Specialty Corner: Disorders of the Triglyceride-HDL Axis in Insulin Resistance

Disorders of the triglyceride-high-density lipoprotein (TG-HDL) axis, i.e. high TGs and low HDL cholesterol (HDL-C), are well documented in the medical literature,¹ and are of particular importance to clinicians treating patients who are insulin resistant (IR) or who have diabetes mellitus (diabetes). We all see this in clinic ever y day, because there are now approximately 115 million Americans who are IR or who have diabetes.²

As I speak to colleagues in my community, I realize that TG-HDL axis disorders are underappreciated and undertreated.

Even worse, many choose to focus on the issue of low HDL-C, which is really just a biomarker of the condition, and ignore the real villain, high TGs. The American Heart Association (AHA) scientific statement on TGs and cardiovascular disease states that during the past three to four decades, mean TG levels have increased in the U.S. while mean low-density lipoprotein cholesterol (LDL-C) levels have decreased.³

A recently published analysis of the Copenhagen City Heart Study and the Copenhagen General Population Study suggested that elevated TG levels should be a potential therapeutic target. This analysis examined non-fasting TGs and the risk of ischemic vascular disease and ischemic heart disease in more than 75,000 individuals during a median follow- up of 34 years. There was a clear increase in risk for ischemic cardiovascular disease in patients with elevated TGs. In addition, the incidence of diabetes rose with each increasing quintile of TG levels.⁴

TG-HDL Axis in Insulin Resistance
Insulin resistance induces many physiologic changes in those affected, and it is these changes that confer the increased cardiovascular risk. Insulin-resistant patients, who are often overweight or obese, have elevated TGs as a result of reduced visceral adipocyte sensitivity to endogenous circulating insulin as adiponectin levels decrease. This results in increased activity of hormone-sensitive lipase, which induces hydrolysis of TGs and release of fatty acids. In turn, these fatty acids travel via the portal circulation to the liver where they have a negative impact on circulating lipids. Within the liver they are reincorporated into atherogenic, TG-rich apolipoprotein (Apo) B-containing, very-low-density lipoprotein (VLDL) particles. These particles ultimately are converted into other atherogenic Apo B-containing lipoproteins — intermediate- density lipoproteins (IDLs) and then LDLs. However, as the VLDL load accumulates, cholesterol ester transfer protein (CETP) facilitates an exchange of TG for cholesterol ester within HDL particles. These newly TG-laden HDL particles are now a substrate for multiple lipases. The action of the lipases ultimately helps reduce serum HDL-C concentration as particles lose triglyceride content and become smaller. As these particles remodel, they become so small that they are excreted via the megalin-cubilin complex in the kidney. Thus the low HDL-C and high TG concentrations of the TG-HDL axis is created. Further insults to the system include the down-regulation of scavenger receptor B1, which results in less cholesterol being trafficked back to hepatocytes by HDL particles, as well as reduced macrophage cholesterol transport due to the inflamed adipocytes’ down-regulation of ATP binding cassette transporter-A1. This reduces the lipidation of HDL particles in what is possibly their most cardioprotective role, both lowering HDL-C and impairing removal of atherogenic cholesterol from lipid-laden macrophages in the endothelium. (Figure 1)

To complete this biochemical assault on the vasculature, the prolonged exposure of elevated serum glucose seen in IR results in increased TG production as the glucose enters hepatic cells and fuels lipogenesis. I outlined these biochemical pathways in an article in an earlier edition of LipidSpin.⁵

Clinical Management of Insulin Resistance
There are biomarker abnormalities unique to the IR patient that can help us to more effectively treat them. LDL-C has been shown to be less accurate for cardiovascular risk prediction than Apo B or low-density lipoprotein particle number (LDL-P) measurements, particularly in this group. IR patients exhibit the highest degree of discordance between the standard lipid panel and the atherogenic particle load.6  Indeed, the National Lipid Association has endorsed testing this patient population as a reasonable measure with advanced biomarkers including  Apo B and LDL-P.7   As early as 2008, the American College of Cardiology/American Diabetes Association  (ACC/ADA) joint position paper opined that the IR patient population is best served with measurement of Apo B or LDL-P both for diagnosis and to assist achievement of therapeutic goals. As my own clinical practice experience has documented, it is quite common to see Apo B or LDL-P elevations even when the LDL-C concentration is at a level that many clinicians would consider to be at goal in IR patients.⁶

Insulin-resistant patients are “diabetics in training.” As the severity of IR progresses over time, they generally display a disorder of the TG-HDL axis during laboratory evaluation. I believe we should treat the IR and resultant TG-HDL axis disorder early and aggressively to help prevent cardiovascular events. This thought has, of course, become a little more challenging with the release last year of the National Heart, Lung & Blood Institute (NHLBI)-funded ACC/AHA treatment guidelines. I certainly do not believe that these guidelines represent genuine help to clinicians who intend to provide comprehensive therapy for lipid disorders, including those of the TG-HDL axis. However, this discussion has already been aired in the medical literature, and I will only register my opinion.

Since the new ACC/AHA guidelines are not rules, I believe we must use human physiology and ever y shred of data we find credible to treat patients for which no Level 1 evidence-based medicine exists. I urge clinicians to treat IR, and disorders of the TG-HDL axis, and not to ignore it while waiting for more evidence.

Of course, first-line therapy remains diet, exercise, and weight loss where appropriate. This cannot be emphasized enough or just taken as “lip service” before the first prescription is written.

The pharmacologic options to treat IR are well known. Treating ever y facet of IR is critical, in my opinion. Normalizing glucose levels is important to reduce lipogenesis. I believe metformin to be baseline therapy, but reviewing all other glucose-lowering agents is beyond the scope of this article. Note that, to date, it has been difficult to prove that just lowering glycated hemoglobin (HBA1c) will prevent any macrovascular events. It is my opinion this is because of the contributions of the TG- HDL axis to this patient type.

Much the same can be said for treating elevated blood pressures. With new guidelines for blood pressure as well, the clinician is obligated to apply them to each patient, considering all the individual characteristics that unique patient exhibits.⁸

From a lipid perspective, there are multiple agents that may be utilized after baseline statin therapy is in place. These agents include primarily fibrates, n-3 fatty acids, and niacin. Yes, niacin, not to raise HDL-C but to reduce TGs and further reduce the atherogenic particle concentration. The evidence on lowering TGs to prevent cardiovascular events is not yet “iron clad.” However, I believe that treating high TGs in the IR patient population is justified based on the physiology and data noted above. It is my clinical goal to minimize risk by treating ever y risk factor I can with the smallest number of pharmacologic interventions. This truly is a difficult balance to achieve. I believe ever y patient deserves an individualized approach based on the totality of the evidence that we have viewed through the lens of best clinical judgment.

Disclosure Statement: Dr. Lillo has received speaker honorarium from Merck & Co., Sanofi-Aventis, Amira, Amgen, Novartis, Forest Laboratories, AstraZeneca, GlaxoSmithKline, Cohera Medical, and Kowa Pharmaceuticals.  Dr. Lillo received salary for Phase III Clinical Research from Amgen and Pfizer.

References are listed on page 34 of the PDF.