Two Positive Recommendations by a Regulatory Agency for SGLT Use in Adults with Type 1 Diabetes
By Jeemin Kwon and Emily Fitts
Farxiga and Zynquista are recommended for approval for people with type 1 diabetes in Europe with emphasis on DKA safety; EMA approval likely in coming months and hope for approval in US
Editor's note: This article was updated on March 1, 2019.
A European Medicines Agency (EMA) committee has recommended approval of Farxiga (an SGLT-2 inhibitor pill called Forxiga in Europe) for adults with type 1 diabetes. Soon after, the EMA committee also recommended approval of Zynquista (an SGLT-1/2 dual inhibitor) for adults with type 1.
These recommendations are part of a larger discussion around whether or not to approve use of SGLT inhibitors such as Farxiga, Invokana, Jardiance, and Zynquista for people with type 1. An official approval in the EU, which is likely to happen in the coming months, would be a huge milestone marking SGLT inhibitors as the first “adjunct,” or add-on, pill approved for people with type 1 to take with insulin. Given the ambiguous outcome of the FDA advisory committee meeting on Zynquista in January 2019, these recommendations are especially exciting for this patient-driven movement to get more treatment options approved. For more background on this topic, click here.
Notably, Zynquista is a new therapy intended for use in type 1 diabetes; Farxiga on the other hand has been approved for people with type 2 since 2012 in Europe and 2014 in the US. To read more about Farxiga and Zynquista, click here.
EMA’s decision to recommend approval of Farxiga was based on data from the DEPICT drug trials, which were sponsored by the manufacturer of Farxiga. DEPICT 1 showed that type 1 participants on Farxiga:
Reduced A1C by 0.4 - 0.5% from an average starting A1C of 8.5%
Increased their time in range (70-180 mg/dl) by about 2-3 hours per day, generally increasing from 10.5 hours to about 13 hours.
Lost about 5-7 pounds from an average starting weight of about 180 pounds, compared with no weight change for those taking a placebo
Decreased their total daily insulin dose by 9-13%, or about five to eight fewer units.
For Zynquista, EMA evaluated the pill based on the results from the inTandem drug trials, which were sponsored by the manufacturer of Zynquista. inTandem showed that compared to placebo (a “nothing” pill) type 1 participants on the smaller 200 mg dose of Zynquista:
- Reduced A1C by 0.25% from an average starting A1C of 7.6%
- Increased time in range (70-80 mg/dl) by 1.3 hours
- Lost about 5 pounds from an average starting weight of 192 pounds, while those in the placebo group gained an average of 2 pounds
- Decreased their total daily insulin dose by 4%, or about two units
The EMA recommends Farxiga and Zynquista for people with type 1 who have a BMI of 27 or more (see here for a BMI calculator). While we do not have the detailed reasoning behind this recommendation, it is likely that people with a higher BMI are at lower risk for diabetic ketoacidosis (DKA), which is the main safety concern about people with type 1 using SGLT inhibitors. 1-2% of people on Farxiga experienced DKA during the study, compared to about 1% of people in the placebo group. The Zynquista trials showed slightly higher rates of DKA – 3% of people taking Zynquista experienced DKA, compared to about 1% of people on placebo.
Understanding how SGLT inhibitors work helps explain the increased risk for DKA. SGLT inhibitors lower blood sugars independently of insulin by allowing glucose to be excreted through the urine. As blood sugars start to decline, healthcare providers commonly lower insulin doses for their type 1 patients. However, the body needs insulin to convert glucose into energy. When insulin or carb 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, which is a potentially life-threatening problem. It often occurs in people with diabetes who need insulin but don’t take enough, or those who run very high blood sugars for a length of time (sometimes high blood sugars can be an indication that not enough glucose is entering cells). Many of the DKA cases in type 1s taking an SGLT inhibitor have occurred at “normal” blood glucose levels (225 mg/dl or lower) rather than the super high levels normally associated with DKA. This is called “euglycemic DKA.”
To further reduce the risk of DKA, the EMA also recommended:
Excluding those with low insulin requirements from taking Farxiga or Zynquista
For those taking Farxiga or Zynquista, changing insulin doses carefully under the supervision of specialist healthcare providers
Educating people on risk factors for DKA and how to recognize signs and symptoms. One great way of addressing this is for patients to measure their ketones regularly or if they feel any sign of DKA symptoms, which include nausea, vomiting, stomach pain, fatigue, dry mouth, shortness of breath, and excessive thirst.
See our infographic on additional things people can do to reduce risk for DKA here.
Given the distressing data provided by the T1D Exchange on outcomes in type 1 – only 17% of youth and 21% of adults seeing endocrinologists are meeting A1C goals – the need for additional therapies on top of insulin is all too urgent. This news brings hope to many who were expecting a more positive outcome from the US FDA advisory committee, whose vote came to an 8-8 tie on whether or not to approve Zynquista for type 1 in the US. Notably, in Japan, an SGLT inhibitor called Suglat (ipragliflozin) has recently been approved for type 1s as an add-on treatment to insulin.