SGLT Trials Show Lower A1Cs, Higher Chance of DKA


The type 1 diabetes (T1D) treatment world is filled with complex acronyms, drug names, emerging treatments and more. Case in point: SGLT-1 and SGLT-2 inhibitors. This newer class of drugs and their efficacy in treating type 1 diabetes were discussed in depth earlier this summer at the American Diabetes Association’s (ADA) 78th Scientific Sessions conference in Orlando, Florida.

If you’re currently asking, “SGLT-what?” well, we’re here to help. Inhibitors are the class of oral drugs that include AstraZeneca’s Farxiga (SGLT-2), Boehringer Ingelheim’s Jardiance (SGLT-2) and Lexicon’s Zynquista (the first dual SGLT-1 and SGLT-2 inhibitor). The drugs work by inhibiting the body’s productions of sodium-glucose transport proteins, which are the proteins that reabsorb glucose. SGLT-2 inhibitors focus on the type 2 protein and work by stopping the kidneys from reabsorbing glucose back into the blood. Instead of staying in the bloodstream, excess sugars are expelled from the body via urine, lowering overall blood glucose levels (BGLs). SGLT-1 inhibitors perform a similar function, but focus on the type 1 protein, which controls glucose reabsorption primarily in the intestines, as opposed to kidneys.

While inhibitors used alongside insulin have shown the ability to improve blood glucose control before and after mealtimes and improve A1C results, they have always carried an increased risk of diabetic ketoacidosis (DKA), a serious complication that occurs when the body produces high levels of blood acids called ketones. The condition, which is serious, normally occurs when the body doesn’t have enough insulin. Cells can’t use stored blood sugar for energy, so instead begin burning fat as fuel.

The drugs have been used for a few years to treat patients with type 2 diabetes, where DKA is less of a risk, insulin therapy is uncommon and the side benefit of weight loss is often more necessary.

In Orlando, data were reported from inTandem1, a study of the safety and efficacy of the dual inhibitor Zynquista as a companion treatment alongside insulin therapy in T1D adults, and from DEPICT-2, a trial of the SGLT-2 inhibitor Farixa, which was also paired with insulin for treatment of adults with type 1 diabetes. Results for the inTandem1 study were published in Diabetes Care in June.

During the double-blind, 52-week phase 3 trial inTandem1 trial, patients were either given a placebo dose, 200 mg of Zynquista, or 400 mg of Zynquista after six weeks of insulin optimization. A drop under 7 percent A1C was seen by 15.7%, 27.2% and 40.3% of patients respectively, evidencing that the dual inhibitor did decrease A1C.

The study conclusions found that Zynquista combined with optimized insulin therapy was associated with sustained A1C reduction, weight loss, lowered insulin doses, fewer episodes of severe hypoglycemia and improved patient-reported outcomes.

However, some patients did see an elevated risk of DKA when using these drugs along with insulin. The authors of the studies were Dr. John Buse of the University of North Carolina Chapel Hill and Dr. Chantal Mathieu from the University of Leuven in Belgium. In presentations, both felt the study data showed an overall benefit that outweighed the risk of DKA risk and other possible side effects, like diarrhea and genital infection.

Dr. Anne Peters, MD, and a diabetologist at USC, has been using SGLT-2 inhibitors both in her research and practice for years with extremely positive results. “My patients love them,” she said. “They feel that their diabetes management is better, their variability is less and their time in range is greater. I teach my patients how to avoid going into ketoacidosis and so they don’t.”

Cases of SGLT-2 inhibitor-associated DKA have also been previously reported in patients with type 2 diabetes, and among type 1 patients given the drugs off-label (none of the drugs in the class are currently approved for treating type 1). Several years ago, the U.S. Food and Drug Administration (FDA) issued a warning about the DKA risk.

All study participants started with stable, low A1Cs. In the inTandem1 trial the mean A1C reductions ranged from 0.25 to 0.39 percentage points, depending on dose and duration. Some might argue that reductions that small are not enough to justify the risk of DKA and other side effects.

Dr. Chantal Mathieu said that DKA risk could be mitigated with adequate provider and patient training, pointing to the importance of educating treatment teams and patients so they’ll understand how to measure ketones and the importance of measuring them, as opposed to just dosing insulin.

“We believe we can make mitigation plans to educate doctors and educators involved in treating people with type 1 diabetes,” Mathieu said in Orlando.

Dr. Buse was optimistic as well. “It’s really remarkable how much patients with type 1 diabetes like these drugs,” he said. “But I think patient selection and the expertise of the treating team with regard to educating patients is going to be critical.”

Anne Peters echoed the importance of education in preventing DKA in patients using the SGLT-2 inhibitors. “First and foremost it’s about education,” she said, “This drug makes blood sugars lower, so you can be in ketoacidosis with a really normal blood sugar level, and therefore if people feel sick or are dehydrated or doing some activity that might make them prone to being insulin resistive, I have them check their ketones.

“If their ketones are elevated, then that means that person needs to eat carbohydrate and take insulin. A lot of time when people are talking about DKA, they think of just giving them fluids and giving them insulin. But that is not so here. You have to eat carbs and dose insulin.

“To prepare my patients I start them by testing ketones for a week or so before I put them on the SGLT-2 inhibitors so that they know what their baseline is. And then I begin by giving out a quarter or half a pill because I don’t want anything worsening.

“You can’t reduce the insulin a lot because people are more a risk. It’s all about the balance, and how much insulin your body needs in order to not go into diabetic ketoacidosis. I adjust the insulin a little bit and honestly I just give them a little bit less. For example, if you are doing less then don’t take your pill that morning. Some of my patients like to go drinking on a Friday night. And I tell them, well drinking can put you at risk for ketones. Don’t take your pill on Friday. I work with people to understand the circumstance in which they are gonna be to determine if they might become more ketonic.”

The potential negative side effects and the hassle of having to measure ketones may keep some patients skeptical. Despite the added things to consider, it’s a treatment with apparent validity. And it seems that FDA approval may be coming in the near future for Jardiance for type 1 treatment. The drug was approved for type 2 treatment in 2014.

While results were not announced, Boehringer Ingelheim and Eli Lilly said in June that in a completed phase 3 trial for T1D treatment all three tested doses of Jardiance met the the primary efficacy goal for A1C lowering after 26 weeks of treatment.

Nearly 1,700 patients were enrolled into the two Jardiance trials, called EASE-2 and EASE-3. The company said full results won’t be available, however, until October, during the annual meeting of the European Association for the Study of Diabetes.

Read more on Type 2 diabetes medications for Type 1 treatment.

WRITTEN BY Greg Brown, POSTED 08/14/18, UPDATED 10/29/22

Greg Brown is a freelance health, finance and environmental writer living in the mountains of western Maine. He has written for Consumer Reports Magazine, Consumer Reports Online, The New York Times and The Chicago Tribune, among other publications. He holds an MFA in Fiction Writing from the University of Iowa Writers’ Workshop and an MS in Journalism from Columbia University.