Reviewed and updated by Myrna Buiser Schnur, MSN, RN: April 10, 2024

Diabetes mellitus remains a very complex disorder to medically manage requiring insulin for Type 1 diabetes mellitus (T1DM) and lifestyle modifications such as diet, exercise, and weight loss along with oral or injected antidiabetic medications for Type 2 diabetes mellitus (T2DM). Among the oral meds available, sodium-glucose co-transporters (SGLTs) are one class of drug used to manage T2DM. Several SGLT2 inhibitors have been on the market for years while one combination SGLT1/SGLT2 inhibitor was recently approved by the Food and Drug Administration (FDA). Let’s take a closer look at SGLT2 and SGLT1 inhibitors.

What do SGLT2 and SGLT1 do?

Glucose moves in and out of our cells by proteins divided into two classes: glucose transporters (GLUTs) that work by facilitated diffusion and SGLTs that actively transport glucose along with sodium into the cells using the sodium concentration gradient (Sano, Shinozaki & Ohta, 2020). Of the six different types of SGLT proteins in the body, two have been studied for their role in glucose absorption: SGLT1 acts mainly in the small intestine while SGLT2 works primarily in the kidney.

The glomerulus of the kidneys filter about 180 grams of glucose each day, most of which is reabsorbed in the proximal tubule. SGLT2 is a high-capacity, low affinity glucose co-transport protein which helps to reabsorb about 90-95% of glucose (160-180 g/d) in the S1 and S2 segments of the proximal tubule of the kidneys. SGLT1 is a low-capacity, high-affinity transporter that mediates approximately 5-10% of glucose reabsorption in the S3 (distal) segment of the proximal tubule and may help with additional renal glucose reabsorption. When blood glucose levels surpass the 180–200 g/d capacity of the glucose cotransporters, excess glucose appears in the urine which may indicate diabetes mellitus. SGLT1 is also found in the skeletal muscles and heart and is a primary mediator for glucose absorption in the small intestine.

Comparison of SGLT1 and SGLT2 (Novak & Kruger, 2017)
	SGLT1	SGLT2
Description	Low-capacity, high affinity glucose co-transport protein	High-capacity, low affinity glucose co-transport protein
Location of action in proximal tubule	Distal S3 segment	S1 and S2 segments
Renal glucose absorption capacity	5–10%	90–95% 160-180 grams per day
Additional action in small intestine	Yes	No

The following SGLTs have been approved by the FDA and are currently on the market (Facts and Comparisons, 2024b).

Selective SGLT2 inhibitors	Dual SGLT2 & SGLT1 inhibitor	Combination Drugs
Bexagliflozin (Brenzavvy)	Sotagliflozin (Inpefa)
Canagliflozin (Invokana)		Canagliflozin/metformin (Invokamet, Invokamet XR)
Dapagliflozin (Farxiga)		Dapagliflozin/metformin (Xigduo XR) Dapagliflozin/saxagliptin (Qtern)
Empagliflozin (Jardiance)		Empagliflozin/linagliptin (Glyxambi) Empagliflozin/metformin (Synjardy, Synjardy XR)
Ertugliflozin (Steglaro)		Ertugliflozin/metformin (Segluromet) Ertugliflozin/sitagliptin (Steglujan)

SGLT2 Inhibitors (DeSantis, 2024)                   

SGLT2 inhibitors promote the renal excretion of glucose, lowering elevated blood glucose levels in patients with T2DM. SGLT2 inhibitors are not typically used as initial therapy, however these medications have been helpful in patients with cardiovascular and kidney disease. They are beneficial in the following situations:

• In patients with atherosclerotic cardiovascular disease (CVD) or heart failure who can’t reach glycemic goals with metformin and lifestyle modifications
• To slow the decline in estimated glomerular filtration rate (eGFR) in patients with eGFR less than 90 mL/min/1.73 m²
• As a third-line agent in patients not meeting glycemic goals on two oral agents (i.e., metformin and sulfonylurea) if metformin and insulin are not therapeutic options
• As a third-line agent in patients with inadequate glycemic control on metformin and insulin therapy, where glucagon-like peptide 1 (GLP-1) receptor agonists are contraindicated and increasing insulin dosing would result in weight gain
• As a second agent in patients with inadequate glycemic control on metformin who aren’t willing or not able to consider injection therapy in whom weight gain or risk of hypoglycemia is an issue

Contraindications and precautions (DeSantis, 2024)
SGLT2 inhibitors should be avoided in the treatment of hyperglycemia in patients with:

• Type 1 diabetes
• Type 2 diabetes and eGFR less than 45 mL/min/1.73 m² (ertugliflozin), or less than 30 mL/min/1.73 m² (empagliflozin, canagliflozin, dapagliflozin, bexagliflozin)
• History of diabetic ketoacidosis (DKA)

SGLT2 inhibitors should be used with caution in patients with:

• Frequent bacterial urinary tract infections or genitourinary yeast infections
• Low bone density and high risk for falls, fractures, and foot ulcerations
• Factors predisposing to DKA (i.e., pancreatic insufficiency, drug or alcohol use disorder, ketogenic diets)

Dual SGLT1/s Inhibitors

Sotagliflozin (Inpefa) is a dual SGLT1/2 inhibitor approved by the FDA to reduce the risk of cardiovascular mortality and hospitalization for heart failure in adults with T2DM, chronic kidney disease, and other cardiovascular risk factors (Facts and Comparisons, 2024a). Sotagliflozin had been studied as an adjunctive therapy in T1DM. While phase III trials showed an improvement in A1C tests after 24 weeks, the rate of DKA was higher in the sotagliflozin group compared to placebo and therefore is not recommended as a treatment for T1DM (Weinstock, 2024).

Clinical considerations (Desantis, 2024; Padda, Mahtani & Parmar, 2023)

Prior to beginning treatment with SGLT inhibitors, assess the patient’s:

• Volume status and risk for hypovolemia and hypotension
  • Correct hypovolemia prior to starting therapy
  • Adjust diuretics and blood pressure medications as needed

• Renal function - efficacy will decline with decreasing estimated glomerular filtration rate (eGFR)
  • Contraindicated in patients with end-stage renal disease or on dialysis
  • Dapagliflozin and ertugliflozin are contraindicated for eGFR less than 60 mL/min
  • Canagliflozin and empagliflozin are contraindicated for eGFR less than 45 mL/min

• Liver function before starting canagliflozin or dapagliflozin
• Bone density for patients at risk for falls and bone fracture
• Use of insulin or insulin secretagogues (sulfonylureas, glinides); reduce insulin dosage to decrease the risk of hypoglycemia
• History of recurring genital infections or urinary tract infections
• Neuropathy, foot deformity, vascular disease, and history of prior foot ulceration

For patients on SGLT2 therapy (American Diabetes Association, 2024; DeSantis, 2024):

• Monitor for signs of diabetic ketoacidosis (DKA); evaluate and treat promptly if suspected.
• Monitor volume status and kidney function (serum creatinine and eGFR).
• Monitor for signs and symptoms of genitourinary tract infections and foot ulcerations.
• Discontinue the SGLT2 about 3-4 days prior to scheduled surgery.
• Discontinue SGLT2 during critical illness or during prolonged fasting.

Be sure to stay current with the research as SGLT2 and SGLT1 inhibitors have the potential to positively impact clinical management and the outcomes of patients with T2DM and other chronic conditions. For complete information, please consult the drug’s specific package insert or the Nursing2024 Drug Handbook® + Drug Updates.
 

References
American Diabetes Association Professional Practice Committee (2024). 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes-2024. Diabetes care, 47(Suppl 1), S158–S178. https://doi.org/10.2337/dc24-S009

DeSantis, A. (2024, March 19). Sodium-glucose co-transporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus. UpToDate. Retrieved from  https://www.uptodate.com/contents/sodium-glucose-cotransporter-2-inhibitors-for-the-treatment-of-hyperglycemia-in-type-2-diabetes-mellitus

Facts and Comparisons (2024a, February 26). Sotagliflozin Oral. Facts and Comparisons. https://fco.factsandcomparisons.com/lco/action/doc/retrieve/docid/fc_dfc/7346202?cesid=7DJZjAhjRd9

Facts and Comparisons (2024b, January 31). Sodium-Glucose Co-Transporter 2 Inhibitors. Facts and Comparisons. https://fco.factsandcomparisons.com/lco/action/doc/retrieve/docid/fc_dfc/5545822?cesid=1tMly08RUaQ

Novak, L. M., & Kruger, D. F. (2017). Bolstering your armamentarium with SGLT2 inhibitors. The Nurse practitioner, 42(10), 28–34. https://doi.org/10.1097/01.NPR.0000524665.16846.63

Padda, I. S., Mahtani, A. U., & Parmar, M. (2023). Sodium-Glucose Transport Protein 2 (SGLT2) Inhibitors. In StatPearls. StatPearls Publishing.

Sano, R., Shinozaki, Y., & Ohta, T. (2020). Sodium-glucose cotransporters: Functional properties and pharmaceutical potential. Journal of diabetes investigation, 11(4), 770–782. https://doi.org/10.1111/jdi.13255

Weinstock, R.S. (2024, January 2). Management of blood glucose in adults with type 1 diabetes mellitus. UpToDate. https://www.uptodate.com/contents/management-of-blood-glucose-in-adults-with-type-1-diabetes-mellitus

Zhao, M., Li, N., & Zhou, H. (2023). SGLT1: A Potential Drug Target for Cardiovascular Disease. Drug design, development, and therapy, 17, 2011–2023. https://doi.org/10.2147/DDDT.S418321

 

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