Impact of Hyperinsulinemia on Long-Term Clinical Outcomes of Percutaneous Coronary Intervention in Patients without Diabetes Who Have Acute Myocardial Syndrome

Introduction

Metabolic syndrome (MetS) has a high prevalence worldwide.¹ MetS is associated with the development of coronary atherosclerosis, plaque instability, and cardiovascular events in patients with and without type 2 diabetes.^2,3 The core components of MetS are insulin resistance (IR) and hyperinsulinemia.⁴ A new concept of selective IR proposes that tissues become resistant to the effect of insulin on glucose transport but remain sensitive to its lipogenic effect.⁵ IR may be compensatory in the body’s response to preventing MetS. Hyperinsulinemia is more common than IR and may play a primary role in the development of cardiovascular impairment in patients with MetS.⁶

Previous studies show that hyperinsulinemia is associated with hypertension, obesity, and dyslipoproteinemia, which are risk factors for coronary artery disease.^7,8 Other studies have indicated that hyperinsulinemia interferes with arteriolar vasodilation and bioavailability of nitric oxide (NO) in obese, insulin-resistant, and healthy individuals.^4,9 Our previous study demonstrated that hyperinsulinemia impairs the functions of endothelial progenitor cells, which play a key role in maintaining endothelial function and vascular repair.¹⁰ However, the impact of hyperinsulinemia on major clinical outcomes following percutaneous coronary intervention (PCI) is largely unknown.

The aim of this study was to evaluate the impact of hyperinsulinemia on major clinical outcomes in patients with acute myocardial syndrome (ACS) undergoing PCI. Many studies have shown that diabetes mellitus is associated with ischemic events in patients undergoing PCI.^11–13 Therefore, to avoid the influence of hyperglycemia on clinical outcomes of PCI, we excluded patients with diabetes mellitus in this study.

Methods

Study Population

This was a retrospective observational study. Between March 2016 and January 2019, patients with ACS who received PCI were retrospectively enrolled. The inclusion criteria were 1) patients at least 18 years old who had ACS; ACS was defined as ST segment elevated myocardial infarction (STEMI), non-ST segment elevated myocardial infarction (MI), and unstable angina.¹⁴ 2) Patients who underwent primary PCI with a drug-eluting stent (DES). The following were excluded from the study: 1) patients diagnosed with diabetes mellitus, defined according to American Diabetes Association criteria.¹⁵ 2) Patients without previously known diabetes but with glycated hemoglobin A1c>6.5% on admission. 3) Patient angiography showing in-stent restenosis. 4) Patients who used insulin or insulin sensitizer within the past 3 months.

This study was approved by the ethics committee of Qinhuangdao First Hospital, and all patients provided their written informed consent.

Biochemical Examination

Venous blood samples were collected after an overnight fast. Plasma glucose and insulin were measured as well as other parameters including cholesterol, triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein (HDL-C), creatinine, high-sensitivity C-reactive protein, troponin-I, and B-type natriuretic peptide. Fasting insulin (FINS) levels were measured using a double-antibody sandwich immunoassay (Elecsys 1010 analyzer, Roche Diagnostics, Mannheim, Germany). IR was assessed using the homeostasis model assessment for insulin resistance (HOMA-IR) and the following formula: HOMA-IR (mmol/L×µU/mL) = fasting glucose (mmol/L)×fasting insulin (µU/mL)/22.5.¹⁶

Interventional Procedure

Patients were administered 300mg of aspirin and a loading dose of 300 mg clopidogrel or 180 mg ticagrelor. Coronary angiography and percutaneous coronary intervention were performed in all patients via a transradial or transfemoral approach. The angiographic findings were analyzed using a quantitative coronary angiography (QCA) system (GEQCA, CentricityAI1000–GEMnetVersion4.1.15.07). With the outer diameter of the contrast-filled catheter as the calibration standard, the minimal lumen diameter and lesion length were measured on diastolic frames. The SYNTAX score was calculated for each patient according to the results of coronary angiography.

Follow-Up and Study Endpoints

All patients received aspirin (100mg QD) during follow-up and clopidogrel (75mg QD) or ticagrelor (90mg BID) for at least one year. Patients underwent clinical observation for at least 24 months. Clinical follow-up was performed at 1, 6, 12, and 24 months.

The primary endpoint was major adverse cardiac events (MACE), including overall death, non-fatal MI, and target vessel revascularization (TVR). MI was diagnosed with an elevation in serum creatine kinase or troponin I three times the upper limit of normal, together with chest pain lasting more than 30 minutes.¹⁷ TVR was defined as any repeat revascularization of the stent-treated vessel.¹⁷ The secondary endpoint was angina pectoris requiring hospitalization.

Statistics Analysis

All statistical analyses were performed using SPSS17 (SPSS, Chicago, IL, USA). Continuous variables are presented as mean±standard deviation if consistent with a normal distribution; otherwise, these are presented as median and interquartile range. Categorical variables are expressed as numbers and percentages. One-way analysis of variance or the Kruskal–Wallis H-test was applied to analyze differences in continuous variables between groups. Categorical variables were compared with the χ² or Fisher’s exact test.

Cox proportional hazards regression analysis was conducted to estimate the hazard ratios (HR) and their 95% confidence intervals (CI) of developing the primary endpoint. Variables with a P value<0.10 in the univariate analysis were included in a multivariate analysis. MACE incidence rates of 24 months were estimated using the Kaplan–Meier method. A probability value<0.05 was considered statistically significant.

Results

The enrolled patients were divided into three groups according to tertiles of FINS level (T1, low-insulin group: FINS<7.89μIU/mL; T2, medium-insulin group: 7.89μIU/mL≤FINS<14.33μIU/mL; T3, high-insulin group: FINS≥14.33μIU/mL). Patients’ baseline clinical characteristics are shown in Table 1. The three groups were balanced in terms of age, sex, family history, hypertension, smoking, prior MI, and clinical presentation. There were no significant differences in laboratory characteristics such as left ventricular ejection fraction (LVEF), cholesterol, TG, and LDL-C. Patients in the low-insulin group had higher HDL-C than those in the high-insulin group (P<0.05). BMI, waistline, HOMA-IR, and serum urine in the high-insulin group were higher than those in the low-and medium-insulin groups. The angiographic and procedural characteristics are shown in Table 1. The target vessel showed no significant difference among the three groups. QCA analysis revealed that the high-insulin group had longer lesion length and longer stents than the low-insulin group. SYNTAX scores were higher in the high-insulin group than in the low-insulin group. Patients in the high-insulin group also had more target vessel stenosis and bifurcation lesions than those in the low-insulin group.

Table 1 Comparison of Clinical and Angiographic Characteristics According to FINS Status

The baseline clinical characteristics of patients, stratified by the primary endpoint, are summarized in Table 2. Compared with the event-free group, patients with MACE had higher levels of FINS. Patients with MACE also showed higher rates of prior myocardial infarction and higher values for the HOMA-IR, BMI, creatinine, and waistline measures. As shown in Table 2, patients with MACE had smaller vessel diameter, higher SYNTAX scores, and longer lesion length.

Table 2 Clinical and Angiographic Characteristics of MACE and Non-MACE Group

Clinical follow-up was completed in all surviving patients. Kaplan–Meier survival analyses showed that patients in the high-insulin group had an unfavorable prognosis, with higher rates of MACE and angina hospitalization than patients in the other two groups at 24 months (Figures 1 and 2). As shown in Table 3, the incidence of the primary endpoint in the high-insulin group was significantly higher than that in the low-insulin group (P<0.05). This difference was mainly driven by the increase in TVR. However, the incidences of overall death and non-fatal MI during follow-up were similar among the FINS tertiles.

Table 3 Comparison of Clinical Outcomes After Primary PCI During 24-Month Follow-Up According to FINS Status

Figure 1 Comparison of MACE-free survival among different insulin groups.

Figure 2 Comparison of angina-hospitalization among different insulin groups.

Multivariate analysis and predictors for MACE within 24 months after PCI are presented in Table 4 and Supplementary Table 1. As a categorical variable, hyperinsulinemia (T3, FINS≥14.33μIU/mL) showed an increased HR for the incidence of MACE (HR2.586, 95% CI 1.694–3.950; P=0.000) in univariate analysis. After adjustment for multiple confounders, multivariate analysis showed a similar result (HR1.870, 95% CI 1.202–2.909; P=0.001). Multivariate Cox regression also revealed that bifurcation lesion, small-vessel lesion, stent length, and SYNTAX score were associated with an increased HR for MACE in patients with ACS after PCI (all P<0.05).

Table 4 Cox Proportional Hazards Model Regression of Major Adverse Events in Patients Undergoing PCI with ACS

Insulin level as a continuous variable was associated with an HR of 1.062 (95% CI1.025–1.010; P=0.001) in univariate analysis. However, in multivariate analysis, the association between insulin level and MACE was not significant after adjusting for confounding factors (HR1.036, 95% CI 0.997–1.077, P=0.071) (Supplementary Table 2).

Discussion

The main finding of this study is that a high insulin level was associated with an increased risk of MACE in patients with ACS and without diabetes mellitus who were undergoing PCI. Hyperinsulinemia might be a valid predictor of clinical outcomes in patients with ACS undergoing PCI.

Weakened insulin signaling or insulin resistance, together with the associated diminution in glucose transport, promotes a compensatory increase of insulin that results in hyperinsulinemia.¹⁸ It is known that insulin has a double-phase effect on atherogenesis. Under physiological conditions, insulin stimulates the uptake of glucose and maintains glucose homeostasis.¹⁹ However, at hyper-physiological concentrations, insulin stimulates the proliferation of vascular smooth muscle cells and triggers inflammation.²⁰ Clinical and experimental evidence suggests that hyperinsulinemia can promote obesity and endothelial dysfunction.^21,22

In the current study, we found that patients with hyperinsulinemia but without diabetes had an increased rate of MACE after undergoing PCI. As far as we know, this is the first study to discuss the direct impact of hyperinsulinemia on clinical outcomes of PCI. Our findings showed that the incidence of MACE was mainly driven by the increase in TVR. Results of multivariate analysis showed that hyperinsulinemia (as a categorical variable), but not the HOMA index, was an independent risk factor of MACE. IR is usually measured using the HOMA index, which takes into account both fasting glycemia and insulin level. Several studies have indicated that increased HOMA level is an important prognostic indicator in patients who have undergone PCI.^23,24 However, these studies included patients both with and without diabetes mellitus. In patients without diabetes who underwent PCI, the value of the HOMA index in predicting clinical outcomes remains controversial. Yun et al analyzed 98 consecutive patients without diabetes who underwent elective coronary angioplasty and revealed that IR (HOMA index≥2.6) was an independent predictor of in-hospital and 30-day MACE rates.²⁵ Hwang et al evaluated 1-year outcomes in 229 consecutive patients with CAD and without diabetes who were treated with DES. The results showed that despite a worsening trend in angiographic outcomes in the IR group (HOMA index≥2.5), this did not translate into worse 1-year major clinical outcomes following PCI with DES, as compared to the non-IR group.²⁶ Based on previous research and the current research results, hyperinsulinemia may be a more valuable predictor than the HOMA index in patients without diabetes.

Although the mechanism underlying the association of hyperinsulinemia with adverse cardiovascular outcomes has not been elucidated, it may be linked to chronic inflammation and endothelial dysfunction. Hyperinsulinemia triggers oxidative stress and inflammation in macrophages and endothelial cells.²⁷ These cells produce pro-inflammatory cytokines and interleukins that contribute to vascular endothelial damage.²⁸ In this study, we also found that patients with hyperinsulinemia had more frequent angina hospitalization than patients with low and medium insulin levels. The mechanism of angina may be impaired microcirculation. Impaired coronary microcirculation is frequently observed in patients with IR and type 2 diabetes mellitus.²⁹ This impairment is driven by reduced levels of bioavailable NO. Our previous study demonstrated that hyperinsulinemia impairs endothelial progenitor cell function by down regulation of the PI-3K/Akt/eNOS pathway.¹⁰ NO is a key regulator in modulating endothelial function. Impaired NO reproduction may explain the results of the current study.

Limitations

This study has several limitations. First, this was a single-center study, and the sample size was relatively small. Second, this was a retrospective study and not a randomized controlled study; therefore, selection bias may be present. The third limitation is the relatively short duration (24 months) of follow-up. This may be a limiting factor in evaluating important clinical effects of hyperinsulinemia. Further investigation is necessary to clarify the impact of insulin among patients undergoing PCI.

Conclusions

In this study, we found an association between higher insulin levels and increased risk of MACE in patients with ACS who did not have diabetes. Hyperinsulinemia might be a valid predictor of clinical outcomes in patients with ACS and without diabetes who underwent PCI.