Usual risk factors for coronary artery disease account for only 25-50% of increased
atherosclerotic risk in diabetes mellitus. Other obvious risk factors are hyperglycemia
and dyslipidemia. However, hyperglycemia is a very late stage in the sequence of events
from insulin resistance to frank diabetes, whereas lipoprotein abnormalities are manifested
during the largely asymptomatic diabetic prodrome and contribute substantially to
the increased risk of macrovascular disease. The insulin-resistant diabetes course
affects virtually all lipids and lipoproteins. Chylomicron and very-low-density lipoprotein
(VLDL) remnants accumulate, and triglycerides enrich high-density lipoprotein (HDL)
and low-density lipoprotein (LDL), leading to high levels of potentially atherogenic
particles and low levels of HDL cholesterol. Hyperglycemia eventually impairs removal
of triglyceride-rich lipoproteins, the accumulation of which accentuates hypertriglyceridemia.
As triglycerides increase-still within the so-called normal range-abnormalities in
HDL and LDL became more apparent. Thus, when triglycerides are >200 mg/dL, LDL particles
are small and dense (when they are <90 mg/dL, the particles are of the large, buoyant
variety). The atherogenicity of small, dense LDL particles is attributed to their
increased susceptibility to oxidation, but in many patients they may be a marker for
insulin resistance or the presence of atherogenic VLDL. Hypertriglyceridemia is associated
with atherosclerosis because (1) it is a marker for insulin resistance and atherogenic
metabolic abnormalities; and (2) the small size of triglyceride-enriched lipoproteins
enables them to infiltrate the blood vessel wall where they are oxidized, bind to
receptors on macrophages, and ingested, leading to the development of the atherosclerotic
lesion. Various studies (primary prevention with gemfibrozil: Helsinki Heart Study;
secondary prevention with simvastatin and pravastatin: Scandinavian Simvastatin Survival
Study [4S] and Cholesterol and Recurrent Events [CARE], respectively) have demonstrated
that lipid-lowering therapy in type 2 diabetes is effective in decreasing the number
of cardiac events. Risk reduction was 22% to 50% (statins) and approximately 65% (fibrate)
relative to placebo. It was also noted (in 4S and CARE) that the risk of major coronary
events in untreated diabetic patients was 1.5-1.7-fold greater than in untreated nondiabetic
patients. Although gemfibrozil (fibric acid derivative) is more effective in decreasing
triglycerides and increasing HDL cholesterol in diabetic patients than the statins,
it does not change and may even increase LDL-cholesterol levels (fenofibrate may be
an exception, decreasing LDL cholesterol by 20-25% in some studies). However, gemfibrozil
does increase LDL particle size. Nevertheless, the statins are the current lipid-lowering
drugs of choice because the change in LDL-cholesterol-to-HDL-cholesterol ratio is
better than with gemfibrozil. Moreover, the diabetic patient may be more likely to
benefit from statin therapy than the nondiabetic patient. It should be noted that,
in theory, nicotinic acid can correct or improve all lipid or lipoprotein abnormalities
in patients with type 2 diabetes. Unfortunately, it is relatively contraindicated
because it causes insulin resistance and may precipitate or aggravate hyperglycemia
(in addition to its other well-known side effects such as flushing, gastric irritation,
development of hepatotoxicity, and hyperuricemia). It is unknown at present whether
newer formulations such as once-daily Niaspan may be better tolerated in diabetes.
In any case, most patients with type 2 diabetes have risk factors for coronary artery
disease and qualify for aggressive LDL cholesterol-lowering therapy. At the same time,
it is presently unknown whether improved glycemic control decreases coronary artery
disease risk in such patients.