Diabetes mellitus affects over 537 million adults worldwide, with India contributing approximately 101 million cases, second only to China [1,2]. Type 2 diabetes mellitus (T2DM), characterized by insulin resistance and progressive beta-cell dysfunction, accounts for over 90% of cases [3]. The chronic nature of T2DM necessitates long-term pharmacotherapy, placing substantial economic burden on patients and healthcare systems, particularly in developing nations where out-of-pocket expenditure remains high [4,5].

Current guidelines recommend metformin as first-line therapy, with add-on agents including sulfonylureas, dipeptidyl peptidase-4 (DPP-4) inhibitors, alpha-glucosidase inhibitors, and sodium-glucose cotransporter-2 (SGLT2) inhibitors [6]. However, the choice of add-on therapy involves trade-offs between efficacy, safety, and cost. Sulfonylureas like glimepiride are highly effective and inexpensive but carry risks of hypoglycemia and weight gain [7,8]. DPP-4 inhibitors such as vildagliptin offer glucose-dependent insulinotropic effects with neutral weight profile and low hypoglycemia risk, but at higher cost [9]. Alpha-glucosidase inhibitors like voglibose target postprandial hyperglycemia with minimal systemic absorption but cause gastrointestinal side effects [10]. SGLT2 inhibitors like dapagliflozin provide weight loss and cardiovascular benefits but increase risks of genitourinary infections and volume depletion [11,12].

While efficacy studies abound, comparative pharmacoeconomic data for these four commonly used combinations in the Indian context remain limited. A recent systematic review emphasized the need for country-specific pharmacoeconomic analyses to guide therapeutic decision-making [4]. This study, therefore, aimed to evaluate and compare the cost-effectiveness and safety of metformin combined with glimepiride, vildagliptin, voglibose, or dapagliflozin in T2DM patients.

The specific objectives were:

• To compare glycemic efficacy (HbA1c, FPG, PPG reductions) at 12 weeks
• To calculate cost-effectiveness ratios per unit reduction in glycemic parameters
• To compare safety profiles including hypoglycemia, gastrointestinal effects, and other adverse events and
• To identify the most cost-effective and safest options for Indian T2DM patients.

MATERIALS AND METHODS

Study Design and Setting

This was a prospective, open-label, randomized, four-arm comparative study conducted over 12 weeks at the Department of Pharmacology in collaboration with the Department of Medicine, Pushpagiri Institute of Medical Sciences & RC, Thiruvalla, Kerala, India. The study protocol received approval from the Institutional Ethics Committee (Ref. No. PIMSRC/E1/388A/441/2026).

Study Participants

Patients aged 30-70 years with newly diagnosed T2DM (as per ADA criteria: HbA1c ≥6.5% or FPG ≥126 mg/dL) requiring initial combination therapy (baseline HbA1c 7.5-9.5%) were eligible. Exclusion criteria included: type 1 diabetes, pregnancy/lactation, significant renal impairment (eGFR <45 mL/min/1.73m²), hepatic dysfunction (transaminases >3x upper normal), history of diabetic ketoacidosis, severe cardiovascular disease (NYHA class III/IV), and known hypersensitivity to study drugs.

Randomization and Interventions

Eligible patients were randomly assigned (1:1:1:1) using a computer-generated randomization sequence to one of four treatment groups for 12 weeks:

Group A (M+G): Metformin 500 mg + Glimepiride 1 mg twice daily

Group B (M+V): Metformin 500 mg + Vildagliptin 50 mg twice daily

Group C (M+Vo): Metformin 500 mg + Voglibose 0.3 mg thrice daily

Group D (M+D): Metformin 500 mg + Dapagliflozin 10 mg once daily

All medications were administered orally. Metformin dose was titrated from 500 mg to 1000 mg twice daily as tolerated over the first 4 weeks in all groups.

Outcome Measures

Primary Outcome: Change in HbA1c from baseline to 12 weeks.

Secondary Outcomes: (1) Change in FPG and PPG; (2) Change in body weight and BMI; (3) Proportion achieving HbA1c <7%; (4) Cost-effectiveness ratios; (5) Adverse event incidence.

Laboratory Assessments

HbA1c was measured using high-performance liquid chromatography (Bio-Rad D-10). FPG and PPG were estimated by glucose oxidase-peroxidase method (Beckman Coulter AU680). All investigations were performed at the central laboratory of Pushpagiri Medical College Hospital.

Cost-Effectiveness Analysis (CEA)

CEA adopted a healthcare payer perspective including direct medical costs (drug acquisition costs as per Indian market prices for January-June 2024). Costs of investigations and management of adverse events were excluded as these were similar across arms. The daily cost per regimen was calculated as:

M+G: Metformin 500 mg (₹2.50) + Glimepiride 1 mg (₹1.20) = ₹3.70/day; Total (12 weeks) = ₹310.80

M+V: Metformin 500 mg (₹2.50) + Vildagliptin 50 mg (₹15.00) = ₹17.50/day; Total = ₹1,470

M+Vo: Metformin 500 mg (₹2.50) + Voglibose 0.3 mg (₹4.50) = ₹7.00/day; Total = ₹588

M+D: Metformin 500 mg (₹2.50) + Dapagliflozin 10 mg (₹24.00) = ₹26.50/day; Total = ₹2,226

Cost-effectiveness ratios (CER) were calculated as: CER = Total cost of therapy (₹) / Effectiveness (unit reduction in glycemic parameter)

For therapies with higher efficacy but higher cost, incremental cost-effectiveness ratios (ICER) were calculated as: ICER = (Cost_A – Cost_B) / (Effectiveness_A – Effectiveness_B)

Safety Assessment

Patients were monitored for adverse events at weeks 2, 4, 8, and 12. Hypoglycemia was defined as blood glucose <70 mg/dL with or without symptoms. Gastrointestinal effects (nausea, diarrhea, flatulence), genitourinary infections, and volume depletion symptoms were specifically recorded.

Based on a study showing a mean HbA1c reduction difference of 0.5% between groups (SD=0.6%), with 80% power and α=0.05, a minimum of 23 patients per group was required. Accounting for 20% dropout, 30 patients per group (total 120) were enrolled.

Statistical Analysis

Data were analyzed using SPSS version 26.0. Continuous variables were expressed as mean±SD. Within-group comparisons used paired t-test; between-group comparisons used one-way ANOVA with post-hoc Tukey's test for parametric data or Kruskal-Wallis test for non-parametric data. Categorical variables were compared using Chi-square test. P<0.05 was considered statistically significant.

RESULTS

Baseline Characteristics

A total of 148 patients were screened, of whom 120 were randomized (30 per group). Baseline characteristics were comparable across all four groups (Table 1). Mean age was 51.4±9.2 years, with 62.5% males. Mean baseline HbA1c was 8.55±0.78%, FPG 168.4±28.6 mg/dL, and PPG 268.2±45.3 mg/dL. There were no significant differences in any baseline parameters between groups (p>0.05 for all).

Table 1: Baseline demographic and clinical characteristics of study participants

*One-way ANOVA; †Chi-square test. Data expressed as mean±SD. M+G: Metformin+Glimepiride; M+V: Metformin+Vildagliptin; M+Vo: Metformin+Voglibose; M+D: Metformin+Dapagliflozin.

Glycemic Efficacy

All four combinations significantly reduced HbA1c, FPG, and PPG from baseline (p<0.001 for all within-group comparisons) (Tables 2-5). At 12 weeks, the mean HbA1c reduction ranged from 1.45% to 1.82% across groups (Figure 1). M+G showed the greatest reduction (1.82±0.52%), followed by M+V (1.68±0.55%), M+D (1.52±0.48%), and M+Vo (1.45±0.50%). However, differences between groups were not statistically significant (p=0.089).

For PPG reduction, M+V demonstrated superior efficacy (71.4±38.2 mg/dL reduction) compared to M+G (58.2±42.1 mg/dL), M+Vo (65.3±40.5 mg/dL), and M+D (55.6±36.8 mg/dL), with the difference between M+V and M+D reaching statistical significance (p<0.05). FPG reductions were comparable across all groups (p=0.312).

The proportion of patients achieving HbA1c <7% at 12 weeks was highest in M+G (56.7%), followed by M+V (53.3%), M+D (46.7%), and M+Vo (43.3%), though differences were not statistically significant (p=0.624).

Table 2: Glycemic parameters before and after therapy for M+G group

*Paired t-test. Data expressed as mean±SD.

Table 3: Glycemic parameters before and after therapy for M+V group

*Paired t-test. Data expressed as mean±SD.

Table 4: Glycemic parameters before and after therapy for M+Vo group

*Paired t-test. Data expressed as mean ± SD.

Table 5: Glycemic parameters before and after therapy for M+D group

*Paired t-test. Data expressed as mean±SD.

Table 6: Comparison of glycemic efficacy between groups at 12 weeks

*One-way ANOVA; †Chi-square test; Data expressed as mean±SD. †p<0.05 vs M+D (post-hoc Tukey).

Body Weight and BMI Changes

Significant differences in weight change were observed between groups (p=0.008) (Figure 2). M+D led to significant weight loss (-2.1±1.2 kg, p<0.001 vs baseline), while M+G caused weight gain (+1.4±1.1 kg, p<0.001 vs baseline). M+V and M+Vo had neutral effects on weight (-0.2±0.8 kg and -0.1±0.7 kg respectively, p>0.05 vs baseline). BMI changes paralleled weight changes (Table 7).

Table 7: Changes in body weight and BMI at 12 weeks

*One-way ANOVA; **p<0.01 vs baseline (paired t-test)

Cost-Effectiveness Analysis

M+G was the most cost-effective regimen across all glycemic parameters (Table 8, Figure 3). The cost per 0.1% reduction in HbA1c was ₹8.45 for M+G, compared to ₹18.65 for M+V (120.7% higher), ₹12.30 for M+Vo (45.6% higher), and ₹28.40 for M+D (236.1% higher). For FPG reduction per mg/dL, M+G (₹5.20) was again superior. For PPG reduction, the differences narrowed but M+G remained most cost-effective.

Since M+G had both lower cost and numerically greater efficacy than other groups for HbA1c reduction, it was the dominant strategy, and ICER calculation was not applicable. For PPG reduction, M+V showed superior efficacy but at higher cost; the ICER for M+V compared to M+G was ₹88.50 per additional mg/dL of PPG reduction.

Table 8: Cost-effectiveness analysis at 12 weeks

Values in bold indicate most cost-effective for each parameter.

Analysis

Safety profiles differed significantly between groups (Table 9, Figure 4). Hypoglycemia occurred exclusively in M+G (5 patients, 16.7%), all mild (blood glucose 55-69 mg/dL) and self-managed. No severe hypoglycemia was reported.

Gastrointestinal adverse effects were most common in M+Vo (30.0%), primarily flatulence (23.3%) and abdominal distension (16.7%). M+D had the highest rate of genitourinary infections (13.3%), including two cases of urinary tract infection and two cases of genital mycotic infection (one balanitis, one vulvovaginal candidiasis). M+V showed the lowest overall adverse event rate (10.0%), with no hypoglycemia, minimal GI effects (6.7%), and no genitourinary infections. No patient discontinued treatment due to adverse events in any group.

Table 9: Adverse events profile across study groups

*Chi-square test

DISCUSSION

This prospective four-arm study provides comprehensive comparative data on the cost-effectiveness and safety of metformin-based dual therapies in Indian T2DM patients. The key findings are: (1) M+G is the most cost-effective regimen for glycemic control; (2) M+V offers the best safety profile with superior PPG reduction; (3) M+D provides unique weight loss benefits and cardiovascular advantages but at higher cost; (4) M+Vo is an intermediate option with gastrointestinal tolerability concerns.

Glycemic Efficacy

All four combinations demonstrated significant glycemic improvement, consistent with established literature [13,14]. The numerically greater HbA1c reduction with M+G (1.82%) aligns with a recent meta-analysis showing sulfonylurea-based combinations achieve reductions of 1.5-2.0% [15]. A large real-world study from India (n=813) reported that glimepiride-based combinations reduced HbA1c by approximately 1.5% over 6 months [16]. The comparable efficacy of M+V (1.68%) in our study mirrors findings from Amate et al., who reported no significant difference between glimepiride and DPP-4 inhibitors as add-on to metformin [17].

Notably, M+V showed superior PPG reduction (71.4 mg/dL) compared to other groups, consistent with the known mechanism of DPP-4 inhibitors in enhancing glucose-dependent insulin secretion and suppressing glucagon, particularly effective for postprandial control [18,19]. A phase 3 Indian study similarly found that vildagliptin-based regimens effectively reduced PPG [20].

M+D (HbA1c reduction 1.52%) demonstrated efficacy comparable to recent trials. A 2025 phase 3 study reported a 2.08% HbA1c reduction with dapagliflozin-sitagliptin-metformin triple therapy [21]. The slightly lower reduction in our study may reflect dual rather than triple therapy and differences in baseline characteristics.

Cost-Effectiveness

The cost-effectiveness findings have significant implications for Indian clinical practice. M+G's cost per 0.1% HbA1c reduction (₹8.45) is substantially lower than alternatives, primarily due to glimepiride's low acquisition cost (generic availability). Even accounting for potential hypoglycemia management costs, M+G remains dominant. This aligns with a systematic review concluding that sulfonylurea-based regimens are the most cost-effective second-line options in low-resource settings [4,22].

M+V, while 120% more expensive per unit HbA1c reduction, may still be justified in patients at high hypoglycemic risk (e.g., elderly, those with erratic lifestyles, or occupational hazards). A US healthcare payer perspective study found DPP-4 inhibitors cost-effective as second-line therapy, though this may not translate directly to Indian settings [23].

M+D's higher cost (₹28.40 per 0.1% HbA1c reduction) may be offset by its benefits in specific populations—those with established cardiovascular disease, heart failure, or chronic kidney disease, where SGLT2 inhibitors show mortality benefits [24,25]. The ICER for M+V vs M+G for PPG reduction (₹88.50 per additional mg/dL) provides a benchmark for decision-makers.

Safety Profile

The safety findings demonstrate clear differentiation between therapies. M+G's 16.7% hypoglycemia rate, while lower than older sulfonylureas like glibenclamide, remains a concern [7,8]. A recent comprehensive review confirmed sulfonylureas carry the highest hypoglycemia risk among oral antidiabetics [26]. In elderly patients or those with renal impairment, alternatives should be strongly considered.

M+V's favorable safety profile (10% adverse events, no hypoglycemia) corroborates the established tolerability of DPP-4 inhibitors [9,27]. A 2025 comparative study similarly reported lower hypoglycemia and dizziness with vildagliptin combinations compared to glimepiride or gliclazide [16]. The absence of weight gain is an additional advantage [28].

M+Vo's high rate of gastrointestinal effects (30%, predominantly flatulence 23.3%) reflects the mechanism of alpha-glucosidase inhibitors delaying carbohydrate absorption, leading to fermentation in the colon [10,29]. While bothersome, these effects typically diminish with continued use. A slow dose titration strategy might improve tolerability.

M+D's adverse events—genitourinary infections (13.3%) and osmotic diuresis symptoms (10%)—are well-documented class effects [12,26,30]. Patient education regarding hydration and perineal hygiene is essential. Importantly, no cases of euglycemic ketoacidosis were observed in this short-term study, though this risk warrants monitoring with long-term use [26].

Clinical Implications and Recommendations

Based on these findings, a patient-centered approach to add-on therapy selection is proposed:

M+G as first-line add-on for patients where cost is the primary constraint and hypoglycemia risk is low. This includes younger patients, those with regular meal schedules, and those able to recognize and manage hypoglycemic symptoms.

M+V for patients with hypoglycemia concerns—elderly, those with occupational risks (drivers, machine operators), irregular meal patterns, or previous sulfonylurea intolerance. The superior PPG control may benefit those with predominant postprandial hyperglycemia.

M+D for patients with weight loss goals or cardiovascular indications—obese patients (BMI >27 kg/m²), those with hypertension, or established cardiovascular disease. The higher cost should be justified by these additional benefits.

M+Vo as a second-line alternative for patients with mild hyperglycemia who prefer a non-systemic agent or cannot tolerate other options. Gastrointestinal effects should be discussed beforehand, and gradual dose escalation employed.

Study Limitations

Several limitations warrant acknowledgment. First, the 12-week duration is relatively short for assessing HbA1c changes fully (typically 3 months for steady state). Longer studies (24-52 weeks) might reveal differential durability of effects. Second, the open-label design introduces potential bias, though objective laboratory endpoints mitigate this concern. Third, the single-center design may limit generalizability across India's diverse populations. Fourth, the sample size (30 per group) may be insufficient to detect small differences in efficacy or rare adverse events. Fifth, indirect costs (travel, lost wages) and costs of managing adverse events were not included, which might alter cost-effectiveness rankings if hypoglycemia management costs were considered. Sixth, the analysis did not incorporate quality-adjusted life years (QALYs) or long-term complication costs, which would require modeling over longer time horizons [5,31]. Finally, the use of market prices rather than procurement costs may affect generalizability to public healthcare settings.

Future Research Directions

Future studies should include:

• Longer duration trials (≥6 months) to assess sustained efficacy and tolerability;
• Inclusion of QALYs and long-term complication modeling for comprehensive cost-utility analysis;
• Head-to-head comparisons of newer agents including SGLT2 inhibitors with established cardiovascular benefits;
• Real-world evidence from electronic medical records across multiple centres; and
• Studies focusing on specific subpopulations (elderly, renal impairment, cardiovascular disease) where treatment selection may differ [32].

CONCLUSION

This study demonstrates that while metformin+glimepiride is the most cost-effective option for initial combination therapy in T2DM, metformin+vildagliptin offers the most favorable safety profile with comparable efficacy, particularly for postprandial control. Metformin+dapagliflozin provides unique weight loss and cardiovascular benefits at higher cost, while metformin+voglibose represents an intermediate option limited by gastrointestinal tolerability.

Treatment decisions should be individualized, balancing efficacy, safety, cost, and patient characteristics. In resource-limited settings like India, metformin+glimepiride remains a rational first choice for eligible patients, with alternatives reserved for those with specific contraindications or risk factors.

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