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Alberto Lorenzatti, MD
Comité de Epidemiología
y Prevención de la FAC, Fundación Rusculleda
para la Investigación, Docencia y Asistencia en Medicina, Córdoba, Argentina
Diabetes is really becoming epidemic. It is
believed that within the next 20 years the number of people affected in the
world will grow in approximately 120 %, such phenomenon will be more significant
in developing countries.
The social implications of this panorama are obvious if we just consider the mere fact that vascular disease, and especially Coronary Artery Disease (CAD), is the main cause of morbidity and mortality among diabetic patients.
EXCESS IN CARDIOVASCULAR RISK
Atherosclerosis is certainly responsible for approximately 80 % of the total mortality in these patients (75 % is attributed to a coronary disease and the other 25 % to cerebrovascular or peripheral arterial disease). In the same way, approximately half of the subjects with a recent diagnosis of type 2 diabetes (DBT2), already present a macrovascular disease, which many times is sub clinical.
This may be explained, mainly, by the conjunction of multiple risk factors, especially dyslipidemia (DLP). Moreover, we should notice that diabetics who have not undergone an Acute Myocardial Infarction, have potentially the same risk than non-diabetic patients with infarction antecedents. In other words, their risk is equivalent to non-diabetics in Secondary Prevention stage. Diabetics also show an even grater morbidity and mortality after suffering a coronary event.
These observations indicate that diabetics, even without an evident coronary disease, may present a large atherosclerotic burden that alerts physicians to increase caution.
The role of blood glucose in the development of atherosclerosis could be explained due to by different mechanisms including endothelial dysfunction, platelet dysfunction, procoagulatory conditions, non enzymatic glycosilation and lipid abnormalities which evidence an atherogenic pattern. However, it is convenient to point out that while blood glucose is better correlated with a microvascular disease, dyslipidemia does it with a macrovascular disease. In that sense, we must remember that 2/3 of diabetic patients show different lipid abnormalities, that is why it is essential to understand and treat diabetic-dyslipidemia.
TYPE 1 DIABETES
Classically, lipid abnormalities in these patients have been related to a poor or deficient blood glucose control. The hypetrygliceridemia (HTG) is the most common pattern, mainly related to a deficiency in the proteinlipase enzyme (LPL) activity with the subsequent reduction of plasmatic clearance of Chylomicrons and VLDL.
An adequate blood glucose control may contribute to improve the abnormal lipid pattern that may include low HDL and mildly elevated LDL, being this more common among young women.
In a parallel way, the presence of Diabetic Nephropathy, even in an initial albuminury state, may accompany secondary lipid abnormalities.
TYPE 2 DIABETES
The prevalence of DLP in type 2 diabetics is double with respect to the general population. These are more complex abnormalities that, in general, are caused by the interrelation among obesity, insulin resistance and hyperinsulinism.
The most common abnormality is the HTG with low HDL; and although if LDL might not be higher, its metabolism is abnormal. With a tight glucose control, blood lipids might get better, however, almost never do they reach normal levels.
Usually, these patients present both, over production and low catabolism of LDL and of apo B. Such abnormality of the catabolism may occur even when LPL activity is normal. Lowering HDL can also be explained by an increased catabolism, the decrease in the VLDL clearance and in a LPL deficient activity.
We should also consider, important qualitative abnormalities in diabetic dyslipidemia such as glycosilation and a higher oxidation of the LDL and the significant presence of small and dense LDL -more atherogenic-; which strongly contribute to promote a macrovascular disease in these patients. The predominance of small and dense LDL particles has also been described as an independent -of age, gender, blood glucose tolerance and BMI- risk factor for the future development of DBT2, which reinforces the role of such lipoproteins as markers for insulin resistance.
The Lp (a) role in diabetes is not known, its levels do not seem to be linked to the blood glucose control, and unlike the observed general population trend, the few available series in diabetics which analyzed the relation between Lp (a) and CAD reported lack of association.
To conclude, the quantitative and qualitative abnormalities of lipids in diabetic patients are numerous: small and dense LDL, Hypertrygliceridemia, higher IDL and higher apoB, low HDL and low apo AI. Their occurrence is more common in type 2 diabetics, and such abnormalities could explain, at least in part, the excess of coronary risk in these patients.
DESIDERABLE LIPID LEVELS
Different guidelines coincide in establishing strict objectives for diabetic patients. The strongest emphasis in the treatment of diabetic dyslipidemia should be put on reaching LDL levels < 100 mg/dL, due to the higher risk in these patients, whether or not CAD manifestations occur; as proposed by the American Diabetes Association (ADA) and by the recently published ATP III' report.
In the same way, and due to some study results, we believe that the TGs should be also managed aggressively, and specially in diabetics with a known vascular disease. The objective should be TG <150 mg/dL. As regards HDL the target levels should be > 45 mg/dL.
CLINICAL STUDIES THAT SUPPORT THIS APPROACH
Although only a few studies have been specially designed to investigate the benefits of the lipid lowering treatment in diabetics, -and the ones which pursue such an objective are still being developed-, nevertheless, the available data of patients in secondary prevention are sufficient to promote an aggressive approach.
In 4S study, during 5 years, diabetic patients treated with simvastatin showed a 55% reduction in mayor coronary events (p=0.002), also cardiovascular mortality was reduced by 36% and the total mortality by 43%, with respect to placebo treated patients; however it is important to point out that, possibly, due to the small number of diabetic patients (less than 5 % of the total) the statistic significance was not achieved.
In CARE, 714 diabetics were included. The lipid levels improved in patients with or without DBT who received pravastatin treatment. It was verified a statistically significant 25% reduction in major coronary events, confirming the 4S study findings.
These studies reinforce the value of lowering LDL in diabetic patients with previous cardiovascular events. However, it is important to point out that these patients have had LDL levels relatively elevated (4S) or mildly elevated (CARE), but in both cases the TGs level was lower than 200 mg/dL. In other words , they did not provide a clear answer to the most common lipid pattern in diabetic patients (TG↑, HDL↓ and LDL = or↑).
Recently, was published the DAIS study, -an angiographic secondary prevention trial-. More than 400 type 2 diabetic patients with DLP were randomized to treatment with mycronized fenofibrate (200 mg) or placebo with an average follow up of over 3 years. More than 40 % reduction in the progression rate of coronary lesions in patients treated with active drug was observed. In this way, the therapeutic intervention showed angiographic benefits similar to those described in non-diabetic patients. This study was not addressed to evaluate clinical end-points, anyway, fibrates treated patients showed a 23 % risk reduction, which even though did not achieve clinical significance, shows once more, a clear benefit in favor of such treatment.
In a similar way, in VA-HIT study (patients with low HDL as the main abnormality and history of cardiovascular disease, distributed in two groups: gemfibrozil or placebo) 627 diabetic patients were involved. It was observed a reduction of 24 % of relative risk in patients treated with fibrates who had reached an increase of 6 % in HDL and a reduction of 31 % in TGs level, after a year of treatment.
Although, there are no concluding studies in Primary Prevention in diabetics, the benefit of an aggressive lipid treatment herein commented for in Secondary Prevention patients might be transferred to those without coronary disease manifestations.
In the Helsinski Heart Study a reduced number of diabetics were present, however the ones who received Gemfibrozil presented a 3.4 % of cardiovascular events while the ones treated with placebo showed a 10.5 % at the end of study.
Nevertheless in the near future on going study results with a large number of diabetic patients involved, will be available. Such patients will be aggressively treated with lipid lowering drugs, to correct the DLP, and will probably clarify the role of such drugs in primary prevention of cardiovascular disease in diabetics. Among them , the studies: FIELD (fenofibrate), ASPEN and CARDS(atrovastatin) are included.
NON- PHARMACOLOGICAL TREATMENT
The management of lipids in Diabetes must begin by keeping the best possible blood glucose control, and implement a loss of weight, if there is obesity.
The election of the diet arises some questions. The ADA recommends a diet low in fat and rich in carbohydrates. This may contribute to increase the TGs and to lower the HDL in these patients. In fact, this does not occur when it is accompanied by a loss of weight, but if this is not the case and the TGs levels do not improve, complex carbohydrates and monounsaturated fatty acids may be combined. Adding a large amount of fibers, especially of soluble diet fiber, may contribute not only to improve the blood glucose control, but to lower lipid levels as well.
An adequate exercise plan must be indicated
as part of the treatment, with the previous evaluation of myocardial ischemic
presence or other conditions such as neuropathy, peripheral vascular disease
or development of hypoglycemia, that will force us to take the adequate precautions.
Statins are first election drugs in a diabetic patient even when LDL is "normal" or mildly elevated, given that such levels may result more atherogenic than in non-diabetics due to qualitative modifications (small and dense particles) already described . Additionally, and even if later confirmations may be needed, we can not help speculating with the interesting possibility that these drugs themselves may lower the incidence of new cases of diabetes, according to the observations in a recent sub-analysis of the WOSCOPS study (30 % of risk reduction, p=0.042).
Fibrates are elected in patients with TGs increase. For patients in the range of 200 and 400 mg/dL and with no evidence of macrovascular disease, the beginning of the pharmacological therapy should be carried out taking into account each case separately, but in those patients whose levels are over 400 mg/dL a pharmacological approach must not be postponed.
Resins are potentially useful when hypercholesterolemia is present , but since they may elevate TGs, their use in diabetes must be restricted to those infrequent isolated cholesterol increase. Although, niacin for its good effects on LDL, TG and HDL may seems ideal, its use is relatively contraindicated due to the fact that it may exacerbate diabetes and may increase the insulin resistance.
Omega 3 fatty acids have good effects, especially upon TGs, but some studies had shown blood glucose, LDL and Total Cholesterol elevations. For that reason we have to be careful when using it.
Finally, when in certain patients, target levels cannot be reached through monotherapy treatment, drug combination must be considered for them. This need though, has diminished with the use of statins in high dose that also moderately reduce TGs and slightly increase HDL. Despite the fact that this additive therapy appears attractive to be used in patients in need for it, one must bear in mind, that the combination of statins and fibrates or of statins and niacin, -being this last one very effective in diabetic dyslipidemia-, may increase the risk of myophaty, even very serious ones. For this reason such associations must be conveniently monitorized with extreme care.
Dyslipidemia is a frequent condition in diabetics, and it may also contribute to exaggerate cardiovascular risk in these patients. Its more common characteristics are: a normal or slightly increased LDL, high TGs and low HDL. At present there is enough evidence to claim that at least half of type 2 diabetics already present some form of a macrovascular disease by the time their condition is diagnosed.
We do not exaggerate then when we state that "Diabetes is Atheroesclerosis" and that it is therefore necessary to consider strict therapeutic objectives. The treatment must be aggressive, especially in patient with an elevated LDL. Glucose control, an appropriate diet, loss of weight, and physical activity can improve this lipid profile and so diminish cardiovascular risk. Anyway, most patients would probably require the use of drugs such as statins and fibrates since they have already demonstrated to be able to diminish cardiovascular events as well as the progression of lesions, and to be safe and well tolerated.
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