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Therapeutic inertia is common in lipid management of CKD patients. LDL reduction should be considered as the primary target of therapy and pharmacologic intervention using statins with or without ezetimibe is recommended in all patients with stage 3–4 CKD irrespective of baseline values to achieve CV protection. The effect of lipid-lowering treatment on proteinuria and renal disease progression requires further evaluation. |
Therapeutic targets of LDL-cholesterol and triglycerides
Guideline | Population | CKD stage | Treatment recommendations |
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KDIGO (2013) | Adults ≥ 50 years | 1–2 | Statin |
3–5 (not on dialysis) | Statin; Statin + Ezetimibe | ||
Adults 18–49 years + ≥ 1 of the following: 1. known coronary disease 2.DM 3. Prior ischemic stroke 4. estimated 10 years incidence of coronary death or non fatal MI > 10% | 1–5 (not on dialysis) | Statin | |
Adults with dialysis-dependent CKD | 5 (HD or PD) | Statins or statin combinations should not be initiated; they can be continued if already received at the time of dialysis initiation | |
Adult kidney transplant recipient | 1–5 | Statin | |
ACC/AHA (2018) | Adults with clinical ASCVD | 1–5 (not on dialysis) | High-intensity statin preferred; moderate-intensity statin if not a candidate for high-intensity |
Adults with LDL-cholesterol ≥ 190 mg/dL | 1–5 (not on dialysis) | High-intensity statin preferred; moderate-intensity statin if not a candidate for high-intensity | |
Adults 40–75 years with DM and LDL-cholesterol 70–189 mg/dL (no ASCVD) | 1–5 (not on dialysis) | High-intensity statin if estimated 10-years ASCVD risk ≥7.5%; moderate-intensity statin if not a candidate for high-intensity | |
Adults 40–75 years with estimated 10-years ASCVD risk ≥ 7.5% (no DM or ASCVD) | 1–5 (not on dialysis) | Moderate- or high-intensity statin | |
Adults with dialysis-dependent CKD and kidney transplant recipients | 5 (HD or PD) or 1–5 in kidney transplant recipient | No recommendation | |
ESC/EAS (2019) | Adults | 1–5 (not on dialysis) | Statin; Statin + Ezetimibe |
Patients with dialysis-dependent CKD and free of atherosclerotic CVD | 5 (HD or PD) | Statins should not be initiated; in patients already on treatment at the time of dialysis initiation, these drugs should be continued, particularly in patients with CVD | |
Adult kidney transplant recipients | 1–5 | Treatment with statins may be considered |
Consensus statement 3 | |
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Patients with stage 3 CKD are considered to be at high risk and patients with stage 4–5 CKD or on dialysis at very high risk In the setting of non-dialysis CKD, goal of therapy is LDL < 70 mg/dL in high risk CKD patients and < 55 mg/dL in very high-risk patients. |