The word diabetes mellitus (DM) is generated combination of Greek and Latin words. Diabetes (Greek word) is to siphon or drain off and mellitus (Latin word) is sweet. The term “mellitus” was first given by Britain John Roll in late 1700s. DM is a metabolic endocrine condition with a higher blood glucose level. ^[1]  DM alters metabolism of carbohydrates, fats and proteins and disturb insulin synthesis. This leads to elevated fasting and post-prandial blood glucose levels. If this altered homeostasis continues for prolonged period of time, it may causes hyperglycemia which is commonly known as DM. ^[2]

The estimated number of worldwide diabetes cases by 2030 is approx 434 million. North America, Japan and Europe have the highest prevalence of diabetes and India is supposed to surpass them with 79 million cases of diabetes by 2030. The development of T2DM occurs after 50 and 60 years of age and slowly progresses in most cases. ^[3] There has been a substantial rise in the number of younger people with T2DM in recent years, many of them under the age of 20. This trend is largely the result of increased obesity prevalence; the most significant risk factor for T2DM in both adults and children. ^[4]

T2DM is known to trigger hyperlipidemia via several metabolic derangements. Insulin deficiency induces lypolysis in adipose tissue and causes hyperlipidemia and fatty liver, causing hypercholesterolemia and hypertriglyceridemia to occur frequently in diabetes. ^[5] Hyperlipidemia is a lipid metabolism disorder characterized by elevating the plasma concentrations of the different fractions of lipids and lipoproteins, which is the primary risk factor for cardiovascular disorders and has been stated as the most prevalent cause of death. ^[6]

Chronic effects of elevated blood glucose levels further lead to complications that can be categorized into macrovascular and microvascular, where complications related to macro blood vessels incorporate peripheral arterial disease, stroke, coronary artery disease and complications related to micro blood vessels include diabetic retinopathy, neuropathy, nephropathy. Diabetes is classified as: type-I, type-II and gestational diabetes (American Diabetes Association, 2024). ^[7]

Another category of antidiabetic drugs include α-glucosidase inhibitors that inhibit α-glucosidase enzymes in the intestine by inhibiting the polysaccharide reabsorption. Recent drug therapy, DPP4 inhibitors class of drugs act by inhibiting the dipeptidyl peptidase-4 (DPP-4) enzyme which further prolong the glucagon-like peptide’ action which inhibits glucagon release and increases insulin secretion, thus decreasing glucose levels and SGLT2 class, that act by targeting proximal tubules of renal glomeruli to inhibit sodium-glucose cotransporter-2 present that leads to suppression of glucose reabsorption. [8] But these therapies are not able to reverse hyperglycemia completely because of their limitations and side effects include hypoglycemia, weight gain, nausea, dizziness, lactic acidosis, kidney toxicity, liver toxicity and gastrointestinal disturbances. [9].

This is a Prospective, randomized, Open-label was conducted among Type 2 DM patients attending the outpatient department of Medicine in Index Medical College and Hospital over a period of 2 years.

Inclusion Criteria:

Male or female patients between 40 to 60 years of age. Patients with type 2 diabetes who had not used any glucose-lowering agents within 8 weeks before consenting, or those who had used only metformin; Patients those with HbA1c (NGSP values) levels of ≥ 7.1%. Patients willing to take medications as directed & willing to come for the follow.

Exclusion Criteria:

Patients with history of Alcohol intake & Smoking. Patients with known history of Type 1 Diabetes and hypertension. Patients with severe cardiac, liver and renal disease. Patients with GIT diseases. Patients with a history of lactic acidosis. Patients with hypothyroidism and hyperthyroidism. Patients taking vitamin B₁₂,  folate, steroid, oral contraceptives & hormone replacement therapy. Pregnant and breast-feeding females. Patients with polycystic ovarian disease.

Ethics, consent and permissions:

The study was conducted after approval from Institutional Ethics Committee for Medical Research. All the Type 2 DM patients were provided written, vernacular, witnessed, informed consent to participate in the study.  Study was conducted as per Declaration of Helsinki, ICH good Clinical Practice (GCP) guidelines and the ICMR guidelines for Biomedical Research on Human Subjects, 2006.

Methodology

Al    l the Type 2 DM patients attending outpatient department (OPD) of Medicine were randomly divided into Dapagliflozin Group and Sitagliptin Group. Subjects willing to participate and written informed consent was obtained from each participant before study. Permission from treating consultant was obtained for subjects to participate in the study. Subjects were screened for selection criteria. Baseline evaluation included recording of demographic details, BMI, medical history, general and systemic examination and laboratory investigations, which included complete haemogram, hepatic and renal function tests and routine urine analysis. The eligible patients were enrolled as randomization.

Treatment:

The treatment drug (dapagliflozin 10 mg/day and sitagliptin 100 mg/day) was administered for 12 weeks. 

Follow-up Visits:

Follow-up visits were scheduled at the end of every month for 12 weeks for assessment, including measurement of weight and general and systemic examination.

Sample collection:

Samples of venous blood was collected from a forearm vein, at baseline and after 12 weeks. Blood samples were centrifuged at 3000 rpm for 15 min to separate the serum, and serum was stored at 4 °C for further assays. 

Biochemical Parameters:

The following laboratory investigation was performed on sample of Type 2 DM patients before and after Dapagliflozin and Sitagliptin therapy.

1. Adiponectin was estimated by DRG Diagnostic adiponectin Enzyme linked immune sorbent assay (ELISA) Kit. (B-Bridge International Inc., San Jose, CA, USA) with range of assay between 83-104 pg/Ml.
2. Leptin Level was estimated by ELISA. The sensitivity limit of total ghrelin was 0.1 ng/mL.

Statistical Analysis:

The collected data was compiled in MS Excel sheet for analysis in Statistical Package for the Social Sciences (SPSS) version 29^th was applied. The qualitative data was represented in the form of frequencies and percentage also represented in visual impression like bar diagram, pie diagram etc. For quantitative data was represented in the form of mean and standard deviation. To check significance difference between baseline and after three months effect of Dapagliflozin and Sitagliptin group on various parameters level in Type 2 DM patient. A paired ‘t’ test was applied and also quantitative data was represented in the form of pie diagram and bar diagram. p value was check at 0.05 % level of significance.

Patient were randomly assigned to receive dapagliflozin 10 mg (n = 110), sitagliptin 100 mg (n = 110).

Table 1 Baseline characteristics of the study participants

In table 1, Mean age among Dapagliflozin group was 59.9 ± 9.5 years and Sitagliptin group 57.8 ± 8.8 years. Whereas, there were no significant differences between two groups. parameters among the two study groups.  In our study 78 were male and 32 were female among Dapagliflozin group and in Sitagliptin group was 76 was male and 34 were female.

Table 2 Baseline characteristics of the study participants of comorbidities

In table 2, Hypertension was seen in 10 (9.1%) in Dapagliflozin group and Sitagliptin group was 45 (40.9). However, there were no significant differences between among two study groups.

Table 3 Effects of dapagliflozin and sitagliptin on Serum adiponectin at 12 weeks

The change in serum adiponectin level from baseline to week 12 increased significantly only in the dapagliflozin group (P = 0.005) (Table 3). The mean ± SD change in Serum adiponectin at 12 weeks from baseline to 12 weeks were 0.79 ± 1.05 and 0.15 ± 0.06 in the dapagliflozin and sitagliptin groups, respectively.

Table 4 Effects of dapagliflozin and sitagliptin on Serum Leptin at 12 weeks

The change in serum Leptin level from baseline to week 12 increased significantly only in the dapagliflozin group (P = 0.005) (Table 4). The mean ± SD change in Serum adiponectin at 12 weeks from baseline to 12 weeks were 0.79 ± 1.05 and 0.15 ± 0.06 in the dapagliflozin and sitagliptin groups, respectively.

Table 5 Effects of dapagliflozin and sitagliptin on Lipid profile at 12 weeks

In Table 5 shows the subgroup analysis results for patients categorized according to their Lipid Profile at baseline into two groups. The changes in Lipid Profile from baseline to week 12 improved in two study groups.

The change in serum adiponectin level from baseline to week 12 increased significantly only in the dapagliflozin group (P = 0.004). The mean ± SD change in Serum adiponectin at 12 weeks from baseline to 12 weeks were 0.75 ± 1.03 and 0.11 ± 0.05 in the dapagliflozin and sitagliptin groups, respectively. The present study revealed that dapagliflozin exerts a glucose-lowering effect comparable to that of the alternative first-line medications, metformin and sitagliptin. Besides its hypoglycemic action, dapagliflozin significantly lowered body weight and increased serum adiponectin levels in participants. It has also been suggested that dapagliflozin may protect pancreatic β cells by diminishing plasma insulin levels, which may be a pivotal feature to control type 2 diabetes patients for a long time. ^[10]

The most important role of this finding of our study was the positive relationship between serum leptin and serum insulin, that is, increased serum leptin with increases in insulin levels, our study found the same results as those of ADA criteria. ^[11] Therefore, in IR syndrome, if there is a hyperinsulinemic state, we predict that there are high leptin levels. Leptin resistance is more common in T2DM people which also lead to IR, implying that leptin plays a role in T2DM pathogenesis. ^[12] According to Welsh et al, ^[13] leptin is a predictor of T2DM risk factors in men. Higher leptin levels indicated a higher risk of T2DM, ^[14] These are the potential pathway by which leptin levels in T2DM are linked to IR. ^[15] Serum leptin is a good indicator of IR syndrome.

In a previous report that compared dapagliflozin and gemigliptin, gemigliptin had similar glucose-lowering efficacy after 12 weeks of treatment in Korean patients. ^[16] Interestingly, a greater reduction in glycaemic variability (SD, CV and MAGE) was observed in the gemigliptin group than in the dapagliflozin group. The authors explained these results on the basis that, compared with SGLT2 inhibitors, DPP-4 inhibitors increase insulin secretion more rapidly, with higher C-peptide and intact glucagon-like peptide-1 levels and glucose dependence. Furthermore, in that study, ^[17] the TIR after 12 weeks of treatment was significantly increased in both the groups, with a more significant increase in the gemigliptin groups than in the dapagliflozin group.

Dapagliflozin also showed stronger therapeutic effects on other indices that might contribute to the prevention of cardiovascular events. For example, the increase in HDL cholesterol was significantly more pronounced in the dapagliflozin group than in the sitagliptin group. Previous studies reported that an increase in HDL cholesterol concentration is associated with a decrease in the risk of coronary artery disease. ^[18] The increase in hematocrit count was also significantly more pronounced in the dapagliflozin group. Ferrannini et al. indicated that SGLT2 inhibitors may increase hematocrit count by stimulating erythropoiesis, which increases oxygen transport to the tissues and protects from cardiovascular events. ^[19] 

Furthermore, dapagliflozin significantly reduced body weight and insulin AUC levels and improved serum adiponectin levels without inducing hypoglycemia. These results suggest that along with metformin and DPP-4 inhibitors, SGLT2 inhibitors could be a viable first-line treatment option for drug-naïve Japanese patients with type 2 diabetes because of their optimum glucose-lowering properties, ability to avoid hypoglycemia or weight gain, and tolerability over a wide range of ages.

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