Prof. Jean Charles Fruchart, Prof. Michel Hermans, Prof. Pierre Amarenco
Genetic studies show that elevated triglycerides (a marker for triglyceride-rich lipoproteins and their remnants) are causal for atherosclerotic cardiovascular disease
1,2. Yet definitive evidence for a relationship between achieved triglycerides and progression of atherosclerotic plaque, as previously demonstrated for low-density lipoprotein cholesterol (LDL-C)
3, has been lacking. Consequently, this month’s Focus article
4, the first study to show that on-treatment triglyceride levels, especially above 200 mg/dl (2.3 mmol/L) associate with coronary plaque progression, even in patients with controlled LDL-C levels, is of paramount importance. Importantly, atheroma progression was more closely associated with non-high-density lipoprotein cholesterol (non-HDL-C) levels, representing all atherogenic apolipoprotein (apo)B lipoproteins, rather than LDL-C levels. Indeed, lower achieved non-HDL-C and triglycerides levels were shown to associate with plaque regression across broad categories of cardiovascular risk.
Defining the key contributors to residual cardiovascular risk has long been regarded as the ‘holy grail’ for clinicians. There has been considerable focus on lipid-related contributors to this risk, given that dyslipidaemia is recognized as one of the major risk factors for cardiovascular disease. In the INTERHEART study, a landmark global case-control study, dyslipidaemia (defined as an elevated ratio of apoB100: apoA-I lipoproteins) was one of the key risk factors accounting for the risk of myocardial infarction world-wide
5. These findings initiated a flurry of clinical trial activity, aimed at targeting apoB lipoproteins (including LDL-C and triglycerides) as well as apoA lipoproteins (as in HDL). The failure of the HDL-targeted therapies (including niacin, torcetrapib, dalcetrapib, and most recently evacetrapib) has left the door open to apoB-targeted approaches, beyond LDL-C. Yet even trials of these approaches have so far been less than definitive. For example, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial showed a lack of benefit with fenofibrate against a background of well controlled LDL-C levels with simvastatin in type 2 diabetes, although subgroup analysis did indicate benefit in patients with both elevated triglycerides and low HDL-C (atherogenic dyslipidaemia) at baseline
6. This finding was confirmed in a subsequent post hoc meta-analysis of the fibrate trials in patients with this dyslipidaemia
7. The lack of benefit seen in the overall ACCORD study may be explained by the fact that baseline triglyceride levels were too low (1.83 mmol/L or 162 mg/dl). This is supported by the study by Puri and colleagues
4 which clearly show that coronary disease progression is well established in patients with triglycerides ?200 mg/dl (2.3 mmol/L) and therefore this group is most likely to benefit from intervention targeting elevated triglycerides.
The other key finding in this month’s Focus article, that coronary progression was more closely related to non-HDL-C than LDL-C levels, supports recent guidance, including that proposed by the Residual Risk Reduction Initiative
8, recommending the use of non-HDL-C as a target, especially in statin-treated patients. Indeed, by definition, non-HDL-C encompasses all atherogenic apoB lipoproteins, including LDL-C, and therefore more effectively accounts for elevated triglyceride-rich lipoproteins and their remnants.
However, other factors beyond lipids may be relevant to residual cardiovascular risk. There has been considerable discussion of the role of inflammation given the chronic inflammatory nature of atherosclerosis
9. The lack of benefit observed in the Targeting Inflammation Using Salsalate in Cardiovascular Disease (TINSAL-CVD) trial does not rule out this possibility
11. Indeed, in an accompanying editorial to the study
11 it was suggested that a number of reasons may explain this, including difficulties in showing significant treatment benefit in the setting of best evidence-based treatment in patients with established coronary artery disease, as well as the underlying mechanism of anti-inflammatory action. We await the results of two ongoing major prospective studies to evaluate the role of anti-inflammatory therapies in targeting residual cardiovascular risk.
References
1. Do R, Willer CJ, Schmidt EM et al. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat Genet 2013;45:1345–52.
2. Varbo A, Benn M, Tybjærg-Hansen A et al. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol 2013;61:427–36.
3. Nicholls SJ, Ballantyne CM, Barter PJ et al. Effect of two intensive statin regimens on progression of coronary disease. N Engl J Med 2011;365:2078-87.
4. Puri R, Nissen SE, Shao M et al. Non-HDL cholesterol and triglycerides. Implications for coronary atheroma progression and clinical events. Arterioscler Thromb Vasc Biol 2016; DOI: 10.1161/ATVBAHA.116.307601.
5. Yusuf S, Hawken S, Ounpuu S et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004;364:937-52.
6. Ginsberg HN, Elam MB, Lovato LC et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362:1563–74.
7. Sacks FM, Carey VJ, Fruchart JC. Combination lipid therapy in type 2 diabetes. N Engl J Med 2010;363:692-4.
8. Fruchart JC, Davignon J, Hermans MP et al. Residual macrovascular risk in 2013: what have we learned? Cardiovasc Diabetol 2014;13:26.
9. Ridker PM. Residual inflammatory risk: addressing the obverse side of the atherosclerosis prevention coin. Eur Heart J 2016;37:1720-2.
10. Hauser TH, Salastekar N, Schaefer EJ et al. Effect of targeting inflammation with salsalate: the TINSAL-CVD randomized clinical trial on progression of coronary plaque in overweight and obese patients using statins. JAMA Cardiol 2016;1:413-23.
11. Ridker PM. Informative neutral studies matter.-Why the Targeting Inflammation With Salsalate in Cardiovascular Disease (TINSAL-CVD) Trial deserves our attention. JAMA Cardiol 2016;1:423-4.