Introduction

Type-2 diabetes mellitus (T2DM) is caused by insulin resistance and impaired β-cell function, along with multiple organ defects (the “ominous octet”) that contribute to chronic hyperglycemia. This understanding has led to treatments targeting different pathways involved in glucose regulation. Over the past two decades, dipeptidyl peptidase (DPP)-4) inhibitors and sodium glucose cotransporter (SGLT)-2 inhibitors have improved T2DM management, with SGLT-2 inhibitors providing significant cardiovascular and kidney benefits. Metformin, with its established benefits, tackles insulin sensitivity and hepatic gluconeogenesis, and its combination with various antidiabetic medications has been beneficial. Triple oral therapy combining metformin, sodium-glucose cotransporter 2 inhibitor, and a dipeptidyl peptidase-4 inhibitor has been proposed as a synergistic approach to intensify glycemic control in patients with T2DM. studies have suggested that early combination therapy rather than sequential escalation yields superior glycemic control. Nevertheless, long-term benefits, cost-effectiveness, and patient selection for this triple combination remain uncertain.

Aim

To evaluate the efficacy and safety of triple combination therapy (compared to dual therapy in patients with T2DM

Methods

Study Design

Study Selection Criteria

• Randomized controlled trials (RCTs) comparing triple vs. dual antidiabetic therapy in adults with T2DM were included in the systematic review and meta-analysis. 
• The triple therapy comprised of: SGLT-2 inhibitors (e.g., dapagliflozin, empagliflozin, ertugliflozin, or ipragliflozin), DPP-4 inhibitors (e.g., saxagliptin, sitagliptin, or linagliptin), and metformin. Dual therapy comprised of SGLT-2 inhibitor or DPP-4 inhibitors with metformin.

Outcomes

• Changes in glycosylated hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), body weight
• Likelihood of achieving an HbA1c target < 7%
• Incidence of adverse events (AEs). 
• Random-effects models were used to calculate pooled standardized mean differences (SMDs) and risk ratios (RRs).

Results

• The meta-analysis included 9 RCTs with 2,606 participants, comparing SGLT-2 inhibitor + DPP-4 inhibitor + metformin therapy (n=1,307) vs. control groups (placebo or metformin-based regimens; n=1,099).
• The mean age of the study population ranged from 42.8-to-59.2 years. The body mass index (BMI) was comparable between the study groups and ranged from 23.3-to-32.5 kg/m². 
• Intervention regimens combined various SGLT-2 inhibitors (dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin) with DPP-4 inhibitors (saxagliptin, sitagliptin, linagliptin) and metformin. Diabetes duration varied across studies, with some reporting over 7 years duration.
• Patients treated with the triple combination had a significantly greater improvement in HbA1c, as compared to those treated with the dual combination (SMD: −1.40, 95% CI: −1.82 to −0.99; P < 0.00001), demonstrating superior glycemic control in T2DM.
• As per a sub-group analysis, dapagliflozin + sitagliptin + metformin showed the greatest HbA1c reduction (SMD: −2.46; P = 0.0003).), followed by ertugliflozin + sitagliptin +metformin (−1.60; P < 0.00001) and ipragliflozin+ sitagliptin + metformin (−1.22; P < 0.00001), highlighting the effectiveness of SGLT-2/DPP-4 inhibitor combinations.
• The combination of empagliflozin + linagliptin + metformin also reduced HbA1c significantly (SMD: −0.82 for 10 mg and −0.71 for 25 mg), although the effect was less pronounced than that seen with dapagliflozin- or ertugliflozin-based combinations.
• Overall, a triple therapy (SGLT-2 inhibitor + DPP-4 inhibitor + metformin) achieved significantly greater HbA1c reduction than dual therapy (SMD: −0.54, 95% CI: −0.92 to −0.16; P = 0.005), supporting its superiority for glycemic control in T2DM.
• The greatest benefit was observed with ertugliflozin 15 mg + sitagliptin + metformin (SMD: −1.50, P < 0.00001), while ipragliflozin- and dapagliflozin-based combinations showed no significant advantage over comparator regimens in individual studies.
• At 16 to 26 weeks, combination therapy with SGLT-2 inhibitors, DPP-4 inhibitors, and metformin significantly reduced FPG compared with control treatment (overall SMD: −0.81, 95% CI −0.91 to −0.71; P < 0.00001). As per a subgroup analysis, significant reductions were observed with ipragliflozin 50 mg + metformin + sitagliptin (SMD: −0.71; P < 0.0001), ertugliflozin 5 mg + metformin + sitagliptin (SMD: −0.81; P < 0.00001), and ertugliflozin 15 mg + metformin + sitagliptin (SMD: −1.00; P < 0.00001), with the greatest FPG reduction seen with ertugliflozin 15 mg, suggesting a dose-dependent benefit.
• As per the findings from one of the studies, dapagliflozin + metformin + sitagliptin produced a marked reduction in FPG (SMD: −0.97; P < 0.00001). On similar lines, empagliflozin combinations also significantly improved FPG, with 10 mg achieving an SMD of −0.69 and 25 mg an SMD of −0.86 (both P < 0.00001). While effective, the FPG-lowering effect of empagliflozin was generally less pronounced than that observed with dapagliflozin- or ertugliflozin-based combinations.
• On comparing the FPG in the control and the triple therapy groups, the triple therapy showed a trend toward lower FPG, vs. the controls, but the overall effect did not reach statistical significance (SMD: −0.30; 95% CI: −0.62 to 0.01; P = 0.06). Subgroup analyses showed a minimal, non-significant effect with ipragliflozin 50 mg + metformin + sitagliptin (SMD: 0.20; P = .24, probably due to data availability from just one study), while ertugliflozin 5 mg + metformin + sitagliptin produced a small but significant improvement (SMD: 0.28; P = 0.002). The greatest benefit was observed with ertugliflozin 15 mg + metformin + sitagliptin (SMD: −0.32; P = 0.0005), suggesting a dose-dependent effect on FPG control.
• Studies with Empagliflozin + metformin + linagliptin, showed significant reduction in FPG, with 10 mg showing an SMD of −0.47 (P = 0.0007) and 25 mg an SMD of −0.62 (P < 0.00001), indicating greater efficacy with the higher dose. In contrast, two studies showed that dapagliflozin + metformin + saxagliptin had a moderate but non-significant reduction in FPG (SMD: −0.70; P =0 .08), suggesting less robust evidence of benefit compared with the empagliflozin-based combination.
• With regards to change in pre- and post-intervention body weight change, at 16 to 26 weeks, combination therapy with SGLT-2 inhibitors, DPP-4 inhibitors, and metformin resulted in a modest but significant reduction in body weight (SMD: −0.14; 95% CI: −0.22 to −0.07; P = 0.0002). Among individual regimens, ertugliflozin 15 mg + metformin + sitagliptin showed a significant weight reduction (SMD: −0.20; P = 0.03), whereas ipragliflozin 50 mg + metformin + sitagliptin (SMD: −0.21; P = 0.20) and ertugliflozin 5 mg + metformin + sitagliptin (SMD: −0.17; P = 0.06) demonstrated small, non-significant decreases. These findings suggest a modest weight-loss benefit, with higher-dose ertugliflozin providing the most consistent effect.
• As per a further analysis, dapagliflozin + metformin + saxagliptin showed a small, non-significant reduction in body weight (SMD: −0.11; P = 0.08), while dapagliflozin + metformin + sitagliptin demonstrated a minimal, non-significant effect (SMD: −0.06; P = 0.60). Similarly, empagliflozin + metformin + linagliptin produced only modest, non-significant weight reductions at both 10 mg (SMD: −0.15; P = 0.28) and 25 mg (SMD: −0.13; P = 0.33). Overall, these combination therapies were associated with only minor changes in body weight, with no statistically significant benefit in the individual studies.
• A comparison between intervention (triple therapy) and control groups revealed that the intervention had a trend toward greater weight loss, although the overall effect was not statistically significant (SMD: −0.53; 95% CI: −1.13 to 0.07; P = 0.08). As per subgroup analysis, significant reductions in body weight were observed with ipragliflozin 50 mg + metformin + sitagliptin (SMD: −0.37; P = 0.03), ertugliflozin 5 mg + metformin + sitagliptin (SMD: −1.10; P < 0.00001), and especially ertugliflozin 15 mg + metformin + sitagliptin (SMD: −2.10; P < 0.00001). These findings suggest a dose-dependent weight-loss effect with ertugliflozin, with the 15 mg dose providing the greatest reduction in body weight.
• Two studies demonstrated that dapagliflozin + metformin + saxagliptin was associated with a significant reduction in body weight (SMD: −0.27; P = 0.009), indicating a meaningful weight-loss benefit. In contrast, empagliflozin + metformin + linagliptin showed a less consistent effect, with the 10 mg dose demonstrating a borderline reduction (SMD: 0.27; P = 0.05) and the 25 mg dose showing no significant difference (SMD: 0.10; P = 0.47). Overall, dapagliflozin-based therapy appeared more effective for weight reduction than empagliflozin-based combinations.
• Analysis of five studies revealed that triple therapy with SGLT-2 inhibitors + DPP-4 inhibitors + metformin significantly increased the likelihood of achieving HbA1c <7% compared with control treatment (RR: 2.02; 95% CI: 1.55-2.63; P < 0.0001). Overall, patients receiving triple therapy were about twice as likely to reach the HbA1c target, highlighting its superior efficacy for glycemic control in T2DM.
• Across 8 studies, the incidence of total AEs was similar between the triple therapy and control groups (RR 0.97; 95% CI 0.85-1.11; P = 0.69), with no statistically significant difference observed.
• Analysis from five studies suggested that triple therapy (SGLT-2 inhibitor + DPP-4 inhibitor + metformin) did not significantly increase the risk of severe treatment-related AEs compared with control treatment. While a slight numerical increase was observed (RR 1.16), the evidence did not support a clinically meaningful difference in severe AE risk, indicating an overall acceptable safety profile.
• Across 8 studies, the incidence of hypoglycemia did not differ significantly between the triple therapy and control groups (RR 1.32; 95% CI 0.76-2.30; P = 0.32). Although the point estimate suggested a 32% higher relative risk of hypoglycemic events with triple therapy, the confidence interval crossed 1.0 and the result was not statistically significant.
• Across 7 studies, the risk of urinary tract infections (UTIs) was comparable between the triple therapy and control groups (RR 1.09; 95% CI 0.70-1.70; P = 0.69). The 9% higher relative risk was not statistically significant, indicating that triple therapy does not meaningfully increase UTI risk in patients with T2DM.
• Across 4 studies, patients receiving triple therapy were significantly more likely to discontinue treatment due to adverse events compared with controls (RR 2.62; 95% CI 1.09-6.30; P = 0.03).
• Treatment discontinuation due to AEs was significantly higher (RR 2.62; 95% CI 1.09-6.30; P=0.03), emphasizing the need for monitoring tolerability and adherence.

Conclusions

• Triple oral therapy combining metformin, an SGLT-2 inhibitor, and a DPP-4 inhibitor provided superior glycemic control compared with dual therapy, significantly improving HbA1c reduction and increasing the likelihood of achieving HbA1c <7%. 
• It also offered modest benefits in reducing body weight and fasting plasma glucose. Overall, safety of the triple therapy was comparable to dual therapy, with no significant increase in AEs, hypoglycemia, or UTIs; however, a higher rate of treatment discontinuation due to AEs may affect long-term adherence. 
• These findings support triple therapy as an effective and generally well-tolerated treatment intensification option for patients with T2DM.

Medicine 2026;105:22(e49050).