Endocrinology Advisor: How should this view of HDL-C be revised, especially as it relates to patients with diabetes?

Dr Majithia: The data for HDL as a marker for CV risk stratification is still valid and valuable. A low HDL is part of the diagnosis of metabolic syndrome, and HDL in the context of high triglycerides suggests insulin resistance. Both metabolic syndrome and insulin resistance in T2D are markers of CV risk independent of glucose control. Individuals with diabetes at high CV risk need to have other risk factors addressed aggressively, such as blood pressure, lipids, and weight.

Dr Ayala: Evidence from both Mendelian randomization and randomized clinical trials have failed to prove a causal relationship between HDL-C and CV disease; HDL-C is now considered a risk marker rather than a causal factor.6,7 However, in T2D, low HDL-C should be looked at more carefully, as it can provide more information about HDL metabolism and pathophysiology.

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Patients with T2D typically have hypertriglyceridemia, which is strongly associated with the development of atherosclerosis and leads to low HDL-C levels as explained previously. However, more than just a reduced amount of cholesterol in the HDL particle, clinicians should be aware that the antiatherogenic properties that HDL exerts in normal state, including rCHT and antioxidation, are also reduced, which might further increase the risk for CV events.8

Endocrinology Advisor: What are other relevant treatment recommendations for clinicians?

Dr Majithia: Treat the patient and not the number. HDL must be considered in the context of the entire metabolic panel and patient. Using niacin or recommending certain oils, such as coconut oil, to increase low HDL is not likely to yield clinical benefits. However, when low HDL in context points to metabolic syndrome and insulin resistance, focusing on insulin-sensitizing therapies or using antidiabetic drug classes with proven CV benefit (glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter 2 inhbitors, and pioglitazone in certain cases) is likely to help patients in the long term.

Dr Ayala: Since an isolated static measure of HDL-C does not represent the efficiency of a dynamic HDL transport system, especially in T2D, HDL-C should be considered in conjunction with other lipid markers known to be associated with atherosclerosis that are strongly associated with low HDL-C levels, such as elevated triglycerides or remnant-like lipoproteins. HDL-C also continues to play an important role in risk assessment in primary prevention; for instance, it is used along with total cholesterol levels in the Pooled Cohort Equations [in the American College of Cardiology/American Heart Association CV risk guidelines].9

Furthermore, the REDUCE-IT trial (ClinicalTrials.gov Identifier: NCT01492361), which showed CV risk reduction with icosapent ethyl, included individuals with diabetes who were age ≥50 years and had low HDL-C as part of the primary prevention cohort.10 Therefore, low HDL-C could be used to identify patients with diabetes who might benefit from this medication in addition to other therapeutic agents to further reduce CV risk.

Endocrinology Advisor: What are the remaining research needs pertaining to this topic?

Dr Majithia: The idea that rCHT could be a lever to pull with different pharmacologic agents is still intriguing and has potential. HDL may simply not be the right way to measure rCHT. So, new ways to measure rCHT are needed, and the use of more refined subtypes of HDL is one method being explored to more faithfully capture rCHT.

The review authors also noted that the HDL-lowering trials that failed to show a CV benefit did show improved glycemic control from HDL-increasing therapy in people with diabetes, suggesting that HDL-increasing pharmacologic agents could be useful in diabetes treatment.1 Given the landscape of approved diabetes medication classes, some of which have proven CV benefit in large trials, it would be challenging to find a place for HDL-increasing therapies that lower blood glucose but with no CV benefit in our clinical armamentarium.

Dr Ayala: Evolving understanding of HDL offers the possibility of developing more accurate HDL-based biomarkers, such as HDL particle number and HDL subcomponents, as well as cholesterol efflux capacity (the first step of rCHT). From a therapeutic standpoint, there was a recent shift to HDL mimetics as a pharmacologic option to further induce cholesterol efflux capacity. However, trials have failed to reduce plaque volume in patients with acute coronary syndromes. Nonetheless, the role of rCHT in reducing atherogenesis continues to be a potential target for a novel therapeutic approach.

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1.  Xiang AS, Kingwell BA. Rethinking good cholesterol: a clinicians’ guide to understanding HDL. Lancet Diabetes Endocrinol. 2019;7(7):575-582.

2.      Grant RW, Meigs JB. Prevalence and treatment of low HDL cholesterol among primary care patients with type 2 diabetes: an unmet challenge for cardiovascular risk reduction. Diabetes Care. 2007;30(3):479-484.

3.      Keene D, Price C, Shun-Shin MJ, Francis DP. Effect on cardiovascular risk of high density lipoprotein targeted drug treatments niacin, fibrates, and CETP inhibitors: meta-analysis of randomised controlled trials including 117 411 patients. BMJ. 2014;349:g4379.

4.      Silverman MG, Ference BA, Im K, et al. Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions: a systematic review and meta-analysis. JAMA. 2016;316(12):1289-1297.

5.      Quispe R, Martin SS, Jones SR. Triglycerides to high-density lipoprotein-cholesterol ratio, glycemic control and cardiovascular risk in obese patients with type 2 diabetes. Curr Opin Endocrinol Diabetes Obes. 2016;23(2):150-156.

6.      Voight BF, Peloso GM, Orho-Melander M, et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study [published correction appears in Lancet. 2012;380(9841):564]. Lancet. 2012;380(9841):572-580.

7.      Kaur N, Pandey A, Negi H, et al. Effect of HDL-raising drugs on cardiovascular outcomes: a systematic review and meta-regression. PLoS One. 2014;9(4):e94585.

8.      Ouimet M, Barrett TJ, Fisher EA. HDL and reverse cholesterol transport: basic mechanisms and their roles in vascular health and disease. Circ Res. 2019;124(10):1505-1518.

9.      Goff DC Jr, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk. Circulation. 2014;129:S49-S73.

10.   Bhatt DL, Steg PG, Miller M, et al; for the REDUCE-IT Investigators. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019;380(1):11-22.