Diabetic dyslipidemia: An update

Although cardiovascular disease is still the leading cause of death in the United States, there has been a declining trend of both fatal and nonfatal myocardial infarction in the last decade, thanks to a decrease in the burden of some modifiable risk factors, such as smoking, and an increase in use of medications to lower blood pressure and cholesterol.

John M. Miles, M.D., of the Division of Endocrinology, Diabetes, Metabolism, and Nutrition at Mayo Clinic in Rochester, Minnesota, cautions: "These heartening trends are likely to be reversed, however, because of the increasing incidence of obesity and type 2 diabetes among adolescent and young children.

"During this same period, the prevalence of type 2 diabetes increased by more than 1 percent, and the Centers for Disease Control and Prevention now estimates that 11.3 percent of all people older than age 20 have diabetes. The risk of coronary artery disease is two to four times higher in patients with diabetes than in those without diabetes, and unless urgent steps are taken to effectively prevent and manage diabetes and its complications, we are likely to see a rebound increase in incidence of cardiovascular disease."

Data from the National Health and Nutritional Examination Survey (NHANES) does indicate a modest improvement in control of hemoglobin A1C (HbA1C), LDL cholesterol and blood pressure in patients with diabetes over the last decade, though they were at goal in only approximately 25 percent of the patients.

Vinaya Simha, MBBS, M.D., of the Division of Endocrinology, Diabetes, Metabolism, and Nutrition at Mayo Clinic in Minnesota, comments: "While we need to do a better job of targeting these traditional risk factors, it is also important to look beyond LDL cholesterol if we are to make a significant impact on cardiovascular disease in people with diabetes. In fact, LDL cholesterol levels in patients with type 2 diabetes were not increased compared with levels of those without diabetes in both the Framingham study and the NHANES sample.

"It is now well-recognized that type 2 diabetes is characterized by a unique set of lipid abnormalities comprising elevated serum triglycerides, low HDL cholesterol and increased small-dense LDL particles. The core defect is thought to be insulin resistance at the level of adipose tissue, leading to increased lipolysis and delivery of free fatty acids to the liver. Coupled with increased apolipoprotein B production, this defect results in increased hepatic secretion of large triglyceride-rich VLDL particles.

"Interparticle exchange of triglycerides and cholesterol between these triglyceride-rich VLDL particles and both LDL and HDL particles, mediated by cholesterol ester transfer protein, results in triglyceride-enriched LDL and HDL particles. Subsequent hydrolysis by hepatic lipase and other lipases results in generation of small-dense LDL particles, and small HDL particles that are easily catabolized and excreted by the kidneys, leading to low HDL cholesterol concentration.

"Much progress has been made recently in understanding the subcellular processes linking insulin resistance to this pattern of atherogenic dyslipidemia. While there is much hope that the new information will lead to development of new therapies, current management of diabetic dyslipidemia should focus on both therapeutic lifestyle changes and optimal choice of hypolipidemic and hypoglycemic medications."

Lifestyle changes

Medical nutrition therapy and regular exercise are well-recognized to be the cornerstones of diabetes management, but recent data have reinforced the importance of these measures in ameliorating dyslipidemia as well.

Dr. Miles comments: "Analysis of lipid data from the recently concluded Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study involving 699 obese adolescents with type 2 diabetes showed that, compared with both metformin alone and metformin plus rosiglitazone, the combination of metformin and lifestyle intervention resulted in lower triglycerides and small-dense LDL cholesterol. Further, there was amelioration of the detrimental effect of hyperglycemia on both triglycerides and HDL cholesterol in this group.

"Similarly, a recent subgroup analysis of the Diabetes Prevention Program study revealed that intensive lifestyle intervention led to a decrease in both large VLDL particles and small-dense LDL particles besides raising large HDL particle concentrations. These favorable changes in lipoprotein subfractions, despite minimal to no changes in LDL cholesterol concentration, have the potential to reduce atherosclerosis. It is therefore imperative to emphasize the critical importance of lifestyle intervention to all patients with type 2 diabetes."

Hypolipidemic therapy

The primacy of LDL cholesterol reduction using statin therapy for both primary and secondary prevention of coronary heart disease is well-established, and most, if not all, patients with diabetic dyslipidemia will benefit from statin therapy.

Dr. Simha adds: "Patients with high triglycerides and low HDL cholesterol, however, are very likely to have a discordance between their LDL cholesterol concentration and LDL particle number. The particle number is a better predictor or cardiovascular risk compared with cholesterol concentration. Despite seemingly normal or at-goal LDL cholesterol concentrations, patients with diabetic dyslipidemia have high residual risk due to an elevated LDL particle number, which is reflected by high apolipoprotein B and non-HDL cholesterol concentrations.

"While measurement of LDL particle concentration and apolipoprotein B levels is not widely available or standardized, non-HDL cholesterol can be easily measured and should probably be the primary target in patients with diabetic dyslipidemia. Achieving the non-HDL goal often requires addition of fibrates to statin therapy, as these medications favorably alter LDL particle size and number. However, the enthusiasm for combination therapy has been dampened by the largely negative results of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid trials.

"Nonetheless, careful analysis of these and other major fibrate trials show that the subgroup of patients with categorical atherogenic dyslipidemia (high triglycerides and low HDL cholesterol) derives greater benefit than the general population; a meta-analysis showed a 35 percent reduction in relative risk of cardiovascular events. This outcome contrasts rather dramatically with the rather modest incremental effects of doubling statin doses. Thus, combination therapy with statin and fibrates to achieve non-HDL cholesterol goals may be an effective way to reduce cardiovascular risk associated with diabetic dyslipidemia."

Anti-hyperglycemic therapy

The effect of different classes of anti-hyperglycemic medications on lipid profile is also an important consideration in the treatment of diabetic dyslipidemia.

Dr. Miles notes: "Unfortunately, studies examining the lipid effects of these medications are few and have generally yielded inconsistent results, partly due to variations in glycemic control. Overall, it appears that metformin, especially in higher doses, causes a modest reduction in both total cholesterol and triglycerides, while sulfonylureas and glinides have minimal effects on lipids.

"Insulin therapy can have significant triglyceride-lowering effects in people with poor glycemic control. There is little published data on the lipid effects of insulin in people with fair to good (HbA1C < 8.0 percent) glycemic control, but anecdotal experience suggests that lipid effects of insulin in these patients are minimal. The alpha-glucosidase inhibitors have been reported to raise HDL cholesterol in some studies, as also the thiazolidinediones.

"Among this latter class of drugs, rosiglitazone also causes an increase in LDL cholesterol, which is not seen with pioglitazone. Moreover, pioglitazone, which produces beneficial effects on triglycerides and HDL-C that are not demonstrable with rosiglitazone, reduces small-dense LDL particles and increases the large, buoyant LDL particle number.

"More recently, metformin has been shown to lower small-dense LDL cholesterol particle concentration and increase both small and large HDL particle concentration, an effect that may contribute to its unique cardiovascular benefit in people with type 2 diabetes. There is also considerable interest in the effect of incretin mimetics on lipid profile. While the DPP-4 inhibitors have only mild and inconsistent effects, GLP-1 receptor agonists have been shown to reduce total and LDL cholesterol, and also both fasting and postprandial triglyceride levels with impressive reciprocal increases in HDL-C. The reduction in postprandial lipemia is particularly significant and postulated to reduce cardiovascular risk.

"Ongoing trials such as Exenatide Study of Cardiovascular Event Lowering (EXSCEL) and Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) are likely to provide definitive information about the possible cardiovascular benefits of these drugs."

For more information

Manninen V, et al. Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study. Implications for treatment. Circulation. 1992;85:37.

BIP Study Group. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease. Circulation. 2000;102:21.

Robins SJ, et al. Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT — A randomized controlled trial. Journal of the American Medical Association. 2001;285:1585.

Scott R, et al. Effects of fenofibrate treatment on cardiovascular disease risk in 9,795 individuals with type 2 diabetes and various components of the metabolic syndrome: The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Diabetes Care. 2009;32:493.

Ginsberg HN, et al. Effects of combination lipid therapy in type 2 diabetes mellitus.  New England Journal of Medicine. 2010;362:1563.