SGLT-2 Inhibitors for Blood Glucose Lowering

Canagliflozin, Dapagliflozin, Empagliflozin, Ertugliflozin

Smiling man checking his blood glucose levels

 Hero Images / Getty Images

In This Article

Sodium-glucose co-transporter 2 inhibitors or (SGLT-2 inhibitors) are a class of diabetes medication that has been shown, when used in conjunction with diet and exercise, to reduce the amount of sugar in the blood by excreting it through the urine.

The U.S. Food and Drug Administration (FDA) has approved four SGLT-2 inhibitors for Type 2 diabetes:

  • Invokana (canagliflozin)
  • Farxiga (dapagliflozin)
  • Jardiance (empagliflozin)
  • Steglatro (ertugliflozin)

These medicines have been approved as monotherapy (to be used alone) or in combination with other glucose-lowering drugs.

In most instances, SGLT-2 inhibitors will be added to a diabetes regimen as a second medication in addition to metformin, unless metformin is not tolerated in which case they will be prescribed differently. The exact way they are prescribed depends on a variety of factors, such as a persons diabetes control, other health conditions, past medical history, and current medications.

How SGLT-2 Inhibitors Work to Control Blood Sugar

SGLT-2 inhibitors work with your kidneys to help remove excess glucose (sugar) from your body when you urinate.

The kidneys are partially responsible for the body’s regulation of glucose through glucose production and utilization as well as filtration and reabsorption. As kidney function declines this process becomes less efficient.

SGLT-2 inhibitors work by inhibiting the reabsorption of glucose; instead of sending sugar back into the bloodstream, it is excreted via urine.

As the body removes excess sugar from the blood into the urine, the loss of sugar, often yields weight loss, another critical component to blood sugar control.

The amount of blood sugar reduction will depend on which type of SGLT-2 is being used and the dose, any additional medicines the person with diabetes is taking, diet, and exercise.

The American Diabetes Association (ADA) states, "According to a 2013 meta-analysis, the glucose-lowering efficacy of SGLT-2 is in T2D (Type 2 diabetes) patients without severe renal impairment and baseline HbA1c of 6.9–9.2% is on average 0.79% when used as monotherapy and 0.61% when used as additional therapy." This means that if the SGLT-2 is used alone it can roughly reduce a hemoglobin A1c by 0.79%, and if used as an additional therapy it is estimated to reduce hemoglobin A1c by 0.61%.

For example, if you are a person with Type 2 diabetes who is already taking metformin and have a hemoglobin A1c of 8.0%, starting an SGLT-2 inhibitor may reduce your A1c to around 7.4%. Keep in mind that this is subjective and varies from person to person.

In addition, the ADA suggests that the higher the blood sugars are before starting the medicine the more glucose reduction will be seen. A person's kidney function also plays a role in medicine effectiveness and should be taken into consideration before starting.

SGLT-2 Inhibitors and Other Health Outcomes

Some SGLT-2 inhibitors have been shown to have cardiovascular benefits and are recommended over other types of diabetes medications for those with heart disease.

In 2018 the ADA Standard of Care began calling for the use of a glucose-lowering agent with cardiovascular benefit as second-line therapy in Type 2 diabetes patients with established cardiovascular disease (CVD) who don't meet glycemic targets with lifestyle modification and metformin.

This recommendation was confirmed in 2019 by the ADA, suggesting that SGLT-2 inhibitors be used for those patients with diabetes who have cardiovascular disease. In addition, they recommend, that "among patients with atherosclerotic cardiovascular disease at high risk of heart failure or in whom heart failure coexists, sodium-glucose cotransporter 2 inhibitors are preferred."

Lastly, the ADA recommends that practitioners consider prescribing an SGLT-2 inhibitor for those people with chronic kidney disease as they are shown to reduce the risk of chronic kidney disease progression.

Research has demonstrated cardiovascular benefits by reduction of cardiovascular events, such as mortality and heart failure. Specifically, empagliflozin and canagliflozin have shown cardiovascular benefits in large clinical trials such, EMPA-REG and CANVAS, where both demonstrated a reduction in heart failure and reduction in chronic kidney disease (CKD).

Empagliflozin, in particular, has also been implicated as preventing cardiovascular mortality reduction. Researchers determined in a post hoc analysis, that the use of dapagliflozin (Jardiance) reduced major adverse cardiovascular events, such as all-cause mortality and renal events.

The cardiac benefits of ertugliflozin have not been thoroughly studied, as this medication was recently approved for use in the U.S. in 2017. More studies will likely take place in the future to assess its efficacy on cardiac outcomes.

How and When to Take Them

These types of medications are prescribed in pill form and are usually taken before the first meal of the day. They can be taken with or without food and depending on the brand of medication you are prescribed and your blood sugar control; your dose may be increased as needed.

If you skip a dose, take your next dose when you remember unless it is the usual time of regular dosage, in which case you would skip the missed dose. Do not take two doses at the same time as this can increase your risk of hypoglycemia (low blood sugar).

Additionally, if you are taking an SGLT-2 inhibitor as a combination medication, meaning it is mixed with another type of diabetes medicine such as metformin or a DPP-inhibitor, you may be instructed to take the medicine twice daily.

Whether you are taking an SGLT-2 as a single pill or a combination pill, it is always important to follow careful dosage instructions on your package insert and consult with your health care provider if you have any questions.

Side Effects

Common side effects of SGLT-2 medications include:

In addition, people taking this medicine are at increased risk of dehydration and electrolyte imbalance.

Maria Rodriguez, RD, CDE, and manager of the Diabetes and Cardiovascular Alliance, says, "It's very important for people taking SGLT-2 inhibitors to be educated on the importance of hydration, especially during warm months."

Other less common but potential side effects include:

  • Kidney injury
  • Bone fracture
  • Although it is not a weight-loss drug, weight loss can occur
  • Increased risk of lower limb amputations (more likely to occur when taking canagliflozin or ertugliflozin)
  • Necrotizing fasciitis of the perineum (Fournier’s gangrene)
  • Increased LDL cholesterol

Keep in mind these side effects differ based on the brand of SGLT-2 inhibitor.

Contraindications

This class of diabetes medications is contraindicated in:

  • People with Type 1 diabetes
  • Those in diabetic ketoacidosis (DKA)
  • Those with established kidney disease or those on dialysis

Additionally, people who are allergic to the ingredients in SGLT-2 inhibitors should avoid taking them.

People who have specific pre-existing health conditions should not take certain types of SGLT-2 inhibitors.

For example, those people with a history of peripheral arterial disease, a disease that decreases blood flow to the feet and increases the risk of lower extremity amputation, should not take SGLT-2 inhibitors that have been shown to increase the risk of toe amputation. Women who are pregnant should also avoid this medicine.

Before starting any new medication it's important to discuss all of your health conditions with your health care provider.

In addition, certain medications should not be taken in combination with this class of drug. For example, if you are taking a diuretic that increases your risk of fluid loss, this medication is probably not right for you. Carefully review your medication with your physician before starting this medicine.

Cost

This class of medication is one of the pricier oral diabetes medicines. However, different insurances will have different brands on their formularies, lowering the cost.

To help with the cost of your treatment, pharmaceutical companies can offer discounts and plans to reduce payment. If your doctor has prescribed this and cost is an issue for you, it's important to let them know.

A Word From Verywell

Diabetes medicines are prescribed as an adjunct to diet and exercise to help people with Type 2 diabetes control their blood sugar.

The American Diabetes Association states, " A patient-centered approach should be used to guide the choice of pharmacologic agents. Considerations include comorbidities (atherosclerotic cardiovascular disease, heart failure, chronic kidney disease), hypoglycemia risk, impact on weight, cost, risk for side effects, and patient preferences."

SGLT-2 inhibitors are usually used as a second or third-line medication in the treatment of diabetes. They help the body excrete excess glucose through the urine and may cause weight loss.

Certain types of SGLT-2 inhibitors may provide additional cardiovascular benefits, however, they can be expensive and also increase the risk of other side effects. Therefore, before beginning any new type of medicine, it is important for your health care provider to take careful consideration of your overall medical history, and goals.

Was this page helpful?

Article Sources

  1. van Baar MJB, van Ruiten CC, Muskiet MHA, van Bloemendaal L, IJzerman RG,  van Raalte DH. SGLT2 Inhibitors in Combination Therapy: From Mechanisms to Clinical Considerations in Type 2 Diabetes Management. Diabetes Care. 2018 Aug; 41(8): 1543-1556. doi:10.2337/dc18-0588

  2. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015 Nov 26;373(22):2117-28. doi:10.1056/NEJMoa1504720.

  3. Clegg L, Heerspink HJL, Penland RC, et al. Reduction of cardiovascular risk and improved estimated glomerular filtration rate by SGLT2 Inhibitors, including dapagliflozin, Is consistent across the class: an analysis of the placebo arm of EXSCEL. Diabetes Care. 2019 Feb; 42(2): 318-326. doi:10.2337/dc18-1871

Additional Reading