SUMMARY
Dyslipidemia is one of the major risk factors for cardiovascular disease in diabetes mellitus. The characteristic features of diabetic dyslipidemia are a high plasma triglyceride concentration, low HDL cholesterol concentration and increased concentration of small dense LDL-cholesterol particles. The lipid changes associated with diabetes mellitus are attributed to increased free fatty acid flux secondary to insulin resistance. The availability of multiple lipid-lowering drugs and supplements provides new opportunities for patients to achieve target lipid levels. However, the variety of therapeutic options poses a challenge in the prioritization of drug therapy. The prevalence of hypercholesterolemia is not increased in patients with diabetes mellitus, but mortality from coronary heart disease increases exponentially as a function of serum cholesterol levels, and lowering of cholesterol with statins reduces diabetic patients' relative cardiovascular risk. Although drug therapy for dyslipidemia must be individualized, most people with diabetes mellitus are candidates for statin therapy, and often need treatment with multiple agents to achieve therapeutic goals.
KEY POINTS
- Dyslipidemia contributes to the increased risk of cardiovascular disease in diabetes mellitus
- The characteristic features of diabetic dyslipidemia are high plasma triglyceride concentration, low HDL cholesterol concentration and increased concentration of small dense LDL cholesterol
- The most likely cause of diabetic dyslipidemia is the increased free fatty-acid flux, secondary to insulin resistance
- Although drug therapy for dyslipidemias must be individualized, most people with diabetes mellitus are candidates for statin therapy and often need to be treated with multiple agents to achieve therapeutic goals
INTRODUCTION
Despite advances made in the prevention and management of cardiovascular disease, people with diabetes mellitus continue to have alarmingly high morbidity and mortality secondary to cardiovascular disease. At a time when cardiovascular-disease mortality is decreasing in the general population, mortality in women with diabetes mellitus has increased. Epidemiologic studies have demonstrated that diabetes mellitus is an independent risk factor for cardiovascular disease and that it amplifies the effects of other common risk factors, such as smoking, hypertension and hypercholesterolemia. The mortality associated with a coronary event in people with diabetes mellitus is significantly higher than the mortality in nondiabetic individuals. Furthermore, the mortality risk for people with diabetes mellitus who do not have known clinical coronary heart disease (CHD) is similar to that for those without diabetes mellitus who have already experienced a myocardial infarction. Such observations have led to the recognition of diabetes mellitus as a CHD-risk-equivalent condition (i.e. the risk to patients with diabetes mellitus of dying of a coronary event is as high as it is in nondiabetic individuals with a clinical history of CHD).
The increased risk of atherosclerosis in diabetes mellitus consists of multiple factors. Diabetes-related changes in plasma lipid levels are among the key factors that are amenable to intervention. The spectrum of dyslipidemia in diabetes mellitus can include all the various types of dyslipidemia identified in the general population; however, one phenotype is particularly common in diabetes mellitus, which is attributed mostly to insulin resistance and insulin deficiency. The characteristic features of this phenotype are a high plasma triglyceride concentration, low HDL cholesterol concentration and increased concentration of small dense LDL–cholesterol particles. This Review examines dyslipidemia in type 2 diabetes mellitus (T2DM) only.
PATHOPHYSIOLOGY OF DIABETIC DYSLIPIDEMIA
The precise pathogenesis of diabetic dyslipidemia is not known; nevertheless, a large body of evidence suggests that insulin resistance has a central role in the development of this condition. The main cause of the three cardinal features of diabetic dyslipidemia is the increased free fatty-acid release from insulin-resistant fat cells. The increased flux of free fatty acids into the liver in the presence of adequate glycogen stores promotes triglyceride production, which in turn stimulates the secretion of apolipoprotein B (ApoB) and VLDL cholesterol. The impaired ability of insulin to inhibit free fatty-acid release leads to enhanced hepatic VLDL cholesterol production, which correlates with the degree of hepatic fat accumulation.
Hyperinsulinemia is also associated with low HDL cholesterol levels. The increased number of VLDL cholesterol particles and increased plasma triglyceride levels decrease the level of HDL cholesterol and increase the concentration of small dense LDL-cholesterol particles via several processes: VLDL-transported triglyceride is exchanged for HDL-transported cholesteryl ester through the action of the cholesteryl ester transfer protein (CETP), which results in increased amounts of both atherogenic cholesterol-rich VLDL remnant particles and triglyceride-rich, cholesterol-depleted HDL particles. The triglyceride-enriched HDL is subsequently hydrolyzed by hepatic lipase or lipoprotein lipase; ApoA-I dissociates from the reduced-size HDL, which is filtered by the renal glomeruli and degraded in renal tubular cells (Figure 1). The increased concentration of small dense LDL-cholesterol particles is explained by a similar lipid exchange. Increased levels of VLDL-transported triglyceride enable CETP to promote the transfer of triglyceride into LDL in exchange for LDL-transported cholesteryl ester. The triglyceride-rich LDL undergoes hydrolysis by hepatic lipase or lipoprotein lipase, which results in lipid-depleted small dense LDL particles (Figure 1).
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Figure 1 The role of insulin resistance in diabetic dyslipidemia. |
The relative importance of the above lipid-exchange pathway in individuals with low HDL cholesterol levels who do not have increased VLDL cholesterol production or hypertriglyceridemia is not known. In these patients, inability of insulin to upregulate the ApoA-I production (owing to insulin resistance) might contribute to low HDL cholesterol levels. Furthermore, insulin resistance and low HDL levels might have a common mediator; for example, TNF. TNF is implicated in obesity-related insulin resistance and is known to lower serum HDL cholesterol levels. In addition, several key enzymes that are involved in HDL cholesterol metabolism are altered in people with insulin resistance. Insulin resistance is associated with a decreased ratio of lipoprotein lipase to hepatic lipase in heparin-treated plasma, which contributes to the low HDL-cholesterol level seen in such individuals. In insulin resistance, the esterification of cholesterol (mediated by lecithin-cholesterol acyl transferase) is either modestly increased or unaltered, whereas CETP activity is increased. CETP depletes HDL of its cholesteryl ester and its increased activity contributes to the lowering of HDL cholesterol levels.
Plasma CETP mass is a determinant of cholesteryl ester transfer, and has an increased effect in individuals with high triglyceride levels. In addition, adiponectin might have a direct role on HDL cholesterol catabolism. Kinetic studies show a strong negative correlation between adiponectin level and the ApoA-I fractional clearance rate, which can explain the positive correlation between the levels of HDL cholesterol and adiponectin. This positive correlation occurs independently of obesity, insulin resistance and the triglyceride content of HDL-cholesterol particles. Another important determinant of atherosclerosis is the activity of phospholipid-transfer protein. This protein has been suggested to have a role in the development of obesity and diabetes mellitus; thus, it might become a therapeutic target.
Of note, high triglyceride and low HDL cholesterol levels might occur in familial and sporadic syndromes (e.g. familial combined hyperlipidemia and familial hypertriglyceridemia), but only combined hyperlipidemia seems to be generally associated with increased cardiovascular risk. Specialized lipid tests, such as measurement of plasma ApoB-100 or ApoB-100: ApoA-I ratios, might distinguish between these two phenotypically similar syndromes and identify individuals who have an increased risk of cardiovascular disease. Overall, insulin resistance seems to contribute either directly or indirectly to the triad of plasma lipid abnormalities of diabetes mellitus, namely hypertriglyceridemia, low HDL-cholesterol levels and high small dense LDL-cholesterol levels.
REVIEW
Nature Clinical Practice Endocrinology & Metabolism (2009) 5, 150-159
doi:10.1038/ncpendmet1066
Arshag D Mooradian
Email arshag.mooradian@jax.ufl.edu
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