Type 2 diabetes mellitus is a significant chronic metabolic disorder, which is defined by chronic hyperglycaemia, insulin resistance, and progressive beta-cell dysfunction. In addition to glucose metabolism abnormalities, type 2 diabetes is closely linked to hypertension, dyslipidaemia, obesity, endothelial dysfunction and chronic low-grade inflammation. All of these metabolic disturbances work together to promote atherosclerosis and cardiovascular disease.

Cardiovascular disease is still one of the most significant causes of morbidity and mortality in patients with type 2 diabetes mellitus. A large collaborative meta-analysis of 102 prospective studies showed that diabetes is linked to a significantly higher risk of coronary heart disease, ischaemic stroke, haemorrhagic stroke and other vascular deaths, after accounting for traditional cardiovascular risk factors [1]. Thus, the early detection of simple biochemical markers of cardiovascular risk could be helpful in clinical practice, especially in diabetic patients.

Diabetic dyslipidaemia is often associated with high triglycerides, high small dense low-density lipoprotein cholesterol particles and low high-density lipoprotein cholesterol. HDL cholesterol has been traditionally thought to be protective against atherosclerosis because of its involvement in reverse cholesterol transport, anti-inflammatory properties, antioxidant properties, and endothelial protection [2]. Thus, the lower HDL cholesterol levels seen in type 2 diabetes may be a risk factor for cardiovascular disease.

The end product of purine metabolism, serum uric acid, has also been studied as a cardiometabolic risk marker in recent years. Hyperuricemia is linked to insulin resistance, hypertension, metabolic syndrome, chronic kidney disease, oxidative stress, and endothelial dysfunction. A systematic review and dose-response meta-analysis found that serum uric acid was positively associated with cardiovascular mortality [3]. Likewise, hyperuricaemia has been demonstrated to be a prospective risk factor for morbidity and mortality from coronary heart disease [4].

The uric acid-to-HDL cholesterol ratio is a relatively newer marker that incorporates two biologically important parameters: serum uric acid, which may be a marker of oxidative and inflammatory stress, and HDL cholesterol, which is a marker of anti-atherogenic and vascular protective capacity. This ratio could be a simple, inexpensive, and readily available marker of cardiometabolic risk, as both serum uric acid and HDL cholesterol are commonly measured in clinical practice.

Kocak et al. found that the serum uric acid/HDL cholesterol ratio was a good predictor of metabolic syndrome in type 2 diabetes mellitus patients [5]. Aktas et al. also reported that uric acid/HDL cholesterol ratio was correlated with diabetic control in male type 2 diabetes mellitus patients [6]. Additional data indicate that this ratio could be associated not only with metabolic control but also with vascular complications. Xuan et al. found that the uric acid/HDL cholesterol ratio was positively correlated with diabetic-related complications in men and postmenopausal women with type 2 diabetes mellitus [7].

Recent studies have also shown the possible clinical significance of this ratio. Bazmandegan et al. found that the uric acid/HDL cholesterol ratio can be used to predict metabolic syndrome in type 2 diabetes mellitus patients [8]. Furthermore, Park et al. showed that this ratio was predictive of incident ischaemic heart disease in a large cohort, suggesting its potential as a cardiovascular risk marker [9].

Although there is increasing evidence, information on the relationship between uric acid/HDL cholesterol ratio and cardiovascular risk in type 2 diabetes mellitus is still scarce, particularly in Indian hospital-based settings. Therefore, the present study is designed to evaluate the relationship between uric acid/HDL cholesterol ratio and cardiovascular risk in type 2 diabetes mellitus patients in the Department of General Medicine, Sri Chamundeshwari Medical College Hospital and Research Institute, Channapatna.

Study design and setting This hospital-based cross-sectional study was conducted in the Department of General Medicine, Sri Chamundeshwari Medical College Hospital and Research Institute, Channapatna. The study was carried out over a period of 6 months. Study population The study population included patients with type 2 diabetes mellitus who attended the outpatient department or were admitted under the Department of General Medicine during the study period. A total of 150 eligible patients were enrolled in the study. Sampling technique Patients were selected by consecutive sampling. All eligible patients were screened and recruited after obtaining written informed consent. Inclusion criteria Patients aged 18 years and above with a diagnosis of type 2 diabetes mellitus, who attended the outpatient department or were admitted under the Department of General Medicine and provided written informed consent, were included in the study. Exclusion criteria Patients with type 1 diabetes mellitus, gestational diabetes mellitus, chronic kidney disease, chronic liver disease, known gout, or those receiving uric acid-lowering therapy such as allopurinol or febuxostat were excluded. Patients on medications known to significantly alter serum uric acid or lipid levels, including long-term diuretics, systemic corticosteroids, or lipid-lowering drugs, were also excluded. Pregnant and lactating women, patients with acute infections, inflammatory disorders, malignancy, acute coronary syndrome, stroke, acute medical emergencies, and those unwilling to participate were excluded from the study. Data collection After approval from the Institutional Ethics Committee, eligible participants were enrolled after written informed consent. Data were collected using a predesigned proforma. Demographic details, duration of diabetes, treatment history, smoking status, alcohol intake, physical activity, dietary history, history of hypertension, dyslipidaemia, cardiovascular disease, and family history of cardiovascular disease were recorded. A detailed clinical examination was performed in all participants. Anthropometric and clinical assessment Height and weight were measured using standard methods, and body mass index was calculated as weight in kilograms divided by height in metres squared. Waist circumference was measured at the midpoint between the lower margin of the last palpable rib and the top of the iliac crest. Blood pressure was recorded after the participant had rested for at least 5 minutes. Two readings were taken, and the average was used for analysis. Laboratory investigations Venous blood samples were collected under aseptic precautions, preferably after overnight fasting. Fasting blood sugar, postprandial blood sugar, glycated haemoglobin, serum uric acid, fasting lipid profile including total cholesterol, triglycerides, LDL cholesterol and HDL cholesterol, serum creatinine, blood urea, and other clinically indicated routine investigations were performed. Serum uric acid and lipid profile were measured using standard laboratory methods followed by the institutional biochemistry laboratory. Calculation of uric acid-to-HDL cholesterol ratio The uric acid-to-HDL cholesterol ratio was calculated for each participant using the following formula: Uric acid-to-HDL cholesterol ratio = serum uric acid / HDL cholesterol The calculated ratio was used for statistical analysis. Assessment of cardiovascular risk Cardiovascular risk was assessed using relevant clinical, anthropometric, and biochemical parameters, including age, sex, duration of diabetes mellitus, smoking status, blood pressure, body mass index, waist circumference, glycaemic status, lipid profile, and history of hypertension or cardiovascular disease. Participants were categorized into cardiovascular risk groups using a validated cardiovascular risk assessment tool based on the availability of required variables. The association between uric acid-to-HDL cholesterol ratio and cardiovascular risk was then analyzed. Outcome variables The primary outcome variable was the association between uric acid-to-HDL cholesterol ratio and cardiovascular risk among patients with type 2 diabetes mellitus. Secondary variables included serum uric acid, HDL cholesterol, lipid profile parameters, glycaemic status, blood pressure, body mass index, duration of diabetes mellitus, and other cardiovascular risk factors. Statistical analysis Data were analyzed using IBM SPSS Statistics version 24.0. Continuous variables were expressed as mean ± SD or median with IQR, and categorical variables as frequency and percentage. Kruskal–Wallis test, Chi-square test, Spearman’s correlation, and multivariable linear regression were used as appropriate. A p-value <0.05 was considered statistically significant. Ethical considerations The study was conducted after obtaining approval from the Institutional Ethics Committee of Sri Chamundeshwari Medical College Hospital and Research Institute, Channapatna. Written informed consent was obtained from all participants before enrolment. Confidentiality of patient information was maintained throughout the study. Participation was voluntary, and patients had the right to withdraw from the study at any stage without affecting their treatment.

Study population and baseline clinical profile

A total of 150 patients with type 2 diabetes mellitus were included in the analysis. The mean age was 54.8 ± 9.1 years, and 88 (58.7%) patients were male. Most participants were evaluated in the outpatient setting, with 122 (81.3%) outpatient cases and 28 (18.7%) inpatient cases. The mean duration of diabetes was 8.4 ± 4.3 years. Hypertension was present in 97 (64.7%) patients, while 44 (29.3%) had a known history of cardiovascular disease. The baseline demographic and clinical profile is summarized in Table 1.

Table 1. Baseline demographic and clinical characteristics of the study population

Biochemical profile and uric acid-to-HDL cholesterol ratio

The biochemical profile showed suboptimal glycaemic control, with a mean HbA1c of 7.9 ± 1.0%. The mean serum uric acid level was 5.2 ± 1.1 mg/dL, mean HDL cholesterol was 40.3 ± 6.7 mg/dL, and the mean uric acid-to-HDL cholesterol ratio was 0.134 ± 0.039. The distribution of biochemical variables is shown in Table 2.

Table 2. Biochemical profile and uric acid-to-HDL cholesterol ratio

Cardiovascular risk categorization showed that 8 (5.3%) patients were in the low-risk group, 94 (62.7%) in the moderate-risk group, and 48 (32.0%) in the high-risk group. Based on uric acid-to-HDL cholesterol ratio, 46 (30.7%) patients were in the low-ratio category, 62 (41.3%) in the intermediate-ratio category, and 42 (28.0%) in the high-ratio category. Metabolic syndrome was present in 133 (88.7%) patients (Table 3).

Table 3. Distribution of cardiovascular risk, UA/HDL ratio category, and metabolic syndrome

Clinical and biochemical parameters according to cardiovascular risk category

Patients in the high cardiovascular risk category were older and had longer diabetes duration and higher systolic blood pressure than those in the lower risk categories. Lipid parameters also differed across risk categories, with lower HDL cholesterol and higher total cholesterol, triglycerides, and LDL cholesterol among patients with greater cardiovascular risk. Serum uric acid and the uric acid-to-HDL cholesterol ratio increased progressively across cardiovascular risk categories (Table 4).

Table 4. Comparison of selected clinical and biochemical parameters across cardiovascular risk categories

Values are expressed as mean ± SD. Kruskal–Wallis test was used for comparison across the three risk categories. UA/HDL = uric acid-to-HDL cholesterol ratio.

Association between uric acid-to-HDL cholesterol ratio and cardiovascular risk

The distribution of cardiovascular risk category differed significantly across UA/HDL ratio categories. High cardiovascular risk was observed in 7 (15.2%) patients in the low UA/HDL category, 20 (32.3%) patients in the intermediate category, and 21 (50.0%) patients in the high category (χ² = 22.12, df = 4; p < 0.001). These findings are shown in Table 5.

Table 5. Association between UA/HDL ratio category and cardiovascular risk category

Values are presented as n (% within UA/HDL ratio category). Chi-square test was used.

Correlation analysis demonstrated a significant positive association between UA/HDL ratio and cardiovascular risk score (Spearman’s ρ = 0.409, p < 0.001). Serum uric acid showed a positive correlation with cardiovascular risk score, while HDL cholesterol showed an inverse correlation. UA/HDL ratio also correlated positively with BMI and triglyceride levels (Table 6).

Table 6. Correlation of uric acid, HDL cholesterol, and UA/HDL ratio with cardiovascular risk and metabolic variables

Spearman’s rank correlation was used. UA/HDL = uric acid-to-HDL cholesterol ratio.

                                             Figure 1. UA/HDL ratio versus cardiovascular risk score.

Mean cardiovascular risk score increased progressively across UA/HDL ratio categories, from 15.0 ± 4.8% in the low-ratio category to 18.4 ± 4.5% in the intermediate-ratio category and 19.9 ± 4.8% in the high-ratio category (Kruskal–Wallis H = 20.51, p < 0.001). This trend is depicted in Figure 2.

                   Figure 2. Cardiovascular risk score by UA/HDL ratio category.

Multivariable analysis

In multivariable linear regression, UA/HDL ratio remained independently associated with cardiovascular risk score after adjustment for age, sex, duration of diabetes, BMI, systolic blood pressure, HbA1c, LDL cholesterol, and current smoking. Each 0.05 increase in UA/HDL ratio was associated with a 2.16 percentage-point increase in cardiovascular risk score (95% CI: 1.55 to 2.78; t = 6.97; p < 0.001). The model explained a substantial proportion of variance in cardiovascular risk score (adjusted R² = 0.743; F = 48.94; p < 0.001).

Table 7. Multivariable linear regression analysis for cardiovascular risk score

Dependent variable: cardiovascular risk score (%). UA/HDL = uric acid-to-HDL cholesterol ratio.

The uric acid/HDL cholesterol ratio was significantly associated with cardiovascular risk in the present cross-sectional study of 150 patients with type 2 diabetes mellitus. The mean UA/HDL ratio was 0.134 ± 0.039, and the percentage of patients with high cardiovascular risk was gradually higher in each UA/HDL ratio group, ranging from 15.2% in the low-ratio group to 50.0% in the high-ratio group. The UA/HDL ratio was significantly positively correlated with cardiovascular risk score (Spearman's ρ = 0.409, p < 0.001), and in a multivariable linear regression model, the UA/HDL ratio was independently associated with cardiovascular risk score by 2.16 percentage points for every 0.05 increase in the ratio, after adjusting for age, sex, duration of diabetes, BMI, systolic blood pressure, HbA1c, LDL cholesterol, and smoking status. Recent prospective data have confirmed the association of increased UA/HDL ratio with cardiovascular events in dysglycaemic populations, consistent with the results of the present study. Lai and Chen analyzed NHANES data from 2005 to 2018, which included 18,804 adults with diabetes or prediabetes, and found 2,748 all-cause deaths and 869 cardiovascular deaths over a median follow-up of 80 months. Participants in the highest UA/HDL quartile had significantly higher all-cause mortality (HR 1.24, 95% CI 1.07–1.45) and cardiovascular mortality (HR 1.56, 95% CI 1.19–2.04) compared with the second quartile [10]. The mean UA/HDL ratio in our cohort was about 13.4% (when expressed as a percentage) which was higher than the cardiovascular mortality threshold of 9.39% reported in that study, thus supporting the clinical relevance of elevated UA/HDL ratio among patients with diabetes. In a similar study, Ding et al. studied 5,665 adults with diabetes in NHANES 2005-2018 and found 1,088 all-cause deaths, of which 310 were cardiovascular. They found a non-linear relationship between UA/HDL ratio and mortality, with higher UA/HDL ratio being associated with higher all-cause mortality and cardiovascular mortality; the highest UA/HDL group had 1.33-fold higher all-cause mortality and 1.26-fold higher cardiovascular mortality than the lowest group [11]. Their reported cardiovascular mortality inflection point was 9.86%, which is again below the average UA/HDL ratio in our study. This further supports the notion that the UA/HDL ratio in our high-risk diabetic subpopulation could be a clinically relevant cardiometabolic risk signal. Even when compared with population-based mortality data, the association was relevant. Li et al. evaluated UA/HDL ratio among US adults and found that the highest quintile was associated with increased all-cause mortality (adjusted HR 1.16, 95% CI 1.05–1.29) and cardiovascular mortality (adjusted HR 1.20, 95% CI 1.00–1.45). Importantly, in the diabetes subgroup, the corresponding adjusted HRs were stronger, at 1.32 for all-cause mortality and 1.38 for cardiovascular mortality [12]. This subgroup pattern is in line with our finding that UA/HDL ratio remained independently associated with cardiovascular risk after adjustment for conventional risk factors, implying that this marker may reflect residual metabolic-inflammatory risk in diabetes. Zhou and Xu investigated 2,545 patients with type 2 diabetes mellitus (T2DM) (1,532 males and 1,013 females) and found a metabolic basis for this association. They reported significant correlations between UA/HDL ratio and HOMA-IR in both males (r = 0.274, p < 0.001) and females (r = 0.337, p < 0.001). UA/HDL ratio was independently associated with insulin resistance in males (OR 1.06, 95% CI 1.03–1.08) and females (OR 1.11, 95% CI 1.08–1.15) and demonstrated better discrimination for insulin resistance than uric acid or HDL cholesterol alone [13]. In our study, UA/HDL ratio was positively correlated with BMI and triglycerides, which are closely related to insulin resistance, but not with HbA1c. This indicates that UA/HDL ratio might be a better indicator of insulin resistance and cardiometabolic clustering than short-term glycaemic control alone. The present findings are also supported by the relationship between UA/HDL ratio and adiposity. Sun et al. assessed patients with type 2 diabetes and found that UA/HDL ratio was correlated with visceral fat area [14]. UA/HDL ratio was significantly positively correlated with BMI (ρ = 0.360, p < 0.001) and triglycerides (ρ = 0.257, p = 0.001) in the present study. These results indicate that elevated UA/HDL ratio could be a marker of an unfavourable metabolic phenotype with central adiposity, hypertriglyceridaemia, low HDL cholesterol and high vascular risk. The cardiovascular relevance of UA/HDL ratio is further supported by evidence from patients with known coronary disease. Yang et al. studied 566 patients with coronary chronic total occlusion and followed them for a median of 43 months. Major adverse cardiovascular events were observed in 107 patients (18.9%) and higher UA/HDL ratio was found to be a valuable risk stratification tool in this high-risk coronary population [15]. Our study evaluated estimated cardiovascular risk, not prospective cardiovascular events, but the trend of increasing UA/HDL ratio from low to moderate to high cardiovascular risk categories is consistent with the direction of risk seen in patients with known coronary artery disease. Li et al. also found that UA/HDL ratio was a new indicator for the prediction of functionally significant coronary artery stenosis in patients undergoing coronary evaluation [16]. This is pertinent to our results as 29.3% of our study population had known cardiovascular disease and 32.0% were classified as high cardiovascular risk. Thus, the relationship between UA/HDL ratio and cardiovascular risk score in our cohort may be related to the clustering of metabolic risk factors as well as to the increased risk of underlying atherosclerotic burden. The biological plausibility of our findings is based on the contrasting roles of uric acid and HDL cholesterol. Uric acid can lead to endothelial dysfunction, oxidative stress, vascular inflammation and smooth muscle proliferation, while HDL cholesterol is anti-inflammatory, antioxidant and has reverse cholesterol transport properties. Thus, a higher UA/HDL ratio reflects both increased pro-oxidant/metabolic stress and decreased anti-atherogenic protection. This could be the reason that UA/HDL ratio was more strongly associated with cardiovascular risk score than uric acid or HDL cholesterol alone in our study. The present study has certain strengths. It assessed a biochemical ratio which is simple, inexpensive and readily available in relation to cardiovascular risk in patients with type 2 diabetes mellitus in an Indian hospital-based setting. This association was present even after accounting for other important clinical and biochemical factors such as age, duration of diabetes, systolic blood pressure, HbA1c, LDL cholesterol, and smoking. But there are some drawbacks to consider. The cross-sectional design does not allow causal inferences. Cardiovascular risk was not measured but estimated by prospective cardiovascular events. The study was conducted in a single centre and the sample size was small, which may limit generalizability. Purine intake in the diet, comprehensive drug exposure, inflammatory markers, insulin resistance indices, and long-term cardiovascular outcomes were not evaluated.

The current study shows that the uric acid/HDL cholesterol ratio is significantly associated with cardiovascular risk in type 2 diabetes mellitus patients. This finding is in line with recent data that have shown a correlation between UA/HDL ratio and cardiovascular mortality, insulin resistance, visceral adiposity and poor coronary outcomes. UA/HDL ratio could thus be used as a convenient additional risk marker for cardiovascular risk stratification in type 2 diabetes mellitus, especially in resource-constrained clinical environments.

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