European Journal of Cardiovascular Medicine

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by persistently elevated blood glucose levels resulting from an absolute deficiency of insulin, relative insufficiency, or impaired insulin action. The condition arises either because the pancreas fails to produce sufficient insulin or because the body’s cells do not respond effectively to the insulin that is produced. Among the two major types, type 2 diabetes mellitus (T2DM) is the most prevalent and has become a major global public health challenge. The incidence of T2DM has been rising dramatically worldwide and has now reached epidemic proportions, particularly in developing nations such as India, where rapid urbanization, sedentary lifestyles, and changing dietary patterns contribute significantly to disease burden (1).

The pathophysiology of T2DM is multifactorial, involving not only disturbances in glucose metabolism but also complex interactions with chronic low-grade inflammation. Inflammatory processes are known to play a pivotal role in the onset and progression of T2DM. Hyperglycemia, dyslipidemia, elevated free fatty acids, and hypertension contribute to endothelial dysfunction, oxidative stress, and vascular damage, which together accelerate the inflammatory cascade and lead to diabetic complications (2). Furthermore, subclinical inflammation has been strongly linked to increased cardiovascular morbidity and mortality in individuals with diabetes, emphasizing the need for reliable inflammatory biomarkers in disease assessment and prognosis (2).

In recent years, hematological indices derived from routine complete blood counts (CBC) — particularly leukocytes and their subtypes — have gained increasing attention as markers of systemic inflammation. Among these, the neutrophil-to-lymphocyte ratio (NLR) and monocyte-to-lymphocyte ratio (MLR) have emerged as promising, easily measurable, and cost-effective indicators. These ratios reflect the balance between innate and adaptive immune responses and serve as markers of ongoing systemic inflammation and immune activation (3).

The NLR, in particular, is recognized as a reliable marker of subclinical inflammation and has been associated with both macrovascular and microvascular complications in diabetes, such as coronary artery disease, nephropathy, retinopathy, and neuropathy (3). Similarly, the MLR has been shown to correlate with metabolic disturbances and vascular injury associated with diabetes. The ease of measurement and low cost of these indices make them attractive tools for routine clinical practice, especially in resource-limited settings.

Given their potential prognostic value, these inflammatory markers may also serve as predictors of glycemic control and disease progression. Therefore, the present study was designed to investigate the relationship between glycated hemoglobin (HbA1c) — a gold standard marker of long-term glycemic control — and the inflammatory markers NLR and MLR in patients with controlled and uncontrolled type 2 diabetes mellitus. By elucidating this relationship, we aim to improve the understanding of inflammatory processes in diabetes and explore the potential of NLR and MLR as adjunctive tools in clinical monitoring and risk stratification.

Aim:
To evaluate hematological indices, specifically the neutrophil-to-lymphocyte ratio (NLR) and monocyte-to-lymphocyte ratio (MLR), in patients with controlled and uncontrolled type 2 diabetes mellitus (T2DM).

Objectives:

• To investigate the relationship between glycated hemoglobin (HbA1c) levels and inflammatory markers, namely NLR and MLR, in individuals with type 2 diabetes mellitus.
• To compare and analyze variations in NLR and MLR between controlled and uncontrolled diabetic patients.

This hospital-based cross-sectional observational study was conducted in the Department of Medicine, MKCG Medical College and Hospital, Berhampur, Odisha, India, following approval from the Institutional Ethics Committee. Written informed consent was obtained from all participants before enrollment in the study.

Study Population and Sampling

A total of 180 patients diagnosed with type 2 diabetes mellitus were included using a simple random sampling technique. Patients were recruited from outpatient and inpatient departments during the study period.

Inclusion Criteria

• Diagnosed cases of type 2 diabetes mellitus as per American Diabetes Association (ADA) diagnostic criteria.
• Age between 18 and 70 years.

Exclusion Criteria

Patients with any of the following conditions were excluded from the study: Acute or chronic liver disease, Anemia or known hemoglobinopathies (e.g., thalassemia, sickle cell anemia), Use of medications known to alter HbA1c levels (e.g., aspirin, vitamin E, or vitamin C), Presence of acute infections or chronic inflammatory conditions such as inflammatory bowel disease, osteoarthritis, rheumatoid arthritis, gout, bronchial asthma, or chronic hepatitis, History of acute myocardial infarction or cerebrovascular accident and Refusal to participate in the study.

Data Collection and Clinical Assessment

Detailed clinical history and demographic information were recorded for each participant using a pre-designed and pretested questionnaire. A comprehensive physical examination was performed, followed by collection of blood samples for laboratory investigations.

The following hematological and biochemical parameters were measured:

• Hematological indices: White blood cell (WBC) count, hemoglobin (Hb), hematocrit (HCT), red cell distribution width (RDW), neutrophil and lymphocyte counts.
• Glycemic and inflammatory markers: Glycated hemoglobin (HbA1c), blood glucose, neutrophil-to-lymphocyte ratio (NLR), and monocyte-to-lymphocyte ratio (MLR).

Statistical Analysis

All data were entered into Microsoft Excel and subsequently analyzed using R Software. Categorical variables were summarized as frequencies and percentages, while continuous variables were presented as mean ± standard deviation (SD).
The association between HbA1c levels and inflammatory markers (NLR and MLR) was assessed using the Chi-square test for categorical data and the Student’s t-test for continuous variables. A p-value < 0.05 was considered statistically significant

A total of 180 patients with type 2 diabetes mellitus were included in the study and categorized into controlled (HbA1c < 7.0) and uncontrolled (HbA1c ≥ 7.0) groups based on glycemic status. The mean age of participants was approximately 54.1 ± 8.3 years.

The age-wise distribution of patients is presented in Table 1. Among the controlled group, the majority of patients (46.15%) were in the 50–59 years age group, followed by 26.92% in the 40–49 years group. A similar trend was observed in the uncontrolled group, where 44.81% were in the 50–59 years category and 28.57% were aged 60 years and above.

Regarding gender distribution, males constituted a higher proportion in both groups — 61.54% among controlled and 55.19% among uncontrolled diabetics — while females accounted for 38.46% and 44.81%, respectively. No significant association was found between gender and glycemic control status.

Table 1: Distribution of Study Participants According to Age and Gender

The association between NLR and glycemic status is shown in Table 2. Among controlled diabetic patients, 42.31% had an elevated NLR (>2), whereas a significantly higher proportion (62.99%) of uncontrolled patients exhibited elevated NLR values. This difference was statistically significant (p < 0.05), suggesting a strong correlation between poor glycemic control and elevated NLR levels.

Table 2: Distribution of Participants Based on Neutrophil-to-Lymphocyte Ratio (NLR)

Table 3 illustrates the distribution of patients based on MLR. Elevated MLR (>2) was observed in 34.62% of controlled patients and in a significantly higher proportion (63.64%) of uncontrolled patients. This difference indicates a notable relationship between elevated MLR and poor glycemic control (p < 0.05).

Table 3: Distribution of Participants Based on Monocyte-to-Lymphocyte Ratio (MLR)

Glycated hemoglobin (HbA1c) remains the gold standard for evaluating long-term glycemic control in individuals with type 2 diabetes mellitus (T2DM). However, it reflects only average blood glucose levels over the preceding two to three months and does not adequately capture the underlying inflammatory status associated with diabetic complications. Chronic low-grade inflammation plays a crucial role in the pathogenesis and progression of diabetes and its vascular complications. Therefore, additional inflammatory biomarkers may provide valuable insights into disease activity and progression beyond conventional glycemic indices.

The neutrophil-to-lymphocyte ratio (NLR) is considered a simple and reliable marker of subclinical inflammation and reflects the balance between neutrophil-mediated innate immune responses and lymphocyte-mediated adaptive immunity. Similarly, the monocyte-to-lymphocyte ratio (MLR) is another cost-effective and readily available inflammatory biomarker. Both have been studied extensively as predictors of cardiovascular and metabolic complications in diabetes.

In the present study, the mean age of participants was approximately 55 years, and the highest proportion of patients in both controlled and uncontrolled groups was in the 50–59 years age group. These findings align with previous reports. Selvin et al. (4) reported that individuals diagnosed with diabetes between 30 and 65 years of age exhibited poorer glycemic control compared to those diagnosed after 65 years. Shamshirgaran et al. (5) also observed that younger adults (≤49 years) were more likely to have poor glycemic control compared to middle-aged (50–59 years) and older adults (≥60 years). Similar observations were made by Nanayakkara et al. (6), who associated younger age with inadequate glycemic control and adverse cardiovascular outcomes. In contrast, Kakade et al. (7) reported no significant difference in glycemic control across different age groups.

In our study, males constituted 61.54% of the controlled group and 55.19% of the uncontrolled group, while females constituted 38.46% and 44.81%, respectively. No significant difference was observed between genders, which is consistent with several large-scale studies. A UK cross-sectional study involving 10,663 participants with T2DM (8) and a Canadian study with 5,569 patients (9) also found no significant association between gender and HbA1c levels.

A significant finding of our research was the elevated NLR (>2) in 62.99% of uncontrolled diabetics, compared to 42.31% in the controlled group. This result supports previous studies demonstrating a strong association between NLR and glycemic control. Devamsh et al. (10) reported that NLR positively correlated with HbA1c and indicated poor glycemic control in T2DM. Similarly, increased neutrophil counts were linked with higher HbA1c levels and poorer metabolic control (11). Duman et al. (12) reported a significant positive correlation between neutrophil count and HbA1c (r = 0.49, p < 0.001), and Berberoglu (13) also found higher neutrophil levels among poorly controlled diabetics. Verma et al. (14) concluded that elevated NLR was associated with poor glycemic control and proposed that this parameter could be used as an adjunct marker alongside HbA1c. Mahankali et al. (15) also arrived at similar conclusions. However, Umarani et al. (16) found no significant relationship between NLR and worsening glucose intolerance, indicating some heterogeneity in the literature.

The present study also demonstrated a significant association between MLR and glycemic control, with 63.64% of uncontrolled patients exhibiting MLR > 2 compared to 34.62% in the controlled group. This supports the role of MLR as a potential marker of metabolic dysregulation and chronic inflammation in diabetes. However, Adnyani (17) reported contrasting findings, concluding that MLR did not differ significantly between controlled and uncontrolled diabetes groups.

Collectively, these results indicate that NLR and MLR, both derived from routine hematological tests, can serve as useful adjuncts to HbA1c in assessing metabolic control and systemic inflammation in T2DM. They also offer clinical utility in predicting the risk of complications, particularly in resource-limited healthcare settings where advanced inflammatory markers are not readily available

Diabetes mellitus is one of the most prevalent metabolic disorders, especially in Asian countries, and uncontrolled diabetes is associated with significant microvascular and macrovascular complications. This study highlights a strong positive association between inflammatory markers (NLR and MLR) and poor glycemic control in patients with type 2 diabetes. These markers are inexpensive, widely accessible, and easy to measure, making them valuable tools for routine clinical assessment. Incorporating NLR and MLR measurements along with HbA1c could enhance patient monitoring and help predict disease progression more effectively.

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