EffiCacy and safety of ANagliptin when added to iNsulin and metformin therapy in patients with uncontrolled type 2 diAbetes ; randomized, placebo‐controlled, double‐blind, multicentre trial ( CANNA study)

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Many patients with type 2 diabetes (T2DM) fail to achieve adequate glycaemic control using only oral agents and may require insulin therapy. However, basal or premixed insulin alone may not effectively control glycaemic spikes after meals, although it can significantly lower fasting glucose levels.1 Additionally, the introduction of premeal insulin to manage postprandial hyperglycaemia often increases the risk of hypoglycaemia due to insulin overdosing.1 Weight gain, potentially leading to increased insulin requirements, poses further challenges in adjusting and adhering to insulin therapy.2 Apart from metformin, Dipeptidyl peptidase-4 (DPP-4) inhibitors have demonstrated significant glucose-lowering effects.3 Anagliptin, a novel and selective DPP-4 inhibitor, enhances glycaemic control by boosting insulin secretion through incretin stimulation and reducing excessive glucagon secretion.4, 5 This study aims to assess the efficacy and safety of anagliptin when added to stable insulin therapy combined with metformin in patients with T2DM. This was a multicentre, randomized, double-blind, placebo-controlled, parallel-group, phase IV trial, conducted over a 24-week treatment period between December 2021 and December 2024 (CRIS No: KCT0004092). Patients selection (Figure S1) with inclusion and exclusion criteria were described in Table S1. Eligible patients continued their existing insulin and metformin regimen and underwent a one-week, single-blind, placebo run-in period. After this week, patients demonstrating adequate compliance (≥70% based on pill count) were randomized 1:1 to either anagliptin 100 mg twice daily or placebo for 24 weeks (Figure S2). Stratified randomization was based on HbA1c levels (<8.5% or ≥8.5%) using a computer-generated allocation schedule. The primary outcome was the change in HbA1c level from baseline to Week 24. Secondary outcomes included the change in HbA1c level from baseline to Week 12, the proportion of patients achieving an HbA1c <7% or <6.5% at Week 24, changes in fasting plasma glucose (FPG) level, average four-point self-monitoring of blood glucose levels, body weight, body mass index (BMI), and lipid parameters at Week 24 compared to baseline. Safety was assessed based on treatment-emergent adverse events (TEAEs), adverse drug reactions (ADRs), episodes of hypoglycaemia, vital signs, clinical laboratory parameters, and electrocardiographic findings. Details of the ethics and statistical methods are provided in the Data S1. A total of 57 patients (anagliptin: 28; placebo: 29) completed the 24-week treatment. The baseline characteristics were similar between the two groups (Table S2). The addition of anagliptin to ongoing stable-dose insulin and metformin therapy significantly reduced HbA1c by 0.6% from baseline at Week 24, compared with no change in the placebo group (Table 1). The LS mean ± SE change in HbA1c level at Week 24 from baseline for the anagliptin group was superior to that of the placebo group (−0.56 ± 0.23%, p = 0.009; Figure 1A). This significant reduction in HbA1c level was first observed at Week 12 and the improvement was sustained through Week 24 (Figure 1B). In participants with higher baseline HbA1c levels (≥8.5%), the reduction in HbA1c was significantly greater in the anagliptin group than in the placebo group, with a more pronounced difference (0.58% vs. 0.13%) than in those with lower baseline HbA1c levels (<8.5%). The proportion of participants achieving HbA1c levels <7.0% at Week 24 was higher in the anagliptin group compared to the placebo group (3.4% vs. 21.4%, p = 0.051, Figure S3A). However, the proportion of participants achieving HbA1c levels <6.5% at Week 24 did not reach statistical significance (Figure S3B). The reductions in FPG, mean four-point SMBG, and 2-hour postprandial glucose levels at Week 24 between the anagliptin and placebo groups were not statistically significant (Table 1). The mean daily insulin dose at Week 24 increased significantly in the placebo group, while it remained unchanged in the anagliptin group (Table 1). However, the mean difference in daily insulin dose change was significantly lower, and the proportion of patients with reduced insulin dose at Week 24 was significantly higher in the anagliptin group than in the placebo group (Table S3). HbA1c reduction was more pronounced in the anagliptin group compared to the placebo group (LS mean: −0.80%, p = 0.040) in patients using basal insulin. However, there was no significant difference in HbA1c reduction between the two groups among patients using premeal insulin (Data not shown). Additionally, there were no significant differences in body weight, BMI, or lipid profiles at 24 weeks between the anagliptin and placebo groups (Table 1). The incidences of TEAEs and ADRs were similar between the groups (Table S4). Details of safety outcomes are provided in the Data S1. This study assessed the efficacy and safety of anagliptin in patients with T2DM who were inadequately controlled on insulin with concomitant metformin treatment. The addition of anagliptin significantly reduced HbA1c and prevented an increase in daily insulin dosage. Moreover, anagliptin was generally well-tolerated and weight neutral, with a low risk of hypoglycaemia, even in combination with insulin treatment. DPP-4 inhibitors increase native GLP-1, which can effectively stimulate insulin secretion, suppress glucagon release, and improve glucose control in patients with T2DM.6 A combination of a DPP-4 inhibitor and insulin could be an effective and safe approach to optimize the management of glycaemic control without increasing the risk of hypoglycaemia or excessive weight gain.6, 7 Basal insulin therapy improves FPG levels but usually does not provide adequate postprandial glucose control.8 Therefore, DPP-4 inhibitors may be a good option as add-on therapy to basal insulin because they predominantly reduce postprandial glucose concentrations.9 Although the use of premixed insulin effectively targets both fasting and postprandial blood glucose levels, the addition of a DPP-4 inhibitor could lead to a substantial reduction in postprandial glucose concentrations by stabilizing the active forms of incretins produced during meals.10 In our participants who used basal insulin with and without premeal insulin or premixed insulin, there was a significant reduction in HbA1c after 24 weeks of anagliptin treatment. Both FPG and postprandial glucose levels showed a numerical decrease, despite the reduced dose of insulin used. Furthermore, anagliptin is considered a potent DPP-4 inhibitor. Switching from other DPP-4 inhibitors to anagliptin demonstrated an additional HbA1c reduction of 0.42% after 24 weeks of treatment.4 Furthermore, the study observed no severe hypoglycaemic events or weight gain when anagliptin was added, suggesting that combining ongoing insulin and anagliptin could be effective in achieving glycaemic control without the potential side effects of insulin. This study has several limitations. First, its findings cannot be generalized to different racial groups. Second, the small sample size may have affected the power of the study. Third, other confounding factors could have influenced glycaemic control. Fourth, none of the participants received a GLP-1 receptor agonist or sodium-glucose cotransporter 2 inhibitor, despite the recommendations of current international guidelines. Lastly, while DPP-4 inhibitors might improve β-cell function, this study could not evaluate the index of insulin secretion or resistance. In conclusion, after 24 weeks of treatment, the addition of anagliptin to ongoing insulin and metformin therapy improved glycaemic control in patients with T2DM without affecting body weight. Moreover, it was generally well-tolerated among insulin users, with no reported cases of severe hypoglycaemia. These findings suggest that addition of anagliptin could be an effective treatment option for patients with inadequately controlled T2DM. Conception or design: In-Kyung Jeong. Acquisition, analysis and interpretation of data: In-Kyung Jeong, Sung Hee Choi, Min Kyong Moon, Seung-Hyun Ko, Hae Jin Kim, Kyu Yeon Hur, Eun-Jung Rhee, and Jung Hyun Noh. Drafting the work and revising: Ji Eun Jun and In-Kyung Jeong. Final approval of the manuscript: In-Kyung Jeong, Ji Eun Jun, Sung Hee Choi, Min Kyong Moon, Seung-Hyun Ko, Hae Jin Kim, Kyu Yeon Hur, Eun-Jung Rhee, and Jung Hyun Noh. The authors thank the study participants, trial staff, and investigators who participated in the CANNA trial. This work was financially supported by JW pharmaceutical corporation, Seoul, Republic of Korea. The company funder had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the manuscript; and in the decision to submit the article for publication. No potential conflict of interest relevant to this article was reported. The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/dom.16557. The data cannot be shared because the study participants did not agree to share it. DATA S1. Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.