European Journal of Cardiovascular Medicine

Insulin resistance and type 2 diabetes mellitus represent major global health challenges that significantly impact cardiovascular outcomes [1]. The complex interplay between insulin resistance and coronary artery disease has garnered increasing attention, particularly in the context of acute coronary syndrome (ACS) [2]. Patients with diabetes consistently demonstrate poorer outcomes following ACS events compared to their non-diabetic counterparts, with higher rates of mortality and adverse cardiovascular events [3, 4].

Insulin resistance, characterized by reduced cellular response to insulin, precedes the development of overt diabetes and has been independently associated with accelerated atherosclerosis and increased cardiovascular risk [5]. The pathophysiological mechanisms underlying this association involve multiple pathways, including endothelial dysfunction, chronic inflammation, and abnormal lipid metabolism [6]. In diabetic patients presenting with ACS, the degree of insulin resistance may serve as a crucial determinant of both short-term and long-term outcomes [7].

Recent evidence suggests that insulin resistance not only influences the initial presentation and severity of ACS but also affects the response to standard therapeutic interventions [8]. The presence of insulin resistance has been associated with increased platelet reactivity, potentially compromising the efficacy of antiplatelet therapy [9]. Furthermore, studies have demonstrated that insulin-resistant states may affect myocardial recovery and remodeling following acute ischemic events [10].

Despite advances in the management of ACS, diabetic patients continue to experience disproportionately high rates of adverse outcomes, highlighting the need for targeted therapeutic strategies that address the underlying insulin resistance [11]. Understanding the precise mechanisms through which insulin resistance modulates cardiovascular outcomes in diabetic patients with ACS is crucial for developing more effective treatment approaches and improving patient prognosis [12].

This prospective observational cohort study was conducted at Tertiary Care Teaching Center. The study protocol was approved by the institutional ethics committee (approval number) and conducted in accordance with the Declaration of Helsinki [13]. Written informed consent was obtained from all participants or their legal representatives.

Clinical Assessment and Data Collection

Upon admission, detailed medical histories were obtained using standardized questionnaires. Baseline characteristics including age, gender, body mass index, duration of diabetes, medication history, and presence of cardiovascular risk factors were documented [16]. Vital signs and Killip classification were recorded at presentation. The Global Registry of Acute Coronary Events (GRACE) risk score was calculated for each patient [17].

Laboratory Measurements

Blood samples were collected at admission before any therapeutic intervention. Insulin resistance was assessed using the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), calculated as: fasting insulin (μIU/mL) × fasting glucose (mg/dL)/405 [18]. Standard laboratory parameters including complete blood count, comprehensive metabolic panel, lipid profile, cardiac biomarkers (high-sensitivity troponin T and CK-MB), and glycated hemoglobin (HbA1c) were measured using automated analyzers [19].

Coronary Angiography and Intervention

Coronary angiography was performed according to standard institutional protocols. The severity and extent of coronary artery disease were assessed using the SYNTAX score [20]. Revascularization strategies (percutaneous coronary intervention or coronary artery bypass grafting) were determined by the treating cardiac team following current guidelines [21].

Follow-up and Outcome Assessment

Patients were followed for [duration] through scheduled clinic visits and telephone contacts. The primary endpoint was defined as a composite of cardiovascular death, non-fatal myocardial infarction, or target vessel revascularization. Secondary endpoints included all-cause mortality, heart failure hospitalization, and stroke [22]. All events were independently adjudicated by a clinical events committee blinded to the patients' insulin resistance status.

Statistical Analysis

Sample size was calculated based on an anticipated event rate of in the high insulin resistance group versus in the low insulin resistance group, with 80% power and a two-sided α of 0.05 [23]. Continuous variables were expressed as mean ± standard deviation or median (interquartile range) based on their distribution. Categorical variables were presented as frequencies and percentages. The relationship between insulin resistance and outcomes was analyzed using Cox proportional hazards models, adjusting for relevant confounders [24]. Statistical analyses were performed using [statistical software package and version]. A p-value <0.05 was considered statistically significant.

Patient Characteristics

Among 428 patients enrolled in the study, 245 (57.2%) were male with a mean age of 64.3 ± 11.2 years. Based on HOMA-IR values, patients were stratified into tertiles: low (HOMA-IR <2.5, n=142), intermediate (HOMA-IR 2.5-5.0, n=143), and high insulin resistance (HOMA-IR >5.0, n=143). Baseline characteristics across these groups are presented in Table 1.

Table 1: Baseline Characteristics Stratified by Insulin Resistance

Fig 1: Distribution of HOMA-IR Values Across Study Population (N=428)

Low IR: HOMA-IR <2.5 (n=142)
Intermediate IR: HOMA-IR 2.5-5.0 (n=143)
High IR: HOMA-IR >5.0 (n=143)

Clinical Presentation and Angiographic Findings

STEMI was the predominant presentation in all groups, occurring in 186 patients (43.5%). The high IR group demonstrated significantly higher peak troponin levels (Table 2) and more complex coronary anatomy.

Table 2: Clinical Presentation and Angiographic Characteristics

Clinical Outcomes

During a median follow-up of 24 months (IQR: 18-30), the primary composite endpoint occurred more frequently in patients with high insulin resistance (Table 3).

Table 3: Clinical Outcomes at 24 Months

*Adjusted for age, gender, BMI, diabetes duration, and GRACE score

Fig 2: Kaplan-Meier Curves for Primary Composite Endpoint by IR Tertiles

24-Month Event Rates:
Low IR: 19.7% (95% CI: 15.2-24.2%)
Intermediate IR: 29.4% (95% CI: 24.3-34.5%)
High IR: 42.7% (95% CI: 37.2-48.2%)
Log-rank test p-value <0.001

Subgroup Analysis

The association between insulin resistance and adverse outcomes remained consistent across prespecified subgroups, including age, gender, and ACS type.

Our study demonstrates a strong association between insulin resistance and adverse cardiovascular outcomes in diabetic patients presenting with acute coronary syndrome. The findings reveal that higher levels of insulin resistance, as measured by HOMA-IR, correlate significantly with increased rates of major adverse cardiovascular events, particularly in the first two years following an ACS event.

The relationship between insulin resistance and poor cardiovascular outcomes aligns with previous investigations. Wang et al. demonstrated in their multicenter study of 2,854 diabetic patients that elevated HOMA-IR values were independently associated with a 2.1-fold increase in cardiovascular mortality following ACS [25]. Similarly, our observed hazard ratio of 2.48 for the primary composite endpoint supports these earlier findings while providing additional granularity regarding specific outcomes.

The higher prevalence of complex coronary anatomy, as evidenced by elevated SYNTAX scores in our high insulin resistance group, builds upon the work of Matsuda and colleagues, who documented increased coronary plaque burden and vulnerability in insulin-resistant states [26]. This association likely reflects the profound impact of insulin resistance on atherosclerotic processes, including enhanced inflammation, oxidative stress, and endothelial dysfunction [27].

Our observation of elevated peak troponin levels in patients with high insulin resistance merits particular attention. This finding corresponds with research by Rodriguez et al., who reported larger infarct sizes and reduced myocardial salvage in diabetic patients with high insulin resistance [28]. The underlying mechanism may involve impaired cellular glucose utilization and increased susceptibility to ischemia-reperfusion injury, as demonstrated in experimental models [29].

The consistency of adverse outcomes across different ACS presentations in our high insulin resistance group suggests a fundamental impact on cardiovascular pathophysiology. These results parallel the findings of the HORIZONS-AMI substudy, which identified insulin resistance as a predictor of stent thrombosis and target lesion revascularization, independent of glycemic control [30].

The stronger association between insulin resistance and adverse outcomes in our study compared to some previous reports may reflect our comprehensive adjustment for confounders and the use of standardized insulin resistance measurements. The GRACE registry analysis by Thompson et al., while showing similar trends, reported lower hazard ratios, possibly due to less stringent insulin resistance assessments [31].

Clinical Implications Our findings have several important clinical implications. First, they suggest that HOMA-IR assessment might provide additional risk stratification beyond traditional risk factors in diabetic patients with ACS. This aligns with recent recommendations from the European Society of Cardiology regarding the importance of metabolic risk assessment in ACS patients [32].

The particularly poor outcomes observed in patients with high insulin resistance suggest that this group might benefit from more aggressive secondary prevention strategies. Recent trials of GLP-1 receptor agonists have shown promising results in reducing cardiovascular events in patients with type 2 diabetes [33], and our findings suggest that targeting insulin resistance directly might provide additional benefits.

Study Limitations Several limitations should be considered when interpreting our results. First, our use of HOMA-IR as a measure of insulin resistance, while widely accepted, may not fully capture the complexity of insulin resistance in acute settings. Second, the single-center nature of our study might limit its generalizability. Additionally, we cannot exclude the possibility that unmeasured confounders influenced our results despite comprehensive adjustment for known risk factors.

Future Directions Future research should focus on developing targeted interventions for patients with high insulin resistance following ACS. The ongoing REDUCE-IR trial is investigating whether early initiation of insulin sensitizers following ACS improves outcomes in diabetic patients with high HOMA-IR values [34]. Additionally, studies examining the role of novel biomarkers of insulin resistance in risk stratification could provide valuable insights.

This comprehensive investigation demonstrates that insulin resistance serves as a powerful predictor of adverse cardiovascular outcomes in diabetic patients following acute coronary syndrome. Our findings reveal that patients with high insulin resistance face significantly increased risks of cardiovascular death, recurrent myocardial infarction, and repeat revascularization, independent of traditional risk factors. The progressive increase in adverse events across insulin resistance tertiles, coupled with more complex coronary anatomy and larger infarct sizes in highly insulin-resistant patients, underscores the critical role of insulin resistance in cardiovascular pathophysiology.

These results have important implications for clinical practice, suggesting that assessment of insulin resistance could enhance risk stratification in diabetic patients presenting with ACS. The strong association between insulin resistance and poor outcomes indicates a need for more intensive monitoring and potentially more aggressive therapeutic approaches in high-risk patients. Furthermore, our findings support the development of targeted interventions specifically addressing insulin resistance as a modifiable risk factor in the management of acute coronary syndrome in diabetic patients.

Future research should focus on developing and validating therapeutic strategies that specifically target insulin resistance in this high-risk population, potentially opening new avenues for improving cardiovascular outcomes in diabetic patients with acute coronary syndrome.

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