However, in clinical practice, a stepwise approach to diabetes treatment often leads to clinical inertia [4], where delays in intensifying therapy occur despite suboptimal blood glucose control. This can result in prolonged periods of poor glycemic control, increasing the risk of complications. Early combination therapy, which involves using multiple medications from the start, could be more effective for achieving and maintaining glycemic targets, thereby reducing the risk of complications. The Vildagliptin Efficacy in combination with metfoRmIn For earlY treatment of type 2 diabetes (VERIFY) trial is a notable study that demonstrated the effectiveness of early combination therapy for managing diabetes [5]. This trial provided evidence that starting treatment with a combination of medications early in the disease course leads to better long-term glycemic control compared to initial metformin monotherapy for patients with newly-diagnosed type 2 diabetes mellitus (T2DM). The results indicate the importance of considering early combination therapy for optimal diabetes management.

In addition to initial combination therapy, several recent studies have explored the efficacy and safety of initial triple combination therapy for diabetes management [6-8]. In this article, entitled “Two-year therapeutic efficacy and safety of initial triple combination of metformin, sitagliptin, and empagliflozin in drug-naïve type 2 diabetes mellitus patients,” Park et al. [6] investigated the effectiveness and safety of an initial triple therapy regimen for managing T2DM in drug-naïve patients. They demonstrated that initial triple therapy with metformin, sitagliptin, and empagliflozin significantly reduced glycosylated hemoglobin (HbA1c) levels and improved metabolic function and albuminuria over 24 months in drug-naïve T2DM patients, achieving and maintaining glycemic targets without severe hypoglycemia or serious adverse events. This study was well-structured, following a prospective, observational approach that spanned 2 years. The inclusion criteria were clear, focusing on drug-naïve patients with newly-diagnosed T2DM, which ensured a specific and relevant patient population. This study revealed significant improvement in glycemic control, with a substantial reduction in HbA1c levels from 11.0%±1.8% at baseline to 7.0%±1.7% at 24 months. The rates of achieving target HbA1c levels (<7.0%) were impressive, with 72.5% at 12 months and 61.7% at 24 months. This highlights the potential of initial triple therapy to achieve and maintain glycemic targets more effectively than traditional stepwise approaches. It is intriguing that both insulin sensitivity and β-cell function improved with initial triple therapy, as well as metabolic profiles and albuminuria. Remarkably, the improvement in insulin sensitivity and β-cell function appeared early in the study period (2 months) and was sustained during follow-up (24 months). Furthermore, the study reported a favorable safety profile for triple therapy.

However, it should be noted that for patients whose blood glucose levels are not controlled and who exhibit hyperglycemic symptoms such as weight loss, polydipsia, and polyuria, insulin therapy should be considered a priority [9]. Although the authors stated that patients with symptoms of hyperglycemia were excluded from the study, the average HbA1c level of the study participants at the start was 11.0%. They also mentioned that temporary increases in blood glucose levels during the study were managed with insulin therapy for safety reasons, but they did not report how many patients received insulin treatment. Considering that 48.2% of patients were hospitalized at the beginning of the study, it is possible that short-term insulin therapy or strict dietary control was also implemented. Additionally, it should be confirmed that insulin secretion ability has not significantly declined before considering triple oral therapy. Furthermore, as the authors also noted, while the study demonstrates the effectiveness of triple therapy, it lacks a comparative arm with traditional sequential therapy or other combination therapies. Including a control group with a different treatment regimen would have provided more context for evaluating the relative efficacy and safety of triple combination therapy. Potential bias in subgroup analysis cannot be excluded. The decision to adjust medication regimens after 12 months based on physician judgment introduces potential bias. Subgroup analysis, which compared patients who continued triple therapy with those who reduced to two medications, may also reflect inherent biases related to the physicians’ discretion rather than the efficacy of the treatment protocols. More standardized criteria for these adjustments would have strengthened the study’s conclusions. Lastly, one major limitation is the study’s generalizability. The patient cohort consists exclusively of Korean patients from a single hospital, which may not represent the broader global population with T2DM. Ethnic and genetic differences can influence drug efficacy and safety, and thus the findings may not be directly applicable to other populations without further validation.

I hope that further large prospective studies will reveal the efficacy and safety of initial triple combination therapy, comparing various regimes as well as using a stepwise approach in multiple ethnic groups, which would confirm these findings and broaden their applicability.