Diabetes Metab J > Volume 46(1); 2022 > Article
Moon, Suh, Kim, and Jin: Efficacy and Safety of Treatment with Quadruple Oral Hypoglycemic Agents in Uncontrolled Type 2 Diabetes Mellitus: A Multi-Center, Retrospective, Observational Study (Diabetes Metab J 2021;45:675-83)
We are grateful for the opportunity to respond to Professor Tae Jung Oh’s letter concerning our recent article, “Efficacy and safety of treatment with quadruple oral hypoglycemic agents in uncontrolled type 2 diabetes mellitus: a multi-center, retrospective, observational study” [1]. We would also like to thank Professor Oh for their valuable comments on our article.
We fully agree with the limitations of this study raised by Professor Oh. Our study demonstrated a meaningful glucose lowering effect of 1.1% after the introduction of a quadruple combination. However, the relatively good effect was likely influenced by the high glycosylated hemoglobin (HbA1c) level at baseline. In our study, the proportion of people with HbA1c <7% increased significantly to 25% after treatment with the quadruple combination for 1 year (from 2% at baseline). Thus, three out of four patients failed to reach the target of less than 7% and still had poor blood sugar control. Meanwhile, the glycemic-lowering effect of this quadruple therapy was similar (1.0% to 1.5% in HbA1c) in other observational studies [2-4].
In addition, it is reasonable to assume that reports of side effects including hypoglycemia may have been underestimated due to the retrospective nature of this study. Sulfonylurea accounted for a significant portion of the composition of triple therapy at baseline, but most oral hypoglycemic agents (OHAs) newly added to the quadruple combination were sodium-glucose co-transporter 2 inhibitors, thiazolidinediones or alpha glucosidase inhibitors, which rarely cause hypoglycemia. When dapagliflozin was introduced as the fourth drug in people with poor glycemic control, hypoglycemic events were significantly lower than seen with insulin glargine (1.6% vs. 15.1%) [5].
Although our study was not designed study for comparison with insulin or placebo treatment in triple OHA failure, it reveals the natural course and current status of quadruple OHA therapy in real clinical practice. Most of the current guidelines recommend injection therapy after triple combination; OHA add-on to the triple combination is not covered by health insurance. However, physicians are considering quadruple combination as another option in clinical practice, as noted in our study. When glycemic control is poor on two or more OHAs, treatment intensification, including insulin injection, is often delayed. The higher the number of OHAs used, the slower treatment intensification tends to be [6]. The initiation of insulin was reported to be delayed in Korean patients with type 2 diabetes mellitus uncontrolled by two or more OHAs due to various patient- and physician-related factors [7]. Nevertheless, physicians should not delay the proper use of injection therapy including insulin due to quadruple OHA therapy.



No potential conflict of interest relevant to this article was reported.


1. Moon JS, Suh S, Kim SS, Jin HY, Kim JM, Jang MH, et al. Efficacy and safety of treatment with quadruple oral hypoglycemic agents in uncontrolled type 2 diabetes mellitus: a multi-center, retrospective, observational study. Diabetes Metab J 2021;45:675-83.
2. Cho YK, Lee J, Kim HS, Park JY, Jung CH, Lee WJ. Clinical efficacy of quadruple oral therapy for type 2 diabetes in real-world practice: a retrospective observational study. Diabetes Ther 2020;11:2029-39.
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3. Ku EJ, Lee DH, Jeon HJ, Oh TK. Empagliflozin versus dapagliflozin in patients with type 2 diabetes inadequately controlled with metformin, glimepiride and dipeptidyl peptide 4 inhibitors: a 52-week prospective observational study. Diabetes Res Clin Pract 2019;151:65-73.
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4. Ku EJ, Lee DH, Jeon HJ, Oh TK. Effectiveness and safety of empagliflozin-based quadruple therapy compared with insulin glargine-based therapy in patients with inadequately controlled type 2 diabetes: an observational study in clinical practice. Diabetes Obes Metab 2019;21:173-7.
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5. Jeon HJ, Ku EJ, Oh TK. Dapagliflozin improves blood glucose in diabetes on triple oral hypoglycemic agents having inadequate glucose control. Diabetes Res Clin Pract 2018;142:188-94.
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6. Fu AZ, Sheehan JJ. Treatment intensification for patients with type 2 diabetes and poor glycaemic control. Diabetes Obes Metab 2016;18:892-8.
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7. Kim SG, Kim NH, Ku BJ, Shon HS, Kim DM, Park TS, et al. Delay of insulin initiation in patients with type 2 diabetes mellitus inadequately controlled with oral hypoglycemic agents (analysis of patient- and physician-related factors): a prospective observational DIPP-FACTOR study in Korea. J Diabetes Investig 2017;8:346-53.
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