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Background One of the main risk factors for coronary artery disease (CAD), which is a significant source of morbidity and death, is diabetes mellitus (DM), which also speeds up the disease's course and severity. This study aimed to compare the severity of CAD between diabetic and non-diabetic patients, providing insights to guide clinical decision-making and improve therapeutic outcomes. Methodology A prospective, observational study was conducted at the Sheikh Mohamed Bin Zayed Al Nahyan Institute of Cardiology, Quetta, from August 2018 to July 2019, involving 204 adult patients with CAD, consisting of 102 patients with diabetes and 102 without diabetes. Demographic, clinical, and laboratory data were collected, and coronary angiography was performed to assess the severity of CAD, which was defined as a binary outcome variable (1 = severe CAD, 0 = not severe CAD), based on criteria such as multi-vessel involvement and degree of stenosis. Statistical analysis was carried out using IBM SPSS Statistics for Windows, V. 25.0 (IBM Corp., Armonk, NY, USA), with chi-squared tests used for categorical variables (e.g., number of affected vessels, plaque distribution) and independent t-tests for continuous variables (e.g., fasting blood glucose, hemoglobin A1c(HbA1c) levels, lipid profiles). Logistic regression was employed to identify independent predictors of CAD severity, and odds ratios (ORs) with 95% confidence intervals (CI) were calculated, with statistical significance defined as a p-value of less than 0.05. Results Diabetic patients exhibited significantly higher rates of multi-vessel disease (70 (68.63%) vs. 52 (50.98%); p = 0.02), three-vessel involvement (37 (36.27%) vs. 25 (24.51%); p = 0.01), and severe stenosis (64 (62.75%) vs. 52 (50.98%); p = 0.019) compared to non-diabetic patients. Fasting blood glucose (158.21 ± 45.63 mg/dL vs. 98.31 ± 12.74 mg/dL; p < 0.001) and HbA1c (8.21 ± 1.34% vs. 5.62 ± 0.41%; p < 0.001) levels were significantly higher in diabetics. Multivariate regression analysis revealed that diabetes (OR = 2.12; 95% CI: 1.35-3.32; p = 0.001), hypertension (OR = 1.45; 95% CI: 1.01-2.08; p = 0.04), elevated glucose levels (fasting blood glucose OR = 1.04; 95% CI: 1.02-1.06; p < 0.001; HbA1c OR = 1.27; 95% CI: 1.15-1.41; p < 0.001), and age (OR = 1.03; 95% CI: 1.01-1.05; p = 0.02) were significant predictors of CAD severity, with each increase in fasting blood glucose, HbA1c, and age associated with higher odds of severe CAD. Other variables, such as gender, hyperlipidemia, smoking history, sedentary lifestyle, and regular exercise, did not show significant associations with CAD severity (p > 0.05). However, a family history of CAD was identified as a significant predictor (OR = 1.56; 95% CI: 1.06-2.31; p = 0.02), suggesting that those with a family history of CAD had 56% higher odds of experiencing severe CAD. Systolic blood pressure (OR = 1.18; 95% CI: 1.07-1.30; p = 0.002) was associated with CAD severity, with each 10 mmHg increase in systolic blood pressure increasing the odds of severe CAD.  Conclusion DM is linked to more severe CAD, with high blood pressure, HbA1c, and blood glucose levels contributing to increased severity, emphasizing the need for early detection and aggressive treatment to mitigate its impact on heart health, and further research, including long-term follow-up and therapeutic interventions, is needed to enhance management for diabetic CAD patients., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Sheikh Mohamed Bin Zayed Al Nahyan Institute of Cardiology Institutional Review Board issued approval 173/SMBZ-DOC/2018. The study was approved in July 2018. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2025, Arshad et al.)