What are SGLT1 drugs? A Guide to SGLT1 Inhibitors in Medication

October 7, 2025 •

3 min read

The sodium-glucose cotransporter 1 (SGLT1) protein is largely responsible for the absorption of dietary glucose from the small intestine, but it also plays a compensatory role in the kidneys. SGLT1 drugs are pharmacological agents designed to inhibit the action of this transporter, offering new strategies for managing glucose levels in various metabolic and cardiovascular conditions.

Quick Summary

SGLT1 drugs inhibit the SGLT1 protein in the intestines and kidneys, delaying glucose absorption, reducing post-meal blood sugar spikes, and modulating incretin hormone secretion.

Key Points

Mechanism of Action: SGLT1 drugs delay intestinal absorption of dietary glucose and can increase urinary glucose excretion by inhibiting the sodium-glucose cotransporter 1 (SGLT1) protein.
Difference from SGLT2: Unlike selective SGLT2 inhibitors that primarily target renal reabsorption, SGLT1 drugs primarily target intestinal absorption, complementing the SGLT2 mechanism.
Dual Inhibition: Dual SGLT1/SGLT2 inhibitors, such as sotagliflozin (Inpefa), combine both mechanisms of action for more comprehensive glucose control and cardiovascular benefits.
Therapeutic Uses: SGLT1 drugs and dual inhibitors are used to improve glycemic control in diabetes and have been approved for treating heart failure across the full range of ejection fraction.
Potential Side Effects: Common side effects include gastrointestinal issues like diarrhea and an increased risk of urinary and genital infections. In diabetes, a serious risk is diabetic ketoacidosis.
Future Potential: Research continues to explore the potential benefits of SGLT1 inhibition in a wider range of metabolic and inflammatory disorders beyond diabetes and heart failure.

Understanding SGLT1 and Glucose Transport

Sodium-glucose cotransporters (SGLTs) are proteins that move glucose into cells, with SGLT1 and SGLT2 being key in blood glucose regulation. SGLT1 is primarily located in the small intestine for absorbing dietary glucose and also has a role in kidney glucose reabsorption, particularly when SGLT2 is inhibited or saturated.

SGLT1's Role in the Intestines

SGLT1 in the small intestine absorbs glucose and galactose from food, transporting them into the bloodstream. Inhibiting SGLT1 can delay and reduce dietary glucose uptake, impacting blood sugar after meals.

SGLT1's Role in the Kidneys

In the kidneys, SGLT1 reabsorbs remaining glucose in the proximal tubule after SGLT2. While minor normally, its role increases during hyperglycemia or when SGLT2 is inhibited.

Mechanism of Action of SGLT1 Inhibitors

SGLT1 drugs block the SGLT1 protein, which uses a sodium gradient to move glucose into cells. This inhibition affects both intestinal and renal glucose handling. Key effects include delayed intestinal glucose absorption, blunting post-meal blood sugar spikes. This also increases incretin hormones like GLP-1 and PYY from the gut, which can boost insulin and reduce glucagon. SGLT1 inhibitors can also increase urinary glucose excretion, especially with SGLT2 inhibition or high blood sugar.

SGLT1 Inhibitors vs. SGLT2 Inhibitors

Selective SGLT2 inhibitors are established treatments for type 2 diabetes, heart failure, and chronic kidney disease. Comparing them with SGLT1 inhibitors highlights their different roles.

Comparison of SGLT1 and SGLT2 Inhibitors


Feature	SGLT1 Inhibitors	SGLT2 Inhibitors	Dual SGLT1/SGLT2 Inhibitors
Primary Location of Action	Small intestine (significant), Kidney (minor)	Kidney (major)	Small intestine and Kidney
Primary Mechanism	Delay intestinal glucose absorption; modulate incretins	Block renal glucose reabsorption, increasing urinary excretion	Combine both mechanisms
Effect on Postprandial Glucose	Significant blunting of glucose spikes after meals	Moderate effect on postprandial glucose	Very effective at controlling postprandial glucose
Effect on Renal Glucose Excretion	Minor effect alone; more significant when SGLT2 is inhibited	Large effect, leading to glucosuria	Significant glucosuria, potentially greater than SGLT2 inhibition alone
Key Side Effect Concern	Diarrhea due to osmotic pressure	Genital mycotic infections, urinary tract infections	Both types of side effects are possible

Dual SGLT1 and SGLT2 Inhibitors

Dual SGLT1/SGLT2 inhibitors offer a combined approach. Sotagliflozin is a notable example, showing promise for both diabetes and heart failure.

Sotagliflozin (Inpefa)

Sotagliflozin (Inpefa) received FDA approval in May 2023 for heart failure across all ejection fractions, including in patients without diabetes. Its dual action is thought to provide broader benefits by combining intestinal SGLT1 inhibition with renal SGLT2 inhibition. Sotagliflozin is also being evaluated for glucose control in type 1 and type 2 diabetes, often with insulin.

Clinical Applications and Therapeutic Potential

SGLT1 drugs and dual inhibitors show potential for various conditions:

Diabetes Mellitus: They can improve glucose control in type 1 and type 2 diabetes by reducing post-meal spikes and boosting incretins. In type 1 diabetes, they are used with insulin, but carry a risk of diabetic ketoacidosis (DKA).
Heart Failure: SGLT1 inhibition may offer additional heart protection, potentially by reducing oxidative stress and lowering the risk of heart attack and stroke. Sotagliflozin's broad heart failure indication is a key development.
Other Metabolic Disorders: Research is exploring their use in conditions like metabolic syndrome, obesity, and functional constipation.

Potential Side Effects of SGLT1 Drugs

Side effects can occur with SGLT1 and dual inhibitors, often related to their action.

Gastrointestinal Disturbances: Diarrhea is common due to increased unabsorbed glucose in the intestine.
Genital and Urinary Tract Infections: Increased glucose in urine can lead to a higher risk of infections, similar to SGLT2 inhibitors.
Diabetic Ketoacidosis (DKA): There is an increased risk of DKA, including euglycemic DKA, especially in type 1 diabetes. Ketone monitoring is important in certain situations.
Hypotension and Volume Depletion: The drugs' diuretic effects can cause low blood pressure, particularly in older patients or those on diuretics.

Conclusion

SGLT1 drugs, particularly dual SGLT1/SGLT2 inhibitors, represent a promising approach for managing diabetes and heart failure. By inhibiting intestinal glucose absorption and modulating incretin hormones, they offer a unique way to control post-meal hyperglycemia. However, awareness of potential side effects, such as gastrointestinal issues and DKA risk (especially in type 1 diabetes), is crucial. Continued research into selective and dual SGLT1 inhibitors could expand treatment options for various metabolic and cardiovascular conditions.

For more in-depth information on dual SGLT1 and SGLT2 inhibition, you can read the research published by the American Heart Association Journals.

Frequently Asked Questions

SGLT1 drugs primarily target glucose absorption in the intestines, while SGLT2 drugs primarily target glucose reabsorption in the kidneys. This means SGLT1 inhibitors mainly impact post-meal glucose spikes, while SGLT2 inhibitors promote glucose excretion through urine.

Sotagliflozin is a dual SGLT1 and SGLT2 inhibitor. It is marketed under the brand name Inpefa and is approved by the FDA to treat heart failure in adults, regardless of their ejection fraction.

Yes, SGLT1 drugs and dual SGLT1/SGLT2 inhibitors have been studied for their ability to improve glycemic control in both type 1 and type 2 diabetes. They can be used as an adjunct to insulin, although with precautions regarding the risk of diabetic ketoacidosis.

The most common side effect is diarrhea, which is caused by increased glucose and water remaining in the intestines due to the drug's mechanism. Other potential side effects include urinary and genital infections, volume depletion, and dizziness.

For heart failure, dual SGLT1/SGLT2 inhibitors like sotagliflozin are approved to reduce the risk of cardiovascular death and heart failure events. SGLT1 inhibition may offer additional cardioprotective effects by reducing oxidative stress.

Yes, dual SGLT1/SGLT2 inhibition, like with selective SGLT2 inhibitors, increases the risk of DKA, including euglycemic DKA where blood glucose levels may not be significantly elevated. Close monitoring of ketone levels is essential for patients with diabetes using these drugs.

Inhibiting SGLT1 in the intestines leads to a delay in glucose absorption. This, in turn, can increase the release of incretin hormones such as GLP-1 and PYY from the distal gut, which can enhance insulin secretion and promote satiety.