Type 1 diabetes.Compositional changes in Lipoproteins.
Type 2 diabetes mellitus. Patterns of dyslipidaemia.
Clinical significance of dyslipidaemia in DN.
TREATMENT OF HYPERCHOLESTEROLEMIA IN TYPE 2 DIABETIC PATIENTS WITH DIABETIC NEPHROPATHY. EXPERIENCE BELLVITGE´S HOSPITAL.
Conclusions

Introduction.

Diabetic Nephropathy (DN) is one major complication of diabetes mellitus. In occidental countries, DN is currently the most single important cause of end-stage renal failure. In USA, DN represents 35%-37% of all patients with ESRF initiating renal replacement therapy. In Europe the data of EDTA show that this percentage is around 20%. In Spain, the SEN registry of 1998 shows that 20% ofthe patients initiating renal substitutive therapy were diabetics.

In addition to hypertension, glycemic control and genetic influence, diabetic dyslipidaemia seems to play an important role in the pathogenesis and progression of vascular disease in the diabetic patient and it is under discussion if it plays a role in the evolution of DN.

About 30 to 40% of Diabetes Mellitus (DM) patients develop overt DN which additionally impairs lipidic metabolism. In early and advanced stages of DN lipid disorders may be present. Lipidic metabolism in DM may also be altered when renal replacement therapy is instituted.

The risk of death from coronary heart disease (CHD) is substantially increased in DN patients compared with normal subjects or patients with diabetes without nephropathy (1). Increased levels of triglyceride-rich lipoproteins have been reported in diabetic patients and this atherogenic profile becomes more apparent when DN is present (2).

Atherosclerosis is the main cause of mortality in diabetic patients and, therefore, a better understanding of lipid abnormalities and their pathophysiology in diabetes is a prerequisite for successful prevention of CHD.

Hormones act at multiple sites in lipoprotein metabolism, being powerful modulators of serum lipids and lipoproteins (3).

Physiology of lipid metabolism.

 In order to better understand the deranged metabolism of lipoproteins in DN, we need to consider the normal pathway of the lipoprotein particles.

Triglycerides are delivered to the periphery from the intestine as chylomicrons and from the liver as very-low-density lipoproteins (VLDL). Chylomicrons contain the intestinal apolipoprotein B-48 whereas VLDL contain the liver-specific apo B-100. After taking up apo C-II and apo E from high density lipoproteins (HDL), the triglycerides bound to chylomicrons  and VLDL are rapidly  hydrolized by the action of lipoprotein lipase (LPL) in fat and muscle tissue. The remnants of chylomicrons are taken up via the hepatic apo E receptor. VLDL particles are transformed to intermediate density lipoproteins (IDL) and after that depletion of splacnic triglycerides by hepatic LPL produces low-density lipoproteins (LDL).  Apo C-II and apo E are transferred during this process to HDL particles. LDL are taken up by a receptor-dependent mechanism (apo B/E receptor) in the liver. Free cholesterol in the peripheral circulation is transferred by lecitin-cholesteryl-acyl-transferase into HDL. This is known as  reverse cholesterol-ester transport. Lipoproteins are delivered to hepatic tissue by the action of a cholesteryl-ester-transfer protein.

Type 1 diabetes. Compositional changes in lipoproteins.

Patients with type 1 DM usually have normal concentrations of the major lipoproteins. LDL and VLDL are normal or subnormal, whereas HDL are normal or increased. The degree of glycemic control is an important  determinant of serum lipoprotein concentrations in DM.  Cholesterol concentrations fall by 0.1 mmol (2,2%) and triglycerides  by 0.08 mmol (8%) for each percentage-point fall of glycohaemoglobin. Intensive insulin treatment improves  even the normal concentration of serum lipoproteins. Conventional insulin therapy results in peripheral hyperinsulinemia  whereas insulin concentration is less than normal in portal circulation.

Although the concentrations of serum lipids and lipoproteins in type 1 DM could indicate a less atherogenic profile than those  of non-diabetic subjects, compositional alterations of lipoproteins may be atherogenic in type 1 DM. Lipoprotein particles  display abnormalities in surface versus core lipid distribution. Type 1 DM patients have a high free cholesterol/lecitin ratio in plasma and VLDL-LDL fractions. These abnormalities  may interfere with lipid transport between lipoproteins  and consequently the remodelling of lipoprotein particles. The concentration of phospholipids in HDL is abnormal. The increased cholesterol/lecitin ratio in HDL may impair the capacity of HDL particles to act as receptors for cellular free cholesterol in the reverse cholesterol transport process. LDL subclass abnormalities are present in these patients, - especially in patients with poor glycemic control-,  and these alterations are associated with CHD. Also a relative increase in triglycerides  but a decrease in cholesteryl esters have been observed, as well as a reduction in the apo B/remaining protein (apo Cs+apo E) ratio, indicating an excess of apo C and apo E over apo B. It has been shown an increase of free cholesterol in VLDL. On the other hand, IDL  in type 1 DM patients stimulates cholesteryl ester synthesis and accumulates more than in  normal LDL in human macrophages.

Type 1 diabetics with overt DN  could exhibit an elevated serum  lipoprotein (a) (4).

Type 2 diabetes mellitus. Patterns of dyslipidaemia.

In type 2 DM patiens, moderate hypertriglyceridaemia  with reduced levels of HDL cholesterol is common. Synce glycaemic control is often insufficient, serum triglycerides are elevated. A correlation of hyertriglyceridaemia with glycemic control and obesity can be found. There exists an enhanced hepatic VLDL secretion and dimished VLDL and chylomicrons clearance. The increase in triglyceride-rich lipoproteins induces a mild elevation in total serum cholesterol.. In the case of poor glycemic control, total cholesterol is increased due to an accumulation of LDL.

Chylomicron metabolism.

A decrease clearance of apo B produce hyperchylomicronaemia, due to a reduced activity of LPL. Hyperchylomicromaemia contributes to the hypertriglyceridaemia.

VLDL metabolism.

There exists  an elevation of triglycerides in VLDL. The insulin-resistant state impairs the normal suppression of fatty acids release from adipose tissue in the post prandial state. Insulin resistance enhances hepatic VLDL triglyceride secretion. Biochemical examination of VLDL particles revealed large triglyceride-rich particles. Their  apolipoproteins undergo glycation depending on the quality of glycemic control. Type 2 diabetics exibit a high triglyceride-apo B ratio and an increased apo E.

IDL metabolism.

Joven et al (5) have demonstrated an increase in both cholesterol and triglyceride concentrations of IDL in type 2 diabetics with DN. Increadsed IDL could play a role in the progression of renal failure

(6).

LDL metabolism.

Type 2 DM patients with good or reasonable glycemic control exhibit LDL cholesterol concentrations similar to non-diabetic subjects. In patients with moderately severe diabetes LDL catabolism is impaired. LDL  contains an increased proportion of triglycerides, which impairs their receptor specific uptake. The prevalence of small, dense LDL, glycation of LDL and oxidative modification might contribute to the increase in LDL in poorly controlled diabetic patients. Increased LDL may promote nephropathy and atherosclerosis(7-9).

Glycation of LDL and advanced Glycation end-products (AGEs)

In diabetes, glucose is non-enzymatically bound to lysine in a variety of proteins. Glycation of Apo B alters its biological activity, reduces its affinity to the LDL receptor and interferes with its metabolism, with an accumulation in the circulation. The condensation reaction produces Schiff base intermediates that undergo Amadori rearrangement resulting in the irreversible development of advanced glycation end-products (AGEs). AGEs promote diabetic complications.

Colagen modification by AGEs is cappable of trapping lipoproteins inducing glycoxidative changes and lipid peroxidation. Glycation  and AGEs formation leads to a modification of lipoproteins, wich impair receptor-specific uptake. This leads to accumulation and further modification of lipoproteins closing a vicious circle.

Indeed an AGE,  carboxymethyllysine, accumulates in expanded mesangial matrix and nodular lesions in the kidney. An advanced lipoxidation end product (ALE), malondialdehyde-lysine (MDA), generated  on proteins during lipid peroxidation  also accumulates in these lesions. Both, ALE and AGE are formed by carbonyl amine chemistry between protein and  carbonyl compounds. Their colocalization suggests an increased carbonyl modification of proteins. The examination of human diabetic renal tissues by Miyata et al (10) have demonstrated an intracellular protein-tyrosine phosphorylation in the presence of various kinds of carbonyl compounds. These data suggest a carbonyl-stress participation in diabetic glomerular lesions.

Oxidation of LDL. The lysine groups of the apoproteins are oxidized through free oxygen radicals from carbohydrate molecules. Glycated LDL, and specially small dense LDL,  are even more susceptible to oxidation modification. Oxidized modified lipoproteins could be direct mediators of glomerular injury and might promote diabetic nephropathy. Furthermore,  lipid modification and peroxidation are important promoters of atherosclerosis.

The size and density of LDL is influenced by changes in triglyceride content. Since triglyceride enrichment of LDL modulates particle size and density, small dense triglyceride-rich LDL subfractions are elevated in type 2 DM. Diabetic hyperinsulinaemia and insulin resistance might also  promote the formation of small dense LDL. Small-dense LDL subfractions exhibit enhanced susceptibility to oxidation, which enhances modification.  Small-dense-oxidized LDL show reduced cellular uptake via the LDL receptor leading to an accumulation in the vascular system.

HDL metabolism.

A decrease in HDL  by up to 20% in type 2 diabetes with altered composition of HDL have been described. HDL  particles contain an increased proportion of triglycerides, with  a faster catabolic rate that leads to a lower number of circulating HDL. The decreased LPL activity limits the cholesterol transfer from VLDL to HDL and slows down HDL metabolism. The  decrease in HDL is mostly accounted  for the decrease in the HDL2 subfraction, increasing the concentrations of small dense HDL3 subfractions. HDL metabolism might additionally be influenced by alterations in the size of HDL.

Apolipoproteins.

In diabetes lipoproteins undergo non-enzymatic glycation involving their lysine residues. The glycation af apo B seems to play a major role in impairment of LDL metabolism. Apo B and apo C-II, as well as apo C-III/C-II ratio are increased.since apo C-II is an activator of LPL and apo C-III inhibits LPL and hepatic chylomicron uptake, these findings are consistent with  impaired chylomicron and VLDL metabolism.

Lipoprotein (a).

In contrast to type 1 DM, Lp(a) does not seem to be increased in type 2 DM. Some authors describe reduced levels of Lp(a).  Increased levels are observed in ESRD.

Influence of Renal Replacement Therapy.

Data are contradictory. Some authors describe a reduction of VLDL triglyceride levels in maintenance haemodialysis. An improvement of lipoprotein profile with the use of polysulphone membranes have been described by Seres et al(11). High-flux membranes could induce  an increase in HDL and a reduction of apo C-III (12).

Continuous Ambulatory Peritoneal Dialysis (CAPD) induces important increases of LDL and triglycerides, probably due to the loss of proteins via the peritoneum. The use of recombinant human erythropoetin could induce a decrease in  total cholesterol and apo B.

Clinical significance of dyslipidaemia in  DN.

Impact of dyslipidaemia on the pathogenesis of cardiovascular disease.

Cardiovascular mortality is two to three times more frequent in DM patients than in non-diabetes population. The development of DN accelerates vascular damage inducing CV morbidity and mortality in both type 1 and type 2 DM. The major risk factors for CHD also opperates in DM patients.There is a complex relationship between risk factors, specially when DN is present.

The Multiple Risk Factor Intervention Trial (MRFIT)(13) has shown that the risk  for developing CV events is  two to four times increased in diabetics.

Many authors have found that hypertrygliceridaemia is an independent risk factor for CHD. Uusutipa et al (14) demonstrated that in addition to hypertriglyceridaemia, composition abnormalities of lipoproteins are related to CV mortality.

Laakso et al (15) found a correlation between low HDL and CV mortality in  313 type 2 diabetics followed for up to 7 years. Lehto et al(16) demonstrated that low HDL, hypertriglyceridaemia and poor glycemic control were strongest predictors of CHD in 1059 type 2 diabetes patients.

The 4S study, analysing 202 diabetics revealed that the absolute clinical benefit achieved by cholesterol-lowering therapy was greater in DM than in non-diabetic patients wih preexisting CHD (17).

In the Cholesterol and Recurrent Events  (CARE) study, the treatment with pravastatin reduced the risk of recurrent vascular events. The risk reduction was similar in the subgroup of diabetic patients (n=586) compared to non-diabetic patients (18).

Potential role of lipids in the progression of DN.

Dyslipidaemia has been involved in the development of  direct renal injury in animal models. The treatment of hyperlipidaemia has led to an improvement of glomerular injury in both diabetic and non-diabetic  renal disease.

The altered serum lipoproteins interact with structures of the glomerulus. Glycooxidated modified LDL  exhibited enhanced binding to glycosaminoglycanes of the glomerular basement membrane, inducing an increased poermeability  of these membrane.. The deposition of modified LDL particles in the mesangium induce chemotactic signals for macrophages  and stimulate mesangial cell proliferation. The scavenger-receptor uptake of these modified LDL particles by monocyte and macrophages  is responsible for the formation of glomerular and mesangial foam cells.

The mesangial expansion could be induced by other mechanisms: the accumulation of apo B and apo E leading to a reduction in the glomerular filtration area, an alteration in renal cortical tissue lipids or in the  membrane fluidity and function due to a disturbances in fatty acids concentrations  and alterations in glomerular haemodynamics.

Hyperlipidaemia has been identified as a risk factor  for developing a more rapid decline in GFR and increased mortality in diabetic nephropathy patients.

High triglycerides and low HDL cholesterol has been associated with

more rapid progression of microalbuminuria  in type 2 diabetes with well controlled blood pressure.  Hypertriglyceridaemia and hypertension seems to have a sinergistic effect on the decline of GFR . Some authors (19) have found a more rapid deterioration of renal function in type 1 diabetic patients with total cholesterol above 7 mmol/l when compared with patients with total cholesterol under 7 mmol/l. ACE inhibition associated with lower serum cholesterol was superior to metoprolol associated with higher cholesterol levels in preventing deterioration of renal function  in type 1 patients with DN.

The treatment with HMGCoA reductase inhibitors seems to be effective in the prevention of the decline of the renal function for some authors. Nevertheless, results are controversial (20-30). (See table 1).

Further prospective studies are required to prove the relevance of cholesterol-lowering therapy in retarding the progression of  DN.

Management of lipid disorders in diabetic nephropathy patients.

Dyslipidaemia is closely related to the progression of cardiovascular disease in diabetic patients. Various guidelines giving treatment goals have been published. Since the risk for CHD is excessive in diabetic patients,  recommendations of an aggressive therapy to lower LDL cholesterol levels in non diabetic patients with well established CHD can also be extended to diabetic patients. The US Adult Treatment Pannel II of the National Cholesterol Educational Program (NCEP) recommended that the level of LDL-cholesterol should be 2,6 mmol/l (100 mg/dl). Lipid -lowering drug therapy should be initiated if the LDL-cholesterol level is greater than 3.4 mmol/l (135 mg/dl. Non-HDL must be decreased to less than 4 mmol/l (160 mg/dl) in diabetic patients with total cholesterol > 5,5 mmmol/l. In patients without CHD, lipid lowering therapy should be considered  when serum cholesterol exceeds 6,5 mmol/l (260 mg/dl) (31). (See table 2).

When regarding the potential benefits of lowering hypertriglyceridaemia, the American Diabetes Association (32) recommends the initiation of drug therapy when triglycerides are higher than 4.5 mmol/l (400 mg/dl). In the presence of CHD, pharmacological therapy must be considered when triglycerides are higher than 2.3 mmol/l ( 200 mg/dl) or when triglycerides are higher than 1,7 mmol/l (150 mg/dl) in the presence of clinical vascular disease.

Diabetic nephropathy patients are at high risk for cardiovascular disease, due to microalbuminuria or  overt proteinuria. So it is recommendable  to treat these patients using guidelines for secondary prevention. LDL cholesterol above 3.4 mmol/l  (135 mg/dl) should be lowered to less than 2,6 mmol/l (100 mg/dl) and triglycerides  should be below 1,7 mmol/l (150 mg/dl).

Dietary recommendations.

The  dietary  counselling must take into account the excessive weight, presence of hypertension or renal insufficiency. It is necessary to achieve near normal glycemia. Fat should be reduced to 30% or less of total energy intake, saturated fat representing no more than one-third  of total fat intake, increasing the use of monounsaturated and polyunsaturated fats. In insulin-resistant type 2 diabetics low-fat diet may have a deleterious effect on dyslipidaemia. So  in these patients a low carbohydrate diet enriched with monounsaturated fatty  acids constitutes an alternative approach. A Mediterranean diet enriched in fresh fruits and vegetables is recommended, except in the case of renal failure and hyperkalemia.

Glycemic control.

To improve glycaemic control is mandatory. The use of oral hypoglycaemic agents or insuline reduces the plasma triglyceride levels. HDL cholesterol levels tend to increase  with the improvement of glycaemic control. Optimizing blood glucose control by insulin treatment reduces small dense LDL particles. The use or oral hypoglycaemic agents should be necessary but biguanides are contraindicated in the presence of renal insufficency. In this case, acarbose or metphormin should be preferred. Troglitazone can reduce  in vitro HDL and LDL oxidation.

Dialysis.

Haemodialysis reduces VLDL triglyceride levels, but abnormal VLDL remnant metabolism persists during long-term dialysis. High-flux polysulphone membranes decrease total and VLDL triglycerides. The use of biocompatible membranes, such as polyacrilonitryle can increase LPL  activity, inducing a removal of a circulating inhibitor of LPL, such as apolipoprotein C III.

Peritoneal dialysis induces hypertriglyceridaemia, due to  high glucose concentrations of the peritoneal solutions and to the loss of proteins via peritoneum.

Pharmacological treatment. (Table 3 and 4).

Some hypolipidaemic agents could have deletereous effects in diabetic patients. Nicotinic acid aggravates insulin resistance leading to a deterioration in glycaemic control. Bile acid-binding resines tend to increase  serum triglycerides . Acipimox, a nicotinic acid derivative,  can be useful in hypertriglyceridaemic patients.

Fibric acid derivatives. These agents improve LPL activity and inhibit hepatic synthesis of VLDL cholesterol, reducing the level of  triglycerides and increasing HDL cholesterol. Fibrates do not adversely affect the glycaemic control and could descrease plasma fibrinogen levels. However, fibrates are primarily excreted by the kidney and accumulate  in renal insufficiency. The risk of side effects is increased and rhabdomyolysis could appears. Bezafibrate need to be reduced to 200-400 mg/week. Gemfibrozil at low to moderate doses could be well tolerated. Nevertheless we recommend not to use these drugs in patients with moderate to severe renal insufficiency.

Fish oil is effective on hypertriglyceridaemia in combination with a fibric acid derivative or acipimox, not having influence on glycaemic control. However the doses needed to be effective, 6 to 12 capsules and the taste make it unlikely to be tolerated for prolonged periods.

ACE inhibition. Reducing proteinuria lowers hypercholesterolemia. Some studies have demonstrated that the reduction of proteinuria  by ACE inhibitors  improves lipidic profile and decrease the level of lp(a) (33).

Statins.  HMGCoA reductase inhibitors are the drugs of choice in patients with elevated LDL cholesterol. These drugs are effective in reducing total cholesterol and LDL cholesterol in diabetic and non diabetic patients with chronic renal insufficiency (34). Statins are also effective in lowering atherogenic intermediate density lipoproteins (IDL). In patients with severe renal failure statins are safe and effective. Nevertheless, maximal doses  should  be use with caution in these patients.

Some cases of elevation of AST, ALT or CPK have been reported. Rhabdomyolysis is rare, but can occurs in  patients concomitantely treated with anticalcineurinic agents (35). In these patients renal  and liver function must be carefully monitored.

Other hypolipidaemic drug treatments.

Nicotinic acid and niacine are not very effective on LDL cholesterol. An impairement in both  glycemic control and  hypertrigly ceridemia is possible under its treatment. Doses usually range from 3 to 6 gr/day.

Probucol is not very effective on LDL cholesterol. Usual doses range from  1 to 2 gr/day.

The antioxidant effect of  vitamin C and E has been recognized as a very important tool in order to decrease the oxidizability  of LDL cholesterol. Concomitant treatment with virtamin C and E could  minimize atherogenesis in diabetic nephropathy patients.

Combined treatment.

The combination of statins plus resin cholestiramine is possible. The combination of statins plus fibric acid derivatives is possible, too, but carries a high risk of rhabdomyolysis.

Summary.

Type 1 and type 2 diabetes patients are at high risk of vascular disease. Diabetes patients with concomitant diabetic nephropathy are especially devoted to cardiovascular complications due to the presence of microalbuminuria or proteinuria, that are potent inductors of hypercholesterolemia.

Since dyslipidaemia is closely related to the progression of cardiovascular disease, an aggressive lipid-lowering therapy is recommended, irrespectively of its potential effect on diabetic nephropathy.

The management of diabetic dyslipidaemia should involve attempts to improve glycemic metabolic control, - that is as important in type 1 diabetes as in type 2 diabetes-, weight reduction, exercise , an appropriate diet and hypolipaemic drugs when necessary to achieve the treatment goals of current guidelines.

It has been established that HMGCoA reductase inhibitors are preferable when renal dysfunction is established, being less efficient on hypertriglyceridaemia than fibric acid derivatives. These are agents more potent to lower triglycerides, but its use must be avoided in the case of moderate to severe renal failure.

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TREATMENT OF HYPERCHOLESTEROLEMIA IN TYPE 2 DIABETIC PATIENTS WITH DIABETIC NEPHROPATHY. EXPERIENCE OF  BELLVITGE´S HOSPITAL.

Patients and Method.

We have done an open not randomized  study, with two control groups, analysing 98  type 2 diabetic patients, 61 male and 37 female, mean age 63+16 year old. All of the patients were  diagnosed of DN on the basis of proteinuria above 500  mg/day and the presence of diabetic retinopathy. In the patients without diabetic retinopathy we  performed a kidney biopsy, their pathological diagnosis  being consistent with diabetic nephropathy.

The patients were divided into 4 groups:

- Group I(n=13): hypercholesterolemic patients ( total cholesterol > 6.25 mmol/l = 250 mg/dl) treated with fibric acid derivatives.

- Group II (n=52): hypercholesterolemic patients treated with HMGCoA reductase inhibitors.

- Group III (n= 20) : hypercholesterolemic patients, treated only with fat restriction diet (hypercholesterolemic control group).

- Group IV (n=13): : patients in whom serum total cholesterol maintained under normal limits (< 5,2 mmol/l= 210 mg/dl) along the follow-up, independently of the evolution of HDL and LDL cholesterol levels (normocholesterolemic control group).

Characteristics of the patients are shown in table 5. Biochemistry and haemathology were obtained at 3 month intervals. Lipidic parameters were obtained at  6 month intervals. Apo A1 and Apo B lipoproteins were determined yearly.

An American Heart Association  step 1 cholesterol-restriction diet was instituted for three months. Statins or fibrates treatment was started when total cholesterol was above 6.25 in two consecutive observations. When total cholesterol maintained between 5,2 and 6,25 mmol/l, only diet and moderate exercise were recommended , with the exception of patients with previous CHD. In these cases, if total LDL cholesterol was above 3,4 mmol/l (135 mg%) pharmacologic treatment was started, too.

Lipidic profile.  VLDL and LDL were separated by preparative sequential ultracentrifugation. HDL cholesterol was obtained by selective immunoprecipitation. Cholesterol and triglycerides were determined by enzymatic methods. Apolipoprotein A and B were measured by an immunologic turbidity test.

Pharmacological treatment. Patients treated with fibric acid derivatives received gemfibrozil or fibrates, 600-900 mg/day.

 Those patients who received HMGCOA reductase inhibitors were treated with lovastatina (n=11, 20-40 mg/day), simvastatin (n=14, 10-20 mg/d), pravastatin (n=10, 20-40 mg/d), fluvastatin (n=10, 20-40 mg/d) or atorvastatin (n= 7, 10-20 mg/d).

All the patients were concomitantly treated with ACE inhibitors or A-II-RA (losartan).

Statistics. The comparability of treatment groups at base-line was assessed by means of the analysis of the variance. Comparisons of treatment responses between groups were made using an analisys of the variance. Within-group comparisons were made using the Wilcoxon test.

Results.

Results are shown in tables 5 to 10. Basal characteristics of the patients in the four groups were comparable when reagarding mean age,  age at diagnosis of diabetes mellitus, age at diabetic nephropathy detection and serum creatinine. Poteinuria and LDL-cholesterol were higher in  HGMCoA reductase inhibitors group than in the other. Triglycerides were higher in the fibric acid derivatives-treated group than in the other groups. Proteinuria, triglicerides, LDL-cholesterol and Apo B lipoprotein were lower in the normocolesterolemic control group than in the other, as it was expected. Glucose and HbA1c were lowest in this group, too.

Both treatments, fibric acid derivatives and statins were effective in lowering total cholesterol and LDL cholesterol. Fibric acid derivatives were more efficient than estatins in reducing the level of triglycerides, one and five year post treatment. Proteinuria maintained higher but not significantly  in estatins group  than in the others,  one and five year after treatment.

One patient in the G-I who was treated with gemfibrozil suffered from a rhabdomyolysis episode. His plasma cretinine before initiating gemfibrozil tretament was 350 umol/l. Creatinine rise to 560 umol/l, alanin-amino-transpherase to 230 ukat/l, aspartate-aminotranspherase to 280 ukat/l and creatinphosphokinase to 300 ukat/l. When gemfibrozil was stopped, creatinine and enzymes returned to its previous level.

 Both fibrates and statins were well tolerated, with no increases in hepatic enzymes, creatinphosphokinase orplasma creatinine in the other 62 treated patients.

The incidence of cardiovascular complications was similar in the four groups, including the normocholesterolemic group.

 Diabetic nephropathy progressed and end-stage renal disease occurred in 12 patients into the follow-up period: no patient needed dialysis in the fibrates-treated group, 9 patients (17.3%) started dialysis in the statins- treated group,  for 2 patients  in the hypercholesterolemic non-treated group (10%) and 1  patient (7,7%) in the normocholesterolemic control group. If we consider  toghether G-I and G-II as the same cohort of patients, the differences were not statystically significant.

The group II had a greater   number of severe hypercholesterolemic patients (t-cholesterol > 7 mmol/l)  at base -line (61%) than the other two hypercholesterolaemic patient groups, needing dialysis more frequently  than the others (Table 10-11). Nevertheless,  there were not differences when comparing five-year serum creatinine in the four groups (Table 8)

Mortality was higher but not statystically different in the two control groups when compared to treated groups, the highest mortality  being in the normocholesterolemic control group.

Summary.

1. Fibric acid derivatives are well tolerated in dyslipidaemic diabetic nephropathy patients, being  effective on hypertriglyceridaemia, but  contraindicated when severe renal failure has come.

2. HMGCoA reductase inhibitors are very well tolerated. Its efficacy in decreasing total cholesterol and LDL cholesterol is higher than that of fibric acid derivatives , being less effective on hypertriglyceridaemia.

3. In our study, cardiovascular complications were similar in the four studied groups. Normocholesterolaemic patients  presented with a similar rate of cardiovascular complications to that of the other hypercholesterolaemic groups. The highest incidence of CV complications was observed in hypercholesterolaemic control group patients and in fibrates-treated group.

4. Mortality rate was highest in normocholesterolemic patients, being higher in hypercholesterolemic not-treated patients than in  pharmacologically treated patients, but the difference was not statystically significant.

Conclusions.

1. Goals of current guidelines are very difficult to achieve and even more difficult to maintain in dyslipidaemic   diabetic patients, especially when diabetic nephropathy with overt proteinuria has developed.

2. In DM patients lipoproteins are atherogenic even with normal serum levels.

3. Lipid-lowering therapy could delay but not avoid the progression of diabetic nephropathy.

2. In these patients it is mandatory to establish combined measures in order to    stop micro and macroangiopathy, preserving cardiovascular status  and  also to detect diabetic nephropathy in the early stages, trying to avoid  atherosclerosis and diabetic nephropathy progression.

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TABLE 1. Effect of HMGCoA reductase inhibitors treatment on albuminuria in diabetic patients with DN.

(Modified from Jandeleit-Dahm et al) (20).

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Table 2. Treatment goals of lipid-lowering in DM.

* less than 2,6 mmol/l (100 mg/dl) in secondary prevention.

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Table 3. Lipid-lowering drugs in DN.

* maximum dose 200 mg/48 h. in ESRD. **avoid in severe or ESRF.

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Table 4. Lipid-lowering treatment  choice in DM.

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Table 5. Patient characteristics at base-line.

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Table 6. Serum creatinine, proteinuria, glucose, HbA1c and lipidic profile at base-line.

a,b,c: p<0.05 among groups

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Table 7. Serum creatinine, proteiuria,  glucose, HbA1c and lipidic profile 1 year after treatment.

*= p <0.05 ( intragroup comparison)

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Table 8. Serum creatinine, proteinuria,  glucose, HbA1c and lipidic profile 5 years after treatment.

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Table 9. Cardiovascular complications and mortality.

HD= heart disease. CV=cardiovascular.

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Table 10. Follow-up of patients with t-cholesterol > 7 mmol/l at base-line.

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Table 11. Five-year creatinine and  proteinuria comparison of patiens with t-chol. >7 mmol/l versus t-chol < 7 mmol/l at base line

p n.s.

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