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| 2007 JASN IMPACT FACTOR 7.111 | HOME AUTHOR INFO EDITORIAL BOARD SUBSCRIBE FEEDBACK ALERTS HELP | |||
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Supplement Article |
Diabetes Unit, Department of Clinical and Biological Sciences, Turin University, San Luigi Gonzaga Hospital, Torino, Italy
Correspondence to Dr. Mariella Trovati, Diabetes Unit, Department of Clinical and Biological Sciences, Turin University, San Luigi Gonzaga Hospital, 10043 Orbassano (Torino), Italy. Phone: +39-011-9026612; Fax: +39-011-9038639; E-mail: mariella.trovati{at}unito.it
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Abstract |
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 Top Abstract IntroductionRecommendations for...Renal Disease Is a...Lipid Abnormalities in Diabetes...Statins and the Correction...Lipids and the Progression...Chronic Renal Failure and...Chronic Renal Failure and...Antilipidemic and...References |
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Introduction |
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TopAbstractIntroductionRecommendations for...Renal Disease Is a...Lipid Abnormalities in Diabetes...Statins and the Correction...Lipids and the Progression...Chronic Renal Failure and...Chronic Renal Failure and...Antilipidemic and...References |
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Recommendations for Hypolipidemic and Antiaggregating Therapy in Diabetes |
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TopAbstractIntroductionRecommendations for...Renal Disease Is a...Lipid Abnormalities in Diabetes...Statins and the Correction...Lipids and the Progression...Chronic Renal Failure and...Chronic Renal Failure and...Antilipidemic and...References |
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130 mg/dl. Lifestyle changes to avoid CHD events consist of increased physical activity, weight reduction. and the following dietary advice: (1) total calorie intake chosen to attain/maintain a desirable body weight and to prevent weight gain; (2) daily total fat intake 25 to 35% of total calories: (a) saturated fats (<7% of total calories) and cholesterol <200 mg/d, (b) polyunsaturated fat up to 10% of total calories, and (c) monounsaturated fat up to 20% of total calories; (3) daily carbohydrate intake 50 to 60% of total calories (predominantly from foods rich in complex carbohydrates, including grains, fruits, and vegetables); (4) daily fiber intake 20 to 30 g/d; and (5) daily protein intake 15% of total calories.
The recommendations of NCEP/APT III have been considered in the recent Position Statement of the American Diabetes Association (ADA) focusing on Management of Dyslipidemia in Adults with Diabetes (6). The pharmacologic recommendations, however, are even more aggressive. Taking into account the results of clinical trials of lipid lowering in patients with diabetes, the ADA states that (1) the LDL goal is set at <100 mg/dl: drugs should be initiated with LDL concentrations 130 mg/dl in the absence of coronary, peripheral, and cerebral vascular diseases and at LDL concentrations 100 mg/dl in their presence; (2) the decision to start a pharmacologic treatment for hypertriglyceridemia is set between 200 and 400 mg/dl depending on the clinician’s judgment; (3) in patients who show elevated concentrations of both LDL cholesterol and triglycerides, reduction of LDL cholesterol is the first priority; and (4) recommendations concerning lifestyle (moderate exercise, weight reduction, and diet) are similar to those of NCEP/ATP III (5): a particular emphasis is given to glycemic control and moderation of alcohol intake for the correction of hypertriglyceridemia.
As far as hypolipidemic drugs are concerned, the ADA considers as first-line agents statins for LDL cholesterol lowering and fibric acid derivatives for triglyceride lowering and as second-line agents bile acid–binding resins for LDL cholesterol lowering and nicotinic acid for LDL and triglyceride lowering, underlining that no clinical trial has been carried out with the second-line agents in patients with diabetes and that nicotinic acid worsens glycemic control and bile acid–binding resins increase triglyceride levels (6).
Finally, a position statement of the ADA on Aspirin Therapy in Diabetes (7) gives the following recommendations: (1) use aspirin therapy as a secondary prevention strategy in men and women who have diabetes and evidence of large vessel disease; (2) consider aspirin therapy as a primary prevention strategy in high-risk men and women with type 1 or type 2 diabetes; this includes diabetic subjects with the following: (a) a family history of coronary artery disease, (b) cigarette smoking, (c) obesity, (d) albuminuria (micro or macro), (e) dyslipidemia (cholesterol >200 mg/dl, LDL cholesterol 100 mg/dl, HDL cholesterol <45 mg/dl in men and <55 mg/dl in women, triglycerides >200 mg/dl), and (f) age >30 yr. Other points are the following: (1) clopidogrel may be considered as a substitute in case of aspirin allergy, and (2) agents that block a key platelet receptor (GPIIb/IIIa) are under study.
According to these recommendations (5–7), patients with diabetes and renal disease should (1) be treated with an adequate lifestyle, (2) be treated with aspirin already in primary prevention (because they present both diabetes and albuminuria (micro or macro), and (3) be treated with hypolipidemic drugs if LDL cholesterol is 130 mg/dl in the absence of vascular complications or 100 mg/dl in their presence or if triglycerides are >200 or >400 mg/dl according to individualized clinical evaluation. The hypolipidemic drugs should be statins if the main lipid abnormality is LDL cholesterol elevation; fibrates are contraindicated if renal disease is moderate or severe. The association between statins and fibrates should not be considered because the risk of myositis is inappropriately high in patients with renal disease.
Why should hypolipidemic and antiaggregating therapy be optimized in patients with diabetes and renal disease? Do they need particular cautions before prescribing some drugs? We will answer to these questions in the following paragraphs.
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Renal Disease Is a Cardiovascular Risk Factor "Per Se" |
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The cardiovascular risk increases further with the impairment of renal function. A study carried out by analyzing 3106 patients who were followed up after myocardial infarction at the Mayo Clinic in the 1988 to 2000 period and stratified by kidney function showed that even slight renal function reduction justifies an increased 5-yr mortality (11); in particular, the hazard ratios were 5.4 for ESRD, 1.9 for severe renal failure, 2.2 for moderate renal failure, and 2.4 for mild renal failure. Similar results were obtained by examining a national US cohort of 130,099 elderly patients with myocardial infarction stratified according to serum creatinine levels (12). Actually, the 1-yr mortality showed a twofold increase in patients with mild and a near threefold increase with moderate renal impairment. It is interesting that notwithstanding the tremendous cardiovascular risk presented by nephrotic patients, the presence of impaired kidney function reduced in both studies the intensiveness of medical and revascularization interventions, a fact that plays a role in the poor prognosis.
As mentioned before (11), ESRD provides a dramatic risk for cardiovascular events. In particular, the United States Renal Data System (USRDS) shows that atherosclerotic cardiovascular disease accounts for 55% mortality in ESRD patients in hemodialysis, the risk of CHD being increased 20-fold and the risk of stroke 10-fold when compared with general population (13). Furthermore, patients on hemodialysis show a poor outcome after myocardial infarction. Another study, carried out on the same USRDS database and considering 34,000 dialyzed patients after their first heart attack, showed that ESRD doubles the mortality risk, conferring a risk for death from a cardiac cause of 41% in only 1 yr (14). Not surprising, type 2 diabetes increases the likelihood of death in ESRD patients (14,15). Among the causes of the elevated cardiovascular risk of nephrotic patients, a particular role is played by dyslipidemia (16).
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Lipid Abnormalities in Diabetes and in Renal Disease |
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TopAbstractIntroductionRecommendations for...Renal Disease Is a...Lipid Abnormalities in Diabetes...Statins and the Correction...Lipids and the Progression...Chronic Renal Failure and...Chronic Renal Failure and...Antilipidemic and...References |
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Both remnants and small, dense LDL are very atherogenic; in particular, (1) remnants are smaller in size, more dense, and more atherogenic than larger triglyceride-rich lipoproteins (19); they promote lipid accumulation in macrophages, stimulate whole-blood platelet aggregation, and impair endothelium-dependent vasodilation, a phenomenon strictly correlated with endothelial dysfunction (20); and (2) small, dense LDL show a decreased binding capacity to LDL receptor, an increased affinity for cell surface binding sites and for arterial wall proteoglycans—which account for an enhanced penetration into the intima—and an increased susceptibility to oxidation; for all of these reasons, they have been strictly associated with the pathogenesis of both endothelial dysfunction and atherosclerosis (21,22) and have been strongly correlated with the risk of coronary artery disease (23,24). It is interesting that these alterations are even more severe in patients who have diabetes and nephropathy, both micro- and macroalbuminuric. In particular, the amount of albuminuria is closely associated with the average LDL particle size in type 2 diabetes, also independent of plasma triglyceride concentrations (25), and remnant lipoproteins are increased in patients who have type 2 diabetes and microalbuminuria (26).
Dyslipidemia is a major risk factor for atherosclerosis not only in the first stages of diabetic nephropathy but also in ESRD (27). Patients who have ESRD—also independent of diabetes—present the same cluster of lipid abnormalities that we described as the "diabetic dyslipidemia," characterized by (1) high triglyceride and low HDL cholesterol concentrations (28); (2) accumulation of "remnant particles" (29), which are strictly linked to the atherosclerotic risk also in patients with renal failure (30,31); and (3) the predominance of small, dense LDL particles (32). Cross-sectional studies show that lipid and apolipoprotein abnormalities are already present in the first phases of renal impairment and worsen as renal dysfunction progresses (33). In particular, hypertriglyceridemia is evident when the GFR is <30 ml/min, but elevations of apo CIII and reduction in the ApoA-1/Apo CIII ratio occur earlier in renal disease, as markers of impaired removal of triglyceride-rich lipoproteins (34): elevated triglycerides, apolipoprotein B, and Apo CIII, an inhibitor of LPL function, all contribute to the progression of atherosclerosis in ESRD (35). Furthermore, patients in ESRD present elevated concentrations of lipoprotein (a), which predicts coronary heart disease in these patients (36) as in the general population (37,38).
Finally, lipoproteins undergo in ESRD modifications that increase their atherogenicity, such as oxidation, carbamylation, and modification by advanced-glycosylation end products (39,40), processes that also occur in diabetes per se (41). Thus, (1) ESRD induces processes similar to those that occur in diabetes, because advanced-glycosylation end products and lipoxidation end products are detectable both in patients with diabetes (42) and in patients without diabetes on hemodialysis (43); and (2) patients who have diabetes and ESRD present an atherogenic lipid profile even more severe than nondiabetic patients with ESRD.
It should not be forgotten that in the presence of nephrotic syndrome, LDL concentrations are not only modified but also increased (44). The presence of a very atherogenic cluster of lipid abnormalities in patients with diabetes and renal disease reinforces the need of a very aggressive lipid-lowering therapy.
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Statins and the Correction of Lipid Abnormalities in Renal Disease |
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TopAbstractIntroductionRecommendations for...Renal Disease Is a...Lipid Abnormalities in Diabetes...Statins and the Correction...Lipids and the Progression...Chronic Renal Failure and...Chronic Renal Failure and...Antilipidemic and...References |
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Finally, a trial carried out only in patients with type 2 diabetes showed that atorvastatin reduces total cholesterol, LDL cholesterol, and apolipoprotein B and increases HDL cholesterol and decreases triglycerides—a 25% reduction being achieved already with 10 mg/d—thus correcting all of the abnormalities of diabetic dyslipidemia (50).
But are statins effective also in subjects with renal disease? In short-term studies, they correct lipid changes characterizing chronic renal failure and the nephrotic syndrome (51). A placebo-controlled trial that examined atorvastatin effects in dyslipidemic patients undergoing peritoneal dialysis showed that after 4 wk of treatment, approximately 85% of patients presented an LDL cholesterol value 
135 mg/dl and that after 16 wk, patients on atorvastatin continued to show reductions of total and LDL cholesterol, triglycerides, and total cholesterol:HDL cholesterol ratio and significant increases of HDL cholesterol when compared with placebo patients (52).
Statins also reduce remnant-like particles (53) that are elevated in ESRD patients. Furthermore, they correct endothelial dysfunction, stabilize plaques, and influence coagulative abnormalities (54). Plaque stabilization is a relevant therapeutic goal, because plaque instability leads to plaque rupture, platelet activation, thrombus formation, and vessel lumen occlusion, the more frequent cause of sudden cardiovascular events (55). Finally, because ESRD is accompanied by an increased inflammatory pattern, pathogenetically involved in atherogenesis (16), statins can be useful also owing to their anti-inflammatory properties (56), maintained in hemodialysis patients (57).
The so called "pleiotropic effects" of statins "beyond cholesterol lowering" (54,58) are described briefly in the next section. These effects account for the drug influence on cell proliferation, thrombosis, inflammation, endothelial function, and immunomodulation that could play a pivotal role in the control of both atherogenesis and kidney damage.
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Lipids and the Progression of Kidney Damage: The Protecting Role of Statins |
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TopAbstractIntroductionRecommendations for...Renal Disease Is a...Lipid Abnormalities in Diabetes...Statins and the Correction...Lipids and the Progression...Chronic Renal Failure and...Chronic Renal Failure and...Antilipidemic and...References |
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A meta-analysis of 13 studies—more than half in patients with diabetes—that evaluated the role of lipid lowering in the progression of renal disease in 362 patients demonstrated that lipid reduction has beneficial effects on the decline of the GFR similar to that of converting enzyme inhibitors, the effects on proteinuria being more controversial (70). The authors concluded that, if a randomized trial were to be planned, then 2600 subjects will be needed to reach a sufficient power to examine the impact of lipid reduction on progression of renal disease. This trial, however, would be unethical, because patients with renal disease show so high a cardiovascular risk that statin treatment is mandatory in the presence of hyperlipidemia (71).
As far as diabetic nephropathy is concerned, a kidney protective role of statins has been observed in some (72,73) but not in all of the studies (74). In animal models, statins prevent the development of spontaneous glomerular scarring in the obese Zucker (75,76) and Dahl "S" hypertensive rats (77).
When incubated in vitro, statins reduce proliferation of mesangial cells (78). Furthermore, the statin-induced inhibition of chemotactic factors, growth-promoting cytokines, and matrix components such as collagen and fibronectin (79) could be relevant for kidney protection, whereas the statin-induced improvement of endothelial function that occurs in only 4 wk of treatment could exert potential beneficial hemodynamic effects (80).
Finally, statins reduce T-cell cytotoxicity and might lower the incidence of acute rejection after organ transplantation (81). Thus, statins could protect kidney both by lowering LDL cholesterol and by their pleiotropic effects, likely as a result of isoprenylation processes, and involving antiproliferative effects (82).
It is known that by inhibiting 3-hydroxy-3-methyl-glutaryl CoA reductase activity, statins reduce the synthesis not only of cholesterol but also of a number of nonsterol metabolites derived from the same pathway, in particular of mevalonic acid (83). Phosphorylation of mevalonic acid gives rise to several nonsterol isoprenoids, such as farnesyl pyrophosphate and geranylgeranyl pyrophosphate, which become covalently linked to intracellular proteins and modify their function, a process named "isoprenylation" (84). In particular, farnesyl pyrophosphate and geranylgeranyl pyrophosphate modify posttranslationally some small GTPase proteins, such as Ras and Rho GTPases, which are critically involved in the transduction of signals derived from membrane receptors and modulate renal function by regulating the organization of the actin cytoskeleton, smooth muscle contraction, stress fiber formation, cell migration and cytokinesis, cell proliferation, and protection against apoptosis (85,86). Thus, statins, by inhibiting Rho prenylation and consequently the activation of Rho-kinases, could play an important role in reducing kidney damage. It should be underlined that the lovastatin ability to reduce mesangial cell proliferation is prevented by addition of mevalonate (78) and therefore is attributable to the pleiotropic effects of statins. Prevention of Rho GTPases activation by statins has been involved in the simvastatin-induced inhibition of high glucose–induced proliferation of mesangial cells, a phenomenon that plays a pivotal role in the pathogenesis of diabetic nephropathy (87). The authors concluded that these results provide a new rationale for the use of statins in early stages of diabetic nephropathy independent of cholesterol-lowering properties and that statins should be evaluated in the prevention of diabetic nephropathy.
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Chronic Renal Failure and Bleeding Tendency |
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It should be mentioned, however, that some researchers found that platelet activation is increased in ESRD patients, with formation of erythrocyte/platelet complexes, and that this phenomenon is aggravated by dialysis (92). Furthermore, recent reports indicate that predialysis patients with chronic heart failure as well as dialysis patients present an activated coagulation system, as indicated by the increased markers of activated plasma coagulation (thrombin-antithrombin complex and prothrombin fragments 1 and 2), and that this is further enhanced by dialysis sessions, which are potentially thrombophilic states (93), also because platelets are activated by the dialysis membranes. Thus, platelet and coagulation function in uremic patients on dialysis could fluctuate in pre- and postdialysis periods.
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Chronic Renal Failure and Platelet Antiaggregating Therapy |
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TopAbstractIntroductionRecommendations for...Renal Disease Is a...Lipid Abnormalities in Diabetes...Statins and the Correction...Lipids and the Progression...Chronic Renal Failure and...Chronic Renal Failure and...Antilipidemic and...References |
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The use of aspirin in patients with chronic renal failure has been debated. As already pointed out many years ago, aspirin increases bleeding time in uremic patients more than in healthy subjects (96), encouraging caution in aspirin prescription and suggesting the importance of a pharmacologic gastric protection.
Another reason of caution is the suspicion that aspirin increases the risk of renal impairment. A study described that aspirin use was associated with a risk of chronic renal failure 2.5 times as high as that for non-users; the risk increased with an increasing cumulative lifetime dose of aspirin and with an increasing average dose during periods of regular use but not with an increasing duration of use (97). Even if the possibility of bias is due to triggering of analgesic consumption by predisposing conditions, this recent study opens an old controversy (98).
Owing to all of these problems, antiaggregating agents are administered with the greatest caution in the clinical practice in patients with chronic renal failure. For instance, a survey of >130,000 elderly (65 yr old) patients who were hospitalized for myocardial infarction showed that in-hospital aspirin administration decreased from 72 to 65% and 58% according to the initial serum creatinine values of <1.5, 1.5 to 2.4, and 2.5 to 3.9 mg/dl, respectively. It is interesting that 1-yr survival decreased with the increase of creatinine levels, indicating that renal failure reduces the prognosis, whereas 1-mo mortality hazard ratios showed protective effects of aspirin in the three creatinine categories (0.40, 0.45, and 0.52, respectively) (12). The underutilization of aspirin has been considered to some extent to be responsible for the poor cardiovascular prognosis of patients with renal failure, because a consistent age-adjusted mortality rate reduction with aspirin use after myocardial infarction has been observed across all renal function groups (12,99). However, because it cannot be ruled out that patients who did not receive aspirin may have had a poor outcome owing to the comorbidity preventing the use of aspirin, it also has been suggested that further studies are needed to explore the risk-benefit ratios in these high-risk patients (100).
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Antilipidemic and Antiaggregating Therapy in Patients with Diabetes and Renal Disease: Firm Points and Controversies |
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TopAbstractIntroductionRecommendations for...Renal Disease Is a...Lipid Abnormalities in Diabetes...Statins and the Correction...Lipids and the Progression...Chronic Renal Failure and...Chronic Renal Failure and...Antilipidemic and...References |
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Obviously, no problem exists when subjects present the first stages of diabetic nephropathy, with no or mild renal function impairment and the presence of microalbuminuria. In these patients, all of the above-mentioned recommendations of the scientific societies (5–7) should be reinforced, and all of the appropriate drugs should be administered.
The problems arise when kidney function is moderately or severely reduced. Some recommendations concerning lipid-lowering therapy in these patients were proposed some years ago (51). The safest hypolipidemic drugs are certainly statins, because their tolerability profile is good. Actually, they can be used also in advanced renal failure because of prevalent gastrointestinal excretion (values ranging from 58% for simvastatin to 90% for fluvastatin, with the intermediate values of 70% for atorvastatin and pravastatin) (102). We previously mentioned the satisfactory lipid-lowering results obtained with atorvastatin in dyslipidemic patients on peritoneal dialysis (52), and we are waiting for the results of an ongoing trial examining whether lowering plasma cholesterol and triglycerides with 20 mg/d atorvastatin will decrease the incidence of cardiovascular mortality and nonfatal myocardial infarctions in 1200 patients with type 2 diabetes on hemodialysis (103). Statins should be used also in transplant recipients without relevant risks of rhabdomyolysis, provided that high doses are avoided in patients who are treated with cyclosporin (104,105).
When triglycerides are elevated and HDL cholesterol is reduced, a low-dose fibric acid derivative has been proposed if reinforced therapeutic lifestyle changes are not enough. These drugs, however, should be avoided in moderate or severe renal failure (51). In this case, the triglyceride-lowering ability of atorvastatin should be used (50,52). Furthermore, the use of fish oils could be considered. The recent recommendations from the American Heart Association concerning omega-3 fatty acids—polyunsaturated components of fish oils—and cardiovascular diseases (106) (1) state that they have been shown to decrease risk for arrhythmias, which can lead to sudden cardiac death, reduce the risk of thrombosis, decrease triglyceride and remnant lipoprotein levels, decrease rate of growth of the atherosclerotic plaque, improve endothelial function, slightly lower BP, and reduce inflammatory responses and (2) recommend that all adults eat fish at least two times a week, that patients with documented coronary heart disease eat 1 g of eicosapentaenoic acid and docosahexaenoic acid (combined) per day via consumption of oily fish or via capsules to be taken after consultation with a physician, and that eicosapentaenoic acid + docosahexaenoic acid supplement may be useful in patients with hypertriglyceridemia. Among the several studies carried out, we quote a recent investigation demonstrating that treatment with these compounds induced a 20% reduction in total mortality and a 45% reduction in sudden death in patients who survived a recent myocardial infarction over a 3.5-yr observation period (107). A small randomized and placebo-controlled trial demonstrated that short-term low-dose supplementation with polyunsaturated fatty acids is safe and able to reduce triglycerides in hemodialysis patients (108).
When both LDL cholesterol and triglycerides are elevated, statins should be considered the best choice, and the combination of statins and fibrates should be avoided, owing to the inappropriately high risk of rhabdomyolysis (51). Among statins, atorvastatin has been considered with attention, owing to its ability to reduce triglycerides and its predominant liver excretion (109). A not yet recommended but likely possible therapeutic option when statins alone are not able to induce an appropriate decrease in triglycerides is to associate fish oils.
Obviously, in the presence of moderate or severe renal failure, clinical and laboratory controls to detect drug side effects promptly should be intensified. Particular attention should be paid to the statin-induced rhabdomyolysis.
But what about the platelet antiaggregating therapy? The ADA advises to prescribe aspirin to all patients with diabetes and micro- or macroalbuminuria (7). A low-dose gastric-coated preparation should be considered at present the safest choice. Also in this case, the problems arise in the presence of ESRD, which per se confers an increased bleeding risk (88). A careful evaluation of benefits/risks should be done in these cases. When the final decision is to administer aspirin, the doses should be low, gastroprotection should be prescribed, and a careful monitoring of bleeding should be planned.
In conclusion, patients who have diabetes and renal disease present so huge a cardiovascular risk that an aggressive preventive therapy should be used. The benefits of a multifactorial intervention targeting hyperglycemia, hypertension, dyslipidemia, and microalbuminuria and including aspirin administration have been recently demonstrated by the Steno-2 Study, a clinical investigation carried out in microalbuminuric patients with type 2 diabetes: with a mean follow-up of 7.8 yr, a 50% reduction of both cardiovascular and microvascular events have been demonstrated (110). In this study, statins (atorvastatin in particular) have been used in case of isolated or combined hypercholesterolemia and fibrates in case of isolated hypertriglyceridemia (>350 mg/dl) (110). Obviously, this study does not allow differentiation of the preventive effect of each therapeutic measure but gives new strength to the efforts to optimize the treatment of patients with type 2 diabetes and first phases of renal disease to reduce both the rate of progression of kidney damage and the high cardiovascular risk.
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References |
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