Adding Fourth Oral Drug Beats Metformin Dose Escalation in Uncontrolled Type 2 Diabetes: EFFORT Trial
South Korea: A new multicenter clinical trial published in Diabetes, Obesity & Metabolism suggests that intensifying treatment with a fourth oral antidiabetic agent may provide superior glycaemic control compared with simply increasing the dose of metformin in patients with type 2 diabetes inadequately controlled on triple oral therapy. The study, titled the EFFORT trial, was led by Dr. So Ra Kim from the Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea, along with colleagues.
Many patients with type 2 diabetes fail to achieve recommended glycaemic targets despite being treated with a combination of three oral medications. In such cases, clinicians often face the choice of either escalating the metformin dose or adding another class of glucose-lowering drug. However, comparative data to guide this decision have been limited.
To address this, researchers conducted a 24-week, randomized, open-label trial involving adults with glycated haemoglobin (HbA1C) levels between 7.0% and 9.0% despite receiving triple oral therapy consisting of metformin plus one of the following: a thiazolidinedione (TZD), a sodium–glucose cotransporter 2 inhibitor (SGLT2i), or a dipeptidyl peptidase 4 inhibitor (DPP-4i).
Participants were assigned either to receive an additional oral agent from a class not previously used (quadruple therapy group) or to increase their metformin dose by up to 500 mg daily (metformin uptitration group).
The key findings were as follows:
- A total of 193 participants were analyzed, including 145 in the quadruple therapy group and 48 in the metformin dose-escalation group.
- At 24 weeks, HbA1C reduction was significantly greater with quadruple therapy compared to metformin uptitration.
- Median HbA1C decreased by 0.70% in the quadruple group versus 0.40% in the metformin escalation group.
- A higher proportion of patients in the quadruple therapy group achieved HbA1C ≤7.0% (69.7% vs. 47.9%).
- Improvements in insulin resistance were observed only in the quadruple therapy group.
- Albuminuria was reduced in the quadruple therapy group, indicating potential renal and cardiometabolic benefits.
- Adverse events were mild and comparable between both treatment strategies, with no significant safety differences observed.
The investigators concluded that adding a fourth oral agent provided more robust improvements in glucose control and metabolic parameters without increasing safety risks, compared with simply raising the metformin dose. These findings support oral quadruple therapy as a viable and effective intensification strategy for patients with type 2 diabetes who remain inadequately controlled on triple oral regimens.
Reference:
Kim SR, Hong JH, Kim SG, Kim SK, Kwon HS, Moon JS, Park JH, Yu JM, Cha BS, Lee BW. Efficacy and safety of adding a fourth oral antidiabetic drug versus metformin dose escalation in patients with type 2 diabetes inadequately controlled on triple oral combination therapy (EFFORT): A 24-week, randomized, open-label, multicenter trial. Diabetes Obes Metab. 2026 Feb 3. doi: 10.1111/dom.70527. Epub ahead of print. PMID: 41630635.
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