Target protein for diabetes drug linked to reduced risk of A
A two-sample Mendelian randomization (MR) study design was applied to examine the association between genetic variation in the targets of four anti-diabetic drug classes and AD risk. Genetic summary statistics for blood glucose were analyzed using UK Biobank data of 326,885 participants, while summary statistics for AD were retrieved from previous genome-wide association studies (GWAS) comprising 24,087 clinically diagnosed AD cases and 55,058 controls. Positive control analysis on type 2 diabetes (T2DM), insulin secretion, insulin resistance, and obesity-related traits was conducted to validate the selection of instrumental variables (IVs).

In the positive control analysis, genetic variation in sulfonylurea targets was associated with higher insulin secretion, a lower risk of T2DM, and an increment in body mass index, waist circumference, and hip circumference, consistent with drug mechanistic actions and previous trial evidence. In the primary analysis, genetic variation in sulfonylurea targets was associated with a lower risk of AD (OR=0.38 per 1 mmol/L decrement in blood glucose, 95%CI=0.19-0.72, P=0.0034). These results for sulfonylureas were largely unchanged in the sensitivity analysis using a genetic variant, rs757110, that has been validated to modulate the target proteins of sulfonylureas (OR=0.35 per 1 mmol/L decrement in blood glucose, 95%CI=0.15-0.82, P=0.016). An association between genetic variations in the GLP-1 analogue target and a lower risk of AD was also observed (OR=0.32 per 1 mmol/L decrement in blood glucose, 95%CI=0.13-0.79, P=0.014). However, this result should be interpreted with caution because the positive control analyses for GLP-1 analogues did not comply with a weight-loss effect as shown in previous clinical trials. Results regarding other drug classes were inconclusive.

Source: https://n.neurology.org/content/early/2022/06/02/WNL.0000000000200771
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