We thank Violante-Cumpa et al. (1) for their comments on our article that showed metformin use in older people with type 2 diabetes (diabetes) mitigated cognitive decline and incident dementia risk (2). We here respond to each comment.
First, Violante-Cumpa et al. comment that the metformin group took other glucose-lowering medications (50%) compared with 40% in those not on metformin. While metformin is the recommended first line for treatment of diabetes, many people with diabetes wish to avoid medications and undertake lifestyle changes. While this may bring glycated hemoglobin into the target therapeutic range, it may not diminish the effects of diabetes on the brain, as suggested by our study.
Second, Violante-Cumpa et al. raise the possibility of selection bias: that the accelerated cognitive decline observed in those not receiving metformin was due to renal impairment contraindicating its use. We clarify that metformin nonuse in people with diabetes in the cohort was not due to the contraindication of renal impairment. In Australia, metformin use continues until estimated glomerular filtration rate (eGFR) reduces to under 30 mL/min/1.73 m2. Renal function (measured as creatinine or eGRF) did not differ between participants with diabetes receiving metformin or not. Our laboratory phenotyping did not include measures of urinary albumin.
Finally, Violante-Cumpa et al. propose that future trials of cognitive decline in diabetes include measures of renal function. We agree; however, eGFR measures alone may be insufficient and may simply represent a parallel marker of biological system ageing or decline. In our view, measures of microvascular compromise (such as microalbuminuria or retinal vascular changes) and measures of oxidative stress products may also assist in understanding the mechanisms by which type 2 diabetes promotes accelerated cognitive decline.
Funding. This study was funded by the National Health and Medical Research Council (Australia) (grant no. 510124), which had no role in the study design, data collection, analysis, or interpretation for data collection.
Duality of Interest. P.S.S. holds a board position with the Australian Advisory Board of Biogen. No other potential conflicts of interest relevant to this article were reported.