SGLT1 haplotype linked to reduced cardiometabolic risk
medwireNews: Researchers have identified a haplotype of three missense mutations in the sodium-glucose cotransporter-1 (SGLT1) gene that is associated with a reduced risk for impaired glucose tolerance (IGT), diabetes, and obesity.
In addition, carriers of the Asn51Ser, Ala411Thr, His615Gln haplotype had a lower incidence of heart failure and death than non-carriers, report Scott Solomon (Harvard Medical School and Brigham and Women’s Hospital, Boston, Massachusetts, USA) and colleagues in the Journal of the American College of Cardiology.
They say: “These data suggest that genetic variations in this gene influence the risk of metabolic disease in relation to carbohydrate intake and that selective inhibitors of SGLT1 may be useful in prevention by reducing the burden of metabolic disease and its cardiovascular disease consequences.”
The researchers initially found that carrying at least one nonsynonymous substitution in SGLT1 was associated with significantly lower fasting and postprandial plasma glucose levels, and a lower risk for IGT and obesity in 5687 European–American participants of the ARIC (Atherosclerosis Risk in Communities) study.
Further analysis showed that carriers of the Asn51Ser, Ala411Thr, and His615Gln haplotype had a significantly lower 2-hour blood glucose level (129 vs 139 mg/dL), and were significantly less likely to have IGT (32 vs 41%) or be obese (19 vs 22%) than non-carriers, despite having similar total energy intake. The odds ratios (OR) for IGT and obesity were 0.71 and 0.79, respectively.
Similar results were observed among 2791 African–American ARIC participants and in an external cohort from Finland (n=6784).
When the team looked at clinical outcomes over 25 years, they found that carriers of the Asn51Ser, Ala411Thr, His615Gln haplotype had significantly reduced incidence of diabetes (adjusted hazard ratio [HR]=0.81), initiation of diabetes medication (HR=0.78), heart failure (HR=0.74), and death (HR=0.81) compared with non-carriers.
Furthermore, Mendelian randomization analysis indicated that a 20 mg/dL reduction in 2-hour blood glucose via pharmacologic inhibition of SGLT1 could be associated with a significant long-term reduction in the risk for obesity (adjusted OR=0.43), diabetes (HR=0.58), heart failure (HR=0.53), and mortality (HT=0.66).
Soloman et al conclude that their findings “provide support that reduction of postprandial glucose levels via SGLT1 inhibition may be associated with reduced incidence of [diabetes, heart failure] and/or mortality in certain populations at risk.”
In an accompanying editorial, Ferhaan Ahmad and colleagues from the University of Iowa in Iowa City, USA, say that although SGLT2 is an established therapeutic target for diabetes control, “focus is now shifting to SGLT1 and the role it can play.”
They add that “dual SGLT1/2 inhibitors and SGLT1-selective inhibitors are being developed” and the findings of this study “should accelerate exploration of SGLT1 inhibition as a target for not only diabetes control but also for other cardiometabolic indications.”
By Laura Cowen
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