Dapagliflozin does not show improvement in glycemic control in moderate renal impairment: a question of analytical rigor?
Authors: Anna F. Robson, Kate E. Shipman
Journal: Kidney International (2014)

To the Editor: We read with great interest the remarkable randomized controlled trial by Kohan et al.1Kohan D.E. Fioretto P. Tang W. et al.Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control.Kidney Int. 2014; 85: 962-971Abstract Full Text Full Text PDF PubMed Scopus (487) Google Scholar The authors set out to investigate the effects of dapagliflozin in patients with moderate renal impairment.1Kohan D.E. Fioretto P. Tang W. et al.Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control.Kidney Int. 2014; 85: 962-971Abstract Full Text Full Text PDF PubMed Scopus (487) Google Scholar Reductions in both weight and blood pressure were observed, but no significant improvement in glycemic control was observed, as monitored using HbA1c.1Kohan D.E. Fioretto P. Tang W. et al.Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control.Kidney Int. 2014; 85: 962-971Abstract Full Text Full Text PDF PubMed Scopus (487) Google Scholar Excellence in performance and reporting of clinical trials is vital and is promoted by initiatives such as SPIRIT. However, the SPIRIT checklist lacks rigor with regards to laboratory methods and only requires documentation of ‘a description of study instruments (e.g., questionnaires and laboratory tests) along with their reliability and validity, if known.’2Chan A.W. Tetzlaff J.M. Altman D.G. SPIRIT 2013. Statement: defining standard protocol items for clinical trials.Ann Intern Med. 2013; 158: 200-207Crossref PubMed Scopus (3112) Google Scholar Assays should ideally be chosen to reduce possible interference and be standardized across sites. High-performance liquid chromatography using ion exchange to separate HbA1c is subjected to interference from carbamylated hemoglobin, addition of isocyanic acid derived from urea, which co-elutes with glycated hemoglobin due to its similar charge.3Bruns D.E. Lobo P.I. Savory J. et al.Specific affinity-chromatographic measurement of glycated hemoglobins in uremic patients.Clin Chem. 1984; 30: 569-571PubMed Google Scholar Affinity chromatography is not subjected to this interference;3Bruns D.E. Lobo P.I. Savory J. et al.Specific affinity-chromatographic measurement of glycated hemoglobins in uremic patients.Clin Chem. 1984; 30: 569-571PubMed Google Scholar however, the paper methodology gives no detail as to which technique was used. The paper also describes a ‘colorimetric assay’ for creatinine, which could apply to several methods. For example, the Jaffe method is subjected to positive interferences from both glucose and ketones, whereas alternative enzymatic methods are not.4Peake M. Whiting M. Measurement of serum creatinine—current status and future goals.Clin Biochem Rev. 2006; 27: 173-184PubMed Google Scholar The lack of methodological information in this trial makes results difficult to interpret, as interfering carbamylated hemoglobin could be causing a positive bias to HbA1c measurements. Thus, therapeutic reduction in glucose levels may appear falsely as nonsignificant changes in HbA1c.