ORCID Aurélien Clerc
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Dyslipidemia is extensively analyzed in clinical trials investigating its role as a risk factor for coronary artery disease (CAD). However, its definition varies vastly among studies, leading to different attributions to the variable dyslipidemia. The objectives of this study are to verify the hypothesis of a lack of a consensual definition of dyslipidemia in coronary angiography studies and to propose a consensual definition of dyslipidemia, considering the influence of each serum lipid parameter on mortality. A systematic search of coronary angiography studies focusing on dyslipidemia was conducted. We listed definitions and their references in the 258 articles the research found. Out of the 258 articles retrieved in the search, 52 studies (20%) provided a definition of dyslipidemia, and 20 (8%) mentioned the source. We identified 39 different definitions. To mitigate misinterpretations of cardiovascular risk factors, we propose the use of the “lipid triad” components to define dyslipidemia: LDL-cholesterol >3.0 mmol/L for primary prevention and >2.6 mmol/L or >1.4 mmol/L for secondary prevention in patients over/under 75 years old, respectively;
Cardiovascular diseases stand as the primary cause of morbidity and mortality globally (
The Standardized Nomenclature of Medicine (SNOMED) defines dyslipidemia as a disorder of lipoprotein and/or a disorder of lipid metabolism (
Thus, relying parameters of dyslipidemia to a relevant, global and only health outcome would offer an objective and unbiased perspective. In that sense, mortality seems to be the best catch to build a sound and universal definition.
In coronary angiography trials, dyslipidemia is often collected and analyzed to assess its predictive value or association with CAD. However, its definition varies, sometimes with or without cutoffs, and is barely referenced. One study might use lipid-lowering therapy, such as statins, as a criterion for dyslipidemia, while another may employ thresholds for one or more serum lipids. These discrepancies in defining dyslipidemia can yield different results. The identification of a participant as “dyslipidemia: yes” at >2 or >3 mmol/L LDL-C can significantly alter the number of participants tagged with or without dyslipidemia. Moreover, relying solely to treatment, given the poor adherence to statins (
This paper aims to verify the hypothesis that there is a lack of a consensual and/or systematic definition of dyslipidemia in coronary angiography studies. The secondary objective is to propose a consensual definition of dyslipidemia, considering the influence of each serum lipid parameter on mortality.
To ascertain the true divergence in dyslipidemia definitions within coronary angiology studies, we meticulously cataloged the range of definitions found in a single database. Our systematic literature search on PubMed up to January 15, 2024 employed MeSH terms “coronary angiography” and “dyslipidemia” in the following query: ((coronary angiography[MeSH Terms]) OR (coronary angiography[Title/Abstract])) AND ((dyslip*[Title/Abstract]) OR (dyslip*[MeSH Terms])). It's noteworthy that we focused on one database, as our goal was not an exhaustive review but rather an exercise illustrating our point. The research query, crafted with MeSH terms and title/abstract criteria, aimed to identify studies specifically addressing the subject.
We chose to select the studies written in English that were published in the last five years, because a certain number of guidelines of the ESC/EAS and ACC/AHA were published for the last time in 2019 (
In collecting data from these articles, we tabulated the definitions when explicitly stated. Additionally, we recorded the cited references accompanying these definitions. In cases where an article indicated that the dyslipidemia definition had been reported elsewhere or when the references were imprecise (e.g., without the year of the guidelines), we did not take it into account. If the reference was precise (e.g., 2019 ESC/EAS Guidelines for the management of dyslipidemias) but lacked specific values in the text, we considered the definition as referred.
To exemplify potential discrepancies, we considered two cases. Case #1 involved a middle-aged man with recent CAD, no prior lipid-lowering treatment, treated hypertension, a positive family history, and a history of former smoking. His lipid profile comprised total cholesterol (TC) of 4.8 mmol/L (185 mg/dl), LDL-cholesterol of 3.4 mmol/L (131 mg/dl), HDL of 1.04 mmol/L (40 mg/dl), and triglycerides (TG) of 1.3 mmol/L (115 mg/dl). Case #2 was a 68-year-old woman with recent CAD, no prior lipid-lowering treatment, and only treated hypertension as a cardiovascular risk factor. Her lipid profile comprised TC of 4.5 mmol/L (174 mg/dl), LDL-cholesterol of 3.02 mmol/L (116 mg/dl), HDL of 1.23 mmol/L (48 mg/dl), and TG of 1.14 mmol/L (101 mg/dl). We examined whether both cases met the criteria for “dyslipidemia: yes” or “dyslipidemia: no” based on the definitions proposed in the studies.
Finally, in crafting the most widely accepted definition of dyslipidemia, we primarily considered the association between each serum lipid and mortality, which seems to be one of the most relevant and universal outcome. Indeed, mortality emerged as the most robust indicator for the general population, aligning with many guidelines using mortality or composite endpoints in studies on serum lipids. Moreover, we decided not to consider lipid-lowering therapies as a criterion of the consensual definition, since what matters is the amount of blood lipid particles and not the means to achieve them—which could also be lifestyle by the way. A recent meta-analysis indicated that lipid-lowering therapy (statins) had limited impact on absolute mortality and myocardial infarction rates (
Our research, conducted with defined criteria, yielded 310 articles. After screening, we excluded 24 case reports, 13 studies related to familial hypercholesterolemia, and 15 non-English articles. This left us with 258 studies for the definition listing.
Of these 258 studies, 52 (20%) provided a definition for dyslipidemia. Within these 52 studies, we identified 39 distinct definitions. We excluded one study due to criteria specific to a transplant condition, resulting in 38 definitions from 51 studies summarized in
Criteria characterizing the dyslipidemia in the 51 studies proposing a definition.
| Criterion | Most frequently found | Range of values/diversity |
|---|---|---|
| High total cholesterol (TC) | TC level ≥5.2 mmol/L (200 mg/dl) or ≥6.2 mmol/L (240 mg/dl) | ≥4.9–6.5 mmol/L (190–250 mg/dl) |
| High LDL-cholesterol (LDL-C) | LDL-C level ≥3.4 mmol/L (130 mg/dl), 3.6 mmol/L (140 mg/dl), 4.1 mmol/L (160 mg/dl) | ≥1.4–4.9 mmol/L (55–190 mg/dl) |
| Low HDL-cholesterol (HDL-C) | HDL-C ≤1.3 mmol/L (50 mg/dl) or ≤1 mmol/L (40 mg/dl) by women resp. men | ≤.8–1.3 mmol/L (30–50 mg/dl) |
| High triglycerides (TG) | TG ≥1.7 mmol/L (150 mg/dl) | 1.7–2.8 mmol/L (150–250 mg/dl) |
| Treatment | Use of lipid-lowering therapy | |
| Diagnosis | Diagnosis present in the patient's record |
Among the 258 studies, 20 (8%) referenced their dyslipidemia definition. Excluding one specific to liver transplant, we considered 19 articles, using 13 different references defining dyslipidemia, mostly US, European and Chinese Cardiovascular Societies' guidelines.
To illustrate the discrepancies in defining a subject as positive or negative for the variable “dyslipidemia”, we found that among 38 definitions (51 articles), case #1 would have been labeled “dyslipidemia: yes” in 14 definitions (19 articles) and “dyslipidemia: no” in 24 definitions (32 articles). Specifically, 6 articles attributed it to a low HDL-cholesterol level, 12 articles to an increased LDL-cholesterol level, and 1 article to the status, assuming a physician-defined lower LDL-cholesterol target based on formal smoking, hypertensive status, and positive family history. Case #2 would also have been labeled “dyslipidemia: yes” in 14 definitions (19 articles) and “dyslipidemia: no” in 24 definitions (32 articles). Specifically, 13 articles attributed it to a low HDL-cholesterol level and 6 articles to an increased LDL-cholesterol level.
The association between mortality and the serum lipids is summarized in
Serum lipids and their association with mortality, aiming to define ideal values to craft a consensual definition of dyslipidemia.
| Serum lipid | Nature of the association with mortality | Ideal value(s) |
|---|---|---|
| Total cholesterol (TC) | Overall: negative or U-shaped |
|
| LDL-cholesterol (LDL-C) | Overall: negative or U-shaped |
<3 mmol/L (115 mg/dl) primary prevention |
| HDL-cholesterol (HDL-C) | Negative | >1.3 mmol/L (50 mg/dl) women |
| Triglycerides (TG) | Mostly inconclusive | <1.7 mmol/L (150 mg/dl) |
In this critical analysis of dyslipidemia categorization in clinical trials, our primary objective was to investigate the hypothesis of a lacking consensus in the definition of dyslipidemia. Among the 258 studies included, we found that 80% did not provide a definition of dyslipidemia. Furthermore, of the studies that did specify dyslipidemia classification, we identified 38 different definitions. The lack of references justifying these definitions was also notable, indicating a lack of consensus in criteria across clinical trials.
Dyslipidemia poses a unique challenge in consensus definition compared to other well-established cardiovascular risk factors such as hypertension or smoking. Unlike conditions with clear definitions, dyslipidemia often lacks explicit criteria in studies, as evidenced by the work of Senoner and colleagues (
Several factors contribute to the complexity and lack of consensus in defining dyslipidemia. Firstly, dyslipidemia is not solely characterized by a single criterion (e.g., total cholesterol (TC), LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C), triglycerides (TG)), making it a multivariable equation. Unlike other cardiovascular risk factors such as arterial hypertension, diabetes mellitus, or smoking status, dyslipidemia is more complex to define. Secondly, the modifiability of dyslipidemia parameters varies. LDL-C and TC are effectively reducible through lipid-lowering treatments, while HDL-C and TG respond more to lifestyle changes (
Despite these challenges, having a common definition, similar to hypertension or diabetes, would reduce confusion, as demonstrated in the illustrative examples above.
Few studies have comprehensively compared all serum lipids within the same study. Lower concentrations of TC, LDL-C, and TG, coupled with elevated HDL-C, are mainly associated with mortality, but not consistently with cardiovascular disease (CVD) mortality in men and women (
TC is particularly tested in studies prior to 2000, because it was the more readily available. For overall and non-CVD mortalities, the association with TC is mainly negative or U-shaped (
LDL-C follows logically the same association with mortality as TC. A large number of studies comprising a systematic review found an inverse or U-shaped association between LDL-C and overall mortality (
A low HDL-C level is associated with mortality, particularly CVD mortality. The association is often U-shaped (
The association between TG and mortality is little tested and when tested, the association is mostly inconclusive (
In summary, we propose the following criteria for labeling a subject as “dyslipidemia: yes”:
LDL-C >3 mmol/L (115 mg/dl) (except for people with CVD history for whom a LDL-C >1.4 mmol/L (55 mg/dl) or >2.6 mmol/L (100 mg/dl) should be considered as too high for subjects under resp. over 75 years old) HDL-C <1.3 mmol/L for women (50 mg/dl) and <1 mmol/L (40 mg/dl) for men TG >1.7 mmol/L (150 mg/dl).
These three serum lipids collectively form the “lipid triad” due to atherogenic power (
In our proposed definition, lipid-lowering treatment and a “history” of dyslipidemia are not considered criteria, as the focus is on current lipid levels. Contrary to some studies, these two characteristics are not deemed sound criteria for defining dyslipidemia. Nevertheless, we strongly suggest collecting data on lipid-lowering treatment as a separate variable.
This study critically analyzed dyslipidemia characterization in coronary angiography trials, representing – to our knowledge – the first to undertake such an exercise. While limited to a single scientific database, albeit the most widely used, extending to other databases may further enrich observations. The focus on clinical trials in coronary angiography, while a strength, means the study only covers one facet of cardiovascular research. Broadening the search to encompass all cardiovascular studies would offer a more comprehensive understanding.
This study highlights significant heterogeneity in dyslipidemia characterization within clinical trials, which could potentially lead to misinterpretations of cardiovascular risk factors for coronary artery disease. Proposing a consensual definition based on mortality aims to uniformly classify subjects as positive or negative for this common condition. The proposed definition, derived from numerous studies, provides a more robust basis for data accumulation and comparison within studies.
AC: Writing – original draft, Writing – review & editing. MT: Writing – review & editing. SC: Supervision, Writing – review & editing.
The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was performed within the cardiology research unit of the University of Fribourg, with the financial support of The Fonds Scientifique Cardiovasculaire.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The author(s) declare that no Generative AI was used in the creation of this manuscript.
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