Diabetes mellitus remains a very complex disorder to medically manage, often requiring insulin for Type 1 diabetes mellitus (T1DM) and lifestyle modifications such as diet, exercise, and weight loss along with oral antidiabetic medications for Type 2 diabetes mellitus (T2DM). Sodium-glucose co-transporter 2 (SGLT2) and 1 (SGLT1) inhibitors are relatively new classes of drugs that work by increasing urinary glucose excretion. Several SGLT2 inhibitors are available on the market today while SGLT1 inhibitors are currently being studied and pending Food and Drug Administration (FDA) approval. Let’s take a closer look at SGLT2 and SGLT1 inhibitors.

What do SGLT2 and SGLT1 do? (Hinnen, 2013)

To understand how SGLTs work, we need to review the kidneys’ role in glucose regulation. The kidneys release glucose into the circulation by two processes: through glycogenolysis they break down glycogen into free glucose and via gluconeogenesis they create free glucose from lactate, pyruvate, and amino acids. The kidneys also filter and reabsorb glucose. About 180 grams of glucose are filtered each day by the glomerulus, most of which is reabsorbed by the proximal tubule assisted by active SGLTs and passive glucose transporters (GLUTs).

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. SGLT1 is a low-capacity, high-affinity transporter that mediates approximately 5% of glucose reabsorption in the S3 (distal) segment of the proximal tubule (Novak & Kruger, 2017). SGLT1 may help with additional renal glucose reabsorption that evades SGLT2 either due to overload or SGLT2 inhibition. 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.
 

Comparing SGLT1 and SGLT2
	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% Approximately 10 grams per day	90-95% 160-180 grams per day
Additional action in small intestine	Primary glucose co-transporter	None

 

SGLT2 Inhibitors

SGLT2 inhibitors block the action of SGLT2 proteins and decrease glucose reabsorption. They offer several advantages in controlling blood glucose levels (Hinnen, 2013):

• Decrease the renal glucose threshold so glucose excretion occurs at lower plasma glucose concentrations
• Effect is independent of insulin; lower risk of hypoglycemia when used as monotherapy
• May be beneficial over therapies dependent on declining insulin action (i.e. insulin secretagogues, insulin sensitizers)
• Promotes weight loss by increased excretion of glucose

The American Diabetes Association (ADA) recommends that SGLT2 inhibitors can be used at any stage of T2DM in dual or triple combination with other oral and injectable glucose-lowering agents (Novak & Kruger, 2017). Currently, SGLT2 inhibitors are not indicated to treat people with T1DM.

Four single SGLT2 inhibitors and seven combination oral medications have been approved by the FDA: 
 

SGLT2 Generic (Trade Name)	Combination Drugs
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 (Steglatro)	Ertugliflozin/metformin (Segluromet) Ertugliflozin/sitagliptin (Steglujan)

Clinical considerations (Desantis, 2018; Novak & Kruger, 2017; Ashjian & Tingen, 2017)
Prior to beginning treatment with SGLT2 inhibitors, assess the following:

• Volume status and risk for hypovolemia and hypotension
• Renal function – efficacy will decline with decreased estimated glomerular filtration rate (eGFR)
  • Contraindicated in patients with end-stage renal disease or on dialysis
  • Dapagliflozin and ertugliflozin are contraindicated for eGFR < 60 mL/min.
  • Canagliflozin and empagliflozin are contraindicated for eGFR < 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
• Diuretic use – these medications may be held while using SGLT2
• History of recurring genital infections or urinary tract infections
• Neuropathy, foot deformity, vascular disease, and history of prior foot ulceration
• Use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB)

A few adverse events related to SGLT2 inhibitor use include:

• Genital mycotic infections
• Urinary tract infections
• Diabetic ketoacidosis
• Increased risk of bone fractures
• Increased risk of lower limb amputations with canagliflozin

The FDA (2018) recently issued a warning regarding the occurrence of rare but serious cases of necrotizing fasciitis of the perineum, also known as Fournier’s gangrene, associated with the use of SGLT2 inhibitors. The FDA is requiring a new warning about this risk be added to the prescribing information.

SGLT1 Inhibitors

Inhibition of SGLT1 delays and reduces glucose absorption in the small intestine, thus improving post meal glycemic control. This is beneficial particularly in patients with declining renal function where SGLT2 inhibition is less effective.  While several SGLT1 inhibitors are in the research phase, sotagliflozin is the first oral SGLT1 and SGLT2 inhibitor developed to treat adult patients with T1DM, in conjunction with insulin, to undergo review by the FDA. Studies have shown that people with T1DM who take sotagliflozin in addition to optimized insulin therapy have lower hemoglobin A1c (HbA1c) levels and weight, as well as a low incidence of severe hypoglycemia after a year of treatment, compared to those on placebo (ADA, 2018). Secondary results of the combined therapy show a decrease in bolus insulin requirements per day and systolic blood pressure. However, some patients experienced higher rates of diabetic ketoacidosis due to SGLT2 inhibition (Spatola, Finazzi, Angelini & Dauriz, 2018). Sotagliflozin is pending FDA approval.

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 possibly T1DM.

References: 
American Diabetes Association (2018). Sotagliflozin in conjunction with insulin for type 1 diabetes reduces average blood glucose levels. Retrieved from http://www.diabetes.org/newsroom/press-releases/2018/sotagliflozin-with-insulin-for-t1d-reduces-blood-glucose.html

Ashjian, E. and Tingen, J. (2017). Sodium-glucose cotransporter-2 inhibitors: Expanding oral treatment options for type 2 diabetes mellitus. The Nurse Practitioner, 42(4), 8 – 15. doi: 10.1097/01.NPR.0000513336.46697.77

DeSantis, A. (2018). Sodium-glucose co-transporter 2 inhibitors for the treatment of type 2 diabetes mellitus. UpToDate. Retrieved from https://www.uptodate.com/contents/sodium-glucose-co-transporter-2-inhibitors-for-the-treatment-of-type-2-diabetes-mellitus

Food and Drug Administration (2018). SGLT2 (sodium-glucose cotransporter-2) Inhibitors for Diabetes: Drug safety communication-regarding rare occurrences of a serious infection of the genital area. Retrieve from https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm618908.htm

Hinnen, D. (2013). The role of the kidney in hyperglycemia: A new therapeutic target in type 2 Diabetes Mellitus. Journal of Cardiovascular Nursing, 28(2), 157-165. doi: 10.1097/JCN.0b013e318245633e

Novak, L.M. and Kruger, D.F. (2017). Bolstering your armamentarium with SGLT2 inhibitors. The Nurse Practitioner, 42(10), 28-34. doi: 10.1097/01.NPR.0000524665.16846.63

Spatola, L., Finazzi, S., Angelini, C., Dauriz, M. and Badalamenti, S. (2018). SGLT1 and SGLT1 inhibitors: A role to be assessed in the current clinical practice. Diabetes Therapy, 9, 427-430. doi.org/10.1007/s13300-017-0342-8