Priyadarshini J. L College of Pharmacy, MIDC, Hingna road, Nagpur, Maharashtra , India-440016
Type 2 diabetes mellitus (T2DM) is a long-lasting and progressively worsening metabolic disorder characterized by persistent high blood sugar levels, ineffective insulin action, and diminishing ?-cell functionality. Achieving optimal control of the disease frequently necessitates the use of medications that operate through different but complementary mechanisms. Metformin, gliclazide, and dapagliflozin are three well-recognized treatment options with ample evidence demonstrating their effectiveness, safety, and protective benefits for organs. This review provides a critical overview of their mechanisms of action, pharmacokinetic profiles, clinical effectiveness, and effects on cardiovascular and renal outcomes. Metformin remains the foundational treatment in early therapy due to its strong insulin-sensitizing properties and beneficial cardiometabolic profile. Gliclazide offers significant glycaemic reduction with a relatively lower risk of hypoglycaemia compared to other sulfonylureas. Dapagliflozin, classified as an SGLT2 inhibitor, presents multifaceted advantages, including weight loss, improvement in blood pressure, and considerable cardio-renal protection that is independent of glucose lowering. When these medications are used together, they produce synergistic effects that enhance overall metabolic regulation. This review consolidates the existing clinical evidence to inform rational and tailored therapeutic approaches in the management of T2DM.
Type 2 diabetes mellitus (T2DM) is a chronic metabolic condition distinguished by high blood glucose levels resulting from inadequate insulin secretion, impaired insulin function, or a combination of both factors. The worldwide occurrence of T2DM is rising at an alarming pace [1,2]. In 2021, approximately 537 million adults were impacted, with forecasts indicating this figure could reach almost 783 million by 2054[3]. T2DM disrupts numerous physiological functions regulated by insulin and develops from a complex interaction of genetic factors, metabolic issues, and environmental conditions. People of Indian descent show a greater predisposition to T2DM, which not only heightens their chances of developing the condition but also raises the risk for related complications such as cardiovascular diseases (CVD). Risk factors contributing to this include poor dietary choices, obesity, high blood pressure, elevated blood glucose, increased triglycerides and cholesterol, and diminished levels of high-density lipoprotein [4,5]. T2DM, which represents the majority of diabetes cases, is linked to both microvascular and macrovascular complications that can adversely affect various organ systems. Moreover, the insulin resistance often associated with obesity significantly contributes to the emergence of other cardiovascular risk factors, including dyslipidaemia and hypertension [6,7]. These complications greatly contribute to the higher rates of early disease and mortality found in individuals with diabetes. Consequently, life expectancy tends to decrease, and the overall financial strain on the Indian healthcare system escalates, as complications related to diabetes substantially heighten the overall cost of care [8,9]. Therefore, healthcare professionals and researchers globally are continuously investigating new treatment approaches for T2DM and creating updated evidence to aid in more effective management of this chronic condition. Current medication options for individuals with T2DM comprise a variety of drug classes, such as metformin, sulfonylureas, thiazolidinediones, dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), along with insulin and different insulin analogues [10].The management of diabetes ought to be tailored according to specific patient-related factors, including the existence of atherosclerotic cardiovascular disease (ASCVD), indicators of heightened cardiovascular risk, heart failure (HF), chronic kidney disease (CKD), body weight, and current glycaemic levels. According to the American Association of Clinical Endocrinologists, several factors should be considered in choosing the right therapeutic agent, including its capacity to lower glycated haemoglobin (HbA1c), its impact on body weight and blood pressure (BP), and the likelihood of hypoglycaemia [11]. Metformin, an oral antihyperglycemic medication from the biguanide class, is commonly recommended as the first-line pharmacological treatment for those diagnosed with type 2 diabetes [12]. Newer-generation sulfonylureas, such as gliclazide modified release (MR), are significant in therapy, as they are generally preferred over older agents due to their decreased risk of hypoglycaemia and their mostly neutral cardiovascular profile [13,14]. In recent years, sodium-glucose cotransporter-2 inhibitors (SGLT2i) like Dapagliflozin have gained traction as potential first-line therapeutic agents due to their ability to improve cardiometabolic health and significantly lower adverse cardiovascular and renal outcomes [15]. This review provides a thorough, evidence-based comparison of dapagliflozin, gliclazide, and metformin, focusing on their mechanisms of action, pharmacokinetic characteristics, therapeutic efficacy, safety aspects, and the possible synergistic benefits achieved through combination therapy.
2. MECHANISM OF ACTION:
2.1 Dapagliflozin:
The kidney is crucial for regulating the body’s glucose levels. On a daily basis, around 180 grams of glucose are filtered by the kidneys [16]. Approximately 80–90% of this glucose is reabsorbed in the initial segment of the proximal tubule through SGLT2 transporters, which are highly efficient at transporting glucose. The remaining 10–20% is reabsorbed later in the proximal tubule via SGLT1, which, while having a lower transport capacity, has a greater affinity for glucose. This entire reabsorption mechanism relies on the cotransport of glucose and sodium, which is facilitated by Na?/K?-ATPase pumps. SGLT2 is exclusively located in the kidney, whereas SGLT1 is also found in the gastrointestinal tract, assisting in the absorption of glucose and galactose [17]. In healthy individuals, nearly all filtered glucose is reabsorbed, resulting in urine typically lacking glucose. However, in individuals with type 2 diabetes mellitus (T2DM), the kidneys frequently reabsorb more glucose than usual, potentially due to an increase in SGLT2 expression in response to prolonged elevated blood sugar levels. This leads to excessive glucose retention, further exacerbating hyperglycaemia [16,17]. Dapagliflozin is a selective inhibitor of SGLT2 that functions by blocking SGLT2 activity in the proximal convoluted tubule. This action decreases glucose reabsorption and raises the volume of glucose excreted in the urine, independent of insulin secretion or sensitivity [18]. Dapagliflozin also aids in weight loss by increasing the loss of calories through glucose excretion and lowers blood pressure due to its mild diuretic properties. Additional benefits include lower uric acid levels, reduced oxidative stress, and a potential slowing of atherosclerosis [19]. Collectively, these effects make dapagliflozin particularly beneficial for patients with pre-existing cardiovascular disease or those at elevated cardiovascular risk [18,19]. (Figure1)
Figure 1: Mechanism of dapagliflozin
2.2 Gliclazide:
Under typical physiological conditions, the secretion of insulin from pancreatic β-cells is minimal, and the membrane of β-cells remains in a hyperpolarized state. When glucose is transported into β-cells via the GLUT2 transporter, a cascade of events is initiated that leads to the release of insulin. Inside the cell, glucose is processed, resulting in increased ATP levels. The rise in ATP causes inhibition of ATP-sensitive potassium (K_ATP) channels, which results in membrane depolarization. This depolarization facilitates the entry of calcium ions (Ca²?) into the cell through voltage-gated calcium channels, raising intracellular calcium concentrations. The increase in Ca²? then triggers the exocytosis of insulin-containing granules, leading to the secretion of insulin [20,21].
Sulfonylureas (SUs) function by binding to the sulfonylurea receptor (SUR) portion of the K_ATP channel. This interaction results in the closure of the channel, inducing membrane depolarization without requiring glucose to enter the cell. The subsequent intracellular processes proceed in the same manner, ultimately enhancing insulin release [20,21,22] (figure2).
Figure 2: Mechanism of action of sulfonylureas on pancreatic β cells and cardiomyocytes.
2.3 Metformin:
The ways in which metformin produces its therapeutic effects are complex and not fully understood. In liver cells, metformin is primarily absorbed through the organic cation transporter-1 (OCT1) [23]. Once it enters the cell, it alters the AMP: ATP and ADP:ATP ratios by inhibiting mitochondrial respiratory-chain complex I, leading to decreased ATP production [24]. This shift in energy triggers the activation of AMP-activated protein kinase (AMPK). Additionally, metformin can activate AMPK via a lysosomal pathway. Research indicates that metformin interacts with the v-ATPase–regulator complex, promoting the recruitment of AXIN and LKB1 to the lysosomal surface, which further boosts AMPK activation [25].
Metformin may also affect cellular growth pathways by disrupting the binding of mTORC1 to the v-ATPase/Regulator complex, resulting in its direct inhibition [26]. Moreover, the AMPK activation induced by metformin can also inhibit mTORC1 through the AMPK–TSC2–mTORC1 signaling pathway, in which AMPK phosphorylates TSC2 and Raptor. Since mTORC1 is crucial for regulating anabolic processes, its inhibition plays a role in the metabolic effects of metformin [27].
These molecular interactions are believed to contribute to the cardiovascular benefits attributed to metformin treatment. Prolonged use has been demonstrated to decrease cardiac hypertrophy caused by pressure overload through AMPK activation and associated downstream pathways involving eNOS and nitric oxide (NO). In heart cells, metformin also mitigates the protein synthesis induced by angiotensin II by promoting AMPK and eNOS phosphorylation, which enhances NO production. Furthermore, metformin is known to lower hepatic glucose output by inhibiting the expression and function of Kruppel-like factor 15 (KLF15), a significant transcription factor involved in gluconeogenesis [28].
Figure 3: Mechanism of Metformin
3. PHARMACOKINETICS:
3.1 Dapagliflozin:
After being taken orally, dapagliflozin (DAPA) is quickly absorbed, reaching its highest plasma levels within around 1–2 hours. While consuming food alongside the medication does slightly delay the absorption process, it does not impact the overall systemic level of the drug. Dapagliflozin is widely distributed in extravascular tissues, with an average volume of distribution estimated at about 118 L, and approximately 91% of the medication is attached to plasma proteins. The primary metabolism of dapagliflozin occurs via the enzyme uridine diphosphate-glucuronosyltransferase-1A9 (UGT1A9), transforming it into its main inactive metabolite, dapagliflozin 3-O-glucuronide. Research indicates that the UGT1A9 enzyme present in the kidneys plays a significant role in producing this metabolite. Less than 10% of dapagliflozin is metabolized through oxidation. Only a tiny amount of the parent compound (less than 2%) is excreted unchanged in the urine. On the other hand, its principal metabolite is predominantly eliminated by the kidneys, with approximately 61% of the administered dose found in urine as dapagliflozin 3-O-glucuronide. The elimination half-life following a 10 mg oral dose is roughly 12.9 hours. Notably, no significant differences in dapagliflozin exposure have been observed based on factors like age, sex, race, body weight, food intake, or the presence of type 2 diabetes [29,30].
3.2 Gliclazide:
A single oral administration of gliclazide at doses ranging from 40 to 120 mg leads to a peak plasma concentration (Cmax) between 2.2 and 8.0 µg/mL, usually reached within 2 to 8 hours. Both Cmax and Tmax tend to rise with multiple doses. Steady-state levels are typically attained after two days of continuous use within this dosage range. Gliclazide exhibits a relatively low volume of distribution (13–24 L) in both healthy subjects and patients, which aligns with its high capacity for plasma protein binding of 85–97%. The elimination half-life (t1/2) ranges from 8.1 to 20.5 hours following oral doses of 40–120 mg. Its plasma clearance rate is about 0.78 L/h (13 mL/min). Gliclazide undergoes extensive metabolism into seven different metabolites and is mainly excreted via urine; thus, mild to moderate renal impairment does not notably impact its pharmacokinetic characteristics [31].
3.3 Metformin:
After taking metformin by mouth, the maximum concentration of the drug in the bloodstream (peak plasma concentration) is typically achieved in approximately 3 hours. When an individual consumes a 0.5 g (500 mg) dose, the peak concentration observed in the bloodstream is roughly between 1.0 and 1.6 mg/L. If the dosage is increased to 1.5 g, the concentration may rise to about 3 mg/L. Following the peak concentration, the levels of metformin in the blood decline rapidly. Despite this decrease in blood concentration, metformin continues to be excreted from the body via urine for an extended period. This elimination pattern is comparable to what occurs when the drug is administered intravenously. Based on urinary elimination, the terminal half-life (t½) of metformin is approximately 20 hours, implying that the body requires around 20 hours to eliminate half of the drug [32].
4. CLINICAL EFFICACY:
4.1 Dapagliflozin:
Dapagliflozin has been scrutinized as a standalone treatment in five major clinical studies, which include trials incorporating diet and exercise, comparisons directly with metformin, and investigations involving both treatment-naïve patients and those previously treated. In a notable 24-week placebo-controlled study conducted by Ferrannini et al. (2010), 485 treatment-naïve individuals with HbA1c levels between 7% and 10% were randomly assigned to either a placebo or various doses of dapagliflozin (2.5 mg, 5 mg, or 10 mg), taken in the morning or evening. Additionally, a separate group of 73 patients with very high HbA1c (10.1%–12%) received 5 mg or 10 mg of dapagliflozin. In comparison to the modest HbA1c reduction observed in the placebo group (−0.23%), dapagliflozin led to more pronounced reductions ranging from −0.58% to −0.89%, with similar results for evening dosages. Patients with elevated baseline HbA1c demonstrated the most substantial improvements, achieving reductions between −2.66% and −2.88%. Fasting plasma glucose levels also showed significant declines, dropping by 15–29 mg/dL in the primary cohort and by 77–84 mg/dL in the group with high HbA1c [33].
4.2 Gliclazide:
Gliclazide MR is a modified-release version formulated with a hydrophilic matrix, allowing it to be taken once a day at a reduced total dose (30–120 mg/day) compared to conventional gliclazide tablets (80–320 mg/day, administered twice daily). This formulation ensures effective drug levels are sustained for a complete 24 hours. Importantly, the 60-mg Gliclazide MR tablet is unique as the only long-acting oral antidiabetic agent that can be scored and divided into two halves without compromising its sustained-release characteristics, enhancing patient adherence. Gliclazide MR is commonly recognized as a benchmark sulfonylurea because it significantly improves glycaemic control in both monotherapy and when paired with metformin, while presenting a lower risk of hypoglycaemia and not contributing to increased cardiovascular mortality [34,35].
4.3 Metformin:
Three randomized clinical trials have been conducted to evaluate the cardiovascular impacts of metformin on individuals with type 2 diabetes. The most significant evidence derives from the UK Prospective Diabetes Study (UKPDS), which analyzed intensive glucose management (using oral medications or insulin) against standard care primarily focused on dietary recommendations for newly diagnosed patients. Metformin was introduced later in the study and was only given to overweight participants (those exceeding 120% of their ideal body weight), based on the belief that it would be more effective for individuals with insulin resistance. A total of 1704 overweight participants were divided into groups receiving metformin, sulfonylurea, insulin, or standard care. Out of these, 753 patients were part of the direct comparison between metformin and the control group across 15 UKPDS sites. After approximately ten years of follow-up, metformin treatment showed significant improvements in several crucial outcomes, including overall mortality, myocardial infarction (MI), complications related to diabetes, diabetes-related deaths, and all-cause mortality [36,37].
5. COMBINATION THERAPY BENEFITS:
The use of dapagliflozin in conjunction with metformin results in improved glycaemic control owing to their synergistic mechanisms of action [38,39]. Metformin mainly lowers hepatic glucose production and enhances insulin sensitivity in peripheral tissues, while dapagliflozin
encourages the excretion of glucose through urine by blocking renal SGLT2 transporters. The combination of these mechanisms yields additive decreases in both fasting and postprandial glucose levels, all while keeping the risk of hypoglycaemia low. In addition to lowering glucose levels, both medications also have positive effects on various cardiovascular risk factors, which may enhance their overall cardioprotective properties [40,41].
Fig 4: The complementary mechanism of action of metformin, gliclazide and dapagliflozin contributing to reducing hyperglycaemia in T2DM patients [42].
Effects on Body Weight and Composition
Achieving weight loss is a significant objective in type 2 diabetes mellitus (T2DM), and various research studies demonstrate that the use of dapagliflozin alongside metformin leads to more substantial decreases in body weight, waist size, and fat mass compared to metformin on its own. These results suggest that combination therapy enhances metabolic outcomes for individuals who are overweight or obese [43].
Effects on Blood Pressure
Dapagliflozin–metformin treatment reliably decreases both systolic and diastolic blood pressure more effectively than metformin by itself. Several studies, such as those conducted by Bolinder, Cheng, Phadke, and Nauck, have validated these blood pressure-reducing impacts, which help lower cardiovascular risk [43].
Effects on Lipid Profile
Dapagliflozin has demonstrated the ability to lower triglyceride levels and raise HDL-C, whereas metformin is effective in decreasing total cholesterol, LDL, and triglycerides. Using both medications together yields more significant enhancements in HDL-C and triglycerides compared to using each medication individually [43].
Overall Metabolic Benefits
Dapagliflozin and metformin, when used together, effectively reduce HbA1c, fasting plasma glucose (FPG), and postprandial glucose (PPG), aid in weight loss, decrease blood pressure, and improve lipid profiles, offering extensive metabolic benefits for patients with type 2 diabetes mellitus (T2DM).
Cardiorenal Outcomes
Cardiovascular Effects
SGLT2 inhibitors, such as dapagliflozin, help lower significant cardiovascular risks in individuals with Type 2 diabetes. In the DECLARE–TIMI 58 study, dapagliflozin was shown to decrease the combined outcome of cardiovascular death or hospitalization due to heart failure, primarily by reducing hospitalizations related to heart failure. The advantages were evident among various patient subgroups, albeit without a notable decrease in major adverse cardiovascular events.
The DAPA-HF trial demonstrated that dapagliflozin helped decrease the worsening of heart failure and cardiovascular death in patients with heart failure with reduced ejection fraction (HFrEF), along with additional declines in uric acid levels [44].
Renal Effects
Dapagliflozin enhances kidney function by reestablishing tubuloglomerular feedback, leading to decreased intraglomerular pressure and protein levels in the urine. The DAPA-CKD trial showed that it notably decreased the likelihood of a lasting decline in eGFR, end-stage renal disease (ESRD), and mortality related to renal or cardiovascular issues. Additionally, it lowered albumin levels in the urine, with more pronounced effects seen in individuals with type 2 diabetes mellitus (T2DM) [45].
6. SAFETY PROFILE:
Clinical research indicates that the combination of dapagliflozin and metformin is typically well tolerated, with only a limited number of patients encountering significant side effects. The rate of hypoglycaemia is low, and occurrences of severe episodes are infrequent. Nevertheless, genital and urinary tract infections may be more prevalent, especially in women undergoing combination therapy. Dapagliflozin has also demonstrated its safety and effectiveness in older individuals with advanced type 2 diabetes mellitus (T2DM), cardiovascular conditions, and multiple concurrent medications. While rare, lactic acidosis can occur as a result of metformin buildup [46]. Clinical investigations reveal that the most frequently reported adverse effects linked to dapagliflozin treatment include genital infections, urinary tract infections, volume depletion-related events, and, less often, bladder cancer. Genital and urinary infections are generally mild to moderate in severity and rarely necessitate stopping treatment. No consistent relationship between dose and these events has been identified, and they tend to happen more often in women, with E. coli and fungal species being the usual pathogens. Instances of hypotension, hypovolemia, or dehydration are uncommon but tend to occur more frequently in those taking the 10 mg dose, especially among older patients, those on loop diuretics, or individuals with decreased estimated glomerular filtration rate (eGFR) [47]. Crucially, dapagliflozin does not adversely affect health-related quality of life. Cases of bladder cancer were slightly more frequent in patients treated with dapagliflozin compared to controls, but the clinical significance of this observation remains uncertain, with ongoing studies investigating any causal links. A small number of patients showed elevated liver enzyme levels, with two cases thought to be possibly associated with dapagliflozin. In light of these findings, regulatory bodies such as the FDA have requested further post-marketing studies and pharmacovigilance efforts to better evaluate the risks of bladder cancer, cardiovascular safety, and possible liver effects [48,49].
7. CONCLUSION:
Dapagliflozin, gliclazide, and metformin are three pharmacological agents with distinct mechanisms that work effectively together and continue to be fundamental in the management of type 2 diabetes mellitus (T2DM). Metformin is the foundation of treatment due to its strong evidence backing, sustainable glycaemic control, and wide-ranging benefits for cardiovascular and metabolic health, such as maintaining weight, enhancing insulin sensitivity, and lowering the risk of diabetes-related complications. Gliclazide offers significant glucose-lowering effects through its regulated stimulation of insulin secretion and is regarded as one of the safer options within the sulfonylurea class, given its lower chance of severe hypoglycaemia and positive effects on microvascular health. Conversely, dapagliflozin provides glucose lowering independently of insulin, making it a groundbreaking option with proven cardiovascular and renal protective benefits, including reduced hospitalizations for heart failure, decreased albuminuria, and slowed progression of chronic kidney disease.
These medications collectively offer complementary benefits that tackle several underlying issues of T2DM—hepatic insulin resistance, dysfunction in β-cell function, and renal glucose reabsorption. Data from randomized clinical trials and real-world evidence robustly endorse the use of combined therapy with these drugs to attain thorough glycaemic improvement, reduce risks associated with treatment, and enhance long-term clinical outcomes. The best choice and order of these drugs should be tailored to the individual, considering factors such as patient characteristics, existing cardiovascular or renal conditions, risk of hypoglycaemia, weight issues, and the overall acceptability of the treatments. Implementing a personalized, mechanism-focused strategy with these agents can substantially elevate the standard of diabetes care and diminish long-term complications.
REFERENCES
Prachi Dangre, Alpana Asnani, A Comprehensive Review on the Clinical Pharmacology, Therapeutic Efficacy, and Safety of Dapagliflozin, Gliclazide, and Metformin in Type 2 Diabetes Mellitus, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 12, 3387-3398. https://doi.org/10.5281/zenodo.18021773
10.5281/zenodo.18021773
