SGLT2 inhibitors have been trending in the type 2 diabetes world for years now. In fact, they’ve also become very popular in treating people with heart failure and chronic kidney disease who don’t even have diabetes. These once-daily oral daily medications (sodium-glucose cotransporter inhibitors, if you want to show off to your friends) work by helping the kidneys get rid of excess glucose in the blood through the urine, which gives them diuretic properties as well.
The Benefits of SGLT2s in T2D
All large trials involving SGLT2s like canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance) showed modest hemoglobin A1c and weight reduction, but demonstrated remarkable benefits in preventing heart failure admissions to the hospital, reducing protein spillage by the kidneys, and delaying the progression of kidney disease. Several studies are looking into how and why these cardiovascular and kidney benefits occur with SGLT2s. One school of thought is that their diuretic properties lead to an improvement in blood pressure, and therefore cardiorenal protection.
The burning question, however, is when and how can we use SGLT2 inhibitors in type 1 diabetes, in conjunction with insulin? At the current time, the FDA has only approved them for use in type 2. Can people with type 1 receive the same short- and long-term kidney and heart benefits while achieving weight loss and glucose stability?
The Benefits of SGLT2s in T1D
There have been trials dating back to 2018 looking at the use of SGLT2s in conjunction with insulin in type 1 diabetes. These studies showed benefits in reducing A1c, controlling glucose fluctuations, improving time in range (TIR), observing less insulin use, weight loss, and reduction in protein spillage into the urine, which is a sign of kidney dysfunction from uncontrolled glucose over many years. Large trials like EASE-2, EASE-3, DEPICT 1, DEPICT 2, inTandem1 and inTandem2 have corroborated these benefits.
The FDA Holdup
So what’s Preventing the FDA from Approving SGLT2s for Type 1 Diabetes in the U.S.? The answer is the not-so-trivial 3-4% increase in diabetes ketoacidosis (DKA) seen with all the SGLT2s in these short-term studies in people with type 1. Uniquely, these medications increase the risk of a phenomenon called “euglycemic (normal sugar) ketoacidosis” which presents like DKA, but with normal blood sugars, potentially delaying diagnosis by patients and providers. Most people with T1D had DKA with very high glucose levels when they were first diagnosed with diabetes.
European Approvals of SGLT2s in T1D
In contrast to the FDA, in the spring of 2019, the European Commission approved sotagliflozin (Zynquista) and dapagliflozin (Farxiga) to add to insulin for people with type 1 diabetes, and later also approved canagliflozin (Invokana). On July 12, 2019, the National Institute for Health Care Excellence (NICE) in the U.K. issued draft final guidance on dapagliflozin with insulin for treating type 1 diabetes. In Europe, SGLT2 inhibitor use with insulin is recommended as an option for adults with type 1 diabetes with a BMI of at least 27 kg/m2 when insulin alone does not provide adequate glycemic control. The draft guideline states that dapagliflozin should be considered only when patients have completed a structured education program that includes information about the risk for DKA, how to recognize risk factors for DKA, how and when to monitor blood ketone levels, and what actions to take for elevated blood ketones, even in the absence of high blood glucose levels.
SGLT2 inhibitors have transformed the lives of many people with type 2 diabetes, as well as many people with cardiovascular and kidney diseases. The benefits of controlling high sugars, weight loss, cardiovascular and kidney protection are seen in off-label trials and case studies in people with type 1 diabetes using these medications as a supplement to insulin. But people with type 1 diabetes are certainly at higher risk of DKA with these medications, so regulatory agencies here in the US, medical providers, and those living with type 1 need to be vigilant in monitoring for DKA should SGLT2 inhibitors eventually get the much-needed approval nod from the FDA.
How to Know If You Might Be a Candidate for SGLT2s
Although diabetes technology has come a long way, medication options for type 1 diabetes still consist of just insulin (Symlin is also approved for use in type 1). Tapping into the type 2 diabetes successes and having the ability to use oral and injectable non-insulin drugs with various benefits on other organ systems is integral to minimize long-term complications in type 1 diabetes.
In my opinion, here’s who may benefit from SGLT2 inhibitors use in the type 1 community:
- People who have had type 1 diabetes for a longer duration (>15-20 years), as we know cardiovascular and kidney complications increase with longer-term diabetes, and SGLT2 inhibitors would be a very beneficial addition in this scenario.
- People with a slightly higher BMI, as this will help to prevent the risk of diabetic ketoacidosis
- People with known or pre-existing heart failure, stroke, heart attack, or kidney complications like microalbuminuria (i.e protein spillage in the urine) or worsening kidney function due to diabetes.
- People who meet the first criteria with a propensity toward insulin resistance, and who are also overweight/obese (BMI over 25).
- People who meet one or more of the above criteria and have an understanding of how to monitor ketones after starting an SGLT2.
Here’s who may have adverse effects like DKA with SGLT2 inhibitors and should use caution:
- People who are underweight, who have an eating disorder, who restrict calories, or who are on a low carbohydrate diet (less than 30g/day), as all increase the risk for ketoacidosis.
- People who have uncontrolled diabetes with an A1c over 9%, and/or recurrent DKA episodes.
- People who skip or forget insulin, as lowering or omitting insulin doses in addition to SGLT2i use could put them at a higher risk for DKA.
- Young, lean-to-thin people who have had type 1 diabetes for less than 15 years, with no cardiovascular risk factors. We need more long-term data on young people using SGLT2s as these agents do not have a long duration of follow-up for type 1 diabetes.
- People with poor follow-up or limited access to their HCP.
Get Educated about DKA
If you have type 1 and you are interested in trying an SGLT2, talk to your doctor to see if it would be beneficial for you in off-label use, and get educated about recognizing and treating DKA and euglycemic DKA to prevent a trip to the hospital.
Ongoing Clinical Trials
We feel that SGLT2 inhibitors will become an important class of oral medications for people with T1D to prevent or delay kidney disease, reduce congestive heart failure and other cardiac issues, better control diabetes, and help to reduce excess weight and blood pressure.
Risk mitigation strategies must be in place, which starts with education to the individual with type 1 diabetes who could benefit from these medications. Having supplies to test for ketones in the blood and urine will be important, and there is even talk now of a device that measures ketones continuously in a similar fashion to continuous glucose monitors. Stay tuned as this option of SGLT2s for people with T1D has the potential to make a big impact.