SGLT1 inhibitors are a class of medications that influence the body’s glucose management. They work by interacting with specific proteins involved in sugar transport, offering new approaches for conditions where glucose regulation is a concern.
The Function of SGLT1 Proteins
SGLT1 proteins, also known as sodium-glucose cotransporter 1, are specialized transporters found in various parts of the body. Their primary role involves moving glucose and galactose, along with sodium ions, across cell membranes. They actively pull sugar into cells, using the energy from sodium movement.
A significant concentration of SGLT1 proteins resides in the small intestine, specifically on the brush border membrane of enterocytes. Here, they are responsible for absorbing nearly all the glucose and galactose derived from digested food and moving it from the gut lumen into the bloodstream. This process is the initial step in the body’s uptake of dietary sugars.
SGLT1 proteins also have a presence in the kidneys, though their role there is relatively minor compared to other glucose transporters. In the late proximal tubules of the nephron, SGLT1 contributes to the reabsorption of a small percentage of glucose from the urine back into the blood. Other tissues like the heart and brain also express SGLT1, where it contributes to energy metabolism and glucose uptake across the blood-brain barrier.
Mechanism of Action
SGLT1 inhibitor drugs operate by directly blocking the activity of these sodium-glucose cotransporter 1 proteins. This physical interference prevents SGLT1 from transporting glucose and sodium across cell membranes. This blockage primarily occurs in the small intestine, where SGLT1 proteins are most abundant and active in absorbing dietary sugars.
The direct consequence of this inhibition in the small intestine is that less glucose and sodium from digested food are absorbed into the bloodstream. Instead, the unabsorbed glucose remains within the digestive tract, and this increased presence of glucose in the gut lumen draws water into the intestine. This facilitates its passage through the digestive system, and the unabsorbed sugar is then excreted from the body through stool.
While SGLT1 inhibitors primarily act in the intestine, they can also influence glucose handling in the kidneys to a lesser extent. By reducing glucose reabsorption in the renal tubules, these inhibitors can lead to a modest increase in glucose excretion through urine. This dual effect contributes to lowering overall blood glucose levels, particularly after meals.
Therapeutic Uses and Clinical Trials
SGLT1 inhibitors are being investigated for their applications in managing blood sugar levels, particularly the spikes that occur after meals in individuals with type 1 and type 2 diabetes. By reducing the absorption of dietary glucose from the small intestine, these medications can help flatten post-meal glucose excursions. This mechanism offers a way to improve glycemic control independent of insulin action, which is beneficial for patients with insulin resistance or those requiring insulin therapy.
Sotagliflozin is a notable dual SGLT1/SGLT2 inhibitor. This drug has received approval for use in specific patient populations, including those with type 2 diabetes, chronic kidney disease, and heart failure. Clinical trials such as SOLOIST-WHF and SCORED have demonstrated that sotagliflozin can reduce the risk of cardiovascular death, hospitalizations for heart failure, and urgent visits for heart failure.
The SCORED trial, involving over 10,000 patients with type 2 diabetes and chronic kidney disease, showed that sotagliflozin reduced the rate of heart attacks and strokes. The SOLOIST trial, focusing on patients with type 2 diabetes hospitalized for worsening heart failure, also indicated a reduction in cardiovascular events. These findings highlight the potential of SGLT1 inhibition, especially in combination with SGLT2 inhibition, to provide broader benefits beyond just glucose control, extending to cardiovascular and renal protection.
Comparison to SGLT2 Inhibitors
SGLT1 inhibitors and SGLT2 inhibitors both impact glucose regulation, but they do so primarily at different sites. SGLT1 inhibitors exert their main effects in the small intestine, where they reduce the absorption of glucose from food into the bloodstream. This action directly affects post-meal glucose levels.
In contrast, SGLT2 inhibitors primarily function in the kidneys. They block the SGLT2 proteins in the renal tubules, which are responsible for reabsorbing about 90-95% of the glucose filtered by the kidneys back into the blood. By inhibiting SGLT2, these drugs cause more glucose to be excreted through urine.
The distinct sites of action lead to different primary outcomes: SGLT1 inhibition reduces glucose absorption from the gut, leading to glucose excretion in stool, while SGLT2 inhibition increases glucose excretion in urine. Some medications, like sotagliflozin, are designed to inhibit both SGLT1 and SGLT2, providing a dual mechanism of action that impacts glucose handling in both the intestine and kidneys.
Associated Side Effects
SGLT1 inhibitors prevent sugar absorption in the digestive tract, so their most common side effects are related to the gastrointestinal system. When glucose is not absorbed in the small intestine, it remains in the gut lumen, drawing water into the bowel through osmosis. This increased water content can lead to symptoms such as diarrhea, flatulence, and abdominal discomfort.
Clinical trials have observed these gastrointestinal disturbances, with diarrhea being a frequently reported adverse effect. While these effects are generally manageable, they are a direct consequence of the drug’s mechanism of action. Some patients may also experience symptoms like bloating or stomach cramps.
Other potential concerns, though less common with selective SGLT1 inhibition compared to SGLT2 inhibitors, include dehydration due to increased fluid loss through the bowels. Unlike SGLT2 inhibitors, selective SGLT1 inhibition is less likely to cause genitourinary infections or diabetic ketoacidosis, as it does not significantly increase glucose excretion via the kidneys.