Junichi Okada

Metformin administration attenuates dipeptidyl peptidase-4 inhibitor-induced increases in Krebs von den Lungen-6 (KL-6) levels: Letter to the Editor

Suga et al. reported that patients with idiopathic interstitial pneumonia had accompanying type 2 diabetes mellitus (T2DM). Kuse et al. Ohara et al. and our group recently reported cases of dipeptidyl peptidase-4 (DPP-4) inhibitor-induced interstitial pneumonia. Although metformin has been reported to reverse established lung fibrosis, it has also been reported to have no effect on clinically relevant outcomes in patients with idiopathic pulmonary fibrosis. Given the lack of clarity regarding the benefits of metformin in patients with T2DM who are prescribed DPP-4 inhibitors, we compared Krebs von den Lungen6 (KL-6) levels between patients prescribed DPP-4 inhibitors and those prescribed both a DPP-4 inhibitor and metformin. The study protocol was reviewed and approved by the Kan-etsu Chuo Hospital Review Board and was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants. Statistical analyses were performed and two-tailed P < 0.05 was considered significant. Fifty-four patients were prescribed DPP-4 inhibitors and KL-6 levels were measured in all these patients; 25 patients were prescribed metformin. Thus, patients were categorized into two groups, those taking a DPP-4 inhibitor alone (without metformin; n = 29) and those taking a DPP-4 inhibitor plus metformin (n = 25). Concentrations of KL-6 were significantly higher in those taking the DPP-4 inhibitor alone than in those also taking metformin (mean [ SD] 300.76 155.39 vs 223.96 73.83 U/mL, respectively [P = 0.0281]; reference range < 500 U/mL). Transient increases in KL-6 levels beyond the upper limit of normal was observed in four patients taking the DPP-4 inhibitors along. In the first patient, the KL-6 concentration 2 months after starting the DPP-4 inhibitor was 567 U/mL, and normalized 3 months after cessation of the DPP-4 inhibitor. In the second patient, the KL-6 concentrations 2 and 3 months after starting the DPP-4 inhibitor were 530 and 617 U/mL, respectively; KL-6 levels normalized 2 months after cessation of the DPP-4 inhibitor. In the third patient, KL6 concentrations 4 and 5 months after starting the DPP4 inhibitor were 565 and 591 U/mL, respectively, returning to normal 2 months after cessation of the DPP-4 inhibitor. In the fourth patient, the KL-6 concentrations 2 and 6 months after starting the DPP-4 inhibitor were 745 and 825 U/mL, respectively, and these levels normalized 4 months after stopping the DPP-4 inhibitor. No increases in KL-6 concentrations were seen in any patient in the DPP-4 inhibitor plus metformin group. Despite the small sample size, this clinical study provides important information. One strength of this study is that KL-6 concentrations were measured in all patients with T2DM who were prescribed DPP-4 inhibitors. We confirmed that KL-6 concentrations were in the normal range before patients started on the DPP-4 inhibitor. Moreover, KL-6 concentrations were transiently elevated, but normalized after cessation of the DPP-4 inhibitor. The frequency of increases in KL-6 concentrations due to DPP-4 inhibitor administration was 7.4%, although all participating patients had normal findings on chest X-ray examinations. This incidence is higher than that reported for statin-induced interstitial pneumonia. Metformin may prevent or delay interstitial lung diseases caused by administration of DPP-4 inhibitors. However, KL-6 levels need to be determined in patients being treated with metformin alone.