Lipid Profile Status and Cardiac Risk Factors in Opium Users Versus Non-users with Coronary Artery Disease: Insights from the National Persian Registry of Cardiovascular Disease (N-PROVE)

Opioids are narcotic substances extracted from the poppy plant, and their misuse due to sedative effects dates back to 4000 B.C. (1). Currently, their prevalence is rising in certain parts of the world, including Iran (2), with a reported prevalence of 13.6% among adults in Babol (3). Recent studies indicate significant societal and health impacts due to increased opioid use, contributing to various health burdens across demographics. Opioids can affect different systems of the body, including the central nervous, respiratory, and cardiovascular systems (4). Coronary artery disease (CAD) is the most common cause of mortality worldwide (5), with many individuals having at least one cardiovascular risk factor such as hypertension, smoking, dyslipidemia, obesity, and diabetes mellitus (DM). Research consistently highlights that adverse cardiovascular events can occur even in individuals with a normal lipid profile, emphasizing the need for comprehensive evaluations beyond traditional risk factors (6, 7). Therefore, new indices such as atherogenic indices have been proposed. These indices, calculated using simple mathematical formulas, can indicate the severity of atherosclerosis and are useful in predicting the likelihood of CAD (8-12). The Atherogenic Index, also known as Castelli’s Risk Index I and II (CRI I and CRI II), is derived from dividing total cholesterol (TC) or low-density lipoprotein (LDL) by high-density lipoprotein (HDL) (Table 1). This index has a direct relationship with cardiovascular events and is correlated with the thickness of the intima and media of the carotid artery, a sign of subclinical atherosclerosis (8, 9). Another index introduced for predicting the likelihood of atherosclerosis in coronary arteries is the Atherogenic Index of plasma (AIP) (10). High-density lipoprotein is recognized as a protective lipoprotein against CAD, while LDL is considered an atherogenic factor. Emerging evidence suggests that non-HDL may provide a more accurate measure for predicting atherosclerosis, as it encompasses all lipoproteins containing Apo B, which are implicated in atherogenesis (11). The Triglyceride-Glucose Index (TyG) is also an Alternative Index that indicates insulin resistance. This index is closely associated with the onset of non-communicable diseases such as hypertension, diabetes, CAD, stroke, obesity-related cancers, and even cardiovascular outcomes in diabetic patients (12). Statistics indicate that 36% of CAD patients in Iran consume opium (6). Various articles report different effects on the cardiovascular system and lipid profiles depending on the duration and amount of opium consumption. For instance, some studies indicate that prolonged opium use is associated with an increased risk for acute myocardial infarction and cardiovascular-related mortality (13). Conversely, other studies, such as that by Marmor et al., reported that opium consumption might confer a protective effect against cardiovascular diseases (14). There is also variability in the results regarding opium's effects on lipid profiles, with studies reporting significant lipid reductions, increases, or no impact compared to non-consumers (15-17).

Therefore, considering the rising trend of addiction in society and the increasing prevalence of CVD and their risk factors, particularly dyslipidemia, along with the conflicting reports regarding the effects of opium on lipid profiles and risk factors for cardiovascular diseases, this study aims to clarify the relationship between opium use and cardiovascular risk factors. It hypothesizes that opium consumers may exhibit distinct lipid profile changes and cardiovascular risk factor patterns compared to non-consumers.

Out of 3,479 individuals who underwent coronary angiography at Razi Hospital during the years 2018 - 2020, 1,888 patients had stenosis greater than 50% in at least one coronary artery. Additionally, 1,591 individuals with stenosis less than 50% in coronary arteries or lacking lipid profile or fasting blood sugar data were excluded from the study. Therefore, our study sample consisted of 1,888 individuals (Figure 1).

Figure 1.

Flowchart of study patients

Out of the 1,888 patients included in the study, the majority were male (68.5%). Of these, 463 (24.5%) were opium consumers, and 1,425 (75.5%) were non-consumers. A comparison of demographic characteristics and medical history is presented in Table 2. The mean age of participants in the study was 63.46 ± 11.43 years. Opium consumers were approximately 4 years younger (60.14 ± 11.64 years) than non-consumers (64.38 ± 11.74 years, P < 0.001). Additionally, non-opium consumers exhibited a significantly higher prevalence of hypertension (55.0%), DM (31.0%), and dyslipidemia (28.8%). In contrast, a history of previous percutaneous coronary intervention (PCI) and smoking was significantly higher among opium consumers. Laboratory factors in both groups are examined in Table 3. As shown, TG were significantly lower in opium consumers. The levels of fasting blood sugar, cholesterol, HDL, and LDL showed no significant differences between the two groups. Among the new indices, the AIP, TyG Index, and non-HDL were significantly lower in the opium-consuming group compared to the non-consumers. Other lipid indices did not show statistically significant differences between the groups.

The overall prevalence of opium consumption among our CAD patients was 24.5%. In the study by Aghadavoudi et al. in Isfahan, which involved 325 patients undergoing coronary bypass surgery, the rate of opium consumption was reported to be 36%, and in the study by Davoodi et al., which explored 160 patients with acute myocardial infarction in Tehran, it was 28.1% (6, 19). In the context of our study objectives, it is evident that opium consumption among CAD patients is prevalent and varies across different regions. This underlines the necessity of addressing substance use in the management of cardiovascular risks.

In the current study, the history of DM in opium consumers was lower than in non-consumers. The findings align with studies by Sheikhy et al. (20), Hamrah et al. (1), and Liew et al. (21), which also reported lower DM rates among opium users. Nalini et al. conducted a study on 40,083 participants in the Golestan Cohort Study, which took place from 2004 to 2008 in the Gorgan and Golestan region and involved a 12-year follow-up. The aim was to investigate the long-term relationship between DM and opium; thus, researchers excluded individuals with DM at the beginning of the study and then compared the incidence of DM among opium users and non-users. Results showed that individuals who used opium for a long time (average use duration of about 10 years) had a lower BMI (23.5% vs. 27%) and a lower waist circumference (88.9 cm vs. 95.7 cm), which were statistically significant. Furthermore, the incidence of DM in these individuals was 17% lower than in non-consumers, primarily due to reduced body mass and smaller waist circumference. Researchers attributed the lower blood sugar levels in opium users to lower body mass and less abdominal obesity (22).

In our study, the history of hypertension was less frequent in the opium-consuming group. The blood pressure levels in the opium group were also lower, which was consistent with our study, but in the study by Hamrah et al. (1), elevated blood pressure was reported among opium addicts. This discrepancy may indicate the impact of dosage and duration of opium use on blood pressure regulation; thus, it reflects the complexity of interpreting cardiovascular outcomes among opium users. Low doses and short-term administration of opium typically lower blood pressure through vasodilation and reduced sympathetic tone, while long-term opium use can lead to increased plasma homocysteine, higher oxidative stress, decreased opioid receptor availability, and ultimately increased blood pressure (1).

In this study, triglyceride levels were significantly lower in opium consumers. Additionally, the studies by Asgary et al. (23) and Fatemi et al. (15) reported higher triglyceride levels in the non-opium group compared to the opium-consuming group. This finding underlines the relationship between opium consumption and lipid profiles, suggesting that lower BMI in opium users may contribute to their favorable triglyceride levels. However, it is important to consider potential confounding factors or selection biases that might influence these results. Factors such as dietary habits, levels of physical activity, and other lifestyle choices may have skewed our findings. Further investigation is necessary to determine the extent to which these factors impact lipid profiles in both opium consumers and non-consumers.

Regarding the suggestion that opium could be considered a significant management strategy for reducing cardiac risk factors, we must clarify that while our findings indicate a correlation between opium use and lower triglyceride levels, this does not imply causation or advocate for opium as a treatment modality. The complexities surrounding the consumption of opium, along with its associated health risks, necessitate a cautious interpretation of these results. To strengthen our manuscript, we acknowledge the need for a critical discussion addressing potential mechanisms, limitations, and alternative explanations for our findings. This would provide a more comprehensive understanding of the dynamics at play and ensure that the interpretation of our results is accurate and not misleading.

In our study, there were no significant differences in cholesterol and LDL levels between non-consumers and consumers of opium; however, in the studies by Hamrah et al. (1), Fatemi et al. (15), and Kazemi et al. (8), cholesterol levels were lower in the opium-consuming group compared to non-consumers. In the studies conducted by Aghadavoudi et al. (6), Fatemi et al. (15), and Liew et al. (21), LDL levels were higher in non-consumers compared to users. Dietary habits, socioeconomic status, and unhealthy lifestyle choices may influence lipid profiles and LDL levels in individuals. In the present study, HDL levels did not show significant statistical differences between non-opium users and opium users, which was similar to Liew's study (21).

In our study, the AIP, TyG, and non-HDL were significantly lower in the opium-consuming group compared to the non-consumers. We did not find any similar studies comparing these indices in opium users. This suggests a novel area for further research to comprehensively understand the implications of these indices in assessing cardiovascular risks associated with opium use. Given that in this study, the rate of smoking had a significant positive correlation with opium use (26.2% smokers in the opium group vs. 5.8% smokers in the non-opium group), we explored related studies concerning these new lipid indices among smokers. Baek et al. conducted a study in Korea comparing the TyG Index among the subjects. They found that in smokers or alcohol users, this index was higher compared to non-smokers or non-alcohol users, and those who consumed both (smoking and alcohol) showed significantly higher levels (24). Tobacco and cigarette smoke can produce pro-inflammatory toxic substances. Additionally, oxidative stress and mitochondrial dysfunction in smokers can reduce peripheral insulin and increase sensitivity to it. Direct dysfunction of β-cells has also been reported in smokers (24).

The molecular mechanism of opium in the pathogenesis of CAD remains unclear. Momeni-Moghaddam et al., in a case-control study, compared the expression of receptors CD36, CD68, CD9 as well as levels of inflammatory factors tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), and malondialdehyde (MDA) in three groups (30 addicted CAD patients, 30 non-addicted CAD, and 17 healthy opium users). The results showed that only inflammatory factors were elevated in addicted CAD patients. This finding suggests the need for further investigation into the inflammatory pathways linked to opium use and CAD, which might isolate opium as an independent risk factor despite lower levels of traditional cardiovascular risk factors (25).