SGLT2 Inhibitors

For treating type 2 diabetes, monotherapy may not be as effective as combination therapies, particularly for addressing common comorbidities such as hypertension and overweight/obesity.1 Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a class of medications commonly prescribed as a part of combination therapy for patients with type 2 diabetes.1 In addition to lowering blood glucose concentrations, SGLT2 inhibitors have a wide range of potentially beneficial effects for patients with type 2 diabetes, including reductions in blood pressure, body weight, and risk of adverse cardiovascular events.2-4 This article details the use of SGLT2 inhibitors for type 2 diabetes, including their indications, how they work, dosing regimens, adverse effects, and potential drug interactions.

SGLT2 Inhibitors Indications

The US Food and Drug Administration (FDA) has approved 5 SGLT2 inhibitors5-9:

• Bexagliflozin;
• Canagliflozin;
• Dapagliflozin;
• Empagliflozin; and
• Ertugliflozin.

All 5 SGLT2 inhibitors are FDA-approved in conjunction with diet and exercise to improve glycemic control in adults with type 2 diabetes.5-9 SGLT2 inhibitors are not FDA-approved for treating type 1 diabetes.5-9 In addition to treating type 2 diabetes, canagliflozin, dapagliflozin, and empagliflozin have other FDA-approved indications as described below.6-8

Canagliflozin is also indicated to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes and cardiovascular disease, and to reduce the risk of end-stage kidney disease, doubling of serum creatinine, cardiovascular death, and hospitalization for heart failure in adults with type 2 diabetes and diabetic nephropathy with albuminuria.6

Dapagliflozin is also indicated for adults with chronic kidney disease to reduce the risk of sustained glomerular filtration rate (GFR) decline, end stage kidney disease, cardiovascular death, and hospitalization for heart failure.7 It is indicated to reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visit in adults with heart failure, and to reduce the risk of hospitalization for heart failure in adults with type 2 diabetes and either cardiovascular disease or multiple cardiovascular risk factors.

Empagliflozin is also indicated for adults with heart failure to reduce the risk of cardiovascular death and hospitalization for heart failure; for adults with chronic kidney disease to reduce the risk of sustained decline in GFR, end-stage kidney disease, cardiovascular death, and hospitalization; and for adults with type 2 diabetes and cardiovascular disease to reduce the risk of cardiovascular death.8

Read more: Acute Heart Failure

Mechanism of Action of SGLT2 Inhibitors

SGLT2 inhibitors prevent glucose reabsorption in the kidneys, which results in a range of physiological effects, many of which are beneficial for patients with type 2 diabetes.2-4 

SGLT2 inhibitors block the sodium-dependent glucose transporter-2 in the proximal renal tubule of the kidney, which disrupts the reabsorption of glucose.3 This leads to urinary excretion of glucose, which reduces blood glucose concentrations. This effect is dependent on blood glucose levels and is independent of the action or availability of insulin, which makes SGLT2 inhibitors less likely to cause hypoglycemia.2-4 The excreted glucose results in a substantial calorie loss, indirectly leading to weight loss.4 The fluid lost via increased urine production lowers blood pressure.3,4 Reduction in blood glucose concentrations can lead to fatty acid oxidation and an increase in ketone bodies.3,4 SGLT2 inhibitors increase renal uric acid excretion, which lowers serum uric acid concentrations, thus lowering cardiorenal risks.3,4

Hyperglycemia increases glucose filtration and reabsorption by the kidney, a burden on kidney tissue that eventually causes decreased GFR and kidney disease.10 SGLT2 inhibitors directly reduce hyperfiltration and reabsorption, stabilizing GFR in adults with chronic kidney disease.3 In addition, evidence suggests that SGLT2 inhibitors increase oxygen delivery to kidney tissues, improve overall kidney metabolism, and protect renal mitochondrial function.10 

In animal studies, SGLT2 inhibitors have been associated with a reduction in oxidative stress and inflammation markers, although these finding have not yet been replicated in human studies.3 Some evidence suggests that SGLT2 inhibitors improve liver health and reduce fat deposition in the liver; larger studies are needed to confirm these findings and elucidate the mechanism.2,3 

SGLT2 inhibitors have several mechanisms that may protect cardiovascular function. They are associated with increased hematocrit through reduced plasma volume and potentially from stimulation of erythropoiesis.3 SGLT2 inhibitor treatment has been associated with reductions in cardiac fibrotic tissue and arterial stiffness.3

SGLT2 Dosage and Administration

The Table summarizes the dosing and administration of the 5 FDA-approved SGLT2 inhibitors, all of which are taken as an oral tablet.5-9 Several SGLT2 inhibitors are also available as part of a combination medication that includes metformin or another blood glucose-lowering drug.

Table. SGLT2 Inhibitors Dosing and Administration for Patients With Type 2 Diabetes 

Medication	Starting Dosage	Available Doses, Dosing Schedules	Max Dose
Bexagliflozin	20 mg/d in the morning	20 mg	20 mg/d
Canagliflozin	100 mg/d before first meal	100 mg, 300 mg. Dosage may be increased from 100 mg/d to 300 mg/d as needed for additional glycemic control. Adjustments needed for patients with renal impairment and/or concurrent use with a UGT inducer	300 mg/d
Dapagliflozin	5 mg/d	5 mg, 10 mg. Dosage can be increased from 5 mg/d to 10 mg/d as needed for additional glycemic control. For patients with heart failure or chronic kidney disease, the recommended dosage is 10 mg/d	10 mg/d
Empagliflozin	10 mg/d in the morning	10 mg, 25 mg. Dosage can be increased to 25 mg/d as needed for additional glycemic control in patients who tolerate 10 mg/d	25 mg/d
Ertugliflozin	5 mg/d in the morning	5mg, 15 mg. Dosage can be increased to 15 mg/d as needed for additional glycemic control in patients who tolerate 5 mg/d	15 mg/d

UGT = UDP-glucuronosyltransferase.
From the FDA-approved prescribing information for each medication.5-9 

Warnings and Adverse Reactions

All SGLT2 inhibitors are contraindicated for patients who have hypersensitive reactions to SGLT2 inhibitor treatment.5-9 

Bexagliflozin, canagliflozin, and empagliflozin are not recommended for improving glycemic control in patients with type 2 diabetes who have an eGFR less than 30 mL/min/1.73 m2.5,6,8 Dapagliflozin and ertugliflozin are not recommended for improving glycemic control in patients with type 2 diabetes who have an eGFR less than 45 mL/min/1.73 m2.7,9

Patients treated with SGLT2 inhibitors are at increased risk of developing the following conditions:5-9 

• Increased urination;
• Serious urinary tract infections;
• Hypoglycemia;
• Ketoacidosis;
• Hypotension, particularly in older patients or those treated with diuretics;
• Acute changes in creatinine concentrations;
• Fungal infections of the genitalia; and
• Necrotizing fasciitis of the perineum (Fournier’s gangrene).

Treatment with each SGLT2 inhibitor except dapagliflozin has been associated with a slightly increased risk of experiencing adverse events such as lower limb infections, gangrene, ischemia, and osteomyelitis that could lead to lower limb amputations.5,6,8,9 Canagliflozin use is associated with an increased risk of bone fracture.6 

SGLT2 Inhibitors Drug Interactions

Each of the SGLT2 inhibitors has potential interactions with other medications that could have important clinical ramifications. Several of these potential interactions are shared by all SGLT2 inhibitors, such as their effects on the results of urine glucose testing and the 1,5-anhydroglucitol (1,5-AG) assay.5-9

Bexagliflozin Drug Interactions

Decreased serum lithium concentrations are possible with concomitant use of bexagliflozin and lithium.5 Drugs that induce uridine 5′-diphospho-glucuronosyltransferase (UGT) enzymes may reduce the efficacy of bexagliflozin. The use of bexagliflozin with insulin or insulin secretagogues increases the risk of hypoglycemia. Because it increases urinary glucose excretion, bexagliflozin can produce a positive result on urine glucose testing. When monitoring glycemic control, the 1,5-AG assay is unreliable in patients taking bexagliflozin, and alternative methods of glycemic testing should be used.5

Canagliflozin Drug Interactions 

Concomitant use of canagliflozin and digoxin increases the area under the curve and peak concentration of digoxin.6 Using canagliflozin and lithium together may decrease serum lithium concentrations. UGT enzyme inducers may reduce the efficacy of canagliflozin. The use of canagliflozin with insulin or insulin secretagogues increases the risk of hypoglycemia. Canagliflozin can produce a positive result on urine glucose testing, and the 1,5-AG assay is unreliable in patients taking canagliflozin.6

Dapagliflozin Drug Interactions 

Using dapagliflozin with insulin or insulin secretagogues increases the risk of hypoglycemia, and concomitant use with lithium may decrease serum lithium concentrations.7 Dapagliflozin can produce a positive result on urine glucose testing, and the 1,5-AG assay is unreliable in patients taking dapagliflozin.7

Empagliflozin Drug Interactions 

The simultaneous use of empagliflozin and a diuretic increases urine volume and urination frequency.8 Using empagliflozin with insulin or insulin secretagogues increases the risk of hypoglycemia. Concomitant use of empagliflozin with lithium may decrease serum lithium concentrations. Empagliflozin can produce a positive result on urine glucose testing, and the 1,5-AG assay is unreliable in patients taking empagliflozin.8

Ertugliflozin Drug Interactions

Patients taking ertugliflozin plus insulin or insulin secretagogues have an increased risk of hypoglycemia.9 Use of ertugliflozin with lithium may decrease serum lithium concentrations. Ertugliflozin can produce a positive result on urine glucose testing, and the 1,5-AG assay is unreliable in patients taking empagliflozin.9

Educating Patients About SGLT2 Inhibitors 

Knowing how SGLT2 inhibitors work and what to expect can help patients better manage their diabetes. In addition to recommending that patients review the Medication Guide that is part of the FDA-approved prescribing information for each SGLT2 inhibitor, clinicians can direct patients to several organizations offer patient-targeted information about these medications:

• National Kidney Foundation: Sodium-glucose cotransporter-2 (SGLT2) inhibitors;
• Diabetes UK: SGLT2 inhibitors; and
• FDA: Sodium-glucose cotransporter-2 (SGLT2) inhibitors.

References 

1. Xie X, Wu C, Hao Y, et al. Benefits and risks of drug combination therapy for diabetes mellitus and its complications: A comprehensive review. Front Endocrinol (Lausanne). 2023;14:1301093. doi:10.3389/fendo.2023.1301093
2. Yaribeygi H, Maleki M, Jamialahmadi T, Moallem AS, Sahebkar A. Hepatic benefits of sodium-glucose cotransporter 2 inhibitors in liver disorders. EXCLI J. 2023;22:403-414. doi:10.17179/excli2023-6022
3. Bonora BM, Avogaro A, Fadini GP. Extraglycemic effects of SGLT2 inhibitors: A review of the evidence. Diabetes Metab Syndr Obes. 2020;13:161-174. doi:10.2147/DMSO.S233538
4. Pereira Mj, Eriksson JW. Emerging role of SGLT-2 inhibitors for the treatment of obesity. Drugs. 2019;79:219-230. doi:10.1007/s40265-019-1057-0
5. Brenzavvy. Prescribing information. TheracosBio; 2023. Accessed October 2, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/214373s000lbl.pdf 
6. Invokana. Prescribing information. Janssen Pharmaceuticals; 2024. Accessed October 2, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/204042s041s042lbl.pdf
7. Farxiga. Prescribing information. AstraZeneca Pharmaceuticals; 2024. Accessed October 2, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/202293s031lbl.pdf
8. Jardiance. Prescribing information. Boehringer Ingelheim Pharmaceuticals; 2023. Accessed September 12, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/204629s040lbl.pdf
9. Steglatro. Prescribing information. Merck & Co; 2024. Accessed October 2, 2024. https://www.merck.com/product/usa/pi_circulars/s/steglatro/steglatro_pi.pdf
10. Nespoux J, Vallon V. Renal effects of SGLT2 inhibitors: An update. Curr Opin Nephrol Hypertens. 2020;29(2):190-198. doi:10.1097/MNH.0000000000000584