Anagliptin–Metformin Combo Safe in Type 2 Diabetes With Moderate Renal Impairment: AMELIO Study
Japan: A fixed-dose combination of anagliptin and metformin appears to be safe for patients with type 2 diabetes mellitus (T2DM) who also have moderate renal impairment, according to findings from the AMELIO study published in the Journal of Diabetes Investigation. The study was led by Hiroshi Kajio from the National Center for Global Health and Medicine, Japan Institute for Health Security, Tokyo, along with colleagues.
Metformin remains a cornerstone therapy for T2DM, but its use in patients with impaired kidney function is often approached cautiously because of concerns about lactic acidosis. The AMELIO study was designed to specifically evaluate whether combining metformin with the dipeptidyl peptidase-4 (DPP-4) inhibitor anagliptin affects serum lactic acid levels in this higher-risk population.
The prospective study enrolled Japanese adults with T2DM and moderate renal dysfunction, categorized based on creatinine-based estimated glomerular filtration rate (eGFR). Patients with eGFR between 45 and <60 mL/min/1.73 m² (Group G3a) initially received low-dose anagliptin/metformin combination tablets twice daily for four weeks, followed by a higher-dose formulation until week 16. Participants with more advanced impairment (eGFR ≥30 and <45 mL/min/1.73 m²; Group G3b) were maintained on the low-dose combination throughout the 16-week study period. Serum lactic acid concentrations were assessed at weeks 4, 8, and 16.
The study findings were as follows:
- At 16 weeks, the mean change in serum lactic acid from baseline was −0.09 mmol/L, remaining well within the predefined non-inferiority margin of 0.7 mmol/L.
- Lactic acid levels remained stable throughout the study, with no significant fluctuations observed during ongoing metformin exposure.
- Transient elevations in lactic acid were infrequent and limited in magnitude.
- Four participants recorded lactic acid levels above 2.5 mmol/L, and only one participant exceeded 5.0 mmol/L.
- No participant had plasma metformin concentrations above 2.5 μg/mL, a level commonly associated with increased safety concerns.
The authors concluded that the fixed-dose anagliptin/metformin combination can be safely administered to patients with T2DM and moderate renal impairment when appropriately dosed. Beyond safety, the combination may also offer practical advantages by simplifying treatment regimens and improving medication adherence.
However, the researchers acknowledged several limitations. The study lacked a control group and included a relatively small sample size with demographic imbalances, including a predominance of older, male, and obese participants. Additionally, the follow-up period of 16 weeks may not fully capture long-term metabolic effects or rare adverse events. The findings are also limited to a Japanese population, and differences in drug response across ethnic groups warrant further investigation.
Despite these constraints, the AMELIO study provides reassuring evidence supporting the cautious use of anagliptin/metformin combination therapy in patients with T2DM and moderate renal dysfunction, addressing a clinically important treatment gap.
Reference:
Kajio, H., Bouchi, R., Komatsu, M., Yamazaki, M., Takarabe, D., Okamoto, M., Tanaka, T., Kitazawa, T., Katsuyama, H., Mori, Y., & Noda, M. Safety of anagliptin/metformin combination tablets evaluated by non-inferiority between pre- and post-serum lactic acid levels in Japanese patients with type 2 diabetes and moderate renal impairment (AMELIO STUDY). Journal of Diabetes Investigation. https://doi.org/10.1111/jdi.70253
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