René Rodríguez-Gutiérrez, MD

To the Editor: We found Dr. Vouyiouklis’s article about the recently approved sodium-glucose cotransport 2 (SGLT) inhibitor canagliflozin very useful. However, we strongly believe there are some issues that should be addressed.

In discussing the canagliflozin trials, Dr. Vouyiouklis did not mention a phase III randomized, double-blind, double-arm study, in which canagliflozin (100 and 300 mg) in addition to metformin was compared with placebo and sitagliptin (100 mg) in patients with type 2 diabetes.¹ This study recruited 1,284 participants in 22 countries. At week 52, hemoglobin A_1c levels had declined by 0.73% in the sitagliptin group, 0.73% in the canagliflozin 100 mg group, and 0.88% in the canagliflozin 300 mg group. Thus, canagliflozin 100 mg demonstrated noninferiority, and canagliflozin 300 mg demonstrated superiority. In addition, as previously described by other trials, a significant statistical reduction was observed in weight and blood pressure with modest elevations in LDL cholesterol and the incidence of mycotic urinary infections.

Current guidelines and recommendations give a wide variety of therapeutic options as the second step if lifestyle interventions and metformin fail to achieve glycemic control.² The best combination regimen is still debated and, because of their excellent side-effect profile, dipeptidyl peptidase-4 inhibitors (gliptins) are one of the most used therapeutic classes. We believe this study adds important evidence that could help with decision-making in routine clinical practice.

Also, canagliflozin’s favorable effects on weight and blood pressure inevitably lead to the question, Are the weight loss and decreased systolic blood pressure due to osmotic diuresis or to lean or body fat weight loss? The mechanism of action of SGLT2 inhibitors, per se, favors osmotic diuresis, and several trials have demonstrated this same effect, as well as postural dizziness and orthostatic hypotension.^3,4 Until now, the exact cause of this weight loss has not been elucidated, and no trial has demonstrated with precision a reduction in lean or fat body weight as a direct effect of SGLT2 inhibitors. This, in addition to LDL elevation, could have important clinical implications, as diuretic osmosis will subsequently activate the renin-angiotensin-aldosterone system. This might initially blunt this blood pressure reduction and promote parasympathetic inhibition, sympathetic activation, and myocardial and vascular fibrosis that can potentially lead in the long term to adverse cardiovascular outcomes.⁵

To the Editor: We found Dr. Vouyiouklis’s article about the recently approved sodium-glucose cotransport 2 (SGLT) inhibitor canagliflozin very useful. However, we strongly believe there are some issues that should be addressed.

In discussing the canagliflozin trials, Dr. Vouyiouklis did not mention a phase III randomized, double-blind, double-arm study, in which canagliflozin (100 and 300 mg) in addition to metformin was compared with placebo and sitagliptin (100 mg) in patients with type 2 diabetes.¹ This study recruited 1,284 participants in 22 countries. At week 52, hemoglobin A_1c levels had declined by 0.73% in the sitagliptin group, 0.73% in the canagliflozin 100 mg group, and 0.88% in the canagliflozin 300 mg group. Thus, canagliflozin 100 mg demonstrated noninferiority, and canagliflozin 300 mg demonstrated superiority. In addition, as previously described by other trials, a significant statistical reduction was observed in weight and blood pressure with modest elevations in LDL cholesterol and the incidence of mycotic urinary infections.

Current guidelines and recommendations give a wide variety of therapeutic options as the second step if lifestyle interventions and metformin fail to achieve glycemic control.² The best combination regimen is still debated and, because of their excellent side-effect profile, dipeptidyl peptidase-4 inhibitors (gliptins) are one of the most used therapeutic classes. We believe this study adds important evidence that could help with decision-making in routine clinical practice.

Also, canagliflozin’s favorable effects on weight and blood pressure inevitably lead to the question, Are the weight loss and decreased systolic blood pressure due to osmotic diuresis or to lean or body fat weight loss? The mechanism of action of SGLT2 inhibitors, per se, favors osmotic diuresis, and several trials have demonstrated this same effect, as well as postural dizziness and orthostatic hypotension.^3,4 Until now, the exact cause of this weight loss has not been elucidated, and no trial has demonstrated with precision a reduction in lean or fat body weight as a direct effect of SGLT2 inhibitors. This, in addition to LDL elevation, could have important clinical implications, as diuretic osmosis will subsequently activate the renin-angiotensin-aldosterone system. This might initially blunt this blood pressure reduction and promote parasympathetic inhibition, sympathetic activation, and myocardial and vascular fibrosis that can potentially lead in the long term to adverse cardiovascular outcomes.⁵

To the Editor: We found Dr. Vouyiouklis’s article about the recently approved sodium-glucose cotransport 2 (SGLT) inhibitor canagliflozin very useful. However, we strongly believe there are some issues that should be addressed.

In discussing the canagliflozin trials, Dr. Vouyiouklis did not mention a phase III randomized, double-blind, double-arm study, in which canagliflozin (100 and 300 mg) in addition to metformin was compared with placebo and sitagliptin (100 mg) in patients with type 2 diabetes.¹ This study recruited 1,284 participants in 22 countries. At week 52, hemoglobin A_1c levels had declined by 0.73% in the sitagliptin group, 0.73% in the canagliflozin 100 mg group, and 0.88% in the canagliflozin 300 mg group. Thus, canagliflozin 100 mg demonstrated noninferiority, and canagliflozin 300 mg demonstrated superiority. In addition, as previously described by other trials, a significant statistical reduction was observed in weight and blood pressure with modest elevations in LDL cholesterol and the incidence of mycotic urinary infections.

Current guidelines and recommendations give a wide variety of therapeutic options as the second step if lifestyle interventions and metformin fail to achieve glycemic control.² The best combination regimen is still debated and, because of their excellent side-effect profile, dipeptidyl peptidase-4 inhibitors (gliptins) are one of the most used therapeutic classes. We believe this study adds important evidence that could help with decision-making in routine clinical practice.

Also, canagliflozin’s favorable effects on weight and blood pressure inevitably lead to the question, Are the weight loss and decreased systolic blood pressure due to osmotic diuresis or to lean or body fat weight loss? The mechanism of action of SGLT2 inhibitors, per se, favors osmotic diuresis, and several trials have demonstrated this same effect, as well as postural dizziness and orthostatic hypotension.^3,4 Until now, the exact cause of this weight loss has not been elucidated, and no trial has demonstrated with precision a reduction in lean or fat body weight as a direct effect of SGLT2 inhibitors. This, in addition to LDL elevation, could have important clinical implications, as diuretic osmosis will subsequently activate the renin-angiotensin-aldosterone system. This might initially blunt this blood pressure reduction and promote parasympathetic inhibition, sympathetic activation, and myocardial and vascular fibrosis that can potentially lead in the long term to adverse cardiovascular outcomes.⁵

To the Editor: We found the article by Drs. Lansang and Kramer¹ on glucocorticoid-induced diabetes and adrenal suppression in the November 2011 issue to be a useful and clinically oriented review. However, we strongly believe there is an issue that should be addressed.

It is well accepted that the short cosyntropin (Cortrosyn) stimulation test is the best screening maneuver for assessing adrenocortical insufficiency. The authors state, however, that 250 μg is preferable to lower doses (10 μg or 1 μg), since these are not yet widely accepted, and refer to an article by Axelrod from 1976.²

Based on studies showing that 250 μg of cosyntropin is a pharmacologic rather than a physiologic stimulus that may overstimulate partially atrophied or mildly dysfunctional adrenal glands, multiple studies in the last 20 years have shown that the low-dose test has an equal or better result than the classic 250-μg dose test.³ Dorin et al,⁴ in a meta-analysis of the diagnosis of adrenocortical insufficiency that included more than 30 studies, found similar sensitivity and specificity in primary and secondary adrenal insufficiency comparing the 250-μg dose vs the low dose. In cases of mild primary adrenal failure, the low-dose test has better performance. A previous investigation in our research center contrasting 250 μg vs 10 μg proved that 10 μg had a better sensitivity than the standard dose, with excellent reproducibility and interchangeability.⁵ Similar findings have been shown by other authors contrasting 1 μg vs 250 μg of cosyntropin.⁶

We believe that the limited use of the low-dose cosyntropin test is not a matter of acceptance or performance but a consequence of the lack of vials containing lower doses of cosyntropin (1 to 10 μg), which makes this test technically challenging.^2,4 The steps needed for one-dose testing and the preservation time of the preparation are strong limitations to its wide use in clinical practice and endocrine laboratories.

To the Editor: We found the article by Drs. Lansang and Kramer¹ on glucocorticoid-induced diabetes and adrenal suppression in the November 2011 issue to be a useful and clinically oriented review. However, we strongly believe there is an issue that should be addressed.

It is well accepted that the short cosyntropin (Cortrosyn) stimulation test is the best screening maneuver for assessing adrenocortical insufficiency. The authors state, however, that 250 μg is preferable to lower doses (10 μg or 1 μg), since these are not yet widely accepted, and refer to an article by Axelrod from 1976.²

Based on studies showing that 250 μg of cosyntropin is a pharmacologic rather than a physiologic stimulus that may overstimulate partially atrophied or mildly dysfunctional adrenal glands, multiple studies in the last 20 years have shown that the low-dose test has an equal or better result than the classic 250-μg dose test.³ Dorin et al,⁴ in a meta-analysis of the diagnosis of adrenocortical insufficiency that included more than 30 studies, found similar sensitivity and specificity in primary and secondary adrenal insufficiency comparing the 250-μg dose vs the low dose. In cases of mild primary adrenal failure, the low-dose test has better performance. A previous investigation in our research center contrasting 250 μg vs 10 μg proved that 10 μg had a better sensitivity than the standard dose, with excellent reproducibility and interchangeability.⁵ Similar findings have been shown by other authors contrasting 1 μg vs 250 μg of cosyntropin.⁶

We believe that the limited use of the low-dose cosyntropin test is not a matter of acceptance or performance but a consequence of the lack of vials containing lower doses of cosyntropin (1 to 10 μg), which makes this test technically challenging.^2,4 The steps needed for one-dose testing and the preservation time of the preparation are strong limitations to its wide use in clinical practice and endocrine laboratories.

To the Editor: We found the article by Drs. Lansang and Kramer¹ on glucocorticoid-induced diabetes and adrenal suppression in the November 2011 issue to be a useful and clinically oriented review. However, we strongly believe there is an issue that should be addressed.

It is well accepted that the short cosyntropin (Cortrosyn) stimulation test is the best screening maneuver for assessing adrenocortical insufficiency. The authors state, however, that 250 μg is preferable to lower doses (10 μg or 1 μg), since these are not yet widely accepted, and refer to an article by Axelrod from 1976.²

Based on studies showing that 250 μg of cosyntropin is a pharmacologic rather than a physiologic stimulus that may overstimulate partially atrophied or mildly dysfunctional adrenal glands, multiple studies in the last 20 years have shown that the low-dose test has an equal or better result than the classic 250-μg dose test.³ Dorin et al,⁴ in a meta-analysis of the diagnosis of adrenocortical insufficiency that included more than 30 studies, found similar sensitivity and specificity in primary and secondary adrenal insufficiency comparing the 250-μg dose vs the low dose. In cases of mild primary adrenal failure, the low-dose test has better performance. A previous investigation in our research center contrasting 250 μg vs 10 μg proved that 10 μg had a better sensitivity than the standard dose, with excellent reproducibility and interchangeability.⁵ Similar findings have been shown by other authors contrasting 1 μg vs 250 μg of cosyntropin.⁶

We believe that the limited use of the low-dose cosyntropin test is not a matter of acceptance or performance but a consequence of the lack of vials containing lower doses of cosyntropin (1 to 10 μg), which makes this test technically challenging.^2,4 The steps needed for one-dose testing and the preservation time of the preparation are strong limitations to its wide use in clinical practice and endocrine laboratories.