AT EASD 2017

LISBON (FRONTLINE MEDICAL NEWS) – Further phase 3 trial data show that the investigational dual sodium-glucose cotransporter 1 and 2 (SGLT1/2) inhibitor sotagliflozin added to insulin helped people with type 1 diabetes mellitus (T1DM) to achieve their blood glucose targets, but such treatment is not without its risks, according to results reported at the annual meeting of the European Association for the Study of Diabetes.

In the inTandem3 trial, 28.6% of 699 people with T1DM treated with sotagliflozin on top of their usual insulin therapy achieved the primary composite endpoint, which was a glycated hemoglobin (HbA1c) level of 7% or lower at Week 24, with no episodes of severe hypoglycemia or diabetic ketoacidosis (DKA). In comparison, 15.2% of the 703 individuals who received a placebo in addition to their insulin therapy achieved this endpoint (P less than .001), according to Melanie J. Davies, MD, who presented the inTandem3 study results during a symposium on the sotagliflozin clinical program. The results were published online in the New England Journal of Medicine (2017 Sep 15. doi: 10.1056/NEJMoa1708337 ) to coincide with their presentation at the meeting.

From baseline to week 24, sotagliflozin treatment was also associated with significantly greater decreases versus placebo in glycated hemoglobin (–0.79% vs. –0.33%; P = .001), the mean total (–5.3 units vs. –0.1 units; P less than .001) and basal (–1.7 units vs. 0.9 units; P = .001) dose of insulin, as well as reductions in weight (–2.21 kg vs. 0.77 kg; P = .001) and systolic blood pressure (–9.2 mm Hg vs. –5.7 mm Hg; P = .002), according to the investigators.

However, the overall rate of DKA was higher in the patients treated with sotagliflozin than in those on placebo, at 3% versus 0.6%, respectively. DKA events most often occurred in persons using insulin pumps (4.4% vs. 9.7%) than in those taking insulin via multiple daily injections (2.1% vs 0.5%). Furthermore, in a post-hoc analysis, it was found that the rate of at least one episode of DKA was significantly higher in sotagliflozin- than placebo-treated patients who failed to reach the HbA1c target of below 7% (P less than .003), reported Dr. Davies.

The study findings “build on data seen inTandem 1 and inTandem 2 but in a more pragmatic design,” said study investigator Melanie Davies, MD , professor of diabetes medicine at the University of Leicester (England).

The inTandem studies

Dr. Davies observed that the sotagliflozin clinical trials program in persons with T1DM involved three phase 2 and three phase 3 studies. The latter, inTandem1, inTandem2, and inTandem3, were all 24-week trials, but there were some differences in the design.

inTandem1 and inTandem2 were the pivotal studies, one conducted in 793 patients in North America and the other in 782 patients in Europe and Israel. After a 2-week screening period, participants underwent a 6-week insulin optimization program before they were randomized to one of two doses of sotagliflozin (200 mg or 400 mg) or placebo for 24 weeks, with follow-up out to 52 weeks. The primary endpoint of these studies was the reduction in HbA1c versus placebo at 24 weeks.

By comparison, inTandem3 was a global study involving 1,405 individuals with T1DM who did not undergo the 6-week insulin optimization period. Instead there was a 2-week run-in period after the initial screening, and the study ran for only 24 weeks. Only one dose (400 mg) of sotagliflozin was used and the primary endpoint was a composite to try to see what the net clinical benefit would be, Dr. Davies explained.

The results of inTandem1 and inTandem2 were reported earlier this year at the American Diabetes Association Scientific Sessions, Dr. Davies noted, and sotagliflozin had “a good efficacy and safety profile as an adjunct to insulin in type 1 diabetes.”

The quest for adjunctive treatment

“For years we’ve been looking for adjunctive therapy for people with type 1 diabetes,” said Julio Rosenstock, MD , at the EASD meeting. Dr. Rosenstock, who is the director of the Dallas Diabetes Research Center at Medical City and involved in the sotagliflozin clinical trials program, noted that the quest for an adjunctive treatment was because “glucose control in type 1 diabetes remains tough and costly, despite multiple advances in insulin therapy, delivery systems, and monitoring methods over the years.”

Severe hypoglycemia, weight gain, glucose variability, and increased cardiovascular risk remain issues for managing people with T1DM, Dr. Rosenstock observed, and even in the best treatment centers the incidence of DKA still falls somewhere between 5% and 10%.

Several approaches to adjunctive treatment had been proposed, but so far all with limited value, Dr. Rosenstock maintained. Despite no evidence for a benefit of adding metformin, for example, registry data suggest that up to 5% of people with T1DM are using it.

The recent findings of the REMOVAL trial showed metformin did not help change the HbA1c over time and there was no change in the primary outcome, he observed but a small improvement in a tertiary endpoint. “I can’t think of a more negative cardiovascular outcomes trial,” Dr. Rosenstock asserted. “There is not enough justification to use metformin in type 1 diabetes.”

By contrast there is a strong rationale for using SGLT inhibition, partly as the glucose-lowering effects are independent of insulin’s activity. Through inhibition of SGLT1, sotagliflozin reduces glucose absorption in the proximal intestine, thus blunting or delaying rising postprandial glucose levels. By also targeting SGLT2, sotagliflozin can reduce glucose resorption by the kidneys.

Risks and clinical implications

In an editorial accompanying the published findings, David Nathan, MD , of Massachusetts General Hospital and Harvard Medical School in Boston, is not convinced that using adjunctive treatment is the future for better glycemic control in T1DM and that better automated insulin delivery systems will likely make adjunctive therapy unnecessary.

“Unfortunately, the results of this trial suggest that the increased risk of ketoacidosis counterbalances the increased likelihood of achieving a glycated hemoglobin of less than 7%,” he commented in the New England Journal of Medicine (2017 Sep 15. doi: 10.1056/NEJMe1711296 ). “There is little to suggest that the risk of ketoacidosis would be mitigated over time,” he added. Plus all of the study’s participants were carefully tutored and monitored on DKA in the study.

Dr. Nathan also observed “the rate of severe hypoglycemia in the whole sotagliflozin group was not significantly different from the rate in the placebo group,” and the risks and benefits of any adjunctive therapy for T1DM need to be carefully balanced.

While risks remain, one of the chairs of the session, Chantal Mathieu, MD, professor of medicine at the Katholieke Universiteit Leuven (Belgium), observed that “these are exciting times for all of us and hopefully for our patients.” She cautioned clinicians to remember, however, that “type 1 diabetes is a very different disease from type 2 diabetes, and so when we listen to [information about] all these adjunct[ive] therapies, when we read the papers, please interpret the data carefully.”

Dr. Mathieu added: “All these adjunct[ive] therapies will have to be used by experts because otherwise [we] might endanger [the health] of our patients.”

The trial was funded by Lexicon Pharmaceuticals. Sotagliflozin is being codeveloped with Sanofi. Dr. Davies disclosed acting as an advisor, consultant, or being a member of a speaker’s bureau for Sanofi-Aventis and several other companies. She was an investigator in the inTandem trials and her institution received funding from Lexicon to conduct the inTandem 2 and 3 clinical trials. Dr. Rosenstock disclosed research support and acting as an advisor to multiple pharmaceutical companies. Dr. Nathan had nothing to disclose. Dr. Mathieu chaired the session and did not present disclosures.