Empagliflozin, Pioglitazone or Glimepiride as Third Agents with Metformin + DPP‑4 Inhibitor: Similar HbA1c Drops but Different Trade‑offs

Highlights

– In a multicentre, open‑label, phase 4 randomized trial, adding empagliflozin (10 mg), pioglitazone (15 mg) or glimepiride (2 mg) to metformin plus a DPP‑4 inhibitor produced similar mean HbA1c reductions at 24 weeks (≈0.8–0.9%).

– Glycaemic target attainment (HbA1c <7.0%) was similar across arms (57–66%).

– Empagliflozin led to modest weight loss (≈1.7 kg), whereas pioglitazone and glimepiride produced small weight gains (≈1.1 kg); hypoglycaemia events were observed only with glimepiride.

Background

Type 2 diabetes (T2D) is progressive, commonly requiring sequential escalation from metformin to combination therapies to maintain glycaemic control and reduce the risk of micro‑ and macrovascular complications. Contemporary guidance emphasizes individualization when selecting add‑on agents, taking into account efficacy, weight effects, hypoglycaemia risk, comorbid cardiovascular or renal disease, tolerability, cost and patient preference (e.g., ADA Standards of Care).

When patients are already treated with metformin and a DPP‑4 inhibitor and remain above glycaemic targets, clinicians commonly consider adding an agent from several classes, including sodium‑glucose co‑transporter‑2 (SGLT2) inhibitors, thiazolidinediones (TZDs), or sulfonylureas. Evidence comparing these options directly—particularly in the setting of background DPP‑4 inhibition—is limited, yet clinically important for shared decision‑making.

Study design

The trial by Cho et al. (Diabetes Obes Metab. 2025) is a multicentre, prospective, randomized, open‑label, parallel‑group phase 4 study enrolling adults with T2D inadequately controlled on metformin (≥1,000 mg/day) plus a DPP‑4 inhibitor. Participants were randomized to one of three third‑line additions for 24 weeks: empagliflozin 10 mg/day (n = 61), pioglitazone 15 mg/day (n = 58) or glimepiride 2 mg/day (n = 57). The primary endpoint was change in glycated haemoglobin (HbA1c) at 24 weeks. Secondary assessments included proportion achieving HbA1c <7.0%, changes in body weight, and safety outcomes including hypoglycaemia and adverse events.

Key findings

Population

Mean patient age was 58.5 ± 10.0 years with mean baseline HbA1c 7.8 ± 0.7% and mean diabetes duration 8.1 ± 5.6 years—representing a typical ambulatory T2D population with modest hyperglycaemia despite dual oral therapy.

Glycaemic efficacy (primary outcome)

All three add‑on strategies produced clinically meaningful and statistically significant reductions in HbA1c from baseline at 24 weeks, with no statistically significant difference between treatments:

Empagliflozin: mean HbA1c change −0.78 ± 0.09%
Pioglitazone: mean HbA1c change −0.89 ± 0.09%
Glimepiride: mean HbA1c change −0.93 ± 0.12%

These modest reductions (≈0.8–0.9%) are consistent with the expected incremental efficacy of these classes when added to two oral agents in patients with baseline HbA1c <8–9%.

Glycaemic target attainment

The proportion achieving HbA1c <7.0% at 24 weeks was similar across arms: 65.6% (empagliflozin), 56.9% (pioglitazone), and 63.2% (glimepiride). Differences were small and not reported as statistically significant.

Weight and metabolic effects

Body weight diverged across groups in predictable directions:

Empagliflozin: mean weight change −1.73 ± 3.14 kg (statistically significant weight loss).
Pioglitazone: mean weight change +1.11 ± 3.97 kg.
Glimepiride: mean weight change +1.11 ± 4.07 kg.

The weight loss with empagliflozin reflects its glucosuric mechanism; the weight gain with pioglitazone (a PPAR‑gamma agonist) and glimepiride (insulin secretagogue) is also consistent with known class effects.

Safety

Hypoglycaemia: Four hypoglycaemic episodes were reported in the glimepiride group (6.56% of that arm); none were reported in the empagliflozin or pioglitazone arms. This aligns with known higher hypoglycaemia risk for sulfonylureas compared with SGLT2 inhibitors or TZDs when combined with agents that do not cause hypoglycaemia.

Other adverse events: The summary provided does not detail rates of genital infections, urinary tract infections, fluid retention, peripheral oedema, heart failure, fractures, or changes in renal function—events of particular interest for SGLT2 inhibitors and TZDs. The original article should be consulted for a complete safety table and adjudicated event rates.

Interpretation and clinical implications

This randomized comparison shows broadly similar short‑term glycaemic efficacy for empagliflozin, pioglitazone and low‑dose glimepiride when added to metformin plus a DPP‑4 inhibitor in patients with modest baseline hyperglycaemia. However, important differences in weight and hypoglycaemia risk emerged.

Clinical decision‑making should therefore emphasize the following considerations:

Comorbidity profile: If the patient has established atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease, SGLT2 inhibitors (including empagliflozin) carry evidence for cardiorenal benefits beyond glycaemic control (e.g., EMPA‑REG OUTCOME demonstrated reduced cardiovascular mortality and heart failure hospitalization). Thus, empagliflozin would often be preferred in such patients.
Weight objectives: For patients prioritizing weight loss or avoidance of weight gain, empagliflozin offers an advantage. Pioglitazone and sulfonylureas tend to increase weight.
Hypoglycaemia risk and frailty: Sulfonylureas increase hypoglycaemia risk, which is particularly relevant for older adults, those with renal impairment, or those with limited support; in such patients, empagliflozin or pioglitazone may be safer choices with respect to hypoglycaemia.
Contraindications and adverse‑effect preferences: Pioglitazone may be useful for insulin resistance and has possible benefits for NAFLD/NASH in some studies but carries risks of fluid retention, weight gain, and possibly fracture risk and bladder cancer signals in older datasets; it should be avoided in patients with active heart failure. Empagliflozin has class‑specific adverse effects (genital mycotic infections, euglycaemic ketoacidosis in rare settings, and volume depletion) that must be considered.
Intensity and titration: The study used relatively low doses of pioglitazone (15 mg) and glimepiride (2 mg). In routine practice, these agents are often titrated upward, which could increase both efficacy and adverse events. Empagliflozin at 10 mg is a common starting dose with known cardiorenal data at 10 mg and 25 mg.

Expert commentary: strengths and limitations

Strengths:

Randomized, multicentre design provides head‑to‑head comparative data in a clinically relevant scenario (third agent after metformin + DPP‑4 inhibitor).
Population reflects real‑world patients with moderate hyperglycaemia and established oral therapy.

Limitations:

Open‑label design: Knowledge of assigned treatment can influence reporting of subjective adverse events and adherence.
Sample size and duration: With ~176 participants and 24 weeks follow‑up, the study was adequately powered for moderate HbA1c differences but underpowered for infrequent safety outcomes and cannot address long‑term cardiorenal outcomes.
Dose selection: Low doses of pioglitazone (15 mg) and glimepiride (2 mg) limit extrapolation to higher‑dose use; titration strategies commonly used in practice may yield different efficacy and safety profiles.
Incomplete safety details in the summary: Incidence of SGLT2‑class adverse events (genital/urinary infections), pioglitazone‑related oedema or fracture risk, and renal function trajectories were not described in the summary available here; readers should consult the full article for detailed safety tables.
Generalisability: The study population characteristics (ethnicity, comorbidity burden, renal function distribution) will determine applicability to local practice; these details should be reviewed in the full text.

Biological plausibility and mechanisms

The observed class‑specific effects align with known mechanisms: empagliflozin reduces plasma glucose by promoting urinary glucose excretion (leading to caloric loss and modest weight reduction); pioglitazone improves insulin sensitivity through PPAR‑gamma activation (often causing fluid retention and weight gain); glimepiride augments insulin secretion and therefore frequently causes weight gain and hypoglycaemia. Combining these agents with DPP‑4 inhibitors—which increase endogenous incretin activity and are weight‑neutral with low hypoglycaemia risk—produces additive glycaemic effects driven by complementary mechanisms.

Practical takeaways

When intensifying therapy for patients already on metformin plus a DPP‑4 inhibitor, empagliflozin, pioglitazone and glimepiride produce similar short‑term HbA1c reductions. Choice should therefore be guided by comorbidities, weight goals, hypoglycaemia risk and patient preferences.
Empagliflozin offers weight benefit and potential cardiorenal advantages (important in patients at high CV/renal risk), whereas pioglitazone may benefit patients with marked insulin resistance or certain hepatic steatosis phenotypes but should be avoided in heart failure. Glimepiride remains an effective, low‑cost option but increases hypoglycaemia and weight risk.
Longer‑term outcomes, particularly cardiovascular and renal effects, were not addressed by this 24‑week trial; use of agents with proven cardiorenal benefit should take precedence in patients with those comorbidities per guideline recommendations.

Conclusion

Cho et al. provide useful randomized evidence that adding empagliflozin, pioglitazone or glimepiride to metformin plus a DPP‑4 inhibitor yields comparable HbA1c reductions at 24 weeks, but with divergent effects on weight and hypoglycaemia. These differences—together with comorbidity profiles and long‑term outcome data for specific agents—support individualized third‑line therapy selection rather than a one‑size‑fits‑all approach.

Funding and trial registration

Funding sources and trial registration details were not included in the summary provided here. Readers should consult the original publication for full declarations of funding, conflicts of interest and registry identifiers (Cho YK et al., Diabetes Obes Metab. 2025).

References

1. Cho YK, Cho JH, Hong SM, Park JH, Lee BW, Yoo JH, Kim JH, Chun SW, Hwang YC, Song KH, Lee WJ. Efficacy and safety of pioglitazone, empagliflozin and glimepiride as third‑line agents in patients with type 2 diabetes inadequately controlled with metformin and DPP‑4 inhibitors: A multicentre, phase 4 randomized controlled trial. Diabetes Obes Metab. 2025 Nov;27(11):6375-6385. doi: 10.1111/dom.70030. Epub 2025 Aug 14. PMID: 40808546; PMCID: PMC12515792.

2. Zinman B, Wanner C, Lachin JM, et al.; EMPA‑REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–2128.

3. American Diabetes Association. Standards of Medical Care in Diabetes—2024. Diabetes Care. 2024;47(Suppl 1):S1–S(…). (Refer to current ADA guidance for individualized therapy and cardiorenal considerations.)