Before randomization patients were advised to reduce their basal insulin doses by 20% if their HbA1c was below 8% and by 10% if it was above 8% to reduce the potential hypoglycemia risk. During treatment, they were instructed to titrate their basal and bolus insulin doses to achieve premeal and bedtime glucose levels between 80 and 120 mg/dL. Both doses of canagliflozin reduced the need for total daily insulin, with mean changes from baseline of –4.1 IU/day and –7.6 IU/day for the 100- and 300-mg doses, respectively. Reductions in basal and bolus insulin were –4.3 and –0.3 IU/day for the 100-mg dose and –0.3 and 03.2 for the 300-mg dose.
Patients with severe hypoglycemia or DKA within 6 months of randomization were excluded from the trial, with around 15% and 12%-13% of patients enrolled having had a prior history of either at any time. The rate of treatment-emergent hypoglycemia episodes were similar across the groups, at 97% for placebo and 98%-99% for canagliflozin/patient-year of exposure. Serious ketoacidosis events occurred in 4% and 6% of the canagliflozin 100- and 300-mg groups, but in all cases, there were precipitating factors that likely continued to the event, Dr. Henry said.
“Implementation of additional mitigation strategies in future studies may substantially reduce DKA risk in patients with type 1 diabetes treated with canagliflozin,” he concluded. These strategies included more-frequent monitoring for ketones, dose interruption when patients were ill, under stress, or more active, perhaps using lower doses of canagliflozin, and further education of physicians and patients about the potential risks. A paper on the specifics of the DKA cases seen in the trial is currently under review at Diabetes Care.
Sotagliflozin: Dual inhibition of SGLT1 and SGLT2
Dr. John Buse
Dr. John Buse, professor of medicine and chief of the division of endocrinology at the Center for Diabetes Research at the University of North Carolina at Chapel Hill, presented the findings of a 4-week, randomized, double-blind, placebo-controlled phase II study with the investigational SGLT2 inhibitor sotagliflozin. Unlike other SGLT2 inhibitors already available for type 2 diabetes, sotagliflozin also inhibits SGLT1, meaning that it not only targets glucose reabsorption in the kidneys but also glucose and galactose reabsorption in the gastrointestinal tract. Although promising results have been seen in phase II trials involving patients with type 2 diabetes, the drug’s developer, Lexicon Pharmaceuticals, says it currently has no plans to pursue a license this indication.
The study involved 33 patients with type 1 diabetes aged between 18 and 55 years, 16 of whom were treated with sotagliflozin and 17 with placebo. Patients treated with sotagliflozin were older (median age, 45.5 years) than those randomized to placebo (median age, 34 years), but for a small trial the patients were otherwise “remarkably well matched” in terms of their other baseline characteristics Dr. Buse observed.
Given at a 400-mg daily oral dose, sotagliflozin was shown to improve glycemic control in intensively treated patients with type 1 diabetes after only 28 days vs. placebo, with a decrease in the primary endpoint of daily bolus insulin use (–32% vs. –6.4%; P =.007), but not in total daily basal insulin (–2.4 vs. +0.2%). “This is consistent with SGLT1 inhibition,” Dr. Buse noted, and “different than observed with selective SGLT2 inhibitors in type 1 diabetes.”
The insulin dose at mealtimes was lowered, statistically so at breakfast and numerically at other mealtimes. There was also a numerical reduction in postprandial glucose. A significant decrease in HbA1c was seen vs. placebo (–0.55% vs. –0.06%; P =.002) and there was no increase in daily hypoglycemic events (–0.7 vs. 0.4/patient per day) and there was the added benefit of weight loss (–1.7 kg vs. +0.5 kg; P =.005).
Results from the trial were also presented in a poster and showed that sotagliflozin significantly improved the time that patients blood glucose was within their target range and reduced glycemic variability versus placebo.
There were similar rates of adverse events between the active treatment and placebo groups with the exception of mild nausea (25% vs. 6%) and vomiting (13% vs. 6%) and two cases of ketoacidosis that occurred in the sotagliflozin group and creatinine phosphokinase elevation that occurred in two patients treated with placebo. Both DKA cases were considered to be down to the pump method of insulin administration rather than to be drug related. The safety profile of this particular dose, together with the efficacy seen “supports advancement to phase III studies”, said Dr. Buse.
Another phase II and three phase III trials with sotagliflozin in type 1 diabetes – inTandem1, inTandem2, and inTandem3 – are underway and have started to recruit patients. The phase II trial is expected to be complete by the start of next year, with results of the first two phase III trial to follow in the fall of 2016, and the results of the third by spring 2017.