ABSTRACT
Lipid abnormalities play an important part in raising the cardiovascular risk in diabetic
subjects. The main components of diabetic dyslipidemia are increased plasma triglycerides,
low concentration of high-density lipoprotein cholesterol, preponderance of small,
dense low-density lipoprotein, and excessive postprandial lipemia. Small, dense low-density
lipoprotein, the elevation in remnant triglyceride-rich lipoprotein particles, and
the low high-density lipoprotein are the most powerful atherogenic components. The
coexistence of these three factors strongly aggravates the lipid accumulation in the
arterial wall and the formation of atherosclerotic plaques. The position of diabetes
in cardiovascular risk assessment has been recently reviewed in the Harmonized Clinical
Guidelines on Prevention of Atherosclerotic Vascular Disease. In general, patients
with diabetes carry a high risk for cardiovascular disease, but the absolute risk
varies depending on the type of diabetes, age, and population baseline risk. The Adult
Treatment Program III (ATP III) and the American Heart Association have designated
diabetes as a high-risk condition and recommended intensive risk-factor management.
Concerning therapeutic targets, both ATP III and the American Diabetes Association
(ADA) guidelines have identified low-density lipoprotein cholesterol as the first
priority of lipid lowering, and the optimal level was set at less than 2.6 mmol/L
(100 mg/dL). There is strong evidence, coming from landmark secondary prevention studies,
that LDL lowering in people with diabetes is associated with significant clinical
benefits. The benefits of statin therapy in type 2 diabetics can no longer be questioned.
Ongoing clinical trials will help clarify the question of whether increasing high-density
lipoprotein cholesterol with fibrates in the presence of low low-density lipoprotein
levels (lower than 3.4 mmol/L, or 130 mg/dL) will be more beneficial than statin therapy
alone. The new paradigms in risk-reduction therapies for type 2 diabetic subjects
are focused on cardiovascular disease prevention, rather than only on glucose or lipid
control. Therapeutic lifestyle changes are considered primary therapies for hyperglycemia
and coexisting metabolic syndrome, which can be diagnosed in more than half of type
2 diabetes subjects. New perspectives of lipid management in type 2 diabetes should
take into account that insulin resistance, increased lipolysis, and overproduction
of large, buoyant, very low density lipoprotein particles are at the base of diabetic
dyslipidemia. Accordingly, drugs acting in the regulatory steps of very low density
lipoprotein assembly should be developed. Activation of peroxisome proliferator activated
receptor α (PPARα), as occurs with fibrates, lowers free fatty acids (FFAs) and triglyceride
levels. PPARγ agonism, as demonstrated by the thiazolidinediones, increases triglyceride
lipolysis, FFA transport, and conversion of FFAs to triglycerides. As separate activation
of PPARα and PPARγ improves lipid metabolism, the development of new drugs integrating
PPARα and PPARγ activity (PPAR-α/γ agonists) is a promising line that may further
improve insulin resistance, FFA metabolism, and consequently, atherogenic diabetic
dyslipidemia.
KEYWORDS
Diabetic dyslipidemia - statins - cardiovascular risk - combination therapy
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Prof.
R. Carmena
Department of Medicine, University of Valencia
Avda Blasco Ibañez, 15, 46010 Valencia, Spain
