Using SGLT-2 Inhibitors to Help Manage Type 1 Diabetes

By Ann Carracher and Kelly Close

As early as 2019, the FDA could approve SGLT-2 inhibitors for adults with type 1, but some patients are already using these pills “off label”; see guidance from leading healthcare providers, but the most important suggestion: consult with your provider on any changes to diabetes management

As early as 2019, pending approval, there could be a non-insulin treatment approved to help treat type 1 diabetes: SGLT-2 inhibitors, which are once-daily pills already approved for type 2. As there are currently no other oral non-insulin treatments approved for type 1, this is significant. SGLT-2 inhibitors may help people with type 1 lower their A1C, increase time-in-range (70-180 mg/dl), lose weight, lower insulin doses, and reduce blood pressure. However, these won’t replace insulin, as they are “adjunctive” (add-on) treatments.

Given these benefits, a small but growing number of type 1 patients are already taking SGLT-2s “off label,” presumably working closely with their healthcare providers.  (“Off label” because the drugs are only officially approved for use in type 2.) Please keep in mind: according to the experts, type 1 patients should not take SGLT-2s unless they have consulted with their healthcare team, due to the increased risk of diabetic ketoacidosis (DKA), a complication resulting from having too little insulin available.  

Understanding how SGLT-2s work helps explain the increased risk for DKA. SGLT-2s lower blood sugars by allowing glucose to be excreted through the urine. Since this works independently of insulin, SGLT-2 inhibitors are effective in both type 1 and type 2 diabetes. The other aspect is that with type 1 patients, healthcare providers commonly lower insulin doses as blood sugars start to decline. However, the body needs insulin to convert glucose into energy. When insulin levels go too low in type 1 diabetes, the body turns to breaking down fat for energy, leading to an accumulation of ketones (a byproduct of fat breakdown). While having some ketones in the blood is not harmful – e.g., ketones that appear in low-carb diets – high ketone levels can result in DKA. 

Despite the strong benefits for some, studies of two SGLT-2s, Farxiga and Zynquista (actually an SGLT-1/2 dual inhibitor), showed an increased risk for DKA in type 1 patients compared to placebo. Between 1 – 3% of study participants experienced DKA, compared to 1% of the general type 1 diabetes population who experience DKA. DKA can be treated with insulin and glucose, but it can also lead to hospitalization and death. Ultimately, the FDA will decide whether the DKA risk associated with these drugs can be managed. 

It’s also very important to know that SGLT inhibitors can cause “euglycemic DKA,” or DKA at a blood sugar level much lower than is typical for DKA (i.e., 225 mg/dl or lower is what most experts point to). This is why, when taking an SGLT-2 inhibitor, ketone monitoring (using a blood meter or urine strips to measure ketone levels) is critical when feeling nauseous or otherwise unwell: blood sugar levels can seem normal, but ketone levels may be dangerously high. Click here for more info on how to measure ketones. 

The next section summarizes the positions of four leading endocrinologists about using SGLT-2s for people with type 1 diabetes. It goes without saying that diaTribe does not provide medical advice. Because of the additional risks, please make sure you discuss these issues very carefully with your healthcare provider. 

Click to jump to a section: 

• Who is a “good candidate” for taking an SGLT-2 inhibitor?

• What are “best practices” when taking an SGLT-2 inhibitor?

• What situations are high risk for developing DKA?

• What symptoms of DKA should someone watch out for?

• What is an appropriate response to high ketone levels?

• Background on important items for patients

diaTribe: Who is a “good candidate” for taking an SGLT-2 inhibitor?

Endocrinologists: Someone who can:

• Consistently check blood sugar
• Check ketones as recommended (frequency to be determined with healthcare provider)
• Consistently take insulin

diaTribe: Who is not a “good candidate”?

Endocrinologists: Someone who:

• Has frequent and serious hypoglycemia

• Eats low-carb

• Lives a very active lifestyle (this may include endurance sports)

• Often misses insulin doses or at risk of missing doses 

diaTribe: What are “best practices” when taking an SGLT-2 inhibitor?

Endocrinologists: Any type 1 patient taking an SGLT-2 inhibitor should own a blood ketone meter or have urine test strips available. For more on how to check ketone levels and what a safe range is, read this article. Generally, ketones should be under 1 mmol/l; anything higher brings risk of DKA. People on low-carb diets may see ketones in the 0.5-3 mmol/l range, but higher than that is rare. This threshold in particular is still a topic of hot discussion.

That said, when taking an SGLT-2 inhibitor, endocrinologists currently recommend:

• Starting with the lowest possible dose, and even breaking a pill in half to make sure there aren’t any issues before increasing dosage.

• Measuring ketone levels. Check ketones before starting the SGLT-2 inhibitor, so there is a baseline measurement. It’s recommended to continue checking ketones after the initial start period. Importantly, many people see a consistent, small rise (still below 0.6 mmol/l) in ketone levels on an SGLT-2 inhibitor, but this is not unexpected. See this article on ketones and monitoring for more info.

• Reducing insulin dose. Whether reducing basal or mealtime insulin dose, this should be done carefully with your healthcare provider.

diaTribe: What situations are high risk for developing DKA?

Endocrinologists: Certain lifestyle factors can put someone at a higher risk for developing DKA on an SGLT-2 inhibitor, including the following:

• Low-carb and ketogenic diets

• General dieting (for weight loss)

• Low total daily insulin dose (less than about 40 units)

• Living a very active lifestyle

Additionally, experts say that most – if not all – episodes of DKA associated with SGLT inhibitors are thought to follow a “triggering” event, which can include:

• Missed or heavily reduced insulin dose

• Missed meals

• Pump or infusion set failure/blockage

• High alcohol intake

• Fasting or dieting

• GI distress (nausea, vomiting)

• Other acute illness

• Intense or long-term exercise (even, for example, a day of walking around a city or amusement park in hot weather)

• Surgery

• Excessive stress

Notably, these are all circumstances where someone might decrease their insulin dose. If feeling sick, expecting a “big” workout (such as a long hike or unusually intense gym session), or anticipating any of these other triggers, people should stop the SGLT-2 inhibitor and check ketone levels. It’s okay to “skip” one or two days of the SGLT-2 inhibitor until the situation stabilizes and then start again.

diaTribe: What symptoms of DKA should someone watch out for?

Endocrinologists: In the case of SGLT-2 inhibitor-related DKA, symptoms include:

• Nausea

• Vomiting

• Stomach pain

• Tiredness and malaise

• Excessive thirst or urination

• Dry mouth

• Shortness of breath

With euglycemic DKA, some experts have noticed shortness of breath from the ketoacidosis more so than excessive thirst or urination.

diaTribe: What is an appropriate response to high ketone levels?

Endocrinologists: If elevated ketones levels (greater than 1.0 mmol/l) or symptoms of DKA even without ketones are present, people should stop taking the SGLT-2 inhibitor, continue to measure ketones, proactively treat ketones per their healthcare provider's advice, and contact their healthcare provider. If using urine strips, it is worth testing again if symptoms persist, as it can take more time for ketones to appear in urine than in blood.

Endocrinologists: Treating excess ketones while on an SGLT-2 inhibitor – fast-acting carbs AND insulin

If ketones start climbing above someone’s baseline ketone level (ketones measured before starting an SGLT-2 inhibitor) and do not fall back down, treatment should include stopping the SGLT-2 inhibitor, consuming fast-acting glucose (orange juice, glucose tabs, candy, etc.) and appropriate insulin bolusing every 1-2 hours, plus liquids, until both blood sugar and ketone levels are back to normal. Sports drinks or other sugary beverages are particularly helpful to provide fluids and carbs simultaneously.

Depending on the severity of DKA, people may need to go to the emergency room, particularly when taking insulin and carbs do not lower ketone levels after a period of 4-6 hours, or if vomiting prevents consuming liquids or carbs and taking insulin. At the emergency room, it is critical to communicate that the DKA is probably the result of an SGLT-2 inhibitor and explain any triggering event that might have occurred. DKA is commonly misdiagnosed in the emergency room and not all ER staff will know how to treat it, especially when it results from an SGLT-2 inhibitor or is a case of euglycemic DKA. Once in the ER, the person should also alert his or her endocrinologist or usual diabetes care provider.

Background on important items for patients:

• Talking to your healthcare provider: If interested in asking a healthcare provider for an SGLT-2 inhibitor, you might say, “I’ve heard that some people with type 1 are taking SGLT-2 inhibitors. I know these aren’t approved for type 1 diabetes yet and they carry certain risks, but I’m very interested in seeing if they can help me lower my A1C, spend more time in range, and lose weight.” Here is the Zynquista research study, and here is the Farxiga study.

• Addressing cost: Insurance will not always pay for SGLT-2 inhibitors for type 1 diabetes (yet), but some insurance companies are covering them. As we explain in our access series, some with commercial insurance have been able to use “discount” copay cards, even getting the prescription for free, though this is not to be expected with off-label use.

• Side effects: Two common side effects of SGLT-2 inhibitors are urinary tract infections and yeast infections, because the drug increases sugar in the urine. Typically, these only occur once after starting the drug rather than recurring multiple times, and they respond to usual treatments. Some healthcare providers have recommended using products like petroleum jelly as a physical barrier and being extra-careful with personal hygiene.

• Pediatric use: There is no broadly available evidence for the use of any SGLT-2 inhibitor in those under age 18.

Some providers may not be comfortable using SGLT-2 inhibitors for people with type 1, while other providers have no such reservations. Very importantly, please note that the FDA has not yet recommended or approved SGLT-2 inhibitors for type 1. diaTribe does not endorse “off-label” use of SGLT-2 inhibitors but does know that since some people with type 1 are taking this drug, having access to safety information is key. We hope that this information can enhance the safety for type 1 patients working with their healthcare team.  

Healthcare providers whose statements are reflected in this piece:

• Dr. John Buse, MD, UNC Chapel Hill

• Dr. Thomas Danne, MD, AUF DER BULT, Kinder- und Jugendkrankenhaus

• Dr. Satish Garg, MD, University of Colorado Denver School of Medicine

• Dr. Anne Peters, MD, Keck School of Medicine of USC