EASD: SGLT2 inhibitors show potential in 1DM despite DKA concern

STOCKHOLM – The use of sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with type 1 diabetes looks promising despite concerns over their potential to cause diabetic ketoacidosis (DKA), experts reported here at the annual meeting of the European Association for the Study of Diabetes.

Results of three trials, including the results of an 18-week phase II trial with canagliflozin, a 4-week phase II trial with sotagliflozin, and a 4-week phase II trial with empagliflozin showed that these drugs are effective when used in addition to insulin to lower hemoglobin A_1c and have the added benefit of weight-reduction without increasing the risk for hypoglycemia.

“We must be very careful about using SGLT2 inhibitors in type 1 diabetes,” said Dr. David Matthews, professor of diabetes, emeritus founding chairman, Oxford (England) Centre for Diabetes, Endocrinology and Metabolism, in an interview. “These are preliminary studies, you’d have to use it off label, and you’d have to take responsibility for being very careful about the induction of DKA,” he observed.

Dr. Matthews, who chaired the session during which the canagliflozin results were presented, added: “DKA is clearly one of the risks, and we’ve learned a lot about why this might occur, for instance when there are the additional risks such as illness or with the use of anesthesia.”

DKA: Why the concern?

SGLT2 inhibitors are currently approved for use only in patients with type 2 diabetes when diet and exercise alone are not able to help patients achieve sufficient glycemic control. Recently, however, their potential to cause ketoacidosis even in patients with type 2 diabetes were the focus of a Drug Safety Communication issued by the Food and Drug Administration. The warning applied to all currently available SLGT2 preparations: canagliflozin (Invokana), canagliflozin/metformin (Invokamet), dapagliflozin (Farxiga), dapagliflozin/metformin extended release (Xigduo XR), empagliflozin (Jardiance), and empagliflozin/lingagliptin (Glyxambi); similar warnings followed from the European Medicines Agency.

Dr. Matthews observed that the risk of DKA in patients with type 2 diabetes may be clouded by patients with type 1 being misdiagnosed. “In type 2 diabetes, there is clearly a mix of people with type 1 whom you misdiagnose or who have got latent type 1 diabetes. Those are often the people on insulin, so they fall into the category of type 2 diabetes, and almost by mistake you are treating people with type 1 diabetes.”

Dr. Anne L. Peters of the University of Southern California, Los Angeles, and author of a recent article (Diabetes Care. 2015 Sep;38[9]:1687-93) highlighting the risk for DKA among type 2 diabetics treated with SGLT2 inhibitors, noted that use in type 1 diabetes had been shown to improve glucose control.

“Frankly, we know they work,” she said. “We know that they work in people with type 2 diabetes, and you are about to find out that they work in patients with type 1 diabetes, at least in a phase II trial,” Dr. Peters added.

“We know that the mechanism of action is insulin independent and, by design, [SGLT2 inhibitors] can work in both type 1 and type 2 diabetes,” she said. “But we also know that when we use [these agents] off label in diabetes that there is a signal for an increased risk for diabetic ketoacidosis.”

However, in her experience of using canagliflozin, every case of DKA involved “precipitating factors.” These included infections such as influenza or pneumonia that resulted in the patient not being well and not eating and thus reducing their insulin use or device or compliance issues resulting in reduced insulin dosing.

Dr. Peters suggested that should off-label use be considered outside of a clinical trial, patients must be adherent to routine glucose and ketone testing. She noted that she advised her patients to hold off using an SGLT2 inhibitor if they were going to be doing something different, such being more physically active, or if they had been ill and their insulin dosing had decreased.

Canagliflozin: Phase II study

Dr. Robert R. Henry, professor of medicine at the University of California, San Diego, presented the results of an 18-week, phase II study with canagliflozin, which was completed in June and accepted for publication in Diabetes Care. The double-blind, placebo-controlled, multicenter study involved 351 randomized patients with type 1 diabetes and a mean age of roughly 42 years treated with canagliflozin 100 mg (n = 117), canagliflozin 300 mg (n = 117), or placebo (n =1 17).

The primary efficacy endpoint was the proportion of patients with a decrease in HbA_1c of 0.4% or more and no increase in body weight. This combined endpoint was met by 37% and 41% of the 100-mg and 300-mg canagliflozin-treated patients, respectively, and by 15% of those randomized to placebo (both P less than .001 vs. placebo). Considering each of the components separately showed that a higher percentage of patients achieved an HbA_1c reduction of 0.4% or more (43%-45% vs. 23%) and reduced body weight (84%-96% vs. 49%).

Before randomization patients were advised to reduce their basal insulin doses by 20% if their HbA_1c 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, 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 HbA_1c 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.

Empagliflozin: EASE-1 study findings

Dr. Thomas Pieber of the Medical University of Graz in Austria presented the results of the 4-week phase II EASE-1 study, which included 75 patients with type 1 diabetes who were randomized to received empagliflozin once-daily at doses of 2.5 mg (n = 19), 10 mg (n = 19), or 25 mg (n = 18), or placebo (n = 19) for 28 days as adjunctive treatment to insulin.

The study findings (Diabetes Obes Metab. 2015 Jun 17. doi: 10.1111/dom.12494.) showed that empagliflozin used as an adjunct to insulin significantly increased urinary glucose excretion after 1, 7, and 29 days. Significant improvements in HbA_1c were achieved with lower (12%-14% vs. baseline) total daily doses of insulin being used. Empagliflozin was also associated with weight reduction (–1.4 to –1.7 kg) and generally lower rates of moderate hypoglycemia and no episodes needed assistance, compared with placebo. There were no cases of DKA reported, but fasting beta-hydroxybutyrate was slightly raised at week 4 with all doses of empagliflozin.

One delegate commented after Dr. Pieber’s presentation that, although it was a well-conducted study and provided some evidence of an effect of SGLG2 inhibitors in patients with type 1 diabetes, he had “great reservation” about using this class of antidiabetic drug in this clinical situation. The delegate’s concern was around expanding the use of the drug to all patients, some of whom may not have regular eating patterns or may have abnormal eating behaviors who might be at higher risk for DKA. “Of course, in a controlled study, it is not seen, but you see already some small signal of increase of ketone bodies, so I would say it should be used with great reservation in all patients and can only be used in well-educated, well-monitored patients.”

Dr. Pieber responded: “I think we have to do clinical trials to see if there is a benefit or not for our patients. So this was a study performed as a dose-finding study that led to a phase II program and hopefully will lead to a phase III program.” He added that, bearing in mind the positive findings of the EMPA-REG OUTCOME study showing that empagliflozin reduced major cardiovascular outcomes in patients with type 2 diabetes to be presented later at the meeting, “If something works in type 2 we definitely should test it in type 1 diabetes.”

STOCKHOLM – The use of sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with type 1 diabetes looks promising despite concerns over their potential to cause diabetic ketoacidosis (DKA), experts reported here at the annual meeting of the European Association for the Study of Diabetes.

Results of three trials, including the results of an 18-week phase II trial with canagliflozin, a 4-week phase II trial with sotagliflozin, and a 4-week phase II trial with empagliflozin showed that these drugs are effective when used in addition to insulin to lower hemoglobin A_1c and have the added benefit of weight-reduction without increasing the risk for hypoglycemia.

“We must be very careful about using SGLT2 inhibitors in type 1 diabetes,” said Dr. David Matthews, professor of diabetes, emeritus founding chairman, Oxford (England) Centre for Diabetes, Endocrinology and Metabolism, in an interview. “These are preliminary studies, you’d have to use it off label, and you’d have to take responsibility for being very careful about the induction of DKA,” he observed.

Dr. Matthews, who chaired the session during which the canagliflozin results were presented, added: “DKA is clearly one of the risks, and we’ve learned a lot about why this might occur, for instance when there are the additional risks such as illness or with the use of anesthesia.”

DKA: Why the concern?

SGLT2 inhibitors are currently approved for use only in patients with type 2 diabetes when diet and exercise alone are not able to help patients achieve sufficient glycemic control. Recently, however, their potential to cause ketoacidosis even in patients with type 2 diabetes were the focus of a Drug Safety Communication issued by the Food and Drug Administration. The warning applied to all currently available SLGT2 preparations: canagliflozin (Invokana), canagliflozin/metformin (Invokamet), dapagliflozin (Farxiga), dapagliflozin/metformin extended release (Xigduo XR), empagliflozin (Jardiance), and empagliflozin/lingagliptin (Glyxambi); similar warnings followed from the European Medicines Agency.

Dr. Matthews observed that the risk of DKA in patients with type 2 diabetes may be clouded by patients with type 1 being misdiagnosed. “In type 2 diabetes, there is clearly a mix of people with type 1 whom you misdiagnose or who have got latent type 1 diabetes. Those are often the people on insulin, so they fall into the category of type 2 diabetes, and almost by mistake you are treating people with type 1 diabetes.”

Dr. Anne L. Peters of the University of Southern California, Los Angeles, and author of a recent article (Diabetes Care. 2015 Sep;38[9]:1687-93) highlighting the risk for DKA among type 2 diabetics treated with SGLT2 inhibitors, noted that use in type 1 diabetes had been shown to improve glucose control.

“Frankly, we know they work,” she said. “We know that they work in people with type 2 diabetes, and you are about to find out that they work in patients with type 1 diabetes, at least in a phase II trial,” Dr. Peters added.

“We know that the mechanism of action is insulin independent and, by design, [SGLT2 inhibitors] can work in both type 1 and type 2 diabetes,” she said. “But we also know that when we use [these agents] off label in diabetes that there is a signal for an increased risk for diabetic ketoacidosis.”

However, in her experience of using canagliflozin, every case of DKA involved “precipitating factors.” These included infections such as influenza or pneumonia that resulted in the patient not being well and not eating and thus reducing their insulin use or device or compliance issues resulting in reduced insulin dosing.

Dr. Peters suggested that should off-label use be considered outside of a clinical trial, patients must be adherent to routine glucose and ketone testing. She noted that she advised her patients to hold off using an SGLT2 inhibitor if they were going to be doing something different, such being more physically active, or if they had been ill and their insulin dosing had decreased.

Canagliflozin: Phase II study

Dr. Robert R. Henry, professor of medicine at the University of California, San Diego, presented the results of an 18-week, phase II study with canagliflozin, which was completed in June and accepted for publication in Diabetes Care. The double-blind, placebo-controlled, multicenter study involved 351 randomized patients with type 1 diabetes and a mean age of roughly 42 years treated with canagliflozin 100 mg (n = 117), canagliflozin 300 mg (n = 117), or placebo (n =1 17).

The primary efficacy endpoint was the proportion of patients with a decrease in HbA_1c of 0.4% or more and no increase in body weight. This combined endpoint was met by 37% and 41% of the 100-mg and 300-mg canagliflozin-treated patients, respectively, and by 15% of those randomized to placebo (both P less than .001 vs. placebo). Considering each of the components separately showed that a higher percentage of patients achieved an HbA_1c reduction of 0.4% or more (43%-45% vs. 23%) and reduced body weight (84%-96% vs. 49%).

Before randomization patients were advised to reduce their basal insulin doses by 20% if their HbA_1c 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, 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 HbA_1c 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.

Empagliflozin: EASE-1 study findings

Dr. Thomas Pieber of the Medical University of Graz in Austria presented the results of the 4-week phase II EASE-1 study, which included 75 patients with type 1 diabetes who were randomized to received empagliflozin once-daily at doses of 2.5 mg (n = 19), 10 mg (n = 19), or 25 mg (n = 18), or placebo (n = 19) for 28 days as adjunctive treatment to insulin.

The study findings (Diabetes Obes Metab. 2015 Jun 17. doi: 10.1111/dom.12494.) showed that empagliflozin used as an adjunct to insulin significantly increased urinary glucose excretion after 1, 7, and 29 days. Significant improvements in HbA_1c were achieved with lower (12%-14% vs. baseline) total daily doses of insulin being used. Empagliflozin was also associated with weight reduction (–1.4 to –1.7 kg) and generally lower rates of moderate hypoglycemia and no episodes needed assistance, compared with placebo. There were no cases of DKA reported, but fasting beta-hydroxybutyrate was slightly raised at week 4 with all doses of empagliflozin.

One delegate commented after Dr. Pieber’s presentation that, although it was a well-conducted study and provided some evidence of an effect of SGLG2 inhibitors in patients with type 1 diabetes, he had “great reservation” about using this class of antidiabetic drug in this clinical situation. The delegate’s concern was around expanding the use of the drug to all patients, some of whom may not have regular eating patterns or may have abnormal eating behaviors who might be at higher risk for DKA. “Of course, in a controlled study, it is not seen, but you see already some small signal of increase of ketone bodies, so I would say it should be used with great reservation in all patients and can only be used in well-educated, well-monitored patients.”

Dr. Pieber responded: “I think we have to do clinical trials to see if there is a benefit or not for our patients. So this was a study performed as a dose-finding study that led to a phase II program and hopefully will lead to a phase III program.” He added that, bearing in mind the positive findings of the EMPA-REG OUTCOME study showing that empagliflozin reduced major cardiovascular outcomes in patients with type 2 diabetes to be presented later at the meeting, “If something works in type 2 we definitely should test it in type 1 diabetes.”

STOCKHOLM – The use of sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with type 1 diabetes looks promising despite concerns over their potential to cause diabetic ketoacidosis (DKA), experts reported here at the annual meeting of the European Association for the Study of Diabetes.

Results of three trials, including the results of an 18-week phase II trial with canagliflozin, a 4-week phase II trial with sotagliflozin, and a 4-week phase II trial with empagliflozin showed that these drugs are effective when used in addition to insulin to lower hemoglobin A_1c and have the added benefit of weight-reduction without increasing the risk for hypoglycemia.

“We must be very careful about using SGLT2 inhibitors in type 1 diabetes,” said Dr. David Matthews, professor of diabetes, emeritus founding chairman, Oxford (England) Centre for Diabetes, Endocrinology and Metabolism, in an interview. “These are preliminary studies, you’d have to use it off label, and you’d have to take responsibility for being very careful about the induction of DKA,” he observed.

Dr. Matthews, who chaired the session during which the canagliflozin results were presented, added: “DKA is clearly one of the risks, and we’ve learned a lot about why this might occur, for instance when there are the additional risks such as illness or with the use of anesthesia.”

DKA: Why the concern?

SGLT2 inhibitors are currently approved for use only in patients with type 2 diabetes when diet and exercise alone are not able to help patients achieve sufficient glycemic control. Recently, however, their potential to cause ketoacidosis even in patients with type 2 diabetes were the focus of a Drug Safety Communication issued by the Food and Drug Administration. The warning applied to all currently available SLGT2 preparations: canagliflozin (Invokana), canagliflozin/metformin (Invokamet), dapagliflozin (Farxiga), dapagliflozin/metformin extended release (Xigduo XR), empagliflozin (Jardiance), and empagliflozin/lingagliptin (Glyxambi); similar warnings followed from the European Medicines Agency.

Dr. Matthews observed that the risk of DKA in patients with type 2 diabetes may be clouded by patients with type 1 being misdiagnosed. “In type 2 diabetes, there is clearly a mix of people with type 1 whom you misdiagnose or who have got latent type 1 diabetes. Those are often the people on insulin, so they fall into the category of type 2 diabetes, and almost by mistake you are treating people with type 1 diabetes.”

Dr. Anne L. Peters of the University of Southern California, Los Angeles, and author of a recent article (Diabetes Care. 2015 Sep;38[9]:1687-93) highlighting the risk for DKA among type 2 diabetics treated with SGLT2 inhibitors, noted that use in type 1 diabetes had been shown to improve glucose control.

“Frankly, we know they work,” she said. “We know that they work in people with type 2 diabetes, and you are about to find out that they work in patients with type 1 diabetes, at least in a phase II trial,” Dr. Peters added.

“We know that the mechanism of action is insulin independent and, by design, [SGLT2 inhibitors] can work in both type 1 and type 2 diabetes,” she said. “But we also know that when we use [these agents] off label in diabetes that there is a signal for an increased risk for diabetic ketoacidosis.”

However, in her experience of using canagliflozin, every case of DKA involved “precipitating factors.” These included infections such as influenza or pneumonia that resulted in the patient not being well and not eating and thus reducing their insulin use or device or compliance issues resulting in reduced insulin dosing.

Dr. Peters suggested that should off-label use be considered outside of a clinical trial, patients must be adherent to routine glucose and ketone testing. She noted that she advised her patients to hold off using an SGLT2 inhibitor if they were going to be doing something different, such being more physically active, or if they had been ill and their insulin dosing had decreased.

Canagliflozin: Phase II study

Dr. Robert R. Henry, professor of medicine at the University of California, San Diego, presented the results of an 18-week, phase II study with canagliflozin, which was completed in June and accepted for publication in Diabetes Care. The double-blind, placebo-controlled, multicenter study involved 351 randomized patients with type 1 diabetes and a mean age of roughly 42 years treated with canagliflozin 100 mg (n = 117), canagliflozin 300 mg (n = 117), or placebo (n =1 17).

The primary efficacy endpoint was the proportion of patients with a decrease in HbA_1c of 0.4% or more and no increase in body weight. This combined endpoint was met by 37% and 41% of the 100-mg and 300-mg canagliflozin-treated patients, respectively, and by 15% of those randomized to placebo (both P less than .001 vs. placebo). Considering each of the components separately showed that a higher percentage of patients achieved an HbA_1c reduction of 0.4% or more (43%-45% vs. 23%) and reduced body weight (84%-96% vs. 49%).

Before randomization patients were advised to reduce their basal insulin doses by 20% if their HbA_1c 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, 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 HbA_1c 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.

Empagliflozin: EASE-1 study findings

Dr. Thomas Pieber of the Medical University of Graz in Austria presented the results of the 4-week phase II EASE-1 study, which included 75 patients with type 1 diabetes who were randomized to received empagliflozin once-daily at doses of 2.5 mg (n = 19), 10 mg (n = 19), or 25 mg (n = 18), or placebo (n = 19) for 28 days as adjunctive treatment to insulin.

The study findings (Diabetes Obes Metab. 2015 Jun 17. doi: 10.1111/dom.12494.) showed that empagliflozin used as an adjunct to insulin significantly increased urinary glucose excretion after 1, 7, and 29 days. Significant improvements in HbA_1c were achieved with lower (12%-14% vs. baseline) total daily doses of insulin being used. Empagliflozin was also associated with weight reduction (–1.4 to –1.7 kg) and generally lower rates of moderate hypoglycemia and no episodes needed assistance, compared with placebo. There were no cases of DKA reported, but fasting beta-hydroxybutyrate was slightly raised at week 4 with all doses of empagliflozin.

One delegate commented after Dr. Pieber’s presentation that, although it was a well-conducted study and provided some evidence of an effect of SGLG2 inhibitors in patients with type 1 diabetes, he had “great reservation” about using this class of antidiabetic drug in this clinical situation. The delegate’s concern was around expanding the use of the drug to all patients, some of whom may not have regular eating patterns or may have abnormal eating behaviors who might be at higher risk for DKA. “Of course, in a controlled study, it is not seen, but you see already some small signal of increase of ketone bodies, so I would say it should be used with great reservation in all patients and can only be used in well-educated, well-monitored patients.”

Dr. Pieber responded: “I think we have to do clinical trials to see if there is a benefit or not for our patients. So this was a study performed as a dose-finding study that led to a phase II program and hopefully will lead to a phase III program.” He added that, bearing in mind the positive findings of the EMPA-REG OUTCOME study showing that empagliflozin reduced major cardiovascular outcomes in patients with type 2 diabetes to be presented later at the meeting, “If something works in type 2 we definitely should test it in type 1 diabetes.”