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BARCELONA – Individuals with type 1 diabetes and a high body mass index gain the most benefit with the least risk when sodium-glucose cotransporter 2 (SGLT2) inhibitors are added to insulin therapy, according to data presented at the annual meeting of the European Association for the Study of Diabetes.
Results from new analyses of the inTandem 1 and inTandem 2 trials with sotagliflozin (Zynquista), and the DEPICT-1 and DEPICT-2 trials with dapagliflozin (Farxiga), support the recent decision of the European Medicines Agency to license the use of the drugs only in patients with a BMI of 27 kg/m2 or higher.
inTandem with sotagliflozin
Weight gain is a challenge in patients with type 1 diabetes, said Thomas Danne, MD, who presented post hoc data from the two inTandem studies. “It’s a little bit counterintuitive,” he acknowledged, “but you have to realize, particularly in patients who have hypoglycemia, that they have to take in extra carbohydrates,” which may tip them to becoming overweight or obese.
SGLT2-inhibitor therapy with sotagliflozin or dapagliflozin added to insulin therapy has been shown to reduce body weight in individuals with type 1 diabetes, but there is an increased risk for diabetic ketoacidosis (DKA). That risk, however, seems to be lower in the higher body-weight categories.
Dr. Danne, director of the department of general pediatrics, endocrinology, and diabetology, and clinical research at the Auf der Bult Hospital for Children and Adolescents, at the Hannover (Germany) Medical School, presented data looking at the outcomes of patients treated with sotagliflozin or placebo based on their BMI.
In all, 1,575 patients were included in the analysis, of whom 659 were of normal weight (BMI of less than 27 kg/m2; average mean, 24 kg/m2 at baseline), and 916 had a higher weight (BMI of 27 kg/m2 or higher; average mean, 32 kg/m2 at baseline). The mean age of patients at study entry was 42 years for those with the lower BMI, and 45 years for those with the higher BMI.
Patients in the two inTandem trials had been treated with insulin plus placebo (n = 228, BMI less than 27 kg/m2; n = 298, BMI 27 kg/m2 or higher), or insulin plus sotagliflozin at a dose of 200 mg (n = 219, BMI less than 27 kg/m2; n = 305, BMI 27 kg/m2 or higher) or 400 mg (n = 212; BMI less than 27 kg/m2; n = 313, BMI 27 kg/m2 or higher).
Glycemic control and body weight
Greater reductions in glycated hemoglobin (HbA1c) were seen with sotagliflozin versus placebo, and even more so, if the BMI was 27 kg/m2 or higher. At week 24, the least-squares mean difference in HbA1c comparing sotagliflozin 200 mg and placebo was –0.32 in patients with the lower BMI, compared with –0.39 in those with the higher BMI. Corresponding values for the 400-mg sotagliflozin group in the higher-BMI group were –0.27 and –0.45, respectively (P less than .001 for all comparisons).
In the lower-BMI group, week 24 least-squares mean differences in body weight comparing sotagliflozin and placebo were –2.06 kg for the 200-mg group and –2.55 kg for the 400-mg group, and –2.27 kg and 3.32 kg in the higher-BMI group (P less than .001 for all comparisons).
“This is why this class of drugs holds so much of a promise, [because] it’s not only one good effect regarding improvement of glycemia judged by A1c,” Dr. Danne said.
He also reported that treatment with sotagliflozin was associated with an increased time in range, compared with placebo, again, with greater effects seen in the higher- versus lower-BMI groups. In those with a BMI of 27 kg/m2 or more, there was an additional 1 hour 58 minutes time in range for the 200-mg dose, and 3 hours 37 minutes for the 200-mg dose, compared with an extra 24 minutes and 1 hour 31 minutes, respectively, in the lower-BMI category.
“We also see a trend to improved reduction in systolic blood pressure in those with the higher BMI,” Dr. Danne said.
Risk for DKA
“The big charm of these drugs is that not only do you improve A1c and all the other good things, but also you do this without increasing the risk of hypoglycemia,” said Dr. Danne. “Again, you can see a trend of a lower risk of severe hypoglycemia for both sotagliflozin doses [compared with placebo] in the group with the body mass index of greater than 27 kg/m2 [versus BMI of less than 27 kg/m2].”
The risk of DKA was higher than placebo in both BMI groups, but the number of DKA events was very small when comparing the low and high body weight categories (0 and 1 events, respectively, in the placebo groups; 7 and 9, in the sotagliflozin 200-mg group; and 9 and 11, in the 400-mg group. The absolute risk difference in the exposure adjusted incidence rate was slightly lower in the lower-BMI group, he said, but the numbers were so small that it is difficult to draw conclusions from that finding.
“There is no doubt that we have an increase for the risk of DKA with this class of drugs in general ... but it is futile to discuss whether or not, just on the basis of a body mass index or something else, we will be able to reduce it in a big fashion,” Dr. Danne suggested.
Body weight and composition
Other data on the long-term effect of sotagliflozin on body weight and composition were presented by Sangeeta Sawhney, MD, vice-president of clinical development at Lexicon Pharmaceuticals, Chapel Hill, North Carolina.
She presented data from the DEXA substudy of the inTandem phase 3 studies in which 243 patients underwent fat mass and bone density scanning.
SGLT2 inhibitors are associated with weight loss through glycuresis and net caloric loss, Dr. Sawhney reminded the audience. As sotagliflozin is a dual inhibitor of SGLT1 and SGLT2, however, it is important to estimate the contribution of changes in fat mass and lean mass to the weight loss that could be achieved with the drug.
Pooled data from the inTandem 1 and inTandem 2 studies showed that at week 24, there were reductions in body weight of –1.7 kg and –2.6 kg with sotagliflozin 200 mg and 400 mg, respectively, and at 52 weeks, reductions of –1.9 kg and –2.9 kg. However, there was an increase in body weight with placebo (+0.5 and +0.8 kg, respectively).
For the substudy, patients underwent dual-energy x-ray absorptiometry at baseline and weeks 24 and 52. Fat mass was measured at all three time points, and bone density was evaluated at the start and end of the study.
The least-square mean change in total fat mass from baseline to week 24 and week 52 were +0.6 and +0.1 kg, respectively, for placebo, –1.6 and –1.6 kg for the sotagliflozin 200-mg dose; and –1.9 and –2.1 kg for the 400-mg dose, “which really parallels the reduction in total body weight,” Dr. Sawhney observed.
The changes in total lean mass were much smaller for sotagliflozin, she added, at –0.6 kg at week 24 and 0.3 kg at week 52 for the 200-mg dose, and –0.7 kg and –0.4 kg, respectively, for the 400-mg dose, and rises in lean mass of 0.2 kg and 0.4 kg, respectively, in placebo.
Taken together, these data show that “about 80% of the body weight reduction is really from the fat mass, and a much smaller proportion of the total body weight reduction is really coming from the lean fat mass,” said Dr. Sawhney.
DEPICT with dapagliflozin
In a poster, Paresh Dandona, MD, PhD, of the State University of New York at Buffalo, and associates presented data from a pooled analysis of the DEPICT-1 and DEPICT-2 studies looking at safety and efficacy outcomes with dapagliflozin according to five BMI categories: less than or equal to 23 kg/m2; greater than 23 kg/m2 to less than or equal to 25 kg/m2; greater than 25 kg/m2 to less than or equal to 27 kg/m2; greater than 27 kg/m2 to less than or equal to 30 kg/m2; and greater than 30 kg/m2.
The pooled analysis included 548 patients treated with dapagliflozin 5 mg and 532 who received placebo. The investigators found that patients with higher BMIs who were treated with dapagliflozin had greater weight loss, showed a trend toward achieving an HbA1c reduction of 5.5 mmol/mol (greater than or equal to 0.5%) or more without the risk of severe hypoglycemia, and had fewer episodes of definite DKA, compared with those with those with lower BMIs.
The adjusted mean percentage change from baseline in body weight in the lowest BMI (less than or equal to 23 kg/m2) group at week 24 was +0.06 kg for placebo and –2.71 kg for dapagliflozin, and at week 52, +0.33 kg and –2.91 kg, respectively. Corresponding values comparing placebo and dapagliflozin at 24 and 52 weeks in the highest BMI group (greater than 30 kg/m2) were –0.30 kg and –3.03 kg, and +0.56 and –3.58 kg.
Odds ratios for achieving an HbA1c reduction of 5.5 mmol/mol (greater than or equal to 0.5%) without severe hypoglycemia at week 24 with dapagliflozin, compared with placebo, were, in increasing order of BMI groups: 1.85, 1.93, 3.87, 2.91, and 4.20.
“Generally, more events of definite DKA were observed in patients treated with dapagliflozin than in those treated with placebo,” but there were fewer events as BMI increased, Dr. Dandona and associates reported. “These data should be interpreted with caution due to the low number of events in each subgroup,” they added.
The number of adjudicated DKA events comparing dapagliflozin and placebo across the BMI groups were: 4 versus 1 (BMI less than or equal to 23 kg/m2); 6 versus 1 (BMI greater than 23 kg/m2 to less than or equal to 25 kg/m2); 7 versus 1 (BMI greater than 25 kg/m2 to less than or equal to 27 kg/m2); 3 versus 1 (BMI greater than 27 kg/m2 to less than or equal to 30 kg/m2); and 2 versus 1 (BMI greater than 30 kg/m2).
In regard to limitations, “this was a post hoc analysis,” the investigators noted, adding that the studies were not originally powered for comparison between BMI subgroups, so the results should be considered exploratory. Moreover, DKA and hypoglycemia were strictly monitored in the trials, which “may differ from real-world situations,” they said.
The inTandem studies were sponsored by Lexicon and Sanofi. Dr. Danne disclosed receiving research funding and serving as a consultant, advisory board or steering committee member, or speaker for various companies, including Sanofi. Dr. Sawhney is an employee of and holds stoke in Lexicon. The DEPICT studies were sponsored by AstraZeneca. The lead author, Dr. Dandona, disclosed employment or consultancy services for multiple companies, including AstraZeneca.
SOURCE: Danne T et al. EASD 2018, Oral Presentation 2; Dandona P et al. EASD 2019, ePoster 720; Sawhney S et al. EASD 2019, Oral Presentation 3.
BARCELONA – Individuals with type 1 diabetes and a high body mass index gain the most benefit with the least risk when sodium-glucose cotransporter 2 (SGLT2) inhibitors are added to insulin therapy, according to data presented at the annual meeting of the European Association for the Study of Diabetes.
Results from new analyses of the inTandem 1 and inTandem 2 trials with sotagliflozin (Zynquista), and the DEPICT-1 and DEPICT-2 trials with dapagliflozin (Farxiga), support the recent decision of the European Medicines Agency to license the use of the drugs only in patients with a BMI of 27 kg/m2 or higher.
inTandem with sotagliflozin
Weight gain is a challenge in patients with type 1 diabetes, said Thomas Danne, MD, who presented post hoc data from the two inTandem studies. “It’s a little bit counterintuitive,” he acknowledged, “but you have to realize, particularly in patients who have hypoglycemia, that they have to take in extra carbohydrates,” which may tip them to becoming overweight or obese.
SGLT2-inhibitor therapy with sotagliflozin or dapagliflozin added to insulin therapy has been shown to reduce body weight in individuals with type 1 diabetes, but there is an increased risk for diabetic ketoacidosis (DKA). That risk, however, seems to be lower in the higher body-weight categories.
Dr. Danne, director of the department of general pediatrics, endocrinology, and diabetology, and clinical research at the Auf der Bult Hospital for Children and Adolescents, at the Hannover (Germany) Medical School, presented data looking at the outcomes of patients treated with sotagliflozin or placebo based on their BMI.
In all, 1,575 patients were included in the analysis, of whom 659 were of normal weight (BMI of less than 27 kg/m2; average mean, 24 kg/m2 at baseline), and 916 had a higher weight (BMI of 27 kg/m2 or higher; average mean, 32 kg/m2 at baseline). The mean age of patients at study entry was 42 years for those with the lower BMI, and 45 years for those with the higher BMI.
Patients in the two inTandem trials had been treated with insulin plus placebo (n = 228, BMI less than 27 kg/m2; n = 298, BMI 27 kg/m2 or higher), or insulin plus sotagliflozin at a dose of 200 mg (n = 219, BMI less than 27 kg/m2; n = 305, BMI 27 kg/m2 or higher) or 400 mg (n = 212; BMI less than 27 kg/m2; n = 313, BMI 27 kg/m2 or higher).
Glycemic control and body weight
Greater reductions in glycated hemoglobin (HbA1c) were seen with sotagliflozin versus placebo, and even more so, if the BMI was 27 kg/m2 or higher. At week 24, the least-squares mean difference in HbA1c comparing sotagliflozin 200 mg and placebo was –0.32 in patients with the lower BMI, compared with –0.39 in those with the higher BMI. Corresponding values for the 400-mg sotagliflozin group in the higher-BMI group were –0.27 and –0.45, respectively (P less than .001 for all comparisons).
In the lower-BMI group, week 24 least-squares mean differences in body weight comparing sotagliflozin and placebo were –2.06 kg for the 200-mg group and –2.55 kg for the 400-mg group, and –2.27 kg and 3.32 kg in the higher-BMI group (P less than .001 for all comparisons).
“This is why this class of drugs holds so much of a promise, [because] it’s not only one good effect regarding improvement of glycemia judged by A1c,” Dr. Danne said.
He also reported that treatment with sotagliflozin was associated with an increased time in range, compared with placebo, again, with greater effects seen in the higher- versus lower-BMI groups. In those with a BMI of 27 kg/m2 or more, there was an additional 1 hour 58 minutes time in range for the 200-mg dose, and 3 hours 37 minutes for the 200-mg dose, compared with an extra 24 minutes and 1 hour 31 minutes, respectively, in the lower-BMI category.
“We also see a trend to improved reduction in systolic blood pressure in those with the higher BMI,” Dr. Danne said.
Risk for DKA
“The big charm of these drugs is that not only do you improve A1c and all the other good things, but also you do this without increasing the risk of hypoglycemia,” said Dr. Danne. “Again, you can see a trend of a lower risk of severe hypoglycemia for both sotagliflozin doses [compared with placebo] in the group with the body mass index of greater than 27 kg/m2 [versus BMI of less than 27 kg/m2].”
The risk of DKA was higher than placebo in both BMI groups, but the number of DKA events was very small when comparing the low and high body weight categories (0 and 1 events, respectively, in the placebo groups; 7 and 9, in the sotagliflozin 200-mg group; and 9 and 11, in the 400-mg group. The absolute risk difference in the exposure adjusted incidence rate was slightly lower in the lower-BMI group, he said, but the numbers were so small that it is difficult to draw conclusions from that finding.
“There is no doubt that we have an increase for the risk of DKA with this class of drugs in general ... but it is futile to discuss whether or not, just on the basis of a body mass index or something else, we will be able to reduce it in a big fashion,” Dr. Danne suggested.
Body weight and composition
Other data on the long-term effect of sotagliflozin on body weight and composition were presented by Sangeeta Sawhney, MD, vice-president of clinical development at Lexicon Pharmaceuticals, Chapel Hill, North Carolina.
She presented data from the DEXA substudy of the inTandem phase 3 studies in which 243 patients underwent fat mass and bone density scanning.
SGLT2 inhibitors are associated with weight loss through glycuresis and net caloric loss, Dr. Sawhney reminded the audience. As sotagliflozin is a dual inhibitor of SGLT1 and SGLT2, however, it is important to estimate the contribution of changes in fat mass and lean mass to the weight loss that could be achieved with the drug.
Pooled data from the inTandem 1 and inTandem 2 studies showed that at week 24, there were reductions in body weight of –1.7 kg and –2.6 kg with sotagliflozin 200 mg and 400 mg, respectively, and at 52 weeks, reductions of –1.9 kg and –2.9 kg. However, there was an increase in body weight with placebo (+0.5 and +0.8 kg, respectively).
For the substudy, patients underwent dual-energy x-ray absorptiometry at baseline and weeks 24 and 52. Fat mass was measured at all three time points, and bone density was evaluated at the start and end of the study.
The least-square mean change in total fat mass from baseline to week 24 and week 52 were +0.6 and +0.1 kg, respectively, for placebo, –1.6 and –1.6 kg for the sotagliflozin 200-mg dose; and –1.9 and –2.1 kg for the 400-mg dose, “which really parallels the reduction in total body weight,” Dr. Sawhney observed.
The changes in total lean mass were much smaller for sotagliflozin, she added, at –0.6 kg at week 24 and 0.3 kg at week 52 for the 200-mg dose, and –0.7 kg and –0.4 kg, respectively, for the 400-mg dose, and rises in lean mass of 0.2 kg and 0.4 kg, respectively, in placebo.
Taken together, these data show that “about 80% of the body weight reduction is really from the fat mass, and a much smaller proportion of the total body weight reduction is really coming from the lean fat mass,” said Dr. Sawhney.
DEPICT with dapagliflozin
In a poster, Paresh Dandona, MD, PhD, of the State University of New York at Buffalo, and associates presented data from a pooled analysis of the DEPICT-1 and DEPICT-2 studies looking at safety and efficacy outcomes with dapagliflozin according to five BMI categories: less than or equal to 23 kg/m2; greater than 23 kg/m2 to less than or equal to 25 kg/m2; greater than 25 kg/m2 to less than or equal to 27 kg/m2; greater than 27 kg/m2 to less than or equal to 30 kg/m2; and greater than 30 kg/m2.
The pooled analysis included 548 patients treated with dapagliflozin 5 mg and 532 who received placebo. The investigators found that patients with higher BMIs who were treated with dapagliflozin had greater weight loss, showed a trend toward achieving an HbA1c reduction of 5.5 mmol/mol (greater than or equal to 0.5%) or more without the risk of severe hypoglycemia, and had fewer episodes of definite DKA, compared with those with those with lower BMIs.
The adjusted mean percentage change from baseline in body weight in the lowest BMI (less than or equal to 23 kg/m2) group at week 24 was +0.06 kg for placebo and –2.71 kg for dapagliflozin, and at week 52, +0.33 kg and –2.91 kg, respectively. Corresponding values comparing placebo and dapagliflozin at 24 and 52 weeks in the highest BMI group (greater than 30 kg/m2) were –0.30 kg and –3.03 kg, and +0.56 and –3.58 kg.
Odds ratios for achieving an HbA1c reduction of 5.5 mmol/mol (greater than or equal to 0.5%) without severe hypoglycemia at week 24 with dapagliflozin, compared with placebo, were, in increasing order of BMI groups: 1.85, 1.93, 3.87, 2.91, and 4.20.
“Generally, more events of definite DKA were observed in patients treated with dapagliflozin than in those treated with placebo,” but there were fewer events as BMI increased, Dr. Dandona and associates reported. “These data should be interpreted with caution due to the low number of events in each subgroup,” they added.
The number of adjudicated DKA events comparing dapagliflozin and placebo across the BMI groups were: 4 versus 1 (BMI less than or equal to 23 kg/m2); 6 versus 1 (BMI greater than 23 kg/m2 to less than or equal to 25 kg/m2); 7 versus 1 (BMI greater than 25 kg/m2 to less than or equal to 27 kg/m2); 3 versus 1 (BMI greater than 27 kg/m2 to less than or equal to 30 kg/m2); and 2 versus 1 (BMI greater than 30 kg/m2).
In regard to limitations, “this was a post hoc analysis,” the investigators noted, adding that the studies were not originally powered for comparison between BMI subgroups, so the results should be considered exploratory. Moreover, DKA and hypoglycemia were strictly monitored in the trials, which “may differ from real-world situations,” they said.
The inTandem studies were sponsored by Lexicon and Sanofi. Dr. Danne disclosed receiving research funding and serving as a consultant, advisory board or steering committee member, or speaker for various companies, including Sanofi. Dr. Sawhney is an employee of and holds stoke in Lexicon. The DEPICT studies were sponsored by AstraZeneca. The lead author, Dr. Dandona, disclosed employment or consultancy services for multiple companies, including AstraZeneca.
SOURCE: Danne T et al. EASD 2018, Oral Presentation 2; Dandona P et al. EASD 2019, ePoster 720; Sawhney S et al. EASD 2019, Oral Presentation 3.
BARCELONA – Individuals with type 1 diabetes and a high body mass index gain the most benefit with the least risk when sodium-glucose cotransporter 2 (SGLT2) inhibitors are added to insulin therapy, according to data presented at the annual meeting of the European Association for the Study of Diabetes.
Results from new analyses of the inTandem 1 and inTandem 2 trials with sotagliflozin (Zynquista), and the DEPICT-1 and DEPICT-2 trials with dapagliflozin (Farxiga), support the recent decision of the European Medicines Agency to license the use of the drugs only in patients with a BMI of 27 kg/m2 or higher.
inTandem with sotagliflozin
Weight gain is a challenge in patients with type 1 diabetes, said Thomas Danne, MD, who presented post hoc data from the two inTandem studies. “It’s a little bit counterintuitive,” he acknowledged, “but you have to realize, particularly in patients who have hypoglycemia, that they have to take in extra carbohydrates,” which may tip them to becoming overweight or obese.
SGLT2-inhibitor therapy with sotagliflozin or dapagliflozin added to insulin therapy has been shown to reduce body weight in individuals with type 1 diabetes, but there is an increased risk for diabetic ketoacidosis (DKA). That risk, however, seems to be lower in the higher body-weight categories.
Dr. Danne, director of the department of general pediatrics, endocrinology, and diabetology, and clinical research at the Auf der Bult Hospital for Children and Adolescents, at the Hannover (Germany) Medical School, presented data looking at the outcomes of patients treated with sotagliflozin or placebo based on their BMI.
In all, 1,575 patients were included in the analysis, of whom 659 were of normal weight (BMI of less than 27 kg/m2; average mean, 24 kg/m2 at baseline), and 916 had a higher weight (BMI of 27 kg/m2 or higher; average mean, 32 kg/m2 at baseline). The mean age of patients at study entry was 42 years for those with the lower BMI, and 45 years for those with the higher BMI.
Patients in the two inTandem trials had been treated with insulin plus placebo (n = 228, BMI less than 27 kg/m2; n = 298, BMI 27 kg/m2 or higher), or insulin plus sotagliflozin at a dose of 200 mg (n = 219, BMI less than 27 kg/m2; n = 305, BMI 27 kg/m2 or higher) or 400 mg (n = 212; BMI less than 27 kg/m2; n = 313, BMI 27 kg/m2 or higher).
Glycemic control and body weight
Greater reductions in glycated hemoglobin (HbA1c) were seen with sotagliflozin versus placebo, and even more so, if the BMI was 27 kg/m2 or higher. At week 24, the least-squares mean difference in HbA1c comparing sotagliflozin 200 mg and placebo was –0.32 in patients with the lower BMI, compared with –0.39 in those with the higher BMI. Corresponding values for the 400-mg sotagliflozin group in the higher-BMI group were –0.27 and –0.45, respectively (P less than .001 for all comparisons).
In the lower-BMI group, week 24 least-squares mean differences in body weight comparing sotagliflozin and placebo were –2.06 kg for the 200-mg group and –2.55 kg for the 400-mg group, and –2.27 kg and 3.32 kg in the higher-BMI group (P less than .001 for all comparisons).
“This is why this class of drugs holds so much of a promise, [because] it’s not only one good effect regarding improvement of glycemia judged by A1c,” Dr. Danne said.
He also reported that treatment with sotagliflozin was associated with an increased time in range, compared with placebo, again, with greater effects seen in the higher- versus lower-BMI groups. In those with a BMI of 27 kg/m2 or more, there was an additional 1 hour 58 minutes time in range for the 200-mg dose, and 3 hours 37 minutes for the 200-mg dose, compared with an extra 24 minutes and 1 hour 31 minutes, respectively, in the lower-BMI category.
“We also see a trend to improved reduction in systolic blood pressure in those with the higher BMI,” Dr. Danne said.
Risk for DKA
“The big charm of these drugs is that not only do you improve A1c and all the other good things, but also you do this without increasing the risk of hypoglycemia,” said Dr. Danne. “Again, you can see a trend of a lower risk of severe hypoglycemia for both sotagliflozin doses [compared with placebo] in the group with the body mass index of greater than 27 kg/m2 [versus BMI of less than 27 kg/m2].”
The risk of DKA was higher than placebo in both BMI groups, but the number of DKA events was very small when comparing the low and high body weight categories (0 and 1 events, respectively, in the placebo groups; 7 and 9, in the sotagliflozin 200-mg group; and 9 and 11, in the 400-mg group. The absolute risk difference in the exposure adjusted incidence rate was slightly lower in the lower-BMI group, he said, but the numbers were so small that it is difficult to draw conclusions from that finding.
“There is no doubt that we have an increase for the risk of DKA with this class of drugs in general ... but it is futile to discuss whether or not, just on the basis of a body mass index or something else, we will be able to reduce it in a big fashion,” Dr. Danne suggested.
Body weight and composition
Other data on the long-term effect of sotagliflozin on body weight and composition were presented by Sangeeta Sawhney, MD, vice-president of clinical development at Lexicon Pharmaceuticals, Chapel Hill, North Carolina.
She presented data from the DEXA substudy of the inTandem phase 3 studies in which 243 patients underwent fat mass and bone density scanning.
SGLT2 inhibitors are associated with weight loss through glycuresis and net caloric loss, Dr. Sawhney reminded the audience. As sotagliflozin is a dual inhibitor of SGLT1 and SGLT2, however, it is important to estimate the contribution of changes in fat mass and lean mass to the weight loss that could be achieved with the drug.
Pooled data from the inTandem 1 and inTandem 2 studies showed that at week 24, there were reductions in body weight of –1.7 kg and –2.6 kg with sotagliflozin 200 mg and 400 mg, respectively, and at 52 weeks, reductions of –1.9 kg and –2.9 kg. However, there was an increase in body weight with placebo (+0.5 and +0.8 kg, respectively).
For the substudy, patients underwent dual-energy x-ray absorptiometry at baseline and weeks 24 and 52. Fat mass was measured at all three time points, and bone density was evaluated at the start and end of the study.
The least-square mean change in total fat mass from baseline to week 24 and week 52 were +0.6 and +0.1 kg, respectively, for placebo, –1.6 and –1.6 kg for the sotagliflozin 200-mg dose; and –1.9 and –2.1 kg for the 400-mg dose, “which really parallels the reduction in total body weight,” Dr. Sawhney observed.
The changes in total lean mass were much smaller for sotagliflozin, she added, at –0.6 kg at week 24 and 0.3 kg at week 52 for the 200-mg dose, and –0.7 kg and –0.4 kg, respectively, for the 400-mg dose, and rises in lean mass of 0.2 kg and 0.4 kg, respectively, in placebo.
Taken together, these data show that “about 80% of the body weight reduction is really from the fat mass, and a much smaller proportion of the total body weight reduction is really coming from the lean fat mass,” said Dr. Sawhney.
DEPICT with dapagliflozin
In a poster, Paresh Dandona, MD, PhD, of the State University of New York at Buffalo, and associates presented data from a pooled analysis of the DEPICT-1 and DEPICT-2 studies looking at safety and efficacy outcomes with dapagliflozin according to five BMI categories: less than or equal to 23 kg/m2; greater than 23 kg/m2 to less than or equal to 25 kg/m2; greater than 25 kg/m2 to less than or equal to 27 kg/m2; greater than 27 kg/m2 to less than or equal to 30 kg/m2; and greater than 30 kg/m2.
The pooled analysis included 548 patients treated with dapagliflozin 5 mg and 532 who received placebo. The investigators found that patients with higher BMIs who were treated with dapagliflozin had greater weight loss, showed a trend toward achieving an HbA1c reduction of 5.5 mmol/mol (greater than or equal to 0.5%) or more without the risk of severe hypoglycemia, and had fewer episodes of definite DKA, compared with those with those with lower BMIs.
The adjusted mean percentage change from baseline in body weight in the lowest BMI (less than or equal to 23 kg/m2) group at week 24 was +0.06 kg for placebo and –2.71 kg for dapagliflozin, and at week 52, +0.33 kg and –2.91 kg, respectively. Corresponding values comparing placebo and dapagliflozin at 24 and 52 weeks in the highest BMI group (greater than 30 kg/m2) were –0.30 kg and –3.03 kg, and +0.56 and –3.58 kg.
Odds ratios for achieving an HbA1c reduction of 5.5 mmol/mol (greater than or equal to 0.5%) without severe hypoglycemia at week 24 with dapagliflozin, compared with placebo, were, in increasing order of BMI groups: 1.85, 1.93, 3.87, 2.91, and 4.20.
“Generally, more events of definite DKA were observed in patients treated with dapagliflozin than in those treated with placebo,” but there were fewer events as BMI increased, Dr. Dandona and associates reported. “These data should be interpreted with caution due to the low number of events in each subgroup,” they added.
The number of adjudicated DKA events comparing dapagliflozin and placebo across the BMI groups were: 4 versus 1 (BMI less than or equal to 23 kg/m2); 6 versus 1 (BMI greater than 23 kg/m2 to less than or equal to 25 kg/m2); 7 versus 1 (BMI greater than 25 kg/m2 to less than or equal to 27 kg/m2); 3 versus 1 (BMI greater than 27 kg/m2 to less than or equal to 30 kg/m2); and 2 versus 1 (BMI greater than 30 kg/m2).
In regard to limitations, “this was a post hoc analysis,” the investigators noted, adding that the studies were not originally powered for comparison between BMI subgroups, so the results should be considered exploratory. Moreover, DKA and hypoglycemia were strictly monitored in the trials, which “may differ from real-world situations,” they said.
The inTandem studies were sponsored by Lexicon and Sanofi. Dr. Danne disclosed receiving research funding and serving as a consultant, advisory board or steering committee member, or speaker for various companies, including Sanofi. Dr. Sawhney is an employee of and holds stoke in Lexicon. The DEPICT studies were sponsored by AstraZeneca. The lead author, Dr. Dandona, disclosed employment or consultancy services for multiple companies, including AstraZeneca.
SOURCE: Danne T et al. EASD 2018, Oral Presentation 2; Dandona P et al. EASD 2019, ePoster 720; Sawhney S et al. EASD 2019, Oral Presentation 3.
REPORTING FROM EASD 2019