Scott D. Solomon
Researchers reported that a combination of SGLT1 variants appears to protect from diet-induced hyperglycemia and confers reductions in 25-year risk for HF, diabetes, obesity and death.
If therapies that work via inhibition of SGLT1 could be developed, many people with diabetes, obesity and/or heart disease could benefit, the researchers wrote.
“We’re excited about this study because it helps clarify the link between what we eat, what we absorb and our risk for disease. Knowing this opens the door to improved therapies for cardiometabolic disease,” Scott D. Solomon, MD, professor of medicine at Harvard Medical School and senior physician at Brigham & Women’s Hospital, said in a press release from the NHLBI, which funded the study.
Solomon and colleagues performed whole-exome sequencing in 8,478 participants from the ARIC cohort study. They determined that 6.7% of the cohort had a haplotype of three missense mutations — Asn51Ser, Ala411Thr and His615Gln — of SGLT1 that limits impaired glucose absorption.
In the white participants from ARIC (mean age, 54 years; 47% men), those with the haplotype had lower 2-hour glucose (beta coefficient = –8; 95% CI, –12.7 to –3.3) and lower odds of impaired glucose tolerance (OR = 0.71; 95% CI, 0.59-0.86) compared with those without it.
The findings were validated in the black participants from ARIC (mean age, 54 years; 36% men; beta coefficient for 2-hour glucose = –16.3; 95% CI, –36.6 to 4.1; OR for impaired glucose tolerance = 0.39; 95% CI, 0.17-0.91) and in a European/Finnish cohort (beta coefficient for 2-hour glucose = –3.2; 95% CI, –6.4 to –0.02; OR for impaired glucose tolerance = 0.81; 95% CI, 0.68-0.98).
When the researchers performed a Mendelian randomization analysis in the ARIC cohort, they found that the estimated 25-year effect of reducing 2-hour glucose by 20 mg/dL via SGLT1 inhibition included reducing prevalent obesity (OR = 0.43; 95% CI, 0.23-0.63), incident diabetes (HR = 0.58; 95% CI, 0.35-0.81), incident HF (HR = 0.53; 95% CI, 0.24-0.83) and death (HR = 0.66; 95% CI, 0.42-0.9).
“These data argue for further research into the role of natural variation in SGLT1 in metabolic disease and suggest that more selective ways to inhibit SGLT1 may lead to therapies that reduce the deleterious effects of Western-style diets,” Solomon and colleagues wrote.
The study “is a reminder that although the null state for some genes may be pathogenic, moderate decreases in their function may in fact confer a survival benefit. Furthermore, this study illustrates the utility of genetic studies, of both Mendelian single gene disorders and complex polygenic disorders, in identifying novel therapeutic targets in acquired disease,” Ferhaan Ahmad, MD, PhD, from the division of cardiovascular medicine, department of internal medicine and Abboud Cardiovascular Research Center at Carver College of Medicine, University of Iowa, and colleagues wrote in a related editorial. “The findings ... should accelerate exploration of SGLT1 inhibition as a target for not only diabetes control but also for other cardiometabolic indications.” – by Erik Swain
Disclosures: Solomon reports he has received research grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Bristol-Myers Squibb, Celladon, Gilead, GlaxoSmithKline, Ionis, Lone Star Heart, Mesoblast, MyoKardia, the NIH/NHLBI, Novartis, Sanofi Pasteur and Theracos and has consulted for Alnylam, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Corvia, Gilead, GlaxoSmithKline, Ironwood, Merck, Novartis, Pfizer, Takeda and Theracos, none of which are related to the present study. Please see the full study for the other authors’ relevant financial disclosures. The editorial writers report no relevant financial disclosures.