Professor Hong Chen: From “Glycemic Control” to “Global Control”—Redefining the Value of DPP-4 Inhibitors in the Management of Type 2 Diabetes mellitus

Against the backdrop of a steadily rising prevalence of diabetes in China and mounting pressure on prevention and control, the question of how to move beyond mere glycemic lowering toward more comprehensive glucose management and outcome optimization has become a central clinical concern. In this issue, we have specially invited Professor Hong Chen from Zhujiang Hospital of Southern Medical University to provide an in-depth analysis of the current landscape of type 2 diabetes (T2DM) prevention and treatment, as well as emerging therapeutic strategies. From the evolving multi-drug landscape and patient-centered integrated management approaches to the unique safety and applicability advantages of dipeptidyl peptidase-4 inhibitors (DPP-4i), Professor Chen dissects each aspect systematically and presents the evidence in a clear, accessible manner. In addition, drawing on key research data for the domestically developed, next-generation, highly selective DPP-4i sengliptin, he comprehensively outlines its performance and potential value in both monotherapy and combination therapy. Together, let us explore the broader possibilities and identify the optimal pathways for achieving effective glucose management.

International Diabetes

The current situation regarding the prevention and management of diabetes in China remains challenging. Against the backdrop of an increasingly diverse array of glucose-lowering medications, how do you view the clinical value and positioning of DPP-4 inhibitors?

Professor Chen Hong: According to the latest epidemiological survey data from the Chinese Center for Disease Control and Prevention, the number of people with diabetes in China reached 233 million in 2023. Compared with 2005, the age-standardized prevalence (ASR) has risen from 7.53% to 13.7%, approaching 14% [1]. In other words, approximately one in every seven individuals is living with diabetes. This clearly indicates that the overall prevalence of diabetes in China remains at a high level and has not yet been effectively curbed. Moreover, although awareness (36.7%), treatment (32.9%), and glycemic control (50.1%) rates have all improved in recent years, their overall levels remain relatively low [2], underscoring the continued severity of the prevention and control situation.

The continuous emergence of new antidiabetic agents has brought about a profound transformation in the landscape of diabetes care. Current treatment strategies are increasingly diversified, moving beyond the sole objective of glycemic control to encompass comprehensive goals such as blood glucose management, weight management, and the multifaceted intervention of multiple risk factors. Moreover, the therapeutic paradigm for type 2 diabetes mellitus is placing greater emphasis on a dual approach that integrates “root-cause management” with “outcome improvement”: on the one hand, pharmacologic interventions aim to achieve weight control and reduce visceral fat, thereby addressing the underlying metabolic derangements; on the other hand, attention is focused on improving outcomes for vital organs such as the heart and kidneys, with the goal of reducing the risk of long-term complications. On this basis, glycemic control is viewed as a process-oriented management tool that is integrated with overall risk reduction and prognosis enhancement, ultimately enabling comprehensive, end-to-end management of diabetes.

Against this backdrop, DPP-4 inhibitors (DPP-4i) stand out as an important and well-established class of antidiabetic agents. They are administered orally, are convenient to use—often once daily—and demonstrate robust glycemic control with an excellent safety profile and a neutral impact on body weight, thereby effectively mitigating the risks of hypoglycemia and weight gain associated with certain conventional agents, such as sulfonylureas and insulin. Overall, DPP-4i strike a favorable balance between efficacy and safety, maintaining a prominent position within the current therapeutic landscape for diabetes. They can be used alongside metformin, glucagon-like peptide-1 receptor agonists (GLP-1RAs), and sodium-glucose co-transporter 2 inhibitors (SGLT2is) to form the mainstay of treatment options. In specific patient populations, particularly older adults with diabetes, DPP-4i are recommended as one of the first-line therapeutic choices, reflecting their broad applicability [3].

It is important to emphasize that the pathogenesis of diabetes is complex, and monotherapy often fails to achieve optimal glycemic control. Consequently, clinical management typically involves a combination of multiple agents tailored to each patient’s individual characteristics. In this context, DPP-4 inhibitors, with their outstanding safety profile and consistent efficacy, can play a pivotal role in combination therapy. Although new antihyperglycemic agents have been continuously introduced in recent years, under the patient-centered, comprehensive management paradigm, the coexistence of traditional and novel agents—each complementing the other’s strengths—will likely persist for the foreseeable future, and DPP-4 inhibitors will continue to deliver significant value in appropriate therapeutic settings.

International Diabetes

As a next-generation, highly selective DPP-4 inhibitor, saxagliptin monotherapy has demonstrated outstanding efficacy in patients with type 2 diabetes mellitus. From a clinical perspective and in light of relevant studies, could you please interpret its key findings?

Professor Chen Hong: Saxagliptin is a new-generation DPP-4 inhibitor independently developed in China, characterized by high selectivity and demonstrating superior efficacy and safety. The Phase III monotherapy study [4] was a standard, randomized, double-blind, multicenter, placebo-controlled clinical trial (RCT) that enrolled 504 patients with type 2 diabetes mellitus from more than 60 clinical research centers nationwide, aged 18 to 75 years (inclusive), who had either never used oral hypoglycemic agents or had discontinued such medications within the 8 weeks prior to screening. The primary endpoint was the change in glycated hemoglobin (HbA1c) from baseline at 24 weeks. Key secondary endpoints included the rates of achieving HbA1c targets of <7.0% and <6.5%, among others.

The study results are encouraging: after 24 weeks of monotherapy with saxagliptin in patients with T2DM, HbA1c decreased by 0.72% compared with placebo, a difference that is both statistically significant and clinically meaningful. It is important to note that this figure represents the absolute reduction in HbA1c achieved with saxagliptin, rather than a simple percentage change. In terms of treatment success rates, the proportions of patients achieving HbA1c <7% (the standard glycemic control target) and HbA1c <6.5% (the more stringent glycemic control target) were approximately 3.5-fold and more than 10-fold, respectively, those in the placebo group, resulting in about 45% of patients reaching the standard glycemic control target and about 19% reaching the more stringent target—both substantially higher than in the placebo group.

Subgroup analysis further demonstrated that patients with higher baseline HbA1c levels (>8.5%) experienced more pronounced glycemic reduction, with an average decrease of 1.39%, which represents a clinically very high intensity of glucose lowering and is consistent with the general principle in glucose-lowering therapy that “the higher the baseline, the greater the reduction.” In addition, stable and consistent reductions in HbA1c were observed across subgroups defined by duration of disease history (<1 year, 1–5 years, and >5 years), with shorter disease duration associated with more substantial reductions, suggesting that early initiation of treatment may confer particularly robust benefits.

It also demonstrates particularly robust improvements in the glycemic profile. As is well known, DPP-4 inhibitors offer a distinct advantage in postprandial glucose (PPG) control. The results show that saxagliptin reduces fasting plasma glucose (FPG) by 1.302 mmol/L and 2-hour postprandial glucose (2h-PPG) by approximately 2.996 mmol/L, indicating its efficacy in achieving comprehensive FPG and PPG control. Overall, saxagliptin monotherapy provides comprehensive and significant glycemic improvement in patients with type 2 diabetes mellitus, demonstrating consistent glucose-lowering effects across various baseline HbA1c levels and disease durations, thereby underscoring its high clinical value.

International Diabetes

Combination therapy is the standard of care in the management of T2DM. Could you please provide further insights into the clinical outcomes of saxagliptin combined with metformin, as well as any new findings regarding its multifaceted benefits?

Professor Chen Hong: In the Phase III clinical trial of saxagliptin, in addition to the monotherapy arm, a standard combination therapy with metformin was also evaluated. This study [5] was likewise a multicenter randomized controlled trial that enrolled a total of 446 patients with type 2 diabetes mellitus, with the objective of assessing the efficacy and safety of saxagliptin in combination with metformin in T2DM patients whose glycemic control was suboptimal on metformin monotherapy. The study design and primary endpoints were consistent with those of the monotherapy study.

The results showed that, among patients with inadequate glycemic control on metformin monotherapy, add-on treatment with saxagliptin for 24 weeks led to a further reduction in HbA1c of 1.23%, representing an additional 0.79% reduction compared with the placebo group, thereby demonstrating a remarkably potent glucose-lowering efficacy. In terms of achievement rates, the proportion of patients achieving HbA1c <7% was 51.1%, 3.5 times that of the placebo group; the proportion achieving HbA1c <6.5% was 24.2%, 5.5 times that of the placebo group—both of which are highly impressive outcomes.

Subgroup analyses were consistent with the monotherapy results, demonstrating a clear trend: the greater the baseline HbA1c, the greater the reduction. Patients with a baseline HbA1c <8.5% experienced a reduction of 0.98%, whereas those with a baseline HbA1c ≥8.5% achieved a reduction of up to 1.63%. Across all disease duration subgroups—<1 year, 1–5 years, and >5 years—patients exhibited significant reductions exceeding 1%, with the largest reduction reaching 1.43%. Combination therapy further underscored the robust efficacy of saxagliptin in relatively difficult-to-control populations, while also maintaining substantial glucose-lowering effects across the board: fasting plasma glucose decreased by 1.41 mmol/L, and 2-hour postprandial glucose decreased by 3.42 mmol/L.

In addition to glycemic control, the saxagliptin-based combination regimen provides additional benefits: it significantly improves pancreatic β-cell function (at 24 weeks, the 50 mg group showed a 14.1% improvement and the 100 mg group a 16.2% improvement, outperforming metformin monotherapy) and reduces systolic blood pressure. These findings suggest that this combination regimen offers comprehensive metabolic improvements beyond glycemic control, potentially slowing disease progression at its source.

In terms of safety, saxagliptin demonstrates a favorable safety profile in both monotherapy and combination therapy, with an adverse-event rate comparable to that of placebo. The incidence of common adverse events—such as upper respiratory tract infections, cough, and urinary tract infections—is low (<1%), and no hypoglycemic episodes were observed, underscoring the excellent safety characteristics of DPP-4 inhibitors [4–5]. Overall, this study supports the use of saxagliptin in combination with metformin for further glycemic control, while maintaining a favorable safety profile and delivering multiple metabolic benefits.

International Diabetes

As a new-generation, highly selective DPP-4 inhibitor independently developed in China, saxagliptin represents a breakthrough in domestically innovative pharmaceuticals. What are your prospects for its future clinical development and research directions?

Professor Chen Hong: As a Class 1 innovative drug independently developed in China, saxagliptin has undergone structural optimization targeting the DPP-4 enzyme, achieving high selectivity for this target and thereby demonstrating superior glycemic control and an excellent safety profile in clinical practice. The results of two Phase III studies have provided robust evidence to support these findings. Although clinicians’ real-world experience with its use is still accumulating, the available data clearly highlight the significant advantages conferred by its high selectivity, laying a solid foundation for its widespread future application.

From a clinical development perspective, future real-world studies should further evaluate the long-term efficacy and safety of DPP-4 inhibitors in elderly patients and other special populations with comorbid cardiovascular and renal diseases, thereby strengthening the evidence base for their use across broader patient groups. DPP-4 inhibitors hold significant clinical value in older adults with diabetes and are recommended as one of the first-line options in China’s relevant clinical guidelines, forming a core therapeutic framework alongside metformin and SGLT2 inhibitors [3]. Consequently, there remains considerable scope for further exploration and validation of the advantages of this class of drugs in specific patient populations.

At the level of therapeutic strategy, saxagliptin, owing to its favorable safety profile and pharmacokinetic characteristics, provides a robust foundation for combination therapy. Currently, diabetes treatment is gradually shifting from monotherapy toward multi-mechanism combination regimens, with the “2+2+4” approach—based on metformin combined with DPP-4 inhibitors and SGLT2 inhibitors—emerging as a common paradigm. Fixed-combination formulations are also continuously enhancing patient adherence and overall treatment outcomes. Against this backdrop, clinical studies evaluating saxagliptin in combination with metformin have already been initiated, and in the future, further expansion to combinations with SGLT2 inhibitors, or even triple-drug regimens, is anticipated, thereby establishing optimized treatment pathways that leverage multi-mechanism synergy.

Moreover, as China’s capacity for innovative drug R&D continues to strengthen, an increasing number of drugs with independent intellectual property rights are emerging, signaling a shift in the country’s position in this field from “catching up” to “running alongside” and even “taking the lead.” As a representative achievement of this trend, saxagliptin should also actively pursue international multi-center studies in the future, leveraging global evidence-based data to enhance its international recognition. At the same time, we look forward to continued policy support for domestically developed innovative medicines, enabling more clinically valuable, China-originated drugs to be deployed across broader clinical settings and ultimately benefiting a greater number of patients.