This study systematically analyzed the association between the TG/HDLC ratio and the risks of all-cause mortality and cardiac death in diabetic patients with new-onset ACS. Elevated TG/HDLC ratio was associated with an increased risk of all-cause and cardiac death. As was shown in multivariate Cox regression analysis, TG/HDLC ratio was an risk factor of all-cause and cardiac death risks. In subgroup analysis, there was no statistical difference between TG/HDLC ratio and all-cause and cardiac death risks in terms of age, sex, smoking status, hypertension, LDLC, and HbA1c.
There was an advantage to the TG/HDLC ratio. High TG was a cardiovascular risk factor and was associated with all-cause mortality and the incidence of coronary artery disease (CAD) events. Several epidemiological studies have shown a significant relationship between serum HDLC concentration and CAD risk. The typical lipid profile of diabetes was high TG and low HDLC. TG and HDLC were independent of each other, and in the absence of insulin resistance, a single lipid parameter did not reflect the actual status of plasma atherosclerosis and the risk of CAD. However, TG/HDLC ratio combined them and better evaluated the death risk in diabetic patients with new-onset ACS. It might be a better indicator for primary and secondary prevention of cardiovascular diseases (CVDs)[12-14]. Another study suggested that the TG/HDLC ratio had a better predictive value for mortality than individual lipid parameters. In addition, a high TG/HDLC ratio was a good predictor of the extent of CAD[16, 17]. Elevated TG/HDLC ratio was an independent predictor of long-term all-cause mortality in patients undergoing coronary angiography and was strongly associated with long-term risk of major adverse cardiovascular events. Therefore, the TG/HDLC ratio assessment was of clinical value in diabetic patients with new-onset ACS.
TG/HDLC ratio is associated with a remnant risk of cardiovascular disease. In a certain proportion of patients taking oral statins, however, the incident risk of cardiovascular disease remains despite LDLC compliance. Both remnant lipoprotein particle cholesterol (RLPC) and LDLC are associated with the risk of ischemic heart disease (IHD) and MI. A study showed that residual cholesterol level ≥24 mg/dL was associated with an increased risk of atherosclerosis-associated disease regardless of LDLC level. Increased RLPC concentration was associated with all-cause mortality risk under non-fasting. Through intravascular ultrasound, Bayturan et al. found that LDL-C fell to an average of 58.4 mg/dL (1.5 mmol/L) in approximately twenty percent of intensively treated patients, but plaque numbers were still increasing. RLPC explains part of the remnant risk of all-cause mortality in patients with IHD. However, no biological marker can quantify residue level due to its apparent heterogeneity, lack of universally accepted definition, and absence of precise measurement methods. Although statins did not eliminate the remnant risk of CVDs, Renato et al. demonstrated that TG/HDLC was associated with residual cholesterol. Previous studies revealed that TG/HDLC ratio was closely associated with adverse cardiovascular events in patients with CAD[18, 25, 26]. A study indicated that TG/HDLC ratio was a robust independent predictor of CAD, CVD, and all-cause mortality. Elevated TG/HDLC ratio was reported to be a potentially useful predictor of future cardiovascular events in Chinese patients with DM and stable CAD. Therefore, the TG/HDLC ratio assessment is clinically significant in risk stratification for patients receiving statin therapy.
The predictive value of the TG/HDLC ratio for cardiovascular events in diabetic patients is controversial. However, insulin resistance (IR) may be the culprit of this controversy because it is a critical condition for cardiovascular events in diabetic patients. One study found that high TG and low HDLC levels were significant risk factors for coronary heart disease (CHD) only in the presence of IR. Another study showed that the risk of major cardiovascular events was more significant in the presence of IR, regardless of whether triglyceride and HDL cholesterol levels were high or low. Other studies have shown that IR at any level of obesity exacerbated the risk of developing CHD and T2DM. The mechanisms by which insulin resistance promotes cardiovascular events in diabetic patients are as follows. (1) Triglyceride-enriched VLDL particles are hydrolyzed by lipoprotein lipase or hepatic lipase to produce small dense LDLC (sdLDLC) particles; (2) In the presence of IR and high secretion of VLDL particles, these sdLDLC particles are usually present in high concentrations; (3) Whereas sdLDLC particles are highly atherogenic. Compared to normal LDL particles, they are more easily oxidized, have a higher affinity for the extracellular matrix, and have a higher degree of retention in the arterial wall. In addition, the smaller the LDL, the less it binds to the LDL receptor, and the longer it resides in the circulation.
Summarizing the findings of previous literatures, we found that the relationship between TG/HDLC ratio and death risk in diabetic patients with new-onset ACS was unclear. Clarifying this relationship was extremely important to assess the prognosis of this high-risk population. No papers have revealed this relationship in the published literature. Therefore, to clarify the relationship between the TG/HDL ratio and the death risk in diabetic patients with new-onset ACS, we used COX regression analysis and subgroup analysis to explore this relationship. Eventually, we found that TG/HDLC ratio was positively associated with the death risk in diabetic patients with new-onset ACS.
There may be several potential mechanisms for the association between TG/HDLC ratio and the death risk in patients with DM and new-onset ACS: (1) Elevated TG level and reduced HDLC play a vital role in the progression of atherosclerosis, which may be related to the TG/HDLC ratio as a marker of LDL particle size. Previous studies have reported that a high TG/HDLC ratio was strongly associated with elevated levels of small, dense LDLC, which was considered very atherogenic[35-37]. (2) TG/HDLC ratio is significantly associated with insulin resistance in diabetic patients[38-40]. Furthermore, insulin resistance is associated with the vulnerability of atherosclerotic plaques. (3) TG/HDLC ratio is related to the severity of atherosclerosis because the total plaque area is positively correlated with TG/HDLC ratio. (4) The hyperglycemic environment may lead to systemic macrovascular and microvascular disease in diabetic patients, including diabetic nephropathy, CAD, and ischemic stroke, which may be an additional risk of all-cause and cardiac death[42-44].
However, several limitations of the study should be acknowledged: (1) Follow-up information was collected by telephone or electronic medical record access. This information mainly included survival information. Baseline data after four years of follow-up were not collected. Because blood lipid levels varied by race, it was unclear whether these findings also apply to other races. (2) The complications and severity of new-onset ACS and DM differed, affecting the risks of all-cause mortality and cardiac death. (3) Because blood lipid levels varied by race, it was unclear whether these findings also applied to other races.
The next step is being under consideration. As a new lipid-lowering drug, the proprotein convertase subtilisin/Kexin type 9 (PCSK9) inhibitor is gaining attention. Therefore, we intend to study whether PCSK9 inhibitor can affect TG/HDLC ratio to increase the risk of all-cause and cardiac death in diabetic patients with new-onset ACS.