Introduction

Diabetes is a growing pandemic and the impact of diabetes on health is projected to increase worldwide, mostly driven by increments in lower- and middle-income countries [1]. Individuals with diabetes are at an increased risk of cardiovascular disease and death compared to those without diabetes, mainly due to atherosclerotic cardiovascular disease (ASCVD) [2]. The high burden of ASCVD can be attributed to hyperlipidemia, hypertension, hyperglycemia, insulin resistance, low-grade inflammation, and obesity, [3] risk factors that are highly prevalent in individuals with diabetes, and improved control of these reduces the risk of ASCVD and mortality in this population [4, 5].

Hyperlipidemia in individuals with diabetes is characterized by elevated levels of triglycerides and remnant cholesterol, while levels of low-density lipoproteins (LDL) cholesterol are usually similar or slightly lower compared to levels in individuals without diabetes [6]. Presently, LDL cholesterol is the primary lipid target to reduce the risk of ASCVD in individuals with diabetes [7, 8], but even after LDL cholesterol has been lowered, residual ASCVD risk persists [9]. Part of this residual risk may be attributed to elevated remnant cholesterol [10], as elevated remnant cholesterol has been associated genetically and observationally with an increased risk of ASCVD in the general population [11, 12], and has recently gained attention as an important risk factor for ASCVD in individuals with diabetes as well [13]. Likewise, apolipoprotein B (apoB) and non-high-density lipoprotein (HDL) cholesterol have been postulated as secondary lipid targets in individuals with diabetes, in part because they are good markers of remnant particles and remnant cholesterol, respectively [7, 14]. However, the results of recent clinical trials of drugs which lower levels of remnant cholesterol in individuals with diabetes are conflicting in terms of ASCVD prevention, likely in part because of the neutral effect on total plasma apoB levels, as plasma apoB reflects the total concentration of atherogenic lipid particles [15,16,17,18]. To reduce the risk of ASCVD, new therapies under development should likely aim to reduce both plasma remnant cholesterol and plasma apoB.

In this review, we describe the impact of elevated remnant cholesterol on cardiovascular risk in diabetes, including recent observational, genetic, and clinical trial evidence. Finally, we discuss future perspectives related to elevated remnant cholesterol levels in individuals with diabetes.

Pathophysiology

Remnant Cholesterol and Insulin

The hyperlipidemia in individuals with type 2 diabetes mellitus (the predominant form of diabetes worldwide and referred to simply as diabetes in this article) is characterized by elevated levels of triglycerides, triglyceride-rich lipoproteins, remnant cholesterol (the cholesterol content in triglyceride-rich lipoproteins), non-HDL cholesterol, and apoB. The levels of LDL cholesterol are usually not elevated, although small dense LDL particles are often more abundant [6]. Remnant cholesterol is all cholesterol in plasma not carried in LDL or HDL and can be calculated from a standard lipid profile as total cholesterol minus LDL cholesterol minus HDL cholesterol, or it can be directly measured [12]. Levels of remnant cholesterol depend on a balance between the synthesis, hydrolysis and clearance of liver-derived triglyceride-rich lipoproteins (very-low density lipoproteins (VLDL) containing apoB-100) and intestine-derived triglyceride-rich lipoproteins (chylomicrons, chylomicron remnants, and VLDL containing apoB-48) [12, 19] (Fig. 1). Soon after VLDL and chylomicrons have been synthesized and secreted into the plasma, they are hydrolyzed by lipoprotein lipase (LPL), a key enzyme involved in their catabolism. Triglycerides are liberated from VLDL and chylomicrons by LPL, which leads to formation of smaller, cholesterol-rich particles (remnants and LDL), which in turn are cleared from plasma by LDL receptor-related protein 1 and LDL receptors in the liver [20,21,22] (Fig. 1).

Fig. 1
figure 1

Hyperlipidemia in diabetes and atherosclerosis. The lipid profile in individuals with diabetes is characterized by elevated levels of triglycerides, triglyceride-rich lipoproteins (chylomicrons and VLDL), and remnant cholesterol. Levels of LDL cholesterol are usually not elevated, although levels of small dense LDL particles are typically high. Insulin resistance and hyperglycemia promotes increased synthesis, altered hydrolysis, and delayed clearance, promoting higher levels of triglyceride-rich lipoproteins and their remnants and small dense LDL particles in plasma. In turn, higher levels of these lipoproteins promote development of atherosclerosis. New drugs under development to reduce the levels of remnant cholesterol are targeting ANGPTL3 and apoC-III. ANGPTL: Angiopoietin-like protein, Apo: apolipoprotein. ASO: antisense oligonucleotide, CE: cholesteryl ester, FFA: free-fatty acids, HDL: high-density lipoproteins, HL: hepatic lipase, LDL: low-density lipoproteins, LDLR: LDL receptor, LPL: lipoprotein lipase, LRP1: LDL receptor-related protein 1, siRNA: small interfering RNA, VLDL: very low-density lipoproteins. This figure is original

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Insulin plays an important role in the metabolism of triglyceride-rich lipoproteins: it promotes storage of triglycerides in adipose tissue, exerts an anti-lipolytic effect in adipocytes, stimulates hepatic lipogenesis de novo, regulates hepatic VLDL assembly and secretion, regulates synthesis of apoB-48, regulates assembly and secretion of intestinal chylomicrons and VLDL-apoB-48, stimulates expression and activity of LPL, and suppresses apoC-III expression, a potent inhibitor of LPL activity. [6, 23,24,25,26,27].

Elevated Remnant Cholesterol, Small Dense LDL and Risk of ASCVD in Diabetes

Individuals with diabetes develop insulin resistance, compensatory hyperinsulinemia, and hyperglycemia, which in turn increase remnant cholesterol levels as follows. In the liver, increased influx of free fatty acids and lipogenesis de novo leads to higher production of hepatic VLDL [6, 27]. In the gut, increased expression of apoB-48 and secretion of triglycerides lead to higher production of intestinal chylomicrons and VLDL-apoB-48 lipoproteins [24]. In plasma, reduced expression of LPL and increased levels of apoC-III and angiopoietin-like protein (ANGPTL) 3 collectively lead to reduced LPL activity, decreasing lipolysis of VLDL and chylomicrons [27] (Fig. 1). Taken together, these processes lead to elevated levels of triglyceride-rich lipoproteins and their remnants in plasma in individuals with diabetes.

Diabetic hyperlipidemia is also characterized by elevated levels of small dense LDL particles. Small dense LDL are formed as partially hydrolyzed remnant particles and exchange triglycerides for cholesteryl esters in HDL, a process enhanced by cholesteryl ester transfer protein [27] (Fig. 1). This results in triglyceride-rich LDL particles, which are more susceptible to hepatic lipase-mediated hydrolysis of triglycerides, decreasing their size and turning them into cholesterol-rich, small dense LDL particles [28]. Small dense LDL particles have a greater propensity to be oxidized and a longer half-life in plasma due to their lower affinity with the LDL receptor. Therefore, they are sometimes considered more atherogenic compared to unmodified LDL particles [8].

As triglyceride-rich lipoproteins carry most of the plasma triglycerides, levels of triglyceride-rich lipoproteins and plasma triglycerides are highly correlated. High plasma triglycerides are therefore a marker of high levels of triglyceride-rich lipoproteins in individuals with diabetes. However, it is the remnant cholesterol held in triglyceride-rich lipoproteins that accumulates in atherosclerotic plaques, not the triglycerides, and elevated remnant cholesterol may therefore be responsible for part of the residual risk of ASCVD in diabetes [29].

Mechanistically, both remnant particles and LDL particles (including small dense LDL) can penetrate the arterial endothelium and be retained in the arterial intima through binding of apoB to proteoglycans [21]. The cholesterol in both particles triggers a pro-inflammatory response, leading to accumulation of monocytes in the arterial intima. Monocytes mature into macrophages and engulf cholesterol to become foam cells, a major component of atherosclerotic plaques [30]. Of note, each remnant particle typically has two- to fourfold higher cholesterol mass relative to each unmodified LDL, thereby contributing more cholesterol to the atherosclerotic plaque [31]; thus a remnant cholesterol driven hyperlipidemia, as seen in diabetes, may be more detrimental to the arterial system than solely LDL-driven hyperlipidemia. The foam cells and extracellular cholesterol promote an inflammatory environment, with attraction and accumulation of other proinflammatory immune cells and muscle cells, which in turn promote formation and enlargement of the atherosclerotic plaque [30] (Fig. 1); this is the beginning of a process that may later trigger an ASCVD event (coronary artery disease, ischemic stroke, or peripheral artery disease).

Epidemiology

Observational Epidemiology

Elevated remnant cholesterol has been associated with increased risk of ASCVD in numerous studies of the general population [12, 32,33,34], including coronary artery disease, ischemic stroke, and peripheral artery disease [35]. Furthermore, remnant cholesterol can improve prediction of coronary artery disease risk in primary prevention even above and beyond apolipoprotein B [36, 37].

Remnant cholesterol is often elevated in individuals with obesity and diabetes [13, 23] (Fig. 2). This may explain why elevated remnant cholesterol was associated not only with increased cardiovascular mortality, but also with increased mortality from other causes in a recent study [33]. In that study, individuals with elevated remnant cholesterol had increased mortality especially from infectious and endocrinological diseases. This could suggest that elevated remnant cholesterol is a marker of obesity and diabetes, but it could also be explained by hypertriglyceridemia being linked to inflammatory diseases and a potential link between inflammatory pathways and endocrinological diseases, although this is only speculative.

Fig. 2
figure 2

Elevated remnant cholesterol is characteristic of individuals with diabetes. Levels of remnant cholesterol and LDL cholesterol are shown in 94,311 non-statin users from the Copenhagen General Population Study. Levels of remnant cholesterol are higher in individuals with diabetes compared to individuals without diabetes. By contrast, levels of LDL cholesterol are slightly lower in individuals with diabetes compared to individuals without diabetes. Adapted with permission from Wadstrom BN, et al. Diabetologia. 2023;66:2238–49. IQR: interquartile range. LDL: low-density lipoproteins

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Elevated remnant cholesterol may be an important explanation for the excess risk of ASCVD observed in individuals with obesity and diabetes [13, 32]. However, the composition of remnant cholesterol is generally different in individuals with diabetes compared to individuals without diabetes, as proportionally more remnant cholesterol is typically carried in large apoB-48 VLDL and chylomicrons [24]; this could suggest a different relationship of elevated remnant cholesterol with risk of ASCVD in individuals with diabetes. Nonetheless, elevated remnant cholesterol has been associated with increased risk of ASCVD in individuals with diabetes in various cohorts and national registry studies (Fig. 3) [38,39,40,41,42]. In addition to elevated remnant cholesterol, subclinical inflammation may explain excess risk in individuals with diabetes [41]; elevated remnant cholesterol weakly increases subclinical inflammation [43], but elevated remnant cholesterol and inflammation confer additively increased risk of ASCVD [44]. Consequently, the effects of elevated remnant cholesterol and subclinical inflammation on risk of ASCVD most likely act through separate biological pathways; however, it is also possible that if both are present a synergistical effect on increased risk of ASCVD could occur.

Fig. 3
figure 3

Risk of ASCVD per doubling of remnant cholesterol and LDL-cholesterol in individuals with diabetes from the Copenhagen General Population Study. Higher remnant cholesterol, but not LDL-cholesterol, was associated with increased risk of ASCVD and its components peripheral artery disease, myocardial infarction, and ischemic stroke in individuals with diabetes. Adapted with permission from Wadstrom BN, et al. Diabetologia. 2023;66:2238–49. No.: number

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Genetic Epidemiology

Genetic variation that increases remnant cholesterol is randomly distributed in homogeneous populations, thus genetic variation can be used as proxy for elevated remnant cholesterol in so called Mendelian randomization studies, which minimize confounding and reverse causation. Such studies support that elevated remnant cholesterol is causally associated with ASCVD [45,46,47]. Unfortunately, there are at present no Mendelian randomization studies in individuals with diabetes, which require very large cohorts; additionally, newer adapted methods need to be applied to ensure a random distribution of genetic variation when studying only individuals with diabetes or other diseases [48].

In some studies, elevated remnant cholesterol has also been shown to increase risk of diabetes [49,50,51]. However, since elevated remnant cholesterol does not increase glycated hemoglobin or insulin resistance [52], it may be that individuals with subclinical diabetes and elevated remnant cholesterol and plasma triglycerides are simply more likely to be diagnosed in general practice, compared to individuals with low levels of plasma triglycerides. On the other hand, it is well established that obesity and type 2 diabetes lead to increased levels of remnant cholesterol [53, 54]; this can also occur during hyperglycemia in individuals with type 1 diabetes, but remnant cholesterol and triglycerides levels are usually normalized when hyperglycemia is reversed [55].

Remnant cholesterol is likely elevated in large part due to decreased LPL activity in individuals with diabetes [20]: therefore, genetic variation in the LPL gene may in part be a reasonable proxy for the effect of elevated remnant cholesterol in diabetes. Indeed, genetic variation in LPL, which leads to increased levels of plasma triglycerides, is associated with increased risk of ASCVD in the general population [50, 56,57,58,59]. In a recent study, genetic variants decreasing lipolysis rate, including variants in LPL, were associated with highly increased risk of coronary artery disease per 1 g/L apolipoprotein B increment compared to genetic variants that influenced LDL receptor activity [47]. This indicates that the triglyceride-rich lipoproteins carrying remnant cholesterol may be more atherogenic on a per particle basis compared to LDL, which may be partially due to more cholesterol being carried in each triglyceride-rich lipoproteins compared to LDL [60]. Nonetheless, risk of coronary artery disease was also higher per 39 mg/dL (1 mmol/L) higher non-HDL cholesterol, suggesting that this may not be the full explanation [47]; consequently, the study raises the question of whether LPL deficiency or elevated triglycerides have effects on risk of ASCVD that go beyond those of increased plasma cholesterol. Indeed, LPL deficiency may increase risk of metabolic dysfunction-associated steatotic liver disease independently of its effect on plasma triglycerides [61].

Clinical Trials

Levels of plasma triglycerides reflect levels of triglyceride-rich lipoproteins and their remnants as triglycerides are held mostly in these lipoproteins. Fibrates strongly reduce levels of triglycerides, although they only modestly reduce levels of remnant cholesterol and LDL cholesterol. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, the combination of simvastatin + fenofibrate compared with simvastatin + placebo in individuals with diabetes failed to show a reduction on the risk of ASCVD overall, although there was a non-significant trend towards benefit in a subgroup of patients with high levels of triglycerides and low levels of HDL cholesterol [15]. The mean change in plasma triglycerides with fenofibrate was -22% (-9% placebo) and LDL cholesterol -19% (-21% placebo). The Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) trial investigated the use of pemafibrate compared to placebo on risk of ASCVD or death from cardiovascular causes in individuals with type 2 diabetes [16]. The included individuals were on statins, had levels of triglycerides between 200 and 499 mg/dL (2.3 and 5.6 mmol/L), levels of HDL cholesterol ≤ 40 mg/dL (1.0 mmol/L), and levels of LDL cholesterol ≤ 100 mg/dL (2.6 mmol/L). The PROMINENT trial was stopped for futility after a median follow-up of 3.4 years. The median change in levels of triglycerides with pemafibrate was -31% (-7% placebo), measured remnant cholesterol -44% (-20% placebo), LDL cholesterol + 14% (+ 3% placebo), non-HDL cholesterol -2% (-3% placebo), and apoB + 3% (-2% placebo).

Omega-3 polyunsaturated fatty acid supplementation can effectively reduce levels of triglycerides. In the Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT), individuals on statins with stablished cardiovascular disease or diabetes plus risk factors (58% of the population) were included; levels of triglycerides needed to be between 135 and 499 mg/dL (1.5 and 5.6 mmol/L) and levels of LDL cholesterol < 100 mg/dL (2.6 mmol/L) [17]. The study investigated the use of 2 g of icosapent ethyl twice daily compared to a mineral oil as placebo, and the primary endpoint was risk of ASCVD. The results showed a reduction of 25% in the relative risk of the primary endpoint, with consistent benefit in individuals with and without diabetes, despite very modest changes in lipoprotein levels. The median change in triglycerides was -22% (-7% placebo), LDL cholesterol -1% (+ 7% placebo), non-HDL cholesterol -4% (+ 5% placebo), and apoB -3% (+ 5% placebo); of note, the change in C-reactive protein was -13% (+ 30% placebo). The STRENGTH study tested the use of 4 g of a combination of eicosapentanoic acid and docosahexanoic acid compared to placebo (corn oil) on risk of ASCVD in statin users with high cardiovascular risk (70% with diabetes), triglycerides between 180 to 499 mg/dL (2.0 and 5.6 mmol/L), and low levels of HDL cholesterol [18]. The study was stopped prematurely for futility despite very similar changes in levels of lipoproteins compared with the REDUCE-IT. The median change in triglycerides was -19% (-1% placebo), LDL cholesterol + 1% (-1% placebo), non-HDL cholesterol -6% (-1% placebo), and apoB -2% (-1% placebo); in this study, the change in C-reactive protein was -20% (-6% placebo).

Taken together, the results of recent clinical trials with drugs lowering levels of remnant cholesterol and triglycerides in individuals with diabetes are conflicting (Table 1). Although the REDUCE-IT study showed a decrease in the risk of ASCVD, it is not clear if this was because of the decreased lipid levels or some other effect beyond the lipids.

Table 1 Recent cardiovascular outcome trials for drugs lowering remnant cholesterol and triglycerides. CVD was a composite endpoint consisting of coronary artery disease events, stroke, and death from cardiovascular causes, with minor variations between the included trials. *C-reactive protein was evaluated as inflammatory marker. apo: apolipoprotein, C: cholesterol, CRP: C-reactive protein, CVD: cardiovascular disease, DHA: docosahexaenoic acid, EPA: eicosapentaenoic acid, LDL: low-density lipoproteins, non-HDL: non-high-density lipoproteins, TG: triglycerides
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Guidelines

The current North American and European guidelines to reduce the risk of ASCVD in individuals with diabetes focus on LDL cholesterol as the primary lipid target, while non-HDL cholesterol and apolipoprotein B are recommended as secondary targets [7, 14, 62]. Lowering of LDL cholesterol levels by 39 mg/dL (1 mmol/L) leads to 23% reduction in major cardiovascular events in people with diabetes [63]. Statins are the first line therapy, and treatment can be intensified by adding ezetimibe, proprotein convertase subtisilin/kexin type 9 (PCSK9) inhibitors, or bempedoic acid in those who have not reached the target or as first line therapy in those statin intolerant [7].

Reduction of triglyceride levels as an additional target to reduce risk of ASCVD is not uniformly recommended. All guidelines recommend diet and lifestyle as the mainstay treatment for individuals with elevated triglycerides and diabetes [7, 14, 62, 64, 65]. Secondary causes of hypertriglyceridemia should be ruled out and/or treated, and glycemic control optimized. The 2021 American College of Cardiology Expert Consensus endorsed by the National Lipid Association recommends that in individuals with diabetes age ≥ 50 years with 1 or more ASCVD risk factors and persistent hypertriglyceridemia after maximally tolerated statin therapy, icosapent ethyl may be considered [66]. A similar recommendation is given by the 2023 European Society of Cardiology Guidelines for the management of cardiovascular disease in patients with diabetes [7] (recommendation class IIb).

Non-HDL cholesterol and apoB are recommended as secondary lipid targets in individuals with diabetes in European and North American guidelines, and even as primary lipid targets alongside LDL cholesterol in the Canadian guidelines [7, 14, 62, 64, 65]. Non-HDL cholesterol includes all cholesterol in apoB-containing lipoproteins, which is LDL cholesterol and remnant cholesterol, while apoB counts both LDL and remnant particles. Therefore, high non-HDL cholesterol and apoB despite low LDL cholesterol are signs of elevated remnant cholesterol and remnant particles, respectively [7, 14]. Indeed, elevated non-HDL and apoB better reflect residual risk of ASCVD compared to elevated LDL cholesterol in statin users from the general population [67]. This may be explained by the fact that statins mainly reduce levels of LDL cholesterol, while levels of remnant cholesterol are lowered less.

Future Perspectives

New lipid-lowering therapies targeting remnant cholesterol for reducing ASCVD risk in individuals with diabetes should meet two requirements: i) robust lowering of remnant cholesterol and triglyceride levels, while ii) simultaneously lowering apoB levels, since apoB provides a direct estimate of the total concentration of atherogenic lipid particles. Indeed, clinical trials with neutral effects on total apoB levels and non-HDL cholesterol may potentially explain the lack of cardiovascular benefit of therapies reducing levels of triglycerides and remnant cholesterol [68]. New therapies may aim to enhance hydrolysis and clearance of the triglyceride-rich lipoproteins to effectively reduce ASCVD risk.

As shown in this review, preclinical, observational, and genetic studies indicate an effect of elevated remnant cholesterol on risk of ASCVD in the general population and likely also in individuals with diabetes, suggesting that remnant cholesterol could be a potential treatment target. Of note, genetic studies supporting a causal effect of elevated remnant cholesterol on risk of ASCVD are lacking in individuals with diabetes, although there are several in the general population as described above. The high levels of remnant cholesterol and residual ASCVD risk in individuals with diabetes warrant future studies. Recently, two phase 2b trials with promising results were published [69, 70]. Individuals with mixed hyperlipidemia (40 to 60% of whom had diabetes) were included in studies of small interference RNA therapies targeting expression of ANGPTL3 and APOCIII in the liver compared to placebo [69, 70]. Clear reductions in levels of remnant cholesterol, triglycerides, LDL cholesterol, and apoB were shown with both treatments. Whether the lowering of atherogenic lipoproteins with these therapies translate into lower risk of ASCVD remains to be seen in cardiovascular outcomes studies.

Conclusions

Elevated remnant cholesterol likely confers part of the residual risk of ASCVD in individuals with diabetes. Although statins reduce risk of ASCVD in this population, rates of ASCVD remain high and there is an unmet need for further risk reduction. New remnant cholesterol-lowering therapies for reduction of ASCVD risk in individuals with diabetes should also lower apoB levels, thereby reducing the totality of atherogenic lipoproteins.

Key References

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    • Updated Guideline of the European Society of Cardiology for the management of cardiovascular disease in individuals with diabetes.

  • Taskinen MR, Matikainen N, Bjornson E, Soderlund S, Inkeri J, Hakkarainen A, et al. Contribution of intestinal triglyceride-rich lipoproteins to residual atherosclerotic cardiovascular disease risk in individuals with type 2 diabetes on statin therapy. Diabetologia. 2023;66(12):2307–19. https://doi.org/10.1007/s00125-023-06008-0.

    • The elevated remnant cholesterol in individuals with diabetes may mostly stem from higher levels of large interstinally-derived triglyceride-rich lipoprotens.

  • Wadstrom BN, Pedersen KM, Wulff AB, Nordestgaard BG. Elevated remnant cholesterol and atherosclerotic cardiovascular disease in diabetes: a population-based prospective cohort study. Diabetologia. 2023. https://doi.org/10.1007/s00125-023-06016-0.

    • Elevated remnant cholesterol may explain 24% of the excess risk of atherosclerotic cardiovacular disease conferred by diabetes.

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    • Elevated remnant cholesterol and low-grade inflammation confer additive risk of atherosclerotic cardiovascular disease, suggesting they are part of two independent biological pathways.

  • Bjornson E, Adiels M, Taskinen MR, Burgess S, Rawshani A, Boren J, et al. Triglyceride-rich lipoprotein remnants, low-density lipoproteins, and risk of coronary heart disease: a UK Biobank study. Eur Heart J. 2023. https://doi.org/10.1093/eurheartj/ehad337.

    • Each triglyceride-rich lipoprotein carrying remnant cholesterol increases risk of coronary artery disease more than each LDL.

  • Zhao Y, Zhuang Z, Li Y, Xiao W, Song Z, Huang N, et al. Elevated blood remnant cholesterol and triglycerides are causally related to the risks of cardiometabolic multimorbidity. Nat Commun. 2024;15(1):2451. https://doi.org/10.1038/s41467-024-46686-x.

    • Elevated remnant cholesterol may increase the chance of being diagnosed with diabetes.

  • Das Pradhan A, Glynn RJ, Fruchart JC, MacFadyen JG, Zaharris ES, Everett BM, et al. Triglyceride Lowering with Pemafibrate to Reduce Cardiovascular Risk. N Engl J Med. 2022;387(21):1923–34. https://doi.org/10.1056/NEJMoa2210645.

    • Use of pemafibrate in individuals with type 2 diabetes and hypertriglyceridemia did not reduce the risk of ASCVD.

  • Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, et al. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med. 2019;380(1):11–22. https://doi.org/10.1056/NEJMoa1812792.

    • Use of purified of icosapent ethyl in individuals with high ASCVD risk and hypertriglyceridemia reduced the risk of ASCVD.