InTandem3: Sotagliflozin Has Benefits and Risks in Type 1 Diabetes

Miriam E Tucker

September 13, 2017

LISBON, PORTUGAL — The addition of sotagliflozin to insulin may help improve glycemic control, blood pressure, and body weight in people with type 1 diabetes but at the same time raises the risks of ketoacidosis and other adverse events, new research shows.

Findings from the 24-week Phase 3 Study to Evaluate the Safety of Sotagliflozin in Patients With Type 1 Diabetes Who Have Inadequate Glycemic Control With Insulin Therapy Alone (inTandem3) were presented September 13 here at the European Association for the Study of Diabetes (EASD) 2017 Annual Meeting by Melanie J Davies, MD, of the University Hospitals of Leicester NHS Trust, United Kingdom. They were simultaneously published in the New England Journal of Medicine.

Sotagliflozin is an investigational novel oral inhibitor of the sodium–glucose cotransporters 1 and 2 (SGLT1 and SGLT2). The SGLT1 inhibition impedes glucose absorption in the proximal intestine, which reduces postprandial hyperglycemia, while SGLT2 inhibition decreases renal glucose reabsorption.

The drug was originated by Lexicon Pharmaceuticals, which is now working with Sanofi to develop the product for both type 1 and type 2 diabetes. There is currently only one adjunctive treatment for type 1 diabetes for use with insulin that is commercially available, the injectable pramlintide (Symlin, Amylin Pharmaceuticals). Several SGLT2 (only) inhibitors are currently on the market to treat type 2 diabetes, and some are also being investigated for type 1 diabetes.

inTandem Trials Too Short to Properly Judge Sotagliflozin

The new results are from inTandem3, the largest and the most global of three phase 3 studies of sotagliflozin as adjunctive treatment in patients with type 1 diabetes who don't achieve adequate glycemic control with insulin alone.

The first, inTandem1, was presented in June at the American Diabetes Association meeting. The second, inTandem2, will be presented here at EASD meeting in detail on September 14, but Dr Davies reviewed those data briefly in her presentation of the inTandem3 findings.

InTandem3 differs from the other two in that patients did not undergo a period of insulin optimization, only one dose of sotagliflozin (400 mg) was studied, and the composite end point — HbA1c level lower than 7.0% with no severe hypoglycemia or diabetic ketoacidosis — differed.

However, the findings of the three trials were generally similar in suggesting that sotagliflozin addresses an unmet clinical need in type 1 diabetes patients, both in regard to glycemic control and body weight.

But the increase in diabetic ketoacidosis (DKA) suggests that extra precautions be taken to mitigate that risk, study commentator John B Buse, MD, PhD, chief of endocrinology at the University of North Carolina School of Medicine, Chapel Hill, said.

"SGLT inhibition really does provide meaningful benefits, but at some risk to patients with type 1 diabetes. Therefore, work to minimize the risk," he advised.

Measures to do that include careful patient selection, starting with a low sotagliflozin dose, frequent ketone and glucose monitoring, and holding the drug during illness and for surgery or fasting, Dr Buse recommended.

But in an editorial accompanying the publication on inTandem3, David M Nathan, MD, chief of the Diabetes Center at Massachusetts General Hospital, Boston, suggested that the drug's side-effect profile could outweigh any potential benefit in type 1 diabetes patients.

"Unfortunately, the results of this trial suggest that the increased risk of ketoacidosis counterbalances the increased likelihood of achieving a glycated hemoglobin level of less than 7%," Dr Nathan writes, noting that a previous 18-week study of the SGLT2 inhibitor canagliflozin in type 1 diabetes patients also showed an increased DKA risk.

"The critical information necessary to judge the relative risks and benefits of adjunctive therapy…cannot be gleaned from such short-term studies," he adds.

Moreover, Dr Nathan notes that the ongoing progress in development of "closed-loop" automated insulin-delivery systems is likely to make adjunctive drug therapies for type 1 diabetes unnecessary in the near future, concluding, "Any added benefits of adjunctive therapies for type 1 diabetes must be carefully balanced against their added risks and costs. Physicians and patients should beware."

Benefits Seen for HbA1c, Weight, BP, and Severe Hypoglycemia

The multicenter, randomized, double-blind, placebo-controlled inTandem 3 trial was conducted at 133 sites in 19 countries. A total of 1405 adults with type 1 diabetes and baseline HbA1c 7.0% to 11.0% and body mass index (BMI) of 18.5 kg/m2 or greater were randomized 1:1 to receive either 400-mg/day sotagliflozin or placebo for 24 weeks, in addition to their routine insulin therapy (via pump or injections).

All subjects had baseline HbA1c above 7%, and 70% had BMI greater than 25 kg/m2, Dr Davies noted.  

The primary end point was HbA1c below 7.0% at week 24, with no episodes of severe hypoglycemia or DKA after randomization. The intention-to-treat population included 699 in the sotagliflozin group and 703 placebo patients.

Significantly more patients met the primary end point with sotagliflozin, 28.6% vs 15.2% of the placebo group, with an estimated 13.4-percentage-point difference between the two groups (P < .001).

More of the sotagliflozin group achieved HbA1c below 7.0%, 29.6% vs 15.8%, and the reduction in HbA1c from baseline was greater with sotagliflozin (difference, -0.46 percentage points, < .001), with even greater reductions seen in patients with higher baseline HbA1c.

Sotagliflozin was also associated with a greater reduction in body weight at week 24 (difference -2.98 kg, P < .001) and a greater reduction by week 16 in systolic blood pressure among those with baseline SBP of 130 mm Hg or higher (difference -3.5 mm Hg, = .002).

The proportion of documented hypoglycemia (< 70 mg/dL) was similar in the two groups, 96.3% with sotagliflozin vs 95.3% with placebo. But, the event rate of more severe hypoglycemia (< 55 mg/dL), was significantly reduced in the sotagliflozin group compared with placebo (11.8 vs 15.4 per person-year, respectively).

Downsides Include Higher DKA Risk, Genital Infections, and GI Effects

The overall rate of adverse events of any cause was similar between sotagliflozin and placebo, 55.1% vs 52.5%, and most were of mild to moderate severity.

However, diarrhea was more common with sotagliflozin than placebo (4.1% vs 2.3%), leading to discontinuation in 0.4% of participants overall. Genital mycotic infections occurred in 6.4% with sotagliflozin vs 2.1% with placebo, leading to discontinuation in less than 1% in either group.

And overall serious adverse events were more common with sotagliflozin (6.9% vs 3.3%), and more patients withdrew from the trial because of them (6.3% vs 2.3%).

Acidosis-related adverse events at week 24 occurred in 8.6% with sotagliflozin vs 2.4% with placebo, and one or more adjudicated DKA episodes occurred in 3.0% vs 0.6%. Those rates were 4.4% vs 0.7% among insulin-pump users and 2.1% vs 0.5% in those using injections, suggesting that at least some of the DKA cases related to device failure rather than the drug, Dr Buse pointed out.

Discontinuation due to DKA occurred in 1.6% of the sotagliflozin group vs 0.1% of the placebo group.

Prior to this trial, some had theorized that sotagliflozin's novel combination of SGLT1 and SGLT2 inhibition might result in lower rates of ketoacidosis in type 1 diabetes patients than SGLT2 inhibition alone, given that the SGLT1 inhibition results in less carbohydrate delivery to the circulation and lower urinary glucose excretion, possibly mitigating volume effects.

Also, if SGLT1 inhibition further reduced postprandial glucose levels, the need for reduction of basal insulin would be diminished. Moreover, more distal delivery of carbohydrates could also result in less glucagon production.

But Dr Buse said, "These hormonal subtleties pale in comparison to patient and provider factors in determining the risk of euglycemic DKA."

And, as to whether sotagliflozin's unique dual mechanism might offer greater benefits in type 1 diabetes beyond those of already-available SGLT2 inhibitors "for glycemia and weight, only a head-to-head study would adequately address the question," he asserted.  

The study was funded by Lexicon. Dr Davies is an investigator/consultant/advisory board member and/or speaker for Novo Nordisk, Sanofi, Lilly, Merck, Boehringer Ingelheim, AstraZeneca, Janssen, Servier, Mitsubishi Tanabe Pharma, and Takeda. Dr Buse reports grants, nonfinancial support, and other support from Sanofi and Lexicon and grants and nonfinancial support from National Institutes of Health during the conduct of the study, as well as grants, nonfinancial support, and other support from Eli Lilly, GI Dynamics, Merck, AstraZeneca, Sanofi, Intarcia Therapeutics, Lexicon, Orexigen, Takeda, and Novo Nordisk, nonfinancial support and other supprt from Elcylex Therapeutics, Metavention, vTv Therapeutics, Dance Biopharm, Adocia, and AstraZeneca HealthCare Foundation, other support from PhaseBio Pharmaceuticals, Insulin Algorithms, Dexcom, Fractyl, Shenzen HighTide, and NovaTarg, and grants from Medtronic Minimed, Johnson & Johnson, Boehringer-Ingelheim, GlaxoSmithKline, Scion NeuroStim, Theracos, and Bayer outside the submitted work.  Disclosures for the coauthors are listed on the journal website. Dr Nathan has no relevant financial relationships.  

N Engl J Med. Published online September 13, 2017. Article,  Editorial

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