Original Articles
Diabetic dyslipidemia

https://doi.org/10.1016/S0002-9149(98)00848-0Get rights and content

Abstract

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 ∼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.

Section snippets

Lipid abnormalities in diabetes mellitus

Virtually every lipid and lipoprotein is affected by insulin resistance and diabetes mellitus.1, 4 Chylomicron and very-low-density lipoprotein (VLDL) remnants accumulate, leading to high levels of potentially atherogenic particles; in addition, there is triglyceride enrichment of both HDL and low-density lipoprotein (LDL). Triglyceride enrichment of these particles leads to decreased levels of HDL and small, dense LDL particles. When hyperglycemia occurs, there may be further impairment in

Dyslipidemia and atherogenesis in insulin resistance syndrome and type 2 diabetes

Controversy exists over whether hypertriglyceridemia is a risk factor for coronary artery disease. This, in part, reflects the high biologic variability in triglyceride measurement (Table II)12 and the fact that many studies have used only a single triglyceride measurement, which may not have been a fasting sample.

Hypertriglyceridemia is associated with atherosclerosis for multiple reasons. Hypertriglyceridemia is a marker for insulin resistance and the constellation of atherogenic metabolic

Lipid reduction and coronary artery disease in type 2 diabetes mellitus

There are no published studies that specifically evaluate the effects of lipid-lowering therapy on the development of coronary artery disease in patients with type 2 diabetes mellitus. However, a small number of diabetic patients were included in the Helsinki Heart Study, a primary prevention trial, and in the Scandinavian Simvastatin Survival Study (4S) and Cholesterol and Recurrent Events (CARE) study, secondary prevention trials. The Helsinki Heart Study included 135 patients with type 2

Role of lipid-lowering therapy in preventing macrovascular disease

Studies indicate that patients with type 2 diabetes mellitus who have no history of coronary artery disease have the same risk for cardiac events as do nondiabetic patients with preexisting coronary artery disease (Figure 5; S. M. Haffner, personal communication). This emphasizes the extensive but silent nature of coronary artery disease in patients with diabetes mellitus. Diabetic patients have more diffuse and more nonocclusive coronary artery disease lesions; the latter predispose to acute

Does improving glycemic control decrease coronary artery disease events in patients with type 2 diabetes mellitus?

The data relating glycemic control to coronary artery disease are primarily observational and a correlation is weak at best. In the Wisconsin Retinopathy Study, a 1% increment in hemoglobin A1c increased the risk of retinopathy by 50% but the risk of coronary artery disease by only 5–10% (Figure 6 ).28 In the variable insulin group of the University Group Diabetes Program, better glycemic control was not associated with decreased coronary artery disease events. In fairness, however, the degree

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