In the JournalsPerspective

SGLT1 variants tied to lower risk for HF, diabetes, obesity, death

Scott Solomon_2018
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.

Mutation beneficial

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.

Ferhaan Ahmad
Ferhaan Ahmad

Accelerate exploration

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.

Scott Solomon_2018
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.

Mutation beneficial

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.

Ferhaan Ahmad
Ferhaan Ahmad

Accelerate exploration

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.

    Perspective
    Robert Roberts

    Robert Roberts

    The authors have shown that this loss-of-function variant, which is related to glucose absorption from the gut, is related to less obesity and heart disease. They raise the idea that the genetic regulation of blood glucose, both its absorption and utilization, may be another area one can manipulate to decrease heart disease and obesity. This is a new area that has not been pursued. I would list it as a potential new target to control obesity and heart disease, but it is yet to be explored. We are not yet sure that this is clinically applicable in the same way that genetic risk scores are.

    The area of genetic regulation of glucose, other than what we’re used to in defining whether or not a patient has diabetes, is an area that we need not regulate in the same way. What these genetic variants are saying is that even within a normal range of blood glucose, there are targets that maybe one can develop drugs for that could modulate the yes/no answer for diabetes. This is speculative, but it is exciting because it could help people who become type 2 diabetic because of obesity. We are looking at new targets to prevent that. This would be a totally new approach. At the moment, we run a blood glucose test or look at the hemoglobin A1c, and if it’s above or below a certain area, we say the patient has diabetes or they don’t. This is saying that from the absorption of glucose in the gut all the way to its utilization in the blood, there is significant genetic regulation of that, and there are targets that could be used before you get diabetes or another condition.

    This is in the early stages, and one has to do a lot more work to know whether you can regulate even if you find these targets, and what you can do if you start messing around with the normal homeostasis of glucose. Those answers are a few years down the road.

    • Robert Roberts, MD, MACC, FRSC, FRCPC, LLD (Hon.)
    • Cardiology Today Editorial Board Member
      College of Medicine-Phoenix, University of Arizona

    Disclosures: Roberts reports no relevant financial disclosures.