TBD Meeting (4154-20)

Following a heart attack, there appears to be a “modest” benefit of using flash glucose monitoring over fingerstick testing to monitor blood glucose levels in patients with type 2 diabetes being treated with insulin or a sulfonylurea, according to investigators of the LIBERATES trial.

The results showed a nonsignificant increase in the time that subjects’ blood glucose was spent in the target range of 3.9-10.00 mmol/L (70-180 mg/dL) 3 months after experiencing an acute coronary syndrome (ACS).

At best, flash monitoring using Abbott’s Freestyle Libre system was associated with an increase in time spent in range (TIR) of 17-28 or 48 minutes per day over self-monitoring of blood glucose (SMBG), depending on the type of statistical analysis used. There was no difference in glycated hemoglobin A1c levels between the two groups, but there was a trend for less time spent in hypoglycemia in the flash monitoring arm.

Viewers underwhelmed

“My overall impression is that the effects were less pronounced than anticipated,” Kare Birkeland, MD, PhD, a specialist in internal medicine and endocrinology at Oslo University Hospital, Rikshospitalet, Norway, observed after the findings were presented at the virtual annual meeting of the European Association for the Study of Diabetes.

Others who had watched the live session seemed similarly underwhelmed by the findings, with one viewer questioning the value of devoting an hour-and-a-half session to the phase 2 trial.

However, the session chair Simon Heller, BA, MB, BChir, DM, professor of clinical diabetes at the University of Sheffield, and trial coinvestigator, defended the detailed look at the trial’s findings, noting that it was worthwhile to present the data from the trial as it “really helps explain why we do phase 2 and phase 3 trials.”

Strong rationale for monitoring post-MI

There is a strong rationale for ensuring that blood glucose is well controlled in type 2 diabetes patients who have experienced a myocardial infarction, observed Robert Storey, BSc, BM, DM, professor of cardiology at the University of Sheffield. One way to do that potentially is through improved glucose monitoring.

“There’s clearly a close link between diabetes and the risk of MI: Both high and low HbA1c are associated with adverse outcome, and high and low glucose levels following MI are also associated with adverse outcome,” he observed, noting also that hypoglycemia was not given enough attention in post-ACS patients.

Mitchel L. Zoler/MDedge News

Pragmatic trial design

LIBERATES was a prospective, multicenter, parallel group, randomized controlled trial, explained the study’s statistician Deborah Stocken, PhD, professor of clinical trials research at the University of Leeds. There was “limited ability to blind the interventions,” so it was an open-label design.

“The patient population in LIBERATES was kept as inclusive and as pragmatic as possible to ensure that the results at the end of the trial are generalizable,” said Dr. Stocken. Patients with type 2 diabetes were recruited within 5 days of hospital admission for ACS, which could include both ST- and non-ST elevation MI. In all, 141 of a calculated 150 patients that would be needed were recruited and randomized to the flash monitoring (69) or SMBG (72) arm.

Dr. Stocken noted that early in the recruitment phase, the trials oversight committee recommended that Bayesian methodology should be used as the most robust analytical approach.

“Essentially, a Bayesian approach would avoid a hypothesis test, and instead would provide a probability of there being a treatment benefit for continuous monitoring. And if this probability was high enough, this would warrant further research in the phase 3 setting,” Dr. Stocken said.
 

What else was shown?

“We had a number of prespecified secondary endpoints, which to me are equally important,” said Ramzi Ajjan, MD, MMed.Sci, PhD, associate professor and consultant in diabetes and endocrinology at Leeds University and Leeds Teaching Hospitals Trust.

Among these was the TIR at days 16-30, which showed a 90-minute increase per day in favor of flash monitoring over SMBG. This “seems to be driven by those who are an insulin,” Dr. Ajjan said, adding that “you get almost a 3-hour increase in time in range in people who are on insulin at baseline, and you don’t see that in people who are on sulfonylurea.”

Conversely, sulfonylurea treatment seemed to drive the reduction in the time spent in hypoglycemia defined as 3.9 mmol/L (70 g/dL) at 3 months. For the whole group, there was a 1.3-hour reduction in hypoglycemia per day with flash monitoring versus SMBG, which increased to 2 hours for those on sulfonylureas.

There also was a “pattern of reduction” in time spent in hypoglycemia defined as less than 3.0 mmol/L (54 g/dL) both early on and becoming more pronounced with time.

“Flash glucose monitoring is associated with higher treatment satisfaction score, compared with SMBG,” Dr. Ajjan said.

Although A1c dropped in both groups to a similar extent, he noted that the reduction seen in the flash monitoring group was associated with a decrease in hypoglycemia.

There was a huge amount of data collected during the trial and there are many more analyses that could be done, Dr. Ajjan said. The outcome of those may determine whether a phase 3 trial is likely, assuming sponsorship can be secured.

The LIBERATES Trial was funded by grants from the UK National Institute for Health Research and Abbott Diabetes Care. None of the investigators were additionally compensated for their work within the trial. Dr. Stocken had no disclosures in relation to this trial. Dr. Ajjan has received research funding and other financial support from Abbott, Bayer, Eli Lilly, Johnson & Johnson, and Novo Nordisk.

SOURCE: Ajjan R et al. EASD 2020. S11 – The LIBERATES Trial.

Following a heart attack, there appears to be a “modest” benefit of using flash glucose monitoring over fingerstick testing to monitor blood glucose levels in patients with type 2 diabetes being treated with insulin or a sulfonylurea, according to investigators of the LIBERATES trial.

The results showed a nonsignificant increase in the time that subjects’ blood glucose was spent in the target range of 3.9-10.00 mmol/L (70-180 mg/dL) 3 months after experiencing an acute coronary syndrome (ACS).

At best, flash monitoring using Abbott’s Freestyle Libre system was associated with an increase in time spent in range (TIR) of 17-28 or 48 minutes per day over self-monitoring of blood glucose (SMBG), depending on the type of statistical analysis used. There was no difference in glycated hemoglobin A1c levels between the two groups, but there was a trend for less time spent in hypoglycemia in the flash monitoring arm.

Viewers underwhelmed

“My overall impression is that the effects were less pronounced than anticipated,” Kare Birkeland, MD, PhD, a specialist in internal medicine and endocrinology at Oslo University Hospital, Rikshospitalet, Norway, observed after the findings were presented at the virtual annual meeting of the European Association for the Study of Diabetes.

Others who had watched the live session seemed similarly underwhelmed by the findings, with one viewer questioning the value of devoting an hour-and-a-half session to the phase 2 trial.

However, the session chair Simon Heller, BA, MB, BChir, DM, professor of clinical diabetes at the University of Sheffield, and trial coinvestigator, defended the detailed look at the trial’s findings, noting that it was worthwhile to present the data from the trial as it “really helps explain why we do phase 2 and phase 3 trials.”

Strong rationale for monitoring post-MI

There is a strong rationale for ensuring that blood glucose is well controlled in type 2 diabetes patients who have experienced a myocardial infarction, observed Robert Storey, BSc, BM, DM, professor of cardiology at the University of Sheffield. One way to do that potentially is through improved glucose monitoring.

“There’s clearly a close link between diabetes and the risk of MI: Both high and low HbA1c are associated with adverse outcome, and high and low glucose levels following MI are also associated with adverse outcome,” he observed, noting also that hypoglycemia was not given enough attention in post-ACS patients.

Mitchel L. Zoler/MDedge News

Pragmatic trial design

LIBERATES was a prospective, multicenter, parallel group, randomized controlled trial, explained the study’s statistician Deborah Stocken, PhD, professor of clinical trials research at the University of Leeds. There was “limited ability to blind the interventions,” so it was an open-label design.

“The patient population in LIBERATES was kept as inclusive and as pragmatic as possible to ensure that the results at the end of the trial are generalizable,” said Dr. Stocken. Patients with type 2 diabetes were recruited within 5 days of hospital admission for ACS, which could include both ST- and non-ST elevation MI. In all, 141 of a calculated 150 patients that would be needed were recruited and randomized to the flash monitoring (69) or SMBG (72) arm.

Dr. Stocken noted that early in the recruitment phase, the trials oversight committee recommended that Bayesian methodology should be used as the most robust analytical approach.

“Essentially, a Bayesian approach would avoid a hypothesis test, and instead would provide a probability of there being a treatment benefit for continuous monitoring. And if this probability was high enough, this would warrant further research in the phase 3 setting,” Dr. Stocken said.
 

What else was shown?

“We had a number of prespecified secondary endpoints, which to me are equally important,” said Ramzi Ajjan, MD, MMed.Sci, PhD, associate professor and consultant in diabetes and endocrinology at Leeds University and Leeds Teaching Hospitals Trust.

Among these was the TIR at days 16-30, which showed a 90-minute increase per day in favor of flash monitoring over SMBG. This “seems to be driven by those who are an insulin,” Dr. Ajjan said, adding that “you get almost a 3-hour increase in time in range in people who are on insulin at baseline, and you don’t see that in people who are on sulfonylurea.”

Conversely, sulfonylurea treatment seemed to drive the reduction in the time spent in hypoglycemia defined as 3.9 mmol/L (70 g/dL) at 3 months. For the whole group, there was a 1.3-hour reduction in hypoglycemia per day with flash monitoring versus SMBG, which increased to 2 hours for those on sulfonylureas.

There also was a “pattern of reduction” in time spent in hypoglycemia defined as less than 3.0 mmol/L (54 g/dL) both early on and becoming more pronounced with time.

“Flash glucose monitoring is associated with higher treatment satisfaction score, compared with SMBG,” Dr. Ajjan said.

Although A1c dropped in both groups to a similar extent, he noted that the reduction seen in the flash monitoring group was associated with a decrease in hypoglycemia.

There was a huge amount of data collected during the trial and there are many more analyses that could be done, Dr. Ajjan said. The outcome of those may determine whether a phase 3 trial is likely, assuming sponsorship can be secured.

The LIBERATES Trial was funded by grants from the UK National Institute for Health Research and Abbott Diabetes Care. None of the investigators were additionally compensated for their work within the trial. Dr. Stocken had no disclosures in relation to this trial. Dr. Ajjan has received research funding and other financial support from Abbott, Bayer, Eli Lilly, Johnson & Johnson, and Novo Nordisk.

SOURCE: Ajjan R et al. EASD 2020. S11 – The LIBERATES Trial.

Following a heart attack, there appears to be a “modest” benefit of using flash glucose monitoring over fingerstick testing to monitor blood glucose levels in patients with type 2 diabetes being treated with insulin or a sulfonylurea, according to investigators of the LIBERATES trial.

The results showed a nonsignificant increase in the time that subjects’ blood glucose was spent in the target range of 3.9-10.00 mmol/L (70-180 mg/dL) 3 months after experiencing an acute coronary syndrome (ACS).

At best, flash monitoring using Abbott’s Freestyle Libre system was associated with an increase in time spent in range (TIR) of 17-28 or 48 minutes per day over self-monitoring of blood glucose (SMBG), depending on the type of statistical analysis used. There was no difference in glycated hemoglobin A1c levels between the two groups, but there was a trend for less time spent in hypoglycemia in the flash monitoring arm.

Viewers underwhelmed

“My overall impression is that the effects were less pronounced than anticipated,” Kare Birkeland, MD, PhD, a specialist in internal medicine and endocrinology at Oslo University Hospital, Rikshospitalet, Norway, observed after the findings were presented at the virtual annual meeting of the European Association for the Study of Diabetes.

Others who had watched the live session seemed similarly underwhelmed by the findings, with one viewer questioning the value of devoting an hour-and-a-half session to the phase 2 trial.

However, the session chair Simon Heller, BA, MB, BChir, DM, professor of clinical diabetes at the University of Sheffield, and trial coinvestigator, defended the detailed look at the trial’s findings, noting that it was worthwhile to present the data from the trial as it “really helps explain why we do phase 2 and phase 3 trials.”

Strong rationale for monitoring post-MI

There is a strong rationale for ensuring that blood glucose is well controlled in type 2 diabetes patients who have experienced a myocardial infarction, observed Robert Storey, BSc, BM, DM, professor of cardiology at the University of Sheffield. One way to do that potentially is through improved glucose monitoring.

“There’s clearly a close link between diabetes and the risk of MI: Both high and low HbA1c are associated with adverse outcome, and high and low glucose levels following MI are also associated with adverse outcome,” he observed, noting also that hypoglycemia was not given enough attention in post-ACS patients.

Mitchel L. Zoler/MDedge News

Pragmatic trial design

LIBERATES was a prospective, multicenter, parallel group, randomized controlled trial, explained the study’s statistician Deborah Stocken, PhD, professor of clinical trials research at the University of Leeds. There was “limited ability to blind the interventions,” so it was an open-label design.

“The patient population in LIBERATES was kept as inclusive and as pragmatic as possible to ensure that the results at the end of the trial are generalizable,” said Dr. Stocken. Patients with type 2 diabetes were recruited within 5 days of hospital admission for ACS, which could include both ST- and non-ST elevation MI. In all, 141 of a calculated 150 patients that would be needed were recruited and randomized to the flash monitoring (69) or SMBG (72) arm.

Dr. Stocken noted that early in the recruitment phase, the trials oversight committee recommended that Bayesian methodology should be used as the most robust analytical approach.

“Essentially, a Bayesian approach would avoid a hypothesis test, and instead would provide a probability of there being a treatment benefit for continuous monitoring. And if this probability was high enough, this would warrant further research in the phase 3 setting,” Dr. Stocken said.
 

What else was shown?

“We had a number of prespecified secondary endpoints, which to me are equally important,” said Ramzi Ajjan, MD, MMed.Sci, PhD, associate professor and consultant in diabetes and endocrinology at Leeds University and Leeds Teaching Hospitals Trust.

Among these was the TIR at days 16-30, which showed a 90-minute increase per day in favor of flash monitoring over SMBG. This “seems to be driven by those who are an insulin,” Dr. Ajjan said, adding that “you get almost a 3-hour increase in time in range in people who are on insulin at baseline, and you don’t see that in people who are on sulfonylurea.”

Conversely, sulfonylurea treatment seemed to drive the reduction in the time spent in hypoglycemia defined as 3.9 mmol/L (70 g/dL) at 3 months. For the whole group, there was a 1.3-hour reduction in hypoglycemia per day with flash monitoring versus SMBG, which increased to 2 hours for those on sulfonylureas.

There also was a “pattern of reduction” in time spent in hypoglycemia defined as less than 3.0 mmol/L (54 g/dL) both early on and becoming more pronounced with time.

“Flash glucose monitoring is associated with higher treatment satisfaction score, compared with SMBG,” Dr. Ajjan said.

Although A1c dropped in both groups to a similar extent, he noted that the reduction seen in the flash monitoring group was associated with a decrease in hypoglycemia.

There was a huge amount of data collected during the trial and there are many more analyses that could be done, Dr. Ajjan said. The outcome of those may determine whether a phase 3 trial is likely, assuming sponsorship can be secured.

The LIBERATES Trial was funded by grants from the UK National Institute for Health Research and Abbott Diabetes Care. None of the investigators were additionally compensated for their work within the trial. Dr. Stocken had no disclosures in relation to this trial. Dr. Ajjan has received research funding and other financial support from Abbott, Bayer, Eli Lilly, Johnson & Johnson, and Novo Nordisk.

SOURCE: Ajjan R et al. EASD 2020. S11 – The LIBERATES Trial.

Abnormal mitochondrial activity in pain-processing areas of the brain may explain why some persons with type 2 diabetes experience painful peripheral neuropathy while others do not, new U.K. study findings have suggested.

A greater ratio of adenosine triphosphate (ATP) – “the cellular energy currency of all life” – to phosphocreatine (PCr) was observed in the somatosensory cortex and right thalamus in those with painful diabetic peripheral neuropathy (DPN). Importantly, this correlated with neuropathic pain symptom intensity as measured by the Neuropathic Pain Symptom Inventory (NPSI) and the Doleur Neuroathique en 4 (DN4).

The findings suggest that altered cerebral phosphorus metabolite ratios may serve as a biomarker of DPN, said the study’s investigators.

“Normally the ATP:Cr ratio will be unaltered, but there’s stress to the brain that might change,” Gordon Sloan, a clinical research fellow within the Diabetes Research Unit at the Royal Hallamshire Hospital in Sheffield (England) said at the virtual annual meeting of the European Association for the Study of Diabetes.

DPN affects around a quarter of patients with type 2 diabetes but treatments are “inadequate”, and “unfortunately fewer than a third of individuals receive 50% or greater pain relief from current neuropathic pain treatments,” Mr. Sloan said. “Ultimately, this lack of understanding of the pathophysiology of the condition is therefore clear rationale to investigate the disease mechanisms further and to find novel targets for treatments,” he added.


 

Brain metabolites offer clues to neuropathic pain levels

The thalamus and primary somatosensory cortex are two key areas of the brain that are involved in the perception of painful stimuli, Mr. Sloan explained. “The thalamus receives most of the slowest sensory impulses from the peripheral nervous system modulating and processing them for relaying the signals to the rest of the pain matrix, including the somatosensory cortex where these sensations are interpreted and localized.”

Prior imaging work by Mr. Sloan’s group and others have shown that there are alterations in the functioning of both these brain areas in those with painful DPN versus healthy volunteers and those with type 2 diabetes but no DPN. So for their current study, Mr. Sloan and associates from Sheffield University and Sheffield Teaching Hospitals National Health Service Trust, used an advanced imaging method – phosphorus magnetic resonance spectroscopy (MRS) – to scan the thalamus and somatosensory cortex of 43 persons with type 2 diabetes and 12 healthy volunteers. Of those with diabetes, 11 had no DPN, 12 had DPN but were not currently in pain, and 20 had painful DPN.

From the scans, three phosphorus metabolite ratios were calculated, which gave an indication of mitochondrial activity: first, the ATP to PCr ratio, which gives a measure of cellular energy status; second, the ATP to inorganic phosphate (Pi) ratio, which measures oxidative phosphorylation; and third, the ratio of phosphomonoesters (PME) to phosphodiesters (PDE), which gives a measure of cell membrane turnover.

“We have measured the ratio of high-energy phosphate levels which are an indirect representation of the balance between energy generation, reserve and usage in the brain,” Mr. Sloan said.

The subjects studied were of a similar age, around 63 years on average, and well matched in terms of their sex and body mass index. Those with diabetes of course had higher blood glucose and glycated hemoglobin than did the healthy volunteers during the scans. Among those with diabetes, those with DPN were significantly more likely to have a longer duration of diabetes (12.5 years for painful DPN and 15.8 years for nonpainful DPN) than were those with no DPN (8.7 years).

Furthermore, those with DPN had higher scores on the Neuropathic Pain Symptom Inventory (NPSI) than did those without, although there was not much difference between those with painful or nonpainful DPN. On the other had, those with painful DPN were more likely to have higher scores when using the Doleur Neuroathique en 4 (DN4) to assess their pain level.

Results showed significant changes in cerebral cellular bioenergetics in the pain processing regions of the brain in those with painful DPN. The ATP:PCr at the thalamus and at the somatosensory cortex was significantly higher in those with painful DPN, compared with healthy volunteers. The other measures of phosphorus metabolite levels (ATP:Pi and PME:PDE) were unaltered.

“We hypothesize that the findings of the study are suggestive of increased energy demands in regions of pain perception due to increased neuronal activity” said Dr. Sloan.

The study’s results add further evidence for cerebral alterations playing a key role in the generation and maintenance of pain in painful DPN.

SOURCE: Sloan S et al. EASD 2020, oral presentation 181.




 

Abnormal mitochondrial activity in pain-processing areas of the brain may explain why some persons with type 2 diabetes experience painful peripheral neuropathy while others do not, new U.K. study findings have suggested.

A greater ratio of adenosine triphosphate (ATP) – “the cellular energy currency of all life” – to phosphocreatine (PCr) was observed in the somatosensory cortex and right thalamus in those with painful diabetic peripheral neuropathy (DPN). Importantly, this correlated with neuropathic pain symptom intensity as measured by the Neuropathic Pain Symptom Inventory (NPSI) and the Doleur Neuroathique en 4 (DN4).

The findings suggest that altered cerebral phosphorus metabolite ratios may serve as a biomarker of DPN, said the study’s investigators.

“Normally the ATP:Cr ratio will be unaltered, but there’s stress to the brain that might change,” Gordon Sloan, a clinical research fellow within the Diabetes Research Unit at the Royal Hallamshire Hospital in Sheffield (England) said at the virtual annual meeting of the European Association for the Study of Diabetes.

DPN affects around a quarter of patients with type 2 diabetes but treatments are “inadequate”, and “unfortunately fewer than a third of individuals receive 50% or greater pain relief from current neuropathic pain treatments,” Mr. Sloan said. “Ultimately, this lack of understanding of the pathophysiology of the condition is therefore clear rationale to investigate the disease mechanisms further and to find novel targets for treatments,” he added.


 

Brain metabolites offer clues to neuropathic pain levels

The thalamus and primary somatosensory cortex are two key areas of the brain that are involved in the perception of painful stimuli, Mr. Sloan explained. “The thalamus receives most of the slowest sensory impulses from the peripheral nervous system modulating and processing them for relaying the signals to the rest of the pain matrix, including the somatosensory cortex where these sensations are interpreted and localized.”

Prior imaging work by Mr. Sloan’s group and others have shown that there are alterations in the functioning of both these brain areas in those with painful DPN versus healthy volunteers and those with type 2 diabetes but no DPN. So for their current study, Mr. Sloan and associates from Sheffield University and Sheffield Teaching Hospitals National Health Service Trust, used an advanced imaging method – phosphorus magnetic resonance spectroscopy (MRS) – to scan the thalamus and somatosensory cortex of 43 persons with type 2 diabetes and 12 healthy volunteers. Of those with diabetes, 11 had no DPN, 12 had DPN but were not currently in pain, and 20 had painful DPN.

From the scans, three phosphorus metabolite ratios were calculated, which gave an indication of mitochondrial activity: first, the ATP to PCr ratio, which gives a measure of cellular energy status; second, the ATP to inorganic phosphate (Pi) ratio, which measures oxidative phosphorylation; and third, the ratio of phosphomonoesters (PME) to phosphodiesters (PDE), which gives a measure of cell membrane turnover.

“We have measured the ratio of high-energy phosphate levels which are an indirect representation of the balance between energy generation, reserve and usage in the brain,” Mr. Sloan said.

The subjects studied were of a similar age, around 63 years on average, and well matched in terms of their sex and body mass index. Those with diabetes of course had higher blood glucose and glycated hemoglobin than did the healthy volunteers during the scans. Among those with diabetes, those with DPN were significantly more likely to have a longer duration of diabetes (12.5 years for painful DPN and 15.8 years for nonpainful DPN) than were those with no DPN (8.7 years).

Furthermore, those with DPN had higher scores on the Neuropathic Pain Symptom Inventory (NPSI) than did those without, although there was not much difference between those with painful or nonpainful DPN. On the other had, those with painful DPN were more likely to have higher scores when using the Doleur Neuroathique en 4 (DN4) to assess their pain level.

Results showed significant changes in cerebral cellular bioenergetics in the pain processing regions of the brain in those with painful DPN. The ATP:PCr at the thalamus and at the somatosensory cortex was significantly higher in those with painful DPN, compared with healthy volunteers. The other measures of phosphorus metabolite levels (ATP:Pi and PME:PDE) were unaltered.

“We hypothesize that the findings of the study are suggestive of increased energy demands in regions of pain perception due to increased neuronal activity” said Dr. Sloan.

The study’s results add further evidence for cerebral alterations playing a key role in the generation and maintenance of pain in painful DPN.

SOURCE: Sloan S et al. EASD 2020, oral presentation 181.




 

Abnormal mitochondrial activity in pain-processing areas of the brain may explain why some persons with type 2 diabetes experience painful peripheral neuropathy while others do not, new U.K. study findings have suggested.

A greater ratio of adenosine triphosphate (ATP) – “the cellular energy currency of all life” – to phosphocreatine (PCr) was observed in the somatosensory cortex and right thalamus in those with painful diabetic peripheral neuropathy (DPN). Importantly, this correlated with neuropathic pain symptom intensity as measured by the Neuropathic Pain Symptom Inventory (NPSI) and the Doleur Neuroathique en 4 (DN4).

The findings suggest that altered cerebral phosphorus metabolite ratios may serve as a biomarker of DPN, said the study’s investigators.

“Normally the ATP:Cr ratio will be unaltered, but there’s stress to the brain that might change,” Gordon Sloan, a clinical research fellow within the Diabetes Research Unit at the Royal Hallamshire Hospital in Sheffield (England) said at the virtual annual meeting of the European Association for the Study of Diabetes.

DPN affects around a quarter of patients with type 2 diabetes but treatments are “inadequate”, and “unfortunately fewer than a third of individuals receive 50% or greater pain relief from current neuropathic pain treatments,” Mr. Sloan said. “Ultimately, this lack of understanding of the pathophysiology of the condition is therefore clear rationale to investigate the disease mechanisms further and to find novel targets for treatments,” he added.


 

Brain metabolites offer clues to neuropathic pain levels

The thalamus and primary somatosensory cortex are two key areas of the brain that are involved in the perception of painful stimuli, Mr. Sloan explained. “The thalamus receives most of the slowest sensory impulses from the peripheral nervous system modulating and processing them for relaying the signals to the rest of the pain matrix, including the somatosensory cortex where these sensations are interpreted and localized.”

Prior imaging work by Mr. Sloan’s group and others have shown that there are alterations in the functioning of both these brain areas in those with painful DPN versus healthy volunteers and those with type 2 diabetes but no DPN. So for their current study, Mr. Sloan and associates from Sheffield University and Sheffield Teaching Hospitals National Health Service Trust, used an advanced imaging method – phosphorus magnetic resonance spectroscopy (MRS) – to scan the thalamus and somatosensory cortex of 43 persons with type 2 diabetes and 12 healthy volunteers. Of those with diabetes, 11 had no DPN, 12 had DPN but were not currently in pain, and 20 had painful DPN.

From the scans, three phosphorus metabolite ratios were calculated, which gave an indication of mitochondrial activity: first, the ATP to PCr ratio, which gives a measure of cellular energy status; second, the ATP to inorganic phosphate (Pi) ratio, which measures oxidative phosphorylation; and third, the ratio of phosphomonoesters (PME) to phosphodiesters (PDE), which gives a measure of cell membrane turnover.

“We have measured the ratio of high-energy phosphate levels which are an indirect representation of the balance between energy generation, reserve and usage in the brain,” Mr. Sloan said.

The subjects studied were of a similar age, around 63 years on average, and well matched in terms of their sex and body mass index. Those with diabetes of course had higher blood glucose and glycated hemoglobin than did the healthy volunteers during the scans. Among those with diabetes, those with DPN were significantly more likely to have a longer duration of diabetes (12.5 years for painful DPN and 15.8 years for nonpainful DPN) than were those with no DPN (8.7 years).

Furthermore, those with DPN had higher scores on the Neuropathic Pain Symptom Inventory (NPSI) than did those without, although there was not much difference between those with painful or nonpainful DPN. On the other had, those with painful DPN were more likely to have higher scores when using the Doleur Neuroathique en 4 (DN4) to assess their pain level.

Results showed significant changes in cerebral cellular bioenergetics in the pain processing regions of the brain in those with painful DPN. The ATP:PCr at the thalamus and at the somatosensory cortex was significantly higher in those with painful DPN, compared with healthy volunteers. The other measures of phosphorus metabolite levels (ATP:Pi and PME:PDE) were unaltered.

“We hypothesize that the findings of the study are suggestive of increased energy demands in regions of pain perception due to increased neuronal activity” said Dr. Sloan.

The study’s results add further evidence for cerebral alterations playing a key role in the generation and maintenance of pain in painful DPN.

SOURCE: Sloan S et al. EASD 2020, oral presentation 181.




 

Measuring glycated albumin (glycoalbumin, GA) in tears could be a future way for those with diabetes to monitor their blood sugar levels noninvasively.

In a 100-patient trial, levels of GA in tears were found to be strongly correlated (r = .722; P < .001) with those in the blood.

“GA levels in blood are widely measured in clinical practice in Japan,” said study investigator Masakazu Aihara, MD, PhD, in an interview.

“It’s a biomarker that reflects the 2-week average blood glucose level like fructosamine,” explained the researcher from the department of diabetes and metabolic diseases in the Graduate School of Medicine at the University of Tokyo.

This could make it a better biomarker for detecting earlier changes in blood glucose than glycated hemoglobin (HbA_1c), which reflects changes in blood glucose over the preceding 2-3 months.

Prior studies had shown that glucose levels can be measured in tear samples and that tear glucose levels correlated with blood glucose levels, Dr. Aihara and fellow researchers observed in a poster presentation at the virtual annual meeting of the European Association for the Study of Diabetes.

“While looking for noninvasive diabetes-related markers, we found that tears contained albumin. Based on this fact, we thought that GA could be measured in tears,” Dr. Aihara explained.

Using tears to test for biomarkers is not a new idea – tears not only protect the eye, they contain a variety of large proteins, and their composition can change with disease. Indeed, researchers have been looking at their usefulness in helping find biomarkers for Parkinson’s disease and diabetic peripheral neuropathy.

During their study, Dr. Aihara and associates collected tear and blood samples at the same time. Tear samples were assessed using liquid chromatography (LC) and mass spectrometry (MS). An enzymic method was used to measure GA levels in blood. Several diagnosis assay kits for GA are sold in Japan, Dr. Aihara said, and at least one of these has U.S. Food and Drug Administration approval.

Multiple regression analysis revealed that the correlation between GA levels in tears and in blood was maintained even after adjustment for age, gender, nephropathy stage, and obesity (P < .001). The results obtained from the tests were thought unlikely to be affected by any changes in the concentration or dilution of tear samples.

“Since GA levels in blood are clinically used in all types of diabetes, GA levels in tears is also expected to be useful in all types of diabetes,” Dr. Aihara said, noting that the effects of receiving treatment on GA levels in tears is something that he would like to look at.

The team would also like to optimize how tear samples are collected and reduce the volume of tears that are required for analysis. At the moment tears are collected via a dropper and about 100 mcL of tear fluid is required for measurement.

“At present, it is difficult to measure for dry eye patients because sufficient tears cannot be collected, but if the required amount of tears decreases in the future, it may be indicated for dry eye patients,” Dr. Aihara noted.

Discussing further research plans, he added: “We would like to examine the conditions of LC-MS/MS so that the correlation coefficient with GA in blood can be improved.

“Since LC-MS/MS is a large equipment in the laboratory, I would like to develop a device that can measure at the clinic or at home in the future.”

The study was funded by a grant from the Japan Agency for Medical Research and Development. Dr. Aihara had no conflicts of interest.

SOURCE: Aihara M et al. EASD 2020, poster presentation 624.

Measuring glycated albumin (glycoalbumin, GA) in tears could be a future way for those with diabetes to monitor their blood sugar levels noninvasively.

In a 100-patient trial, levels of GA in tears were found to be strongly correlated (r = .722; P < .001) with those in the blood.

“GA levels in blood are widely measured in clinical practice in Japan,” said study investigator Masakazu Aihara, MD, PhD, in an interview.

“It’s a biomarker that reflects the 2-week average blood glucose level like fructosamine,” explained the researcher from the department of diabetes and metabolic diseases in the Graduate School of Medicine at the University of Tokyo.

This could make it a better biomarker for detecting earlier changes in blood glucose than glycated hemoglobin (HbA_1c), which reflects changes in blood glucose over the preceding 2-3 months.

Prior studies had shown that glucose levels can be measured in tear samples and that tear glucose levels correlated with blood glucose levels, Dr. Aihara and fellow researchers observed in a poster presentation at the virtual annual meeting of the European Association for the Study of Diabetes.

“While looking for noninvasive diabetes-related markers, we found that tears contained albumin. Based on this fact, we thought that GA could be measured in tears,” Dr. Aihara explained.

Using tears to test for biomarkers is not a new idea – tears not only protect the eye, they contain a variety of large proteins, and their composition can change with disease. Indeed, researchers have been looking at their usefulness in helping find biomarkers for Parkinson’s disease and diabetic peripheral neuropathy.

During their study, Dr. Aihara and associates collected tear and blood samples at the same time. Tear samples were assessed using liquid chromatography (LC) and mass spectrometry (MS). An enzymic method was used to measure GA levels in blood. Several diagnosis assay kits for GA are sold in Japan, Dr. Aihara said, and at least one of these has U.S. Food and Drug Administration approval.

Multiple regression analysis revealed that the correlation between GA levels in tears and in blood was maintained even after adjustment for age, gender, nephropathy stage, and obesity (P < .001). The results obtained from the tests were thought unlikely to be affected by any changes in the concentration or dilution of tear samples.

“Since GA levels in blood are clinically used in all types of diabetes, GA levels in tears is also expected to be useful in all types of diabetes,” Dr. Aihara said, noting that the effects of receiving treatment on GA levels in tears is something that he would like to look at.

The team would also like to optimize how tear samples are collected and reduce the volume of tears that are required for analysis. At the moment tears are collected via a dropper and about 100 mcL of tear fluid is required for measurement.

“At present, it is difficult to measure for dry eye patients because sufficient tears cannot be collected, but if the required amount of tears decreases in the future, it may be indicated for dry eye patients,” Dr. Aihara noted.

Discussing further research plans, he added: “We would like to examine the conditions of LC-MS/MS so that the correlation coefficient with GA in blood can be improved.

“Since LC-MS/MS is a large equipment in the laboratory, I would like to develop a device that can measure at the clinic or at home in the future.”

The study was funded by a grant from the Japan Agency for Medical Research and Development. Dr. Aihara had no conflicts of interest.

SOURCE: Aihara M et al. EASD 2020, poster presentation 624.

Measuring glycated albumin (glycoalbumin, GA) in tears could be a future way for those with diabetes to monitor their blood sugar levels noninvasively.

In a 100-patient trial, levels of GA in tears were found to be strongly correlated (r = .722; P < .001) with those in the blood.

“GA levels in blood are widely measured in clinical practice in Japan,” said study investigator Masakazu Aihara, MD, PhD, in an interview.

“It’s a biomarker that reflects the 2-week average blood glucose level like fructosamine,” explained the researcher from the department of diabetes and metabolic diseases in the Graduate School of Medicine at the University of Tokyo.

This could make it a better biomarker for detecting earlier changes in blood glucose than glycated hemoglobin (HbA_1c), which reflects changes in blood glucose over the preceding 2-3 months.

Prior studies had shown that glucose levels can be measured in tear samples and that tear glucose levels correlated with blood glucose levels, Dr. Aihara and fellow researchers observed in a poster presentation at the virtual annual meeting of the European Association for the Study of Diabetes.

“While looking for noninvasive diabetes-related markers, we found that tears contained albumin. Based on this fact, we thought that GA could be measured in tears,” Dr. Aihara explained.

Using tears to test for biomarkers is not a new idea – tears not only protect the eye, they contain a variety of large proteins, and their composition can change with disease. Indeed, researchers have been looking at their usefulness in helping find biomarkers for Parkinson’s disease and diabetic peripheral neuropathy.

During their study, Dr. Aihara and associates collected tear and blood samples at the same time. Tear samples were assessed using liquid chromatography (LC) and mass spectrometry (MS). An enzymic method was used to measure GA levels in blood. Several diagnosis assay kits for GA are sold in Japan, Dr. Aihara said, and at least one of these has U.S. Food and Drug Administration approval.

Multiple regression analysis revealed that the correlation between GA levels in tears and in blood was maintained even after adjustment for age, gender, nephropathy stage, and obesity (P < .001). The results obtained from the tests were thought unlikely to be affected by any changes in the concentration or dilution of tear samples.

“Since GA levels in blood are clinically used in all types of diabetes, GA levels in tears is also expected to be useful in all types of diabetes,” Dr. Aihara said, noting that the effects of receiving treatment on GA levels in tears is something that he would like to look at.

The team would also like to optimize how tear samples are collected and reduce the volume of tears that are required for analysis. At the moment tears are collected via a dropper and about 100 mcL of tear fluid is required for measurement.

“At present, it is difficult to measure for dry eye patients because sufficient tears cannot be collected, but if the required amount of tears decreases in the future, it may be indicated for dry eye patients,” Dr. Aihara noted.

Discussing further research plans, he added: “We would like to examine the conditions of LC-MS/MS so that the correlation coefficient with GA in blood can be improved.

“Since LC-MS/MS is a large equipment in the laboratory, I would like to develop a device that can measure at the clinic or at home in the future.”

The study was funded by a grant from the Japan Agency for Medical Research and Development. Dr. Aihara had no conflicts of interest.

SOURCE: Aihara M et al. EASD 2020, poster presentation 624.

It was no surprise that updated guidelines recently published by the European Society of Cardiology for managing cardiovascular disease in patients with diabetes highlighted optimized treatment from a cardiovascular disease perspective, while a nearly concurrent update from two major diabetes societies saw the same issue from a more glycemic point of view.

This difference led to divergent approaches to managing hyperglycemia in patients with type 2 diabetes (T2D). The two diabetes societies that wrote one set of recommendations, the American Diabetes Association and the European Association for the Study of Diabetes, put metformin at the pinnacle of their drug hierarchy. Patients with T2D and established atherosclerotic cardiovascular disease (CVD), chronic kidney disease, or heart failure should all receive metformin first unless contraindicated or not tolerated, their updated consensus report said.

Once metformin is on board, a clinician can then add a second diabetes agent from among the two drug classes recently proven to also reduce cardiovascular and renal events, either the SGLT2 (sodium-glucose transporter 2) inhibitors, or GLP-1 (glucagonlike peptide–1) receptor agonists, they advised.
 

Cardiovascular disease focus represents a ‘major paradigm shift’

In contrast, the ESC guidelines called for upfront, systematic assessment of CVD risk in patients with T2D before treatment starts, and for patients in high- or very high–risk strata, the guidelines recommended starting the patient first on an SGLT2 inhibitor or a GLP-1 receptor agonist, and only adding metformin in patients who need additional glycemic control.

The guidelines also recommended starting treatment-naive patients with moderate CVD risk on metformin. For patients already on metformin, the new ESC guidelines called for adding an agent from at least one of these two drug classes with proven CVD benefits for those at high or very high CVD risk. The guidelines also note that the CVD benefits of the two newer drug classes differ and hence require further individualization depending on the risks faced by each patient, such as the risk for heart failure hospitalizations.

It’s an approach “driven by data from the cardiovascular outcome trials,” that showed several drugs from both the SGLT2 inhibitor and GLP-1 receptor agonist classes have substantial benefit for preventing cardiovascular events, renal events, hospitalizations for heart failure, and in some studies all-cause mortality, said Francesco Cosentino, MD, during a discussion of the guideline differences at the virtual annual meeting of the European Association for the Study of Diabetes.

The ESC approach also represents “a major paradigm shift,” a “change from a glucose-centric approach to an approach driven by cardiovascular disease events,” summed up Dr. Cosentino, professor of cardiology at the Karolinska Institute in Stockholm and chair of the task force that wrote the ESC’s 2019 updated guidelines. The ESC approach advocates initiating drugs for treating patients with T2D “based on cardiovascular disease risk classification,” he highlighted. Results from some SGLT2 inhibitor cardiovascular outcome trials showed that the CVD benefit was similar regardless of whether or not patients also received metformin.

ADA, EASD call for ‘a different emphasis’

“There is a different emphasis” in the statement issued by the diabetologists of the ADA and EASD, admitted Peter J. Grant, MD, a professor of diabetes and endocrinology at the University of Leeds (England) and cochair of the ESC guidelines task force. Dr. Grant represented the EASD on the task force, and the Association collaborated with the ESC in producing its guidelines.

“The ADA and EASD recommendations “look primarily at glucose control, with cardiovascular disease management as secondary.” In contrast, the ESC guidelines “are primarily cardiovascular disease risk guidelines, with a glucose interest,” Dr. Grant declared.

Despite his involvement in writing the ESC guidelines, Dr. Grant tilted toward the ADA/EASD statement as more globally relevant.

“There is much more to vasculopathy in diabetes than just macrovascular disease. Many patients with type 2 diabetes without macrovascular complications have microvascular disease,” including the potential for retinopathy, nephropathy, and neuropathy, he said. These complications can also have a strong impact on psychological well being and treatment satisfaction.

“It’s important that we’re not glucocentric any more, but it’s equally important that we treat glucose because it has such a benefit for microvascular disease.” Dr. Grant also cited metformin’s long history of safety and good tolerance, clinician comfort prescribing it, and its low price. Heavier reliance on SGLT2 inhibitors and GLP-1 receptor agonists will be expensive for the short term while the cost of these drugs remains high, which places a higher burden on “knowing we’re doing it right,” said Dr. Grant.

Dr. Cosentino pointed out that the higher cost of the drugs in the two classes shown to exert important cardiovascular and renal effects needs to be considered in a cost-effectiveness context, not just by cost alone.
 

‘Clinical inertia’ could be a danger

Dr. Cosentino played down a major disagreement between the two guidelines, suggesting that “focusing on the differences leads to clinical inertia” by the practicing community when they are unsure how to reconcile the two positions.

Dr. Grant agreed that adding a second drug to metformin right away made sense in at least selected patients. “Look at each patient and decide whether they need glycemic control. If so, and if they also have cardiovascular disease, use both drugs,” metformin, plus one agent from one of the two newer classes.

Something both experts agreed on is that it’s time to generally steer clear of sulfonylurea drugs. “We have evidence for harmful effects from sulfonylureas,” Dr. Cosentino said.

“I’d dump sulfonylureas,” was Dr. Grant’s assessment, but he added that they still have a role for patients who need additional glycemic control but can’t afford the newer drugs.

Dr. Cosentino has had financial relationships with Abbott, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck, Mundipharma, Novo Nordisk, and Pfizer, Dr. Grant has lectured on behalf of AstraZeneca, GlaxoSmithKline, Merck, Novo Nordisk, the Medicines Company, and Takeda, and he has been an adviser to Amgen, AstraZeneca, Novartis, Novo Nordisk, and Synexus.

[email protected]

It was no surprise that updated guidelines recently published by the European Society of Cardiology for managing cardiovascular disease in patients with diabetes highlighted optimized treatment from a cardiovascular disease perspective, while a nearly concurrent update from two major diabetes societies saw the same issue from a more glycemic point of view.

This difference led to divergent approaches to managing hyperglycemia in patients with type 2 diabetes (T2D). The two diabetes societies that wrote one set of recommendations, the American Diabetes Association and the European Association for the Study of Diabetes, put metformin at the pinnacle of their drug hierarchy. Patients with T2D and established atherosclerotic cardiovascular disease (CVD), chronic kidney disease, or heart failure should all receive metformin first unless contraindicated or not tolerated, their updated consensus report said.

Once metformin is on board, a clinician can then add a second diabetes agent from among the two drug classes recently proven to also reduce cardiovascular and renal events, either the SGLT2 (sodium-glucose transporter 2) inhibitors, or GLP-1 (glucagonlike peptide–1) receptor agonists, they advised.
 

Cardiovascular disease focus represents a ‘major paradigm shift’

In contrast, the ESC guidelines called for upfront, systematic assessment of CVD risk in patients with T2D before treatment starts, and for patients in high- or very high–risk strata, the guidelines recommended starting the patient first on an SGLT2 inhibitor or a GLP-1 receptor agonist, and only adding metformin in patients who need additional glycemic control.

The guidelines also recommended starting treatment-naive patients with moderate CVD risk on metformin. For patients already on metformin, the new ESC guidelines called for adding an agent from at least one of these two drug classes with proven CVD benefits for those at high or very high CVD risk. The guidelines also note that the CVD benefits of the two newer drug classes differ and hence require further individualization depending on the risks faced by each patient, such as the risk for heart failure hospitalizations.

It’s an approach “driven by data from the cardiovascular outcome trials,” that showed several drugs from both the SGLT2 inhibitor and GLP-1 receptor agonist classes have substantial benefit for preventing cardiovascular events, renal events, hospitalizations for heart failure, and in some studies all-cause mortality, said Francesco Cosentino, MD, during a discussion of the guideline differences at the virtual annual meeting of the European Association for the Study of Diabetes.

The ESC approach also represents “a major paradigm shift,” a “change from a glucose-centric approach to an approach driven by cardiovascular disease events,” summed up Dr. Cosentino, professor of cardiology at the Karolinska Institute in Stockholm and chair of the task force that wrote the ESC’s 2019 updated guidelines. The ESC approach advocates initiating drugs for treating patients with T2D “based on cardiovascular disease risk classification,” he highlighted. Results from some SGLT2 inhibitor cardiovascular outcome trials showed that the CVD benefit was similar regardless of whether or not patients also received metformin.

ADA, EASD call for ‘a different emphasis’

“There is a different emphasis” in the statement issued by the diabetologists of the ADA and EASD, admitted Peter J. Grant, MD, a professor of diabetes and endocrinology at the University of Leeds (England) and cochair of the ESC guidelines task force. Dr. Grant represented the EASD on the task force, and the Association collaborated with the ESC in producing its guidelines.

“The ADA and EASD recommendations “look primarily at glucose control, with cardiovascular disease management as secondary.” In contrast, the ESC guidelines “are primarily cardiovascular disease risk guidelines, with a glucose interest,” Dr. Grant declared.

Despite his involvement in writing the ESC guidelines, Dr. Grant tilted toward the ADA/EASD statement as more globally relevant.

“There is much more to vasculopathy in diabetes than just macrovascular disease. Many patients with type 2 diabetes without macrovascular complications have microvascular disease,” including the potential for retinopathy, nephropathy, and neuropathy, he said. These complications can also have a strong impact on psychological well being and treatment satisfaction.

“It’s important that we’re not glucocentric any more, but it’s equally important that we treat glucose because it has such a benefit for microvascular disease.” Dr. Grant also cited metformin’s long history of safety and good tolerance, clinician comfort prescribing it, and its low price. Heavier reliance on SGLT2 inhibitors and GLP-1 receptor agonists will be expensive for the short term while the cost of these drugs remains high, which places a higher burden on “knowing we’re doing it right,” said Dr. Grant.

Dr. Cosentino pointed out that the higher cost of the drugs in the two classes shown to exert important cardiovascular and renal effects needs to be considered in a cost-effectiveness context, not just by cost alone.
 

‘Clinical inertia’ could be a danger

Dr. Cosentino played down a major disagreement between the two guidelines, suggesting that “focusing on the differences leads to clinical inertia” by the practicing community when they are unsure how to reconcile the two positions.

Dr. Grant agreed that adding a second drug to metformin right away made sense in at least selected patients. “Look at each patient and decide whether they need glycemic control. If so, and if they also have cardiovascular disease, use both drugs,” metformin, plus one agent from one of the two newer classes.

Something both experts agreed on is that it’s time to generally steer clear of sulfonylurea drugs. “We have evidence for harmful effects from sulfonylureas,” Dr. Cosentino said.

“I’d dump sulfonylureas,” was Dr. Grant’s assessment, but he added that they still have a role for patients who need additional glycemic control but can’t afford the newer drugs.

Dr. Cosentino has had financial relationships with Abbott, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck, Mundipharma, Novo Nordisk, and Pfizer, Dr. Grant has lectured on behalf of AstraZeneca, GlaxoSmithKline, Merck, Novo Nordisk, the Medicines Company, and Takeda, and he has been an adviser to Amgen, AstraZeneca, Novartis, Novo Nordisk, and Synexus.

[email protected]

It was no surprise that updated guidelines recently published by the European Society of Cardiology for managing cardiovascular disease in patients with diabetes highlighted optimized treatment from a cardiovascular disease perspective, while a nearly concurrent update from two major diabetes societies saw the same issue from a more glycemic point of view.

This difference led to divergent approaches to managing hyperglycemia in patients with type 2 diabetes (T2D). The two diabetes societies that wrote one set of recommendations, the American Diabetes Association and the European Association for the Study of Diabetes, put metformin at the pinnacle of their drug hierarchy. Patients with T2D and established atherosclerotic cardiovascular disease (CVD), chronic kidney disease, or heart failure should all receive metformin first unless contraindicated or not tolerated, their updated consensus report said.

Once metformin is on board, a clinician can then add a second diabetes agent from among the two drug classes recently proven to also reduce cardiovascular and renal events, either the SGLT2 (sodium-glucose transporter 2) inhibitors, or GLP-1 (glucagonlike peptide–1) receptor agonists, they advised.
 

Cardiovascular disease focus represents a ‘major paradigm shift’

In contrast, the ESC guidelines called for upfront, systematic assessment of CVD risk in patients with T2D before treatment starts, and for patients in high- or very high–risk strata, the guidelines recommended starting the patient first on an SGLT2 inhibitor or a GLP-1 receptor agonist, and only adding metformin in patients who need additional glycemic control.

The guidelines also recommended starting treatment-naive patients with moderate CVD risk on metformin. For patients already on metformin, the new ESC guidelines called for adding an agent from at least one of these two drug classes with proven CVD benefits for those at high or very high CVD risk. The guidelines also note that the CVD benefits of the two newer drug classes differ and hence require further individualization depending on the risks faced by each patient, such as the risk for heart failure hospitalizations.

It’s an approach “driven by data from the cardiovascular outcome trials,” that showed several drugs from both the SGLT2 inhibitor and GLP-1 receptor agonist classes have substantial benefit for preventing cardiovascular events, renal events, hospitalizations for heart failure, and in some studies all-cause mortality, said Francesco Cosentino, MD, during a discussion of the guideline differences at the virtual annual meeting of the European Association for the Study of Diabetes.

The ESC approach also represents “a major paradigm shift,” a “change from a glucose-centric approach to an approach driven by cardiovascular disease events,” summed up Dr. Cosentino, professor of cardiology at the Karolinska Institute in Stockholm and chair of the task force that wrote the ESC’s 2019 updated guidelines. The ESC approach advocates initiating drugs for treating patients with T2D “based on cardiovascular disease risk classification,” he highlighted. Results from some SGLT2 inhibitor cardiovascular outcome trials showed that the CVD benefit was similar regardless of whether or not patients also received metformin.

ADA, EASD call for ‘a different emphasis’

“There is a different emphasis” in the statement issued by the diabetologists of the ADA and EASD, admitted Peter J. Grant, MD, a professor of diabetes and endocrinology at the University of Leeds (England) and cochair of the ESC guidelines task force. Dr. Grant represented the EASD on the task force, and the Association collaborated with the ESC in producing its guidelines.

“The ADA and EASD recommendations “look primarily at glucose control, with cardiovascular disease management as secondary.” In contrast, the ESC guidelines “are primarily cardiovascular disease risk guidelines, with a glucose interest,” Dr. Grant declared.

Despite his involvement in writing the ESC guidelines, Dr. Grant tilted toward the ADA/EASD statement as more globally relevant.

“There is much more to vasculopathy in diabetes than just macrovascular disease. Many patients with type 2 diabetes without macrovascular complications have microvascular disease,” including the potential for retinopathy, nephropathy, and neuropathy, he said. These complications can also have a strong impact on psychological well being and treatment satisfaction.

“It’s important that we’re not glucocentric any more, but it’s equally important that we treat glucose because it has such a benefit for microvascular disease.” Dr. Grant also cited metformin’s long history of safety and good tolerance, clinician comfort prescribing it, and its low price. Heavier reliance on SGLT2 inhibitors and GLP-1 receptor agonists will be expensive for the short term while the cost of these drugs remains high, which places a higher burden on “knowing we’re doing it right,” said Dr. Grant.

Dr. Cosentino pointed out that the higher cost of the drugs in the two classes shown to exert important cardiovascular and renal effects needs to be considered in a cost-effectiveness context, not just by cost alone.
 

‘Clinical inertia’ could be a danger

Dr. Cosentino played down a major disagreement between the two guidelines, suggesting that “focusing on the differences leads to clinical inertia” by the practicing community when they are unsure how to reconcile the two positions.

Dr. Grant agreed that adding a second drug to metformin right away made sense in at least selected patients. “Look at each patient and decide whether they need glycemic control. If so, and if they also have cardiovascular disease, use both drugs,” metformin, plus one agent from one of the two newer classes.

Something both experts agreed on is that it’s time to generally steer clear of sulfonylurea drugs. “We have evidence for harmful effects from sulfonylureas,” Dr. Cosentino said.

“I’d dump sulfonylureas,” was Dr. Grant’s assessment, but he added that they still have a role for patients who need additional glycemic control but can’t afford the newer drugs.

Dr. Cosentino has had financial relationships with Abbott, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck, Mundipharma, Novo Nordisk, and Pfizer, Dr. Grant has lectured on behalf of AstraZeneca, GlaxoSmithKline, Merck, Novo Nordisk, the Medicines Company, and Takeda, and he has been an adviser to Amgen, AstraZeneca, Novartis, Novo Nordisk, and Synexus.

[email protected]

With high rates of fatty liver disease known to occur among people with type 2 diabetes, is it time to introduce routine liver screening into daily diabetes practice? The answer depends on whom you ask, and then there are still some important caveats.

Wavebreakmedia Ltd/ThinkStockPhotos.com

From the hepatologist’s perspective, there is no excuse not to consider liver surveillance now that noninvasive screening methods are available, suggested Michael Trauner, MD, of the Medical University of Vienna.

“From a practical standpoint, I think every type 2 diabetic over 50 years of age is at high risk,” and consequently should be screened at diagnosis, Dr. Trauner said during a debate at the virtual annual meeting of the European Association for the Study of Diabetes. “I would screen at diagnosis and then decide on recall depending on noninvasive fibrosis markers.”

“It’s a rising problem that we are facing these days,” observed Michael Roden, MD, chair and professor of internal medicine, endocrinology and metabolic diseases at Heinrich-Heine University in Düsseldorf, Germany, and who cochaired the session. Not only do people with type 2 diabetes have an increased risk for developing liver diseases, but also there’s a higher risk for those with fatty liver diseases developing type 2 diabetes.

A meta-analysis published in Gut in just last week illustrates just how big a problem this is – nonalcoholic fatty liver disease (NAFLD) “doubled the risk of type 2 diabetes,” said Dr Rosen, who is also the director of the division of endocrinology and diabetology at University Clinics Düsseldorf. That analysis was based on more than 500,000 people, almost 28,000 of whom had incident diabetes over a 5-year period.
 

Screening tools scarce

This makes liver screening in type 2 diabetes patients “a formidable challenge,” cautioned Gianluca Perseghin, MD, professor of endocrinology at the Monza (Italy) Polyclinic and the University of Milano-Bicocca in Milan.

“Hepatologists generally see only the most severe cases,” Dr. Perseghin said. Diabetologists and endocrinologists would be likely to see huge numbers of patients that could potentially be at risk for liver disease and following the recommendations set out in the joint European Association for the Study of the Liver/EASD/European Association for the Study of Obesity guidelines would result in a huge number of patients being identified and potentially needing referral, he argued.

“At this stage, we need to build friendly, reliable and cost-effective screening process to be applied in the health systems,” Dr. Perseghin suggested. He proposed that liver surveillance would need to be not only personalized on a patient level, but also at the infrastructure level. Measuring liver enzymes, for example, was going to be less accurate in picking up liver disease but blood tests were widely available, whereas imaging methods were not going to be something all diabetes clinics would have immediate access to.

“There are clearly a lot of provocative decisions still to be made,” acknowledged Philip Newsome, PhD, FRCPE, an honorary consultant hepatologist at the University of Birmingham (England) and who cochaired the debate.

“We need to demonstrate that looking for the presence of liver disease in this cohort changes their outcomes in a way that is cost effective,” Dr. Newsome, who is also the secretary general of EASL.

“Tests are evolving, but more importantly, treatments are evolving. So, the decision around cost effectiveness will clearly change,” he added.
 

NAFLD therapies unclar

“There are still a lot of questions,” Dr. Newsome said during a Novo-Nordisk–sponsored “Meet the Expert” session discussing EASL-EASD-EASO guidelines. “We don’t have any licensed therapies at the moment. But there’s been a huge amount of investment, looking at all sorts of different approaches.”

Dr. Newsome added: “We also don’t know how to monitor these patients. Most of the noninvasive are very useful for staging patients, but we don’t really understand how useful they are for monitoring changes in fibrosis.”

Diabetologist Hannele Yki-Järvinen, MD, PhD, of the University of Helsinki, gave her thoughts on the topic during the same session.

“We should add FIB-4 [Fibrosis-4 index] to the annual exam and ask the lab to calculate FIB-4 automatically,” Dr. Yki-Järvinen said. FIB-4is calculated using the patients age and the results of readily available blood tests that measure the AST/ALT ratio and the platelet count.

Dr. Trauner has received advisory fees and grant support from various companies with an interest in developing liver-directed therapies, and is also a coinventor of 24-norursodeoxycholic acid under development for cholestatic liver disease and potentially NAFLD. Dr. Perseghin has received honoraria and grant support from various pharmaceutical companies with an interest in diabetes care. Dr. Roden did not provide any disclosures. Dr. Newsome has received research grants from Boehringer Ingelheim and Novo Nordisk and acted as a consultant to many pharmaceutical companies. Dr. Yki-Järvinen disclosed receiving consultancy fees from Eli Lilly, MSD, and Novo Nordisk.

SOURCE: Trauner M; Persghin G. EASD 2020, Session S27.

With high rates of fatty liver disease known to occur among people with type 2 diabetes, is it time to introduce routine liver screening into daily diabetes practice? The answer depends on whom you ask, and then there are still some important caveats.

Wavebreakmedia Ltd/ThinkStockPhotos.com

From the hepatologist’s perspective, there is no excuse not to consider liver surveillance now that noninvasive screening methods are available, suggested Michael Trauner, MD, of the Medical University of Vienna.

“From a practical standpoint, I think every type 2 diabetic over 50 years of age is at high risk,” and consequently should be screened at diagnosis, Dr. Trauner said during a debate at the virtual annual meeting of the European Association for the Study of Diabetes. “I would screen at diagnosis and then decide on recall depending on noninvasive fibrosis markers.”

“It’s a rising problem that we are facing these days,” observed Michael Roden, MD, chair and professor of internal medicine, endocrinology and metabolic diseases at Heinrich-Heine University in Düsseldorf, Germany, and who cochaired the session. Not only do people with type 2 diabetes have an increased risk for developing liver diseases, but also there’s a higher risk for those with fatty liver diseases developing type 2 diabetes.

A meta-analysis published in Gut in just last week illustrates just how big a problem this is – nonalcoholic fatty liver disease (NAFLD) “doubled the risk of type 2 diabetes,” said Dr Rosen, who is also the director of the division of endocrinology and diabetology at University Clinics Düsseldorf. That analysis was based on more than 500,000 people, almost 28,000 of whom had incident diabetes over a 5-year period.
 

Screening tools scarce

This makes liver screening in type 2 diabetes patients “a formidable challenge,” cautioned Gianluca Perseghin, MD, professor of endocrinology at the Monza (Italy) Polyclinic and the University of Milano-Bicocca in Milan.

“Hepatologists generally see only the most severe cases,” Dr. Perseghin said. Diabetologists and endocrinologists would be likely to see huge numbers of patients that could potentially be at risk for liver disease and following the recommendations set out in the joint European Association for the Study of the Liver/EASD/European Association for the Study of Obesity guidelines would result in a huge number of patients being identified and potentially needing referral, he argued.

“At this stage, we need to build friendly, reliable and cost-effective screening process to be applied in the health systems,” Dr. Perseghin suggested. He proposed that liver surveillance would need to be not only personalized on a patient level, but also at the infrastructure level. Measuring liver enzymes, for example, was going to be less accurate in picking up liver disease but blood tests were widely available, whereas imaging methods were not going to be something all diabetes clinics would have immediate access to.

“There are clearly a lot of provocative decisions still to be made,” acknowledged Philip Newsome, PhD, FRCPE, an honorary consultant hepatologist at the University of Birmingham (England) and who cochaired the debate.

“We need to demonstrate that looking for the presence of liver disease in this cohort changes their outcomes in a way that is cost effective,” Dr. Newsome, who is also the secretary general of EASL.

“Tests are evolving, but more importantly, treatments are evolving. So, the decision around cost effectiveness will clearly change,” he added.
 

NAFLD therapies unclar

“There are still a lot of questions,” Dr. Newsome said during a Novo-Nordisk–sponsored “Meet the Expert” session discussing EASL-EASD-EASO guidelines. “We don’t have any licensed therapies at the moment. But there’s been a huge amount of investment, looking at all sorts of different approaches.”

Dr. Newsome added: “We also don’t know how to monitor these patients. Most of the noninvasive are very useful for staging patients, but we don’t really understand how useful they are for monitoring changes in fibrosis.”

Diabetologist Hannele Yki-Järvinen, MD, PhD, of the University of Helsinki, gave her thoughts on the topic during the same session.

“We should add FIB-4 [Fibrosis-4 index] to the annual exam and ask the lab to calculate FIB-4 automatically,” Dr. Yki-Järvinen said. FIB-4is calculated using the patients age and the results of readily available blood tests that measure the AST/ALT ratio and the platelet count.

Dr. Trauner has received advisory fees and grant support from various companies with an interest in developing liver-directed therapies, and is also a coinventor of 24-norursodeoxycholic acid under development for cholestatic liver disease and potentially NAFLD. Dr. Perseghin has received honoraria and grant support from various pharmaceutical companies with an interest in diabetes care. Dr. Roden did not provide any disclosures. Dr. Newsome has received research grants from Boehringer Ingelheim and Novo Nordisk and acted as a consultant to many pharmaceutical companies. Dr. Yki-Järvinen disclosed receiving consultancy fees from Eli Lilly, MSD, and Novo Nordisk.

SOURCE: Trauner M; Persghin G. EASD 2020, Session S27.

With high rates of fatty liver disease known to occur among people with type 2 diabetes, is it time to introduce routine liver screening into daily diabetes practice? The answer depends on whom you ask, and then there are still some important caveats.

Wavebreakmedia Ltd/ThinkStockPhotos.com

From the hepatologist’s perspective, there is no excuse not to consider liver surveillance now that noninvasive screening methods are available, suggested Michael Trauner, MD, of the Medical University of Vienna.

“From a practical standpoint, I think every type 2 diabetic over 50 years of age is at high risk,” and consequently should be screened at diagnosis, Dr. Trauner said during a debate at the virtual annual meeting of the European Association for the Study of Diabetes. “I would screen at diagnosis and then decide on recall depending on noninvasive fibrosis markers.”

“It’s a rising problem that we are facing these days,” observed Michael Roden, MD, chair and professor of internal medicine, endocrinology and metabolic diseases at Heinrich-Heine University in Düsseldorf, Germany, and who cochaired the session. Not only do people with type 2 diabetes have an increased risk for developing liver diseases, but also there’s a higher risk for those with fatty liver diseases developing type 2 diabetes.

A meta-analysis published in Gut in just last week illustrates just how big a problem this is – nonalcoholic fatty liver disease (NAFLD) “doubled the risk of type 2 diabetes,” said Dr Rosen, who is also the director of the division of endocrinology and diabetology at University Clinics Düsseldorf. That analysis was based on more than 500,000 people, almost 28,000 of whom had incident diabetes over a 5-year period.
 

Screening tools scarce

This makes liver screening in type 2 diabetes patients “a formidable challenge,” cautioned Gianluca Perseghin, MD, professor of endocrinology at the Monza (Italy) Polyclinic and the University of Milano-Bicocca in Milan.

“Hepatologists generally see only the most severe cases,” Dr. Perseghin said. Diabetologists and endocrinologists would be likely to see huge numbers of patients that could potentially be at risk for liver disease and following the recommendations set out in the joint European Association for the Study of the Liver/EASD/European Association for the Study of Obesity guidelines would result in a huge number of patients being identified and potentially needing referral, he argued.

“At this stage, we need to build friendly, reliable and cost-effective screening process to be applied in the health systems,” Dr. Perseghin suggested. He proposed that liver surveillance would need to be not only personalized on a patient level, but also at the infrastructure level. Measuring liver enzymes, for example, was going to be less accurate in picking up liver disease but blood tests were widely available, whereas imaging methods were not going to be something all diabetes clinics would have immediate access to.

“There are clearly a lot of provocative decisions still to be made,” acknowledged Philip Newsome, PhD, FRCPE, an honorary consultant hepatologist at the University of Birmingham (England) and who cochaired the debate.

“We need to demonstrate that looking for the presence of liver disease in this cohort changes their outcomes in a way that is cost effective,” Dr. Newsome, who is also the secretary general of EASL.

“Tests are evolving, but more importantly, treatments are evolving. So, the decision around cost effectiveness will clearly change,” he added.
 

NAFLD therapies unclar

“There are still a lot of questions,” Dr. Newsome said during a Novo-Nordisk–sponsored “Meet the Expert” session discussing EASL-EASD-EASO guidelines. “We don’t have any licensed therapies at the moment. But there’s been a huge amount of investment, looking at all sorts of different approaches.”

Dr. Newsome added: “We also don’t know how to monitor these patients. Most of the noninvasive are very useful for staging patients, but we don’t really understand how useful they are for monitoring changes in fibrosis.”

Diabetologist Hannele Yki-Järvinen, MD, PhD, of the University of Helsinki, gave her thoughts on the topic during the same session.

“We should add FIB-4 [Fibrosis-4 index] to the annual exam and ask the lab to calculate FIB-4 automatically,” Dr. Yki-Järvinen said. FIB-4is calculated using the patients age and the results of readily available blood tests that measure the AST/ALT ratio and the platelet count.

Dr. Trauner has received advisory fees and grant support from various companies with an interest in developing liver-directed therapies, and is also a coinventor of 24-norursodeoxycholic acid under development for cholestatic liver disease and potentially NAFLD. Dr. Perseghin has received honoraria and grant support from various pharmaceutical companies with an interest in diabetes care. Dr. Roden did not provide any disclosures. Dr. Newsome has received research grants from Boehringer Ingelheim and Novo Nordisk and acted as a consultant to many pharmaceutical companies. Dr. Yki-Järvinen disclosed receiving consultancy fees from Eli Lilly, MSD, and Novo Nordisk.

SOURCE: Trauner M; Persghin G. EASD 2020, Session S27.

A protocol developed in the United Kingdom that allows commercial pilots with insulin-treated diabetes to fly airplanes has resulted in precise glycemic control during flight and no safety issues, new research finds.

©mico_images/Thinkstock

The results are believed to be the largest-ever dataset for people with insulin-treated diabetes in “safety-critical” occupations, said Gillian L. Garden, MD, who presented the findings this week at the virtual annual meeting of the European Association for the Study of Diabetes.

The protocol, which involves multiple glucose measurements before and throughout flights and corrective action for out-of-range values, resulted in 98% of glucose values in target range with no pilot incapacitation. The results were also published in Diabetes Care earlier this year, noted Dr. Garden, a clinical fellow in diabetes and endocrinology at the Royal Surrey NHS Foundation Trust, Guildford, England.

“There were no safety concerns at all and certainly no episodes of pilot incapacitation throughout the [7.5] years of the study. Our study proves that the protocol is feasible, is practical to implement, and is easily understood by both pilots and copilots,” she observed.

Dr. Garden foresees wider use of this approach: “We believe the study is of international importance and this protocol could be adopted by other aviation authorities to allow more insulin-treated pilots worldwide to be able to fly commercial aircraft.”

“With proper oversight and a defined protocol such as the one that we’ve been working to produce it is possible for anybody with insulin-treated diabetes to, in fact, adequately perform other safety-critical occupations as well, and it would be good to see fewer people being discriminated against on the basis of their diabetes,” she emphasized.
 

‘Impressive’ study of highly motivated individuals

Historically, insulin-treated patients – with both types of diabetes – had been barred from many “safety-critical” occupations, including commercial airline piloting. This was out of concern both for the potential immediate effects of hypoglycemia, including cognitive impairment and slowing of reaction times, as well as the long-term effects of diabetes, including vision loss and nerve damage, Dr. Garden explained.

However, “with advances in diabetes management, including different insulin types, methods of delivery, and glucose-monitoring systems, it’s now possible for individuals to have excellent glycemic control. This, along with the implementation of legislation against discrimination, has allowed insulin-treated people to no longer be debarred from certain employments,” she explained during an EASD press briefing on Sept. 24.

An expert panel convened in 2010 by the U.K. Civil Aviation Authority developed the protocol, and in 2012, the CAA began issuing class 1 medical certificates to insulin-treated pilots. The protocol was subsequently adopted by Ireland in 2015 and by Austria in 2016.

Initial results from nearly 9,000 glucose readings of 26 U.K. pilots who received a certificate between 2012 and 2015 were reported at the EASD 2016 Annual Meeting and published in 2017.

The current study is far larger, with 38,621 glucose readings from 49 pilots from the United Kingdom, Ireland, and Austria who have been using the protocol since 2012. 

Mark Evans, MD, of Addenbrookes Hospital, Cambridge, England, said in an interview that “I thought this was a fascinating paper. ... I was deeply impressed by the data.”

Dr. Evans, who chairs the U.K. Department of Transport advisory panel on driving and diabetes, also noted: “The group of people with insulin-treated diabetes flying planes are a phenomenally motivated group who are prepared to do things that probably most drivers of motor vehicles would find oppressive or very difficult to do.”

“I thought the outcomes were really impressive in terms of the amount of time they were able to maintain themselves within glucose target ranges.”

Indeed, Dr. Garden said, “pilots are typically very organized and used to dealing with strict protocols with regard to all of the processes they have to follow before they fly and the safety checks they have to do. They adapted to this additional safety measure really well.”
 

Traffic light protocol keeps pilots in range

The protocol requires pilots to perform fingerstick glucose checks 30 minutes prior to flight, every hour during flight, and 30 minutes before landing. They must also attend clinical reviews every 6 months.

A traffic light system is used to denote acceptable pre- and in-flight glucose levels, with green meaning acceptable (5.0-15.0 mmol/L [90-270 mg/dL]), amber indicating caution for low (4.0-4.9 mmol/L [72-88 mg/dL]) or high (15.1-20.0 mmol/L [272-360 mg/dL]) blood glucose. Red requires immediate action (low blood glucose <4 mmol/L [72 mg/dL] and high >20 mmol/L [>360 mg/dL]).

Low amber values require the pilot to ingest 10-15 fast-acting carbohydrates and retest after 30 minutes. Low red values indicate the pilot must hand over the controls to the copilot. High readings of >15.0 mmol/L (>270 mg/dL) require an insulin dosing review. A high red value also requires the pilot to hand over the controls.

Of the 49 pilots, 84% had type 1 diabetes and 16% had insulin-treated type 2 diabetes. Most (61%) had class 1 medical certificates (required to validate a commercial pilot license) and 39% had class 2 medical certificates (required to validate a private pilot’s license). Median diabetes duration was 10.9 years.

Of note, all had become pilots prior to diabetes onset. As of now, the EU Aviation Safety Agency doesn’t allow people with preexisting insulin-treated diabetes to become pilots.

“We are fighting to change that, but with the U.K. leaving the EU, the Civil Aviation Authority might pursue it [separately]. We don’t know how that will pan out,” Dr. Garden noted during the briefing.

Over the 7.5 years, 97.7% of readings were within the green range, while just 1.42% were in the low amber range and 0.75% in the high amber range. Just 48 readings (0.12%) were in the low red range and 6 (0.02%) in the high red range. Of the 48 low reds, just 14 were recorded during flight. Of the six high reds, only two occurred during flight.

There were no instances of pilot incapacitation or changes in average hemoglobin A1c.

The results should alleviate concerns expressed after a prior report that pilots’ overall glycemic control could worsen if they pushed too hard to avoid lows, Dr. Garden noted.

The proportion of out-of-range values declined from 5.7% in 2013 to 1.2% in 2019. Low red values didn’t change (0.2% in 2013 and 0.1% in 2019) but high red values had completely disappeared by 2017.
 

What about CGM?

In response to a question during the briefing about use of continuous glucose monitoring, Dr. Garden said that some of the pilots were using CGM in addition to following the fingerstick protocol.

At the time the protocol was developed a decade ago, CGM wasn’t considered accurate enough and there wasn’t evidence for its use at high altitude.

But there has been a great deal more data since then, she said, noting “we believe it would be safer to use now because of how good that equipment is. ... Certainly, there’s a good number [of pilots] using CGM, and hopefully that will increase and the protocol will change to allow them all to use CGM if they want to.

“I think we’ll probably see CGM in the protocol within the next year to 2 years. Hopefully, that will make things a lot easier, so pilots won’t have to prick their fingers while they’re flying.”

Her group is currently conducting a study (DEXFLY) on use of the Dexcom G6 in addition to fingersticks in commercial pilots with insulin-treated diabetes. Results are expected by the end of the year.

Dr. Evans commented: “I think it’s a no-brainer that CGM will become the gold standard. I understand why they’re going to want to be cautious about this, but if they can generate data to show it will be a low-risk change, I think it will come.”

He also noted that it was only a couple of years ago that U.K. law was changed to allow car drivers with insulin-treated diabetes to use CGM as part of their glucose-testing requirements (before driving and every 2 hours). CGM still isn’t approved for use by drivers of trucks or other large vehicles, but “I think at some point in the future it will become more accepted,” Dr. Evans commented.

Dr. Garden reported no relevant financial relationships. Dr. Evans has reported being an advisory board member of, speaker for, and/or grant recipient from Novo Nordisk, Dexcom, Medtronic, Abbott, Eli Lilly, and Roche. 

A version of this article originally appeared on Medscape.com.

A protocol developed in the United Kingdom that allows commercial pilots with insulin-treated diabetes to fly airplanes has resulted in precise glycemic control during flight and no safety issues, new research finds.

©mico_images/Thinkstock

The results are believed to be the largest-ever dataset for people with insulin-treated diabetes in “safety-critical” occupations, said Gillian L. Garden, MD, who presented the findings this week at the virtual annual meeting of the European Association for the Study of Diabetes.

The protocol, which involves multiple glucose measurements before and throughout flights and corrective action for out-of-range values, resulted in 98% of glucose values in target range with no pilot incapacitation. The results were also published in Diabetes Care earlier this year, noted Dr. Garden, a clinical fellow in diabetes and endocrinology at the Royal Surrey NHS Foundation Trust, Guildford, England.

“There were no safety concerns at all and certainly no episodes of pilot incapacitation throughout the [7.5] years of the study. Our study proves that the protocol is feasible, is practical to implement, and is easily understood by both pilots and copilots,” she observed.

Dr. Garden foresees wider use of this approach: “We believe the study is of international importance and this protocol could be adopted by other aviation authorities to allow more insulin-treated pilots worldwide to be able to fly commercial aircraft.”

“With proper oversight and a defined protocol such as the one that we’ve been working to produce it is possible for anybody with insulin-treated diabetes to, in fact, adequately perform other safety-critical occupations as well, and it would be good to see fewer people being discriminated against on the basis of their diabetes,” she emphasized.
 

‘Impressive’ study of highly motivated individuals

Historically, insulin-treated patients – with both types of diabetes – had been barred from many “safety-critical” occupations, including commercial airline piloting. This was out of concern both for the potential immediate effects of hypoglycemia, including cognitive impairment and slowing of reaction times, as well as the long-term effects of diabetes, including vision loss and nerve damage, Dr. Garden explained.

However, “with advances in diabetes management, including different insulin types, methods of delivery, and glucose-monitoring systems, it’s now possible for individuals to have excellent glycemic control. This, along with the implementation of legislation against discrimination, has allowed insulin-treated people to no longer be debarred from certain employments,” she explained during an EASD press briefing on Sept. 24.

An expert panel convened in 2010 by the U.K. Civil Aviation Authority developed the protocol, and in 2012, the CAA began issuing class 1 medical certificates to insulin-treated pilots. The protocol was subsequently adopted by Ireland in 2015 and by Austria in 2016.

Initial results from nearly 9,000 glucose readings of 26 U.K. pilots who received a certificate between 2012 and 2015 were reported at the EASD 2016 Annual Meeting and published in 2017.

The current study is far larger, with 38,621 glucose readings from 49 pilots from the United Kingdom, Ireland, and Austria who have been using the protocol since 2012. 

Mark Evans, MD, of Addenbrookes Hospital, Cambridge, England, said in an interview that “I thought this was a fascinating paper. ... I was deeply impressed by the data.”

Dr. Evans, who chairs the U.K. Department of Transport advisory panel on driving and diabetes, also noted: “The group of people with insulin-treated diabetes flying planes are a phenomenally motivated group who are prepared to do things that probably most drivers of motor vehicles would find oppressive or very difficult to do.”

“I thought the outcomes were really impressive in terms of the amount of time they were able to maintain themselves within glucose target ranges.”

Indeed, Dr. Garden said, “pilots are typically very organized and used to dealing with strict protocols with regard to all of the processes they have to follow before they fly and the safety checks they have to do. They adapted to this additional safety measure really well.”
 

Traffic light protocol keeps pilots in range

The protocol requires pilots to perform fingerstick glucose checks 30 minutes prior to flight, every hour during flight, and 30 minutes before landing. They must also attend clinical reviews every 6 months.

A traffic light system is used to denote acceptable pre- and in-flight glucose levels, with green meaning acceptable (5.0-15.0 mmol/L [90-270 mg/dL]), amber indicating caution for low (4.0-4.9 mmol/L [72-88 mg/dL]) or high (15.1-20.0 mmol/L [272-360 mg/dL]) blood glucose. Red requires immediate action (low blood glucose <4 mmol/L [72 mg/dL] and high >20 mmol/L [>360 mg/dL]).

Low amber values require the pilot to ingest 10-15 fast-acting carbohydrates and retest after 30 minutes. Low red values indicate the pilot must hand over the controls to the copilot. High readings of >15.0 mmol/L (>270 mg/dL) require an insulin dosing review. A high red value also requires the pilot to hand over the controls.

Of the 49 pilots, 84% had type 1 diabetes and 16% had insulin-treated type 2 diabetes. Most (61%) had class 1 medical certificates (required to validate a commercial pilot license) and 39% had class 2 medical certificates (required to validate a private pilot’s license). Median diabetes duration was 10.9 years.

Of note, all had become pilots prior to diabetes onset. As of now, the EU Aviation Safety Agency doesn’t allow people with preexisting insulin-treated diabetes to become pilots.

“We are fighting to change that, but with the U.K. leaving the EU, the Civil Aviation Authority might pursue it [separately]. We don’t know how that will pan out,” Dr. Garden noted during the briefing.

Over the 7.5 years, 97.7% of readings were within the green range, while just 1.42% were in the low amber range and 0.75% in the high amber range. Just 48 readings (0.12%) were in the low red range and 6 (0.02%) in the high red range. Of the 48 low reds, just 14 were recorded during flight. Of the six high reds, only two occurred during flight.

There were no instances of pilot incapacitation or changes in average hemoglobin A1c.

The results should alleviate concerns expressed after a prior report that pilots’ overall glycemic control could worsen if they pushed too hard to avoid lows, Dr. Garden noted.

The proportion of out-of-range values declined from 5.7% in 2013 to 1.2% in 2019. Low red values didn’t change (0.2% in 2013 and 0.1% in 2019) but high red values had completely disappeared by 2017.
 

What about CGM?

In response to a question during the briefing about use of continuous glucose monitoring, Dr. Garden said that some of the pilots were using CGM in addition to following the fingerstick protocol.

At the time the protocol was developed a decade ago, CGM wasn’t considered accurate enough and there wasn’t evidence for its use at high altitude.

But there has been a great deal more data since then, she said, noting “we believe it would be safer to use now because of how good that equipment is. ... Certainly, there’s a good number [of pilots] using CGM, and hopefully that will increase and the protocol will change to allow them all to use CGM if they want to.

“I think we’ll probably see CGM in the protocol within the next year to 2 years. Hopefully, that will make things a lot easier, so pilots won’t have to prick their fingers while they’re flying.”

Her group is currently conducting a study (DEXFLY) on use of the Dexcom G6 in addition to fingersticks in commercial pilots with insulin-treated diabetes. Results are expected by the end of the year.

Dr. Evans commented: “I think it’s a no-brainer that CGM will become the gold standard. I understand why they’re going to want to be cautious about this, but if they can generate data to show it will be a low-risk change, I think it will come.”

He also noted that it was only a couple of years ago that U.K. law was changed to allow car drivers with insulin-treated diabetes to use CGM as part of their glucose-testing requirements (before driving and every 2 hours). CGM still isn’t approved for use by drivers of trucks or other large vehicles, but “I think at some point in the future it will become more accepted,” Dr. Evans commented.

Dr. Garden reported no relevant financial relationships. Dr. Evans has reported being an advisory board member of, speaker for, and/or grant recipient from Novo Nordisk, Dexcom, Medtronic, Abbott, Eli Lilly, and Roche. 

A version of this article originally appeared on Medscape.com.

A protocol developed in the United Kingdom that allows commercial pilots with insulin-treated diabetes to fly airplanes has resulted in precise glycemic control during flight and no safety issues, new research finds.

©mico_images/Thinkstock

The results are believed to be the largest-ever dataset for people with insulin-treated diabetes in “safety-critical” occupations, said Gillian L. Garden, MD, who presented the findings this week at the virtual annual meeting of the European Association for the Study of Diabetes.

The protocol, which involves multiple glucose measurements before and throughout flights and corrective action for out-of-range values, resulted in 98% of glucose values in target range with no pilot incapacitation. The results were also published in Diabetes Care earlier this year, noted Dr. Garden, a clinical fellow in diabetes and endocrinology at the Royal Surrey NHS Foundation Trust, Guildford, England.

“There were no safety concerns at all and certainly no episodes of pilot incapacitation throughout the [7.5] years of the study. Our study proves that the protocol is feasible, is practical to implement, and is easily understood by both pilots and copilots,” she observed.

Dr. Garden foresees wider use of this approach: “We believe the study is of international importance and this protocol could be adopted by other aviation authorities to allow more insulin-treated pilots worldwide to be able to fly commercial aircraft.”

“With proper oversight and a defined protocol such as the one that we’ve been working to produce it is possible for anybody with insulin-treated diabetes to, in fact, adequately perform other safety-critical occupations as well, and it would be good to see fewer people being discriminated against on the basis of their diabetes,” she emphasized.
 

‘Impressive’ study of highly motivated individuals

Historically, insulin-treated patients – with both types of diabetes – had been barred from many “safety-critical” occupations, including commercial airline piloting. This was out of concern both for the potential immediate effects of hypoglycemia, including cognitive impairment and slowing of reaction times, as well as the long-term effects of diabetes, including vision loss and nerve damage, Dr. Garden explained.

However, “with advances in diabetes management, including different insulin types, methods of delivery, and glucose-monitoring systems, it’s now possible for individuals to have excellent glycemic control. This, along with the implementation of legislation against discrimination, has allowed insulin-treated people to no longer be debarred from certain employments,” she explained during an EASD press briefing on Sept. 24.

An expert panel convened in 2010 by the U.K. Civil Aviation Authority developed the protocol, and in 2012, the CAA began issuing class 1 medical certificates to insulin-treated pilots. The protocol was subsequently adopted by Ireland in 2015 and by Austria in 2016.

Initial results from nearly 9,000 glucose readings of 26 U.K. pilots who received a certificate between 2012 and 2015 were reported at the EASD 2016 Annual Meeting and published in 2017.

The current study is far larger, with 38,621 glucose readings from 49 pilots from the United Kingdom, Ireland, and Austria who have been using the protocol since 2012. 

Mark Evans, MD, of Addenbrookes Hospital, Cambridge, England, said in an interview that “I thought this was a fascinating paper. ... I was deeply impressed by the data.”

Dr. Evans, who chairs the U.K. Department of Transport advisory panel on driving and diabetes, also noted: “The group of people with insulin-treated diabetes flying planes are a phenomenally motivated group who are prepared to do things that probably most drivers of motor vehicles would find oppressive or very difficult to do.”

“I thought the outcomes were really impressive in terms of the amount of time they were able to maintain themselves within glucose target ranges.”

Indeed, Dr. Garden said, “pilots are typically very organized and used to dealing with strict protocols with regard to all of the processes they have to follow before they fly and the safety checks they have to do. They adapted to this additional safety measure really well.”
 

Traffic light protocol keeps pilots in range

The protocol requires pilots to perform fingerstick glucose checks 30 minutes prior to flight, every hour during flight, and 30 minutes before landing. They must also attend clinical reviews every 6 months.

A traffic light system is used to denote acceptable pre- and in-flight glucose levels, with green meaning acceptable (5.0-15.0 mmol/L [90-270 mg/dL]), amber indicating caution for low (4.0-4.9 mmol/L [72-88 mg/dL]) or high (15.1-20.0 mmol/L [272-360 mg/dL]) blood glucose. Red requires immediate action (low blood glucose <4 mmol/L [72 mg/dL] and high >20 mmol/L [>360 mg/dL]).

Low amber values require the pilot to ingest 10-15 fast-acting carbohydrates and retest after 30 minutes. Low red values indicate the pilot must hand over the controls to the copilot. High readings of >15.0 mmol/L (>270 mg/dL) require an insulin dosing review. A high red value also requires the pilot to hand over the controls.

Of the 49 pilots, 84% had type 1 diabetes and 16% had insulin-treated type 2 diabetes. Most (61%) had class 1 medical certificates (required to validate a commercial pilot license) and 39% had class 2 medical certificates (required to validate a private pilot’s license). Median diabetes duration was 10.9 years.

Of note, all had become pilots prior to diabetes onset. As of now, the EU Aviation Safety Agency doesn’t allow people with preexisting insulin-treated diabetes to become pilots.

“We are fighting to change that, but with the U.K. leaving the EU, the Civil Aviation Authority might pursue it [separately]. We don’t know how that will pan out,” Dr. Garden noted during the briefing.

Over the 7.5 years, 97.7% of readings were within the green range, while just 1.42% were in the low amber range and 0.75% in the high amber range. Just 48 readings (0.12%) were in the low red range and 6 (0.02%) in the high red range. Of the 48 low reds, just 14 were recorded during flight. Of the six high reds, only two occurred during flight.

There were no instances of pilot incapacitation or changes in average hemoglobin A1c.

The results should alleviate concerns expressed after a prior report that pilots’ overall glycemic control could worsen if they pushed too hard to avoid lows, Dr. Garden noted.

The proportion of out-of-range values declined from 5.7% in 2013 to 1.2% in 2019. Low red values didn’t change (0.2% in 2013 and 0.1% in 2019) but high red values had completely disappeared by 2017.
 

What about CGM?

In response to a question during the briefing about use of continuous glucose monitoring, Dr. Garden said that some of the pilots were using CGM in addition to following the fingerstick protocol.

At the time the protocol was developed a decade ago, CGM wasn’t considered accurate enough and there wasn’t evidence for its use at high altitude.

But there has been a great deal more data since then, she said, noting “we believe it would be safer to use now because of how good that equipment is. ... Certainly, there’s a good number [of pilots] using CGM, and hopefully that will increase and the protocol will change to allow them all to use CGM if they want to.

“I think we’ll probably see CGM in the protocol within the next year to 2 years. Hopefully, that will make things a lot easier, so pilots won’t have to prick their fingers while they’re flying.”

Her group is currently conducting a study (DEXFLY) on use of the Dexcom G6 in addition to fingersticks in commercial pilots with insulin-treated diabetes. Results are expected by the end of the year.

Dr. Evans commented: “I think it’s a no-brainer that CGM will become the gold standard. I understand why they’re going to want to be cautious about this, but if they can generate data to show it will be a low-risk change, I think it will come.”

He also noted that it was only a couple of years ago that U.K. law was changed to allow car drivers with insulin-treated diabetes to use CGM as part of their glucose-testing requirements (before driving and every 2 hours). CGM still isn’t approved for use by drivers of trucks or other large vehicles, but “I think at some point in the future it will become more accepted,” Dr. Evans commented.

Dr. Garden reported no relevant financial relationships. Dr. Evans has reported being an advisory board member of, speaker for, and/or grant recipient from Novo Nordisk, Dexcom, Medtronic, Abbott, Eli Lilly, and Roche. 

A version of this article originally appeared on Medscape.com.

Patients with type 2 or type 1 diabetes who stay in a blood glucose range of 70-180 mg/dL at least 70% of the time have the lowest rates of major adverse coronary events, severe hypoglycemic episodes, and microvascular events, according to a post hoc analysis of data collected from 5,774 patients with type 2 diabetes.

Data collected by the DEVOTE trial showed that every additional 10% of the time that a patient with type 2 diabetes (T2D) spent in their target range for blood glucose linked with a significant 6% reduced rate for developing a major adverse cardiovascular event (MACE), Richard M. Bergenstal, MD, said at the virtual annual meeting of the European Association for the Study of Diabetes.

For every 10% increase in time in range (TIR), patients showed an average 10% drop in their incidence of severe hypoglycemic episodes.
 

Increasing evidence from post hoc analyses

These findings confirmed a prior post hoc analysis of data collected in the DCCT trial (NCT00360815), which were published in the New England Journal of Medicine, although those results showed significant relationships between increased TIR and decreased rates of retinopathy and microalbuminuria. For every 10% drop in TIR, retinopathy rose by 64% and microalbuminuria increased by 40%, according to a post hoc analysis of the DCCT data that Dr. Bergenstal helped run and was published in Diabetes Care.

“It’s becoming clear that time in range is an important metric for diabetes management, and our new findings and those previously reported with the DCCT data make it look like time in range is becoming a good marker for clinical outcomes as well,” said Dr. Bergenstal, an endocrinologist at the Park Nicollet Clinic in Minneapolis.

“It’s a new concept, getting time-in-range data,” said Dr. Bergenstal, who was a coauthor of recommendations from Diabetes Care that were made in 2019 by an expert panel organized by the Advanced Technologies & Treatments for Diabetes Congress. “We think this will be a good marker to keep glycemia in a safe range, and the results look positive.” Patients who stay in the blood glucose range of 70-180 mg/dL (3.9-10.0 mmol/L) at least 70% of the time generally have an hemoglobin A_1c of about 7%, which is what makes it a good target for patients and clinicians to focus on. Patients with a 50% TIR rate generally have an HbA_1c of about 8%.

But a TIR assessment can be more informative than HbA_1c, said the 2019 recommendations document. It called TIR assessments “appropriate and useful as clinical targets and outcome measurements that complement A1c for a wide range of people with diabetes.”
 

Data mining from DEVOTE

The analysis run by Dr. Bergenstal and his associates used data from 5,774 of the 7,637 patients enrolled in the DEVOTE trial, for whom adequate longitudinal blood glucose data were available to derive and track TIR. DEVOTE had the primary aim of comparing two different types of insulin in patients with T2D, according to its explanation in the New England Journal of Medicine. The DEVOTE patients did not undergo routine continuous blood glucose monitoring, so derivation of TIR was the only option with the dataset, Dr. Bergenstal said. “We’re trying to get continuous blood monitoring into T2D trials,” he said.

The post hoc analysis showed that, during the study’s follow-up of just under 2 years, patients who maintained a derived TIR of 70%-100% had about a 6% MACE rate, which peaked at nearly twice that in patients whose TIR was 30% or less. The analysis showed a roughly positive linear relationship between TIR and MACE rates across the range of TIR values. In an adjusted analysis, patients with at least a 70% TIR had a significant 31% lower rate of MACE events, compared with patients whose TIR was 50% or less.

A second analysis that looked for the association between TIR and incidence of hypoglycemic episodes showed a somewhat similar positive relationship, with incidence rates of severe hypoglycemia episodes of about 4%-5% among patients with a TIR of 70% or greater, and a rate of about 7% in patients with a TIR of 30% or less, spiking to 14% among patients with a TIR of 10% or less. In an adjusted analysis, patients with a TIR of at least 70% had a significant 46% lower rate of severe hypoglycemic events, compared with patients whose TIR was 50% or less. This finding belies a common misconception that the tighter glycemic control that produces a higher TIR will lead to increased episodes of severe hypoglycemia, Dr. Bergenstal noted.

He also reported less extensive data on microvascular events. In an adjusted analysis, patients with a TIR of at least 70% had a significant 40% cut in these events compared with patients with 50% or less TIR.

DEVOTE was funded by Novo Nordisk. Dr. Bergenstal has had financial relationships with Novo Nordisk and several other companies.

[email protected]

SOURCE: Bergenstal R et al. EASD 2020, abstract 159.

Patients with type 2 or type 1 diabetes who stay in a blood glucose range of 70-180 mg/dL at least 70% of the time have the lowest rates of major adverse coronary events, severe hypoglycemic episodes, and microvascular events, according to a post hoc analysis of data collected from 5,774 patients with type 2 diabetes.

Data collected by the DEVOTE trial showed that every additional 10% of the time that a patient with type 2 diabetes (T2D) spent in their target range for blood glucose linked with a significant 6% reduced rate for developing a major adverse cardiovascular event (MACE), Richard M. Bergenstal, MD, said at the virtual annual meeting of the European Association for the Study of Diabetes.

For every 10% increase in time in range (TIR), patients showed an average 10% drop in their incidence of severe hypoglycemic episodes.
 

Increasing evidence from post hoc analyses

These findings confirmed a prior post hoc analysis of data collected in the DCCT trial (NCT00360815), which were published in the New England Journal of Medicine, although those results showed significant relationships between increased TIR and decreased rates of retinopathy and microalbuminuria. For every 10% drop in TIR, retinopathy rose by 64% and microalbuminuria increased by 40%, according to a post hoc analysis of the DCCT data that Dr. Bergenstal helped run and was published in Diabetes Care.

“It’s becoming clear that time in range is an important metric for diabetes management, and our new findings and those previously reported with the DCCT data make it look like time in range is becoming a good marker for clinical outcomes as well,” said Dr. Bergenstal, an endocrinologist at the Park Nicollet Clinic in Minneapolis.

“It’s a new concept, getting time-in-range data,” said Dr. Bergenstal, who was a coauthor of recommendations from Diabetes Care that were made in 2019 by an expert panel organized by the Advanced Technologies & Treatments for Diabetes Congress. “We think this will be a good marker to keep glycemia in a safe range, and the results look positive.” Patients who stay in the blood glucose range of 70-180 mg/dL (3.9-10.0 mmol/L) at least 70% of the time generally have an hemoglobin A_1c of about 7%, which is what makes it a good target for patients and clinicians to focus on. Patients with a 50% TIR rate generally have an HbA_1c of about 8%.

But a TIR assessment can be more informative than HbA_1c, said the 2019 recommendations document. It called TIR assessments “appropriate and useful as clinical targets and outcome measurements that complement A1c for a wide range of people with diabetes.”
 

Data mining from DEVOTE

The analysis run by Dr. Bergenstal and his associates used data from 5,774 of the 7,637 patients enrolled in the DEVOTE trial, for whom adequate longitudinal blood glucose data were available to derive and track TIR. DEVOTE had the primary aim of comparing two different types of insulin in patients with T2D, according to its explanation in the New England Journal of Medicine. The DEVOTE patients did not undergo routine continuous blood glucose monitoring, so derivation of TIR was the only option with the dataset, Dr. Bergenstal said. “We’re trying to get continuous blood monitoring into T2D trials,” he said.

The post hoc analysis showed that, during the study’s follow-up of just under 2 years, patients who maintained a derived TIR of 70%-100% had about a 6% MACE rate, which peaked at nearly twice that in patients whose TIR was 30% or less. The analysis showed a roughly positive linear relationship between TIR and MACE rates across the range of TIR values. In an adjusted analysis, patients with at least a 70% TIR had a significant 31% lower rate of MACE events, compared with patients whose TIR was 50% or less.

A second analysis that looked for the association between TIR and incidence of hypoglycemic episodes showed a somewhat similar positive relationship, with incidence rates of severe hypoglycemia episodes of about 4%-5% among patients with a TIR of 70% or greater, and a rate of about 7% in patients with a TIR of 30% or less, spiking to 14% among patients with a TIR of 10% or less. In an adjusted analysis, patients with a TIR of at least 70% had a significant 46% lower rate of severe hypoglycemic events, compared with patients whose TIR was 50% or less. This finding belies a common misconception that the tighter glycemic control that produces a higher TIR will lead to increased episodes of severe hypoglycemia, Dr. Bergenstal noted.

He also reported less extensive data on microvascular events. In an adjusted analysis, patients with a TIR of at least 70% had a significant 40% cut in these events compared with patients with 50% or less TIR.

DEVOTE was funded by Novo Nordisk. Dr. Bergenstal has had financial relationships with Novo Nordisk and several other companies.

[email protected]

SOURCE: Bergenstal R et al. EASD 2020, abstract 159.

Patients with type 2 or type 1 diabetes who stay in a blood glucose range of 70-180 mg/dL at least 70% of the time have the lowest rates of major adverse coronary events, severe hypoglycemic episodes, and microvascular events, according to a post hoc analysis of data collected from 5,774 patients with type 2 diabetes.

Data collected by the DEVOTE trial showed that every additional 10% of the time that a patient with type 2 diabetes (T2D) spent in their target range for blood glucose linked with a significant 6% reduced rate for developing a major adverse cardiovascular event (MACE), Richard M. Bergenstal, MD, said at the virtual annual meeting of the European Association for the Study of Diabetes.

For every 10% increase in time in range (TIR), patients showed an average 10% drop in their incidence of severe hypoglycemic episodes.
 

Increasing evidence from post hoc analyses

These findings confirmed a prior post hoc analysis of data collected in the DCCT trial (NCT00360815), which were published in the New England Journal of Medicine, although those results showed significant relationships between increased TIR and decreased rates of retinopathy and microalbuminuria. For every 10% drop in TIR, retinopathy rose by 64% and microalbuminuria increased by 40%, according to a post hoc analysis of the DCCT data that Dr. Bergenstal helped run and was published in Diabetes Care.

“It’s becoming clear that time in range is an important metric for diabetes management, and our new findings and those previously reported with the DCCT data make it look like time in range is becoming a good marker for clinical outcomes as well,” said Dr. Bergenstal, an endocrinologist at the Park Nicollet Clinic in Minneapolis.

“It’s a new concept, getting time-in-range data,” said Dr. Bergenstal, who was a coauthor of recommendations from Diabetes Care that were made in 2019 by an expert panel organized by the Advanced Technologies & Treatments for Diabetes Congress. “We think this will be a good marker to keep glycemia in a safe range, and the results look positive.” Patients who stay in the blood glucose range of 70-180 mg/dL (3.9-10.0 mmol/L) at least 70% of the time generally have an hemoglobin A_1c of about 7%, which is what makes it a good target for patients and clinicians to focus on. Patients with a 50% TIR rate generally have an HbA_1c of about 8%.

But a TIR assessment can be more informative than HbA_1c, said the 2019 recommendations document. It called TIR assessments “appropriate and useful as clinical targets and outcome measurements that complement A1c for a wide range of people with diabetes.”
 

Data mining from DEVOTE

The analysis run by Dr. Bergenstal and his associates used data from 5,774 of the 7,637 patients enrolled in the DEVOTE trial, for whom adequate longitudinal blood glucose data were available to derive and track TIR. DEVOTE had the primary aim of comparing two different types of insulin in patients with T2D, according to its explanation in the New England Journal of Medicine. The DEVOTE patients did not undergo routine continuous blood glucose monitoring, so derivation of TIR was the only option with the dataset, Dr. Bergenstal said. “We’re trying to get continuous blood monitoring into T2D trials,” he said.

The post hoc analysis showed that, during the study’s follow-up of just under 2 years, patients who maintained a derived TIR of 70%-100% had about a 6% MACE rate, which peaked at nearly twice that in patients whose TIR was 30% or less. The analysis showed a roughly positive linear relationship between TIR and MACE rates across the range of TIR values. In an adjusted analysis, patients with at least a 70% TIR had a significant 31% lower rate of MACE events, compared with patients whose TIR was 50% or less.

A second analysis that looked for the association between TIR and incidence of hypoglycemic episodes showed a somewhat similar positive relationship, with incidence rates of severe hypoglycemia episodes of about 4%-5% among patients with a TIR of 70% or greater, and a rate of about 7% in patients with a TIR of 30% or less, spiking to 14% among patients with a TIR of 10% or less. In an adjusted analysis, patients with a TIR of at least 70% had a significant 46% lower rate of severe hypoglycemic events, compared with patients whose TIR was 50% or less. This finding belies a common misconception that the tighter glycemic control that produces a higher TIR will lead to increased episodes of severe hypoglycemia, Dr. Bergenstal noted.

He also reported less extensive data on microvascular events. In an adjusted analysis, patients with a TIR of at least 70% had a significant 40% cut in these events compared with patients with 50% or less TIR.

DEVOTE was funded by Novo Nordisk. Dr. Bergenstal has had financial relationships with Novo Nordisk and several other companies.

[email protected]

SOURCE: Bergenstal R et al. EASD 2020, abstract 159.

Type 2 diabetes patients could lower their risk for death from any cause by up to a third by exercising at a moderate to high level or by cycling, according to data from two studies reported at the virtual annual meeting of the European Association for the Study of Diabetes.

Yun-Ju Lai, MD, and colleagues from the Puli branch of Taichung Veterans General Hospital in Nantou, Taiwan, found that persons with type 2 diabetes who exercised at moderate to high intensity had a 25%-32% decreased risk for death, compared with those who did not exercise.

In a separate study, Mathias Ried-Larsen, MSc, PhD, group leader at the Centre for Physical Activity Research, Rigshospitalet, Copenhagen, and associates found that cycling was associated with a 25%-31% decreased risk for all-cause death compared to no cycling, and that cycling also reduced cardiovascular mortality.
 

Results fit with ADA recommendations

“There is really nothing surprising about these results as others have shown that regular participation in physical activity lowers both overall mortality rates and morbidity,” commented Sheri Colberg-Ochs, PhD, professor emerita in exercise science at Old Dominion University in Norfolk, Va., in an interview.

“Regular exercise participation lowers the risk of mortality in almost all populations with many different health conditions. It is not specific to people with type 2 diabetes,” Dr. Colberg-Ochs said. “These data add further support to the ADA [American Diabetes Association] recommendations by again suggesting that being more active leads to many health benefits for people with type 2 diabetes.”

Dr. Colberg-Ochs, who was not involved in either study, is recognized by the ADA as an Outstanding Educator in Diabetes. She was also involved in writing the ADA’s position statement on physical activity/exercise in diabetes, which advocate that adults with type 2 diabetes should reduce sedentary time and undertake both aerobic and resistance exercise training to help optimize their glycemic and general health outcomes.
 

Asian population understudied

In an interview Dr. Lai acknowledged that epidemiologic studies had shown that exercise reduced the risk of cardiovascular events and mortality in subjects with type 2 diabetes. “However, the dose of exercise capacity for reducing mortality risk in people with type 2 diabetes was not yet well investigated, especially in the Asian population.”

Dr. Lai and colleagues analyzed data on 4,859 subjects drawn from two Taiwanese databases – the National Health Interview Survey and the National Health Insurance research database – to study what effect exercise “capacity” had on the risk for death in those with type 2 diabetes.

“Information about physical activity during leisure time was collected by asking the questions: ‘How often do you exercise every week? What kind of exercise do you do? How long do you do the exercise?’, Dr. Lai said. “We included nearly all kinds of exercise in the analysis, such as jogging, swimming, walking, dancing, riding, and so on.”

Each exercise had an activity intensity code expressed as kilocalories per minute. This was used to determine the exercise “capacity” by multiplying it by how frequently the exercise was performed per week and for how long each time.

“I don’t think ‘capacity’ is the right word to use here. The equation they used describes their exercise ‘volume,’ not their capacity. Self-reported exercise is notoriously inaccurate,” Dr. Colberg-Ochs observed. Furthermore, “just asking people how much they exercise and at what intensity [without using a validated exercise questionnaire] gives questionable results.”

The study’s findings, however, were clear: Those who exercised at a higher level had a significantly decreased risk for all-cause mortality than did those with no exercise habits. The hazard ratio for death by any cause was 0.75 for those who undertook a moderate level of exercise, burning 0-800 kcal per week. Exercising at a higher level burned more than 800 kcal had a HR of 0.68. A significant (P < .01) trend in favor of more exercise was noted.
 

Cycling reduces all-cause and cardiovascular mortality

In their prospective cohort study, Dr. Ried-Larsen and associates took a more specific look at the effects of exercise on mortality in diabetes by studying a single exercise: cycling. They sampled data on more than 5,000 people collected as part of the European Prospective Investigation into Cancer and Nutrition study. First, they identified participants with diabetes – although they couldn’t distinguish type 1 from type 2 forms because this was self-reported or obtained from registries. They then identified those who reported cycling at their baseline assessment and those who reported a change in cycling habits at their second examination around 5 years later.

At baseline, 38% of participants reported that they cycled every week. The mean age was 56 years, diabetes duration was 8 years, one-fifth were smokers, and the average body mass index was 29 kg/m².

Participants who reported cycling up to 1 hour every week at baseline had a 25% reduction in all-cause mortality, compared with those who did not cycle. The biggest reduction (31%) in all-cause mortality was seen for cycling 2.5-5 hours a week; cycling for 1-2.5 hours, and for more than 5 hours, yielded 23% and 24% risk reductions, respectively.

A reverse J–shaped relationship between cycling duration and reduction in all-cause mortality was seen, Dr. Ried-Larsen noted during a live oral session at the virtual meeting. “The maximum benefit [was at] around 5 hours per week, and the benefits persisted until around 9 hours per week.” Adjustment for the prevalence of stroke, MI, cancer, hyperlipidemia, hypertension, and central obesity did not alter the findings.

“The direction of the association was the same for cardiovascular mortality as all-cause mortality, although a bit weaker, with the maximum benefit being around 4 hours per week, and that persisted up until around 8 hours per week,” Dr. Ried-Larsen said.

The benefits of cycling on all-cause and cardiovascular mortality were lost, however, if those who cycled at baseline stopped by the second examination. Those who did not cycle at the first but did at the second examination got a benefit on both, as did those who continued cycling.

“Cycling is among one of the preferred activities for diabetes patients, so it actually may help them to achieve the recommend level of physical activity,” Dr. Ried-Larsen said.
 

Tailored exercise program important

Advice for exercise “should be tailored to the individual and based on starting fitness levels and activity levels,” Dr. Colberg-Ochs recommended.

“Those who are the most sedentary and the least fit have the most to gain from doing any activity. They should be advised to start out slowly and progress slowly with both aerobic activities and some resistance training,” Dr. Colberg-Ochs said.

She added: “In addition, individuals over 40 should engage in regular balance training, and all individuals should do some flexibility exercises.”

The studies received no commercial funding and all those mentioned in this article had no conflicts of interest to disclose.

SOURCE: Lai Y-J et al. EASD 2020, Poster presentation 267; Ried-Larsen M et al. EASD 2020, Oral presentation 194.

Type 2 diabetes patients could lower their risk for death from any cause by up to a third by exercising at a moderate to high level or by cycling, according to data from two studies reported at the virtual annual meeting of the European Association for the Study of Diabetes.

Yun-Ju Lai, MD, and colleagues from the Puli branch of Taichung Veterans General Hospital in Nantou, Taiwan, found that persons with type 2 diabetes who exercised at moderate to high intensity had a 25%-32% decreased risk for death, compared with those who did not exercise.

In a separate study, Mathias Ried-Larsen, MSc, PhD, group leader at the Centre for Physical Activity Research, Rigshospitalet, Copenhagen, and associates found that cycling was associated with a 25%-31% decreased risk for all-cause death compared to no cycling, and that cycling also reduced cardiovascular mortality.
 

Results fit with ADA recommendations

“There is really nothing surprising about these results as others have shown that regular participation in physical activity lowers both overall mortality rates and morbidity,” commented Sheri Colberg-Ochs, PhD, professor emerita in exercise science at Old Dominion University in Norfolk, Va., in an interview.

“Regular exercise participation lowers the risk of mortality in almost all populations with many different health conditions. It is not specific to people with type 2 diabetes,” Dr. Colberg-Ochs said. “These data add further support to the ADA [American Diabetes Association] recommendations by again suggesting that being more active leads to many health benefits for people with type 2 diabetes.”

Dr. Colberg-Ochs, who was not involved in either study, is recognized by the ADA as an Outstanding Educator in Diabetes. She was also involved in writing the ADA’s position statement on physical activity/exercise in diabetes, which advocate that adults with type 2 diabetes should reduce sedentary time and undertake both aerobic and resistance exercise training to help optimize their glycemic and general health outcomes.
 

Asian population understudied

In an interview Dr. Lai acknowledged that epidemiologic studies had shown that exercise reduced the risk of cardiovascular events and mortality in subjects with type 2 diabetes. “However, the dose of exercise capacity for reducing mortality risk in people with type 2 diabetes was not yet well investigated, especially in the Asian population.”

Dr. Lai and colleagues analyzed data on 4,859 subjects drawn from two Taiwanese databases – the National Health Interview Survey and the National Health Insurance research database – to study what effect exercise “capacity” had on the risk for death in those with type 2 diabetes.

“Information about physical activity during leisure time was collected by asking the questions: ‘How often do you exercise every week? What kind of exercise do you do? How long do you do the exercise?’, Dr. Lai said. “We included nearly all kinds of exercise in the analysis, such as jogging, swimming, walking, dancing, riding, and so on.”

Each exercise had an activity intensity code expressed as kilocalories per minute. This was used to determine the exercise “capacity” by multiplying it by how frequently the exercise was performed per week and for how long each time.

“I don’t think ‘capacity’ is the right word to use here. The equation they used describes their exercise ‘volume,’ not their capacity. Self-reported exercise is notoriously inaccurate,” Dr. Colberg-Ochs observed. Furthermore, “just asking people how much they exercise and at what intensity [without using a validated exercise questionnaire] gives questionable results.”

The study’s findings, however, were clear: Those who exercised at a higher level had a significantly decreased risk for all-cause mortality than did those with no exercise habits. The hazard ratio for death by any cause was 0.75 for those who undertook a moderate level of exercise, burning 0-800 kcal per week. Exercising at a higher level burned more than 800 kcal had a HR of 0.68. A significant (P < .01) trend in favor of more exercise was noted.
 

Cycling reduces all-cause and cardiovascular mortality

In their prospective cohort study, Dr. Ried-Larsen and associates took a more specific look at the effects of exercise on mortality in diabetes by studying a single exercise: cycling. They sampled data on more than 5,000 people collected as part of the European Prospective Investigation into Cancer and Nutrition study. First, they identified participants with diabetes – although they couldn’t distinguish type 1 from type 2 forms because this was self-reported or obtained from registries. They then identified those who reported cycling at their baseline assessment and those who reported a change in cycling habits at their second examination around 5 years later.

At baseline, 38% of participants reported that they cycled every week. The mean age was 56 years, diabetes duration was 8 years, one-fifth were smokers, and the average body mass index was 29 kg/m².

Participants who reported cycling up to 1 hour every week at baseline had a 25% reduction in all-cause mortality, compared with those who did not cycle. The biggest reduction (31%) in all-cause mortality was seen for cycling 2.5-5 hours a week; cycling for 1-2.5 hours, and for more than 5 hours, yielded 23% and 24% risk reductions, respectively.

A reverse J–shaped relationship between cycling duration and reduction in all-cause mortality was seen, Dr. Ried-Larsen noted during a live oral session at the virtual meeting. “The maximum benefit [was at] around 5 hours per week, and the benefits persisted until around 9 hours per week.” Adjustment for the prevalence of stroke, MI, cancer, hyperlipidemia, hypertension, and central obesity did not alter the findings.

“The direction of the association was the same for cardiovascular mortality as all-cause mortality, although a bit weaker, with the maximum benefit being around 4 hours per week, and that persisted up until around 8 hours per week,” Dr. Ried-Larsen said.

The benefits of cycling on all-cause and cardiovascular mortality were lost, however, if those who cycled at baseline stopped by the second examination. Those who did not cycle at the first but did at the second examination got a benefit on both, as did those who continued cycling.

“Cycling is among one of the preferred activities for diabetes patients, so it actually may help them to achieve the recommend level of physical activity,” Dr. Ried-Larsen said.
 

Tailored exercise program important

Advice for exercise “should be tailored to the individual and based on starting fitness levels and activity levels,” Dr. Colberg-Ochs recommended.

“Those who are the most sedentary and the least fit have the most to gain from doing any activity. They should be advised to start out slowly and progress slowly with both aerobic activities and some resistance training,” Dr. Colberg-Ochs said.

She added: “In addition, individuals over 40 should engage in regular balance training, and all individuals should do some flexibility exercises.”

The studies received no commercial funding and all those mentioned in this article had no conflicts of interest to disclose.

SOURCE: Lai Y-J et al. EASD 2020, Poster presentation 267; Ried-Larsen M et al. EASD 2020, Oral presentation 194.

Type 2 diabetes patients could lower their risk for death from any cause by up to a third by exercising at a moderate to high level or by cycling, according to data from two studies reported at the virtual annual meeting of the European Association for the Study of Diabetes.

Yun-Ju Lai, MD, and colleagues from the Puli branch of Taichung Veterans General Hospital in Nantou, Taiwan, found that persons with type 2 diabetes who exercised at moderate to high intensity had a 25%-32% decreased risk for death, compared with those who did not exercise.

In a separate study, Mathias Ried-Larsen, MSc, PhD, group leader at the Centre for Physical Activity Research, Rigshospitalet, Copenhagen, and associates found that cycling was associated with a 25%-31% decreased risk for all-cause death compared to no cycling, and that cycling also reduced cardiovascular mortality.
 

Results fit with ADA recommendations

“There is really nothing surprising about these results as others have shown that regular participation in physical activity lowers both overall mortality rates and morbidity,” commented Sheri Colberg-Ochs, PhD, professor emerita in exercise science at Old Dominion University in Norfolk, Va., in an interview.

“Regular exercise participation lowers the risk of mortality in almost all populations with many different health conditions. It is not specific to people with type 2 diabetes,” Dr. Colberg-Ochs said. “These data add further support to the ADA [American Diabetes Association] recommendations by again suggesting that being more active leads to many health benefits for people with type 2 diabetes.”

Dr. Colberg-Ochs, who was not involved in either study, is recognized by the ADA as an Outstanding Educator in Diabetes. She was also involved in writing the ADA’s position statement on physical activity/exercise in diabetes, which advocate that adults with type 2 diabetes should reduce sedentary time and undertake both aerobic and resistance exercise training to help optimize their glycemic and general health outcomes.
 

Asian population understudied

In an interview Dr. Lai acknowledged that epidemiologic studies had shown that exercise reduced the risk of cardiovascular events and mortality in subjects with type 2 diabetes. “However, the dose of exercise capacity for reducing mortality risk in people with type 2 diabetes was not yet well investigated, especially in the Asian population.”

Dr. Lai and colleagues analyzed data on 4,859 subjects drawn from two Taiwanese databases – the National Health Interview Survey and the National Health Insurance research database – to study what effect exercise “capacity” had on the risk for death in those with type 2 diabetes.

“Information about physical activity during leisure time was collected by asking the questions: ‘How often do you exercise every week? What kind of exercise do you do? How long do you do the exercise?’, Dr. Lai said. “We included nearly all kinds of exercise in the analysis, such as jogging, swimming, walking, dancing, riding, and so on.”

Each exercise had an activity intensity code expressed as kilocalories per minute. This was used to determine the exercise “capacity” by multiplying it by how frequently the exercise was performed per week and for how long each time.

“I don’t think ‘capacity’ is the right word to use here. The equation they used describes their exercise ‘volume,’ not their capacity. Self-reported exercise is notoriously inaccurate,” Dr. Colberg-Ochs observed. Furthermore, “just asking people how much they exercise and at what intensity [without using a validated exercise questionnaire] gives questionable results.”

The study’s findings, however, were clear: Those who exercised at a higher level had a significantly decreased risk for all-cause mortality than did those with no exercise habits. The hazard ratio for death by any cause was 0.75 for those who undertook a moderate level of exercise, burning 0-800 kcal per week. Exercising at a higher level burned more than 800 kcal had a HR of 0.68. A significant (P < .01) trend in favor of more exercise was noted.
 

Cycling reduces all-cause and cardiovascular mortality

In their prospective cohort study, Dr. Ried-Larsen and associates took a more specific look at the effects of exercise on mortality in diabetes by studying a single exercise: cycling. They sampled data on more than 5,000 people collected as part of the European Prospective Investigation into Cancer and Nutrition study. First, they identified participants with diabetes – although they couldn’t distinguish type 1 from type 2 forms because this was self-reported or obtained from registries. They then identified those who reported cycling at their baseline assessment and those who reported a change in cycling habits at their second examination around 5 years later.

At baseline, 38% of participants reported that they cycled every week. The mean age was 56 years, diabetes duration was 8 years, one-fifth were smokers, and the average body mass index was 29 kg/m².

Participants who reported cycling up to 1 hour every week at baseline had a 25% reduction in all-cause mortality, compared with those who did not cycle. The biggest reduction (31%) in all-cause mortality was seen for cycling 2.5-5 hours a week; cycling for 1-2.5 hours, and for more than 5 hours, yielded 23% and 24% risk reductions, respectively.

A reverse J–shaped relationship between cycling duration and reduction in all-cause mortality was seen, Dr. Ried-Larsen noted during a live oral session at the virtual meeting. “The maximum benefit [was at] around 5 hours per week, and the benefits persisted until around 9 hours per week.” Adjustment for the prevalence of stroke, MI, cancer, hyperlipidemia, hypertension, and central obesity did not alter the findings.

“The direction of the association was the same for cardiovascular mortality as all-cause mortality, although a bit weaker, with the maximum benefit being around 4 hours per week, and that persisted up until around 8 hours per week,” Dr. Ried-Larsen said.

The benefits of cycling on all-cause and cardiovascular mortality were lost, however, if those who cycled at baseline stopped by the second examination. Those who did not cycle at the first but did at the second examination got a benefit on both, as did those who continued cycling.

“Cycling is among one of the preferred activities for diabetes patients, so it actually may help them to achieve the recommend level of physical activity,” Dr. Ried-Larsen said.
 

Tailored exercise program important

Advice for exercise “should be tailored to the individual and based on starting fitness levels and activity levels,” Dr. Colberg-Ochs recommended.

“Those who are the most sedentary and the least fit have the most to gain from doing any activity. They should be advised to start out slowly and progress slowly with both aerobic activities and some resistance training,” Dr. Colberg-Ochs said.

She added: “In addition, individuals over 40 should engage in regular balance training, and all individuals should do some flexibility exercises.”

The studies received no commercial funding and all those mentioned in this article had no conflicts of interest to disclose.

SOURCE: Lai Y-J et al. EASD 2020, Poster presentation 267; Ried-Larsen M et al. EASD 2020, Oral presentation 194.

The dramatically positive safety and efficacy results from the DAPA-CKD trial, which showed that treatment with the sodium-glucose transporter 2 (SGLT2) inhibitor dapagliflozin significantly cut both chronic kidney disease progression and all-cause death in patients with or without type 2 diabetes, were also notable for broadening the population of patients eligible for this treatment to those in the upper range of stage 4 CKD.

Courtesy European Society of Cardiology

Of the 4,304 CKD patients enrolled in DAPA-CKD, 624 (14%) had an estimated glomerular filtration rate (eGFR) of 25-29 mL/min per 1.73m², an unprecedented population to receive a drug from the SGLT2 inhibitor class in a reported study. The results provided definitive evidence for efficacy and safety in this range of renal function, said Hiddo J.L. Heerspink, Ph.D., at the virtual annual meeting of the European Association for the Study of Diabetes.

Until now, the widely accepted lowest level for starting an SGLT2 inhibitor in routine practice has been an eGFR as low as 30 mL/min per 1.73 m².
 

Using SGLT2 inhibitors when eGFR is as low as 25

“It’s time to reduce the eGFR level for initiating an SGLT2 inhibitor to as low as 25,” said Dr. Heerspink, a professor of clinical pharmacology at the University of Groningen (the Netherlands).

While conceding that this is primarily a decision to be made by guideline writers and regulatory bodies, he declared what he believed was established by the DAPA-CKD findings: “We’ve shown that dapagliflozin can be safely used in these patients. It is effective across the spectrum of kidney function.”

Other experts not associated with the study agreed.

Sara Freeman/MDedge News

The trial researchers were “brave” to enroll patients with eGFRs as low as 25 mL/min per 1.73 m², and “we urgently need these agents in patients with an eGFR this low,” commented Chantal Mathieu, MD, an endocrinologist and professor of medicine at Catholic University in Leuven, Belgium, and designated discussant for the report. Overall, she called the findings “spectacular,” a “landmark trial,” and a “winner.”

The study also set an new, lower floor for the level of albuminuria that can be usefully treated with dapagliflozin (Farxiga) by enrolling patients with a urinary albumin-to-creatinine ratio as low as 200 mg/g; the previous lower limit had been 300 mg/g, noted Dr. Mathieu. The new findings pose challenges to guideline writers, regulators who approve drug labels, and payers to a quickly make changes that will bring dapagliflozin to a wider number of patients with CKD.

Once the full DAPA-CKD results are reported, “it will change practice, and push the eGFR needle down” to as low as 25. It will also lower the albuminuria threshold for using dapagliflozin or other drugs in the class, commented David Z.I. Cherney, MD, a nephrologist at the University of Toronto. “It’s just one study,” he admitted, but the consistent renal benefits seen across several studies involving all four drugs in the SGLT2 inhibitor class will help hasten this change in identifying treatable patients, as well as expand the drug class to patients with CKD but no type 2 diabetes (T2D).

“I don’t think we’ve ever had stronger evidence” for drugs that can benefit both heart and renal function, plus the drug class is “very safe, and really easy to start” and maintain in patients, Dr. Cherney said in an interview. “It’s wonderful for these patients that we now have something new for treatment,” a drug with a “very favorable benefit-to-risk ratio.”
 

Results show many dapagliflozin benefits

While this broadening of the range of patients proven to tolerate and benefit from an SGLT2 inhibitor was an important consequence of DAPA-CKD, the study’s primary finding – that dapagliflozin was as safe and effective for slowing CKD progression in patients regardless of whether they also had T2D – will have an even bigger impact on expanding the target patient population. Showing efficacy in patients with CKD but without a T2D etiology, the status of about a third of the enrolled 4,304 patients, makes this treatment an option for “millions” of additional patients worldwide, said Dr. Heerspink. “These are the most common patients nephrologists see.” A major challenge now will be to do a better job finding patients with CKD who could benefit from dapagliflozin.

DAPA-CKD enrolled CKD patients based primarily on prespecified albuminuria and eGFR levels at more than 300 centers in 34 countries, including the United States. Virtually all patients, 97%, were on the only treatment now available with proven efficacy for slowing CKD, either an ACE inhibitor or an angiotensin receptor blocker. The small number of patients not on one of these drugs was because of poor tolerance.

The study’s primary endpoint was the combined rate of cardiovascular death, renal death, end-stage renal disease, or a drop in eGFR of at least 50% from baseline. This occurred in 14.5% of patients who received placebo and in 9.2% of those who received dapagliflozin during a median follow-up of 2.4 years, a highly significant 39% relative risk reduction. Concurrently with the report at the virtual meeting the results also appeared online in the New England Journal of Medicine. This 5.3% cut in the absolute rate of the combined, primary adverse outcome converted into a number needed to treat of 19 to prevent 1 event during 2.4 years, a “much lower” number needed to treat than reported for renin-angiotensin system inhibitors in these types of patients, Dr. Heerspink said.

Notable positive secondary outcomes included a significant 31% relative cut (a 2% absolute decline) in all-cause mortality, “a major highlight” of the findings, Dr. Heerspink said. Dapagliflozin treatment also linked with a significant 29% relative cut in the incidence of cardiovascular death or hospitalization for heart failure.

“Cardiovascular disease is the most common cause of death in patients with CKD,” explained David C. Wheeler, MD, a coinvestigator on the study and professor of kidney medicine at University College London. “The heart and kidney are intertwined. This is about cardiorenal disease.”

DAPA-CKD was funded by AstraZeneca, the company that markets dapagliflozin. Dr. Heerspink has been a consultant to and received research funding from AstraZeneca. He has also received personal fees from Mundipharma and Novo Nordisk, and he has also served as consultant to several other companies with the honoraria being paid to his institution. Dr. Mathieu has had relationships with AstraZeneca and several other companies. Dr. Cherney has been a consultant to and has received research funding from AstraZeneca and several other companies. Dr. Wheeler has received personal fees from AstraZeneca and from several other companies.

[email protected]

SOURCE: Heerspink HJL et al. EASD 2020 and N Engl J Med. 2020 Sep 24. doi: 10.1056/NEJMoa2024816.

The dramatically positive safety and efficacy results from the DAPA-CKD trial, which showed that treatment with the sodium-glucose transporter 2 (SGLT2) inhibitor dapagliflozin significantly cut both chronic kidney disease progression and all-cause death in patients with or without type 2 diabetes, were also notable for broadening the population of patients eligible for this treatment to those in the upper range of stage 4 CKD.

Courtesy European Society of Cardiology

Of the 4,304 CKD patients enrolled in DAPA-CKD, 624 (14%) had an estimated glomerular filtration rate (eGFR) of 25-29 mL/min per 1.73m², an unprecedented population to receive a drug from the SGLT2 inhibitor class in a reported study. The results provided definitive evidence for efficacy and safety in this range of renal function, said Hiddo J.L. Heerspink, Ph.D., at the virtual annual meeting of the European Association for the Study of Diabetes.

Until now, the widely accepted lowest level for starting an SGLT2 inhibitor in routine practice has been an eGFR as low as 30 mL/min per 1.73 m².
 

Using SGLT2 inhibitors when eGFR is as low as 25

“It’s time to reduce the eGFR level for initiating an SGLT2 inhibitor to as low as 25,” said Dr. Heerspink, a professor of clinical pharmacology at the University of Groningen (the Netherlands).

While conceding that this is primarily a decision to be made by guideline writers and regulatory bodies, he declared what he believed was established by the DAPA-CKD findings: “We’ve shown that dapagliflozin can be safely used in these patients. It is effective across the spectrum of kidney function.”

Other experts not associated with the study agreed.

Sara Freeman/MDedge News

The trial researchers were “brave” to enroll patients with eGFRs as low as 25 mL/min per 1.73 m², and “we urgently need these agents in patients with an eGFR this low,” commented Chantal Mathieu, MD, an endocrinologist and professor of medicine at Catholic University in Leuven, Belgium, and designated discussant for the report. Overall, she called the findings “spectacular,” a “landmark trial,” and a “winner.”

The study also set an new, lower floor for the level of albuminuria that can be usefully treated with dapagliflozin (Farxiga) by enrolling patients with a urinary albumin-to-creatinine ratio as low as 200 mg/g; the previous lower limit had been 300 mg/g, noted Dr. Mathieu. The new findings pose challenges to guideline writers, regulators who approve drug labels, and payers to a quickly make changes that will bring dapagliflozin to a wider number of patients with CKD.

Once the full DAPA-CKD results are reported, “it will change practice, and push the eGFR needle down” to as low as 25. It will also lower the albuminuria threshold for using dapagliflozin or other drugs in the class, commented David Z.I. Cherney, MD, a nephrologist at the University of Toronto. “It’s just one study,” he admitted, but the consistent renal benefits seen across several studies involving all four drugs in the SGLT2 inhibitor class will help hasten this change in identifying treatable patients, as well as expand the drug class to patients with CKD but no type 2 diabetes (T2D).

“I don’t think we’ve ever had stronger evidence” for drugs that can benefit both heart and renal function, plus the drug class is “very safe, and really easy to start” and maintain in patients, Dr. Cherney said in an interview. “It’s wonderful for these patients that we now have something new for treatment,” a drug with a “very favorable benefit-to-risk ratio.”
 

Results show many dapagliflozin benefits

While this broadening of the range of patients proven to tolerate and benefit from an SGLT2 inhibitor was an important consequence of DAPA-CKD, the study’s primary finding – that dapagliflozin was as safe and effective for slowing CKD progression in patients regardless of whether they also had T2D – will have an even bigger impact on expanding the target patient population. Showing efficacy in patients with CKD but without a T2D etiology, the status of about a third of the enrolled 4,304 patients, makes this treatment an option for “millions” of additional patients worldwide, said Dr. Heerspink. “These are the most common patients nephrologists see.” A major challenge now will be to do a better job finding patients with CKD who could benefit from dapagliflozin.

DAPA-CKD enrolled CKD patients based primarily on prespecified albuminuria and eGFR levels at more than 300 centers in 34 countries, including the United States. Virtually all patients, 97%, were on the only treatment now available with proven efficacy for slowing CKD, either an ACE inhibitor or an angiotensin receptor blocker. The small number of patients not on one of these drugs was because of poor tolerance.

The study’s primary endpoint was the combined rate of cardiovascular death, renal death, end-stage renal disease, or a drop in eGFR of at least 50% from baseline. This occurred in 14.5% of patients who received placebo and in 9.2% of those who received dapagliflozin during a median follow-up of 2.4 years, a highly significant 39% relative risk reduction. Concurrently with the report at the virtual meeting the results also appeared online in the New England Journal of Medicine. This 5.3% cut in the absolute rate of the combined, primary adverse outcome converted into a number needed to treat of 19 to prevent 1 event during 2.4 years, a “much lower” number needed to treat than reported for renin-angiotensin system inhibitors in these types of patients, Dr. Heerspink said.

Notable positive secondary outcomes included a significant 31% relative cut (a 2% absolute decline) in all-cause mortality, “a major highlight” of the findings, Dr. Heerspink said. Dapagliflozin treatment also linked with a significant 29% relative cut in the incidence of cardiovascular death or hospitalization for heart failure.

“Cardiovascular disease is the most common cause of death in patients with CKD,” explained David C. Wheeler, MD, a coinvestigator on the study and professor of kidney medicine at University College London. “The heart and kidney are intertwined. This is about cardiorenal disease.”

DAPA-CKD was funded by AstraZeneca, the company that markets dapagliflozin. Dr. Heerspink has been a consultant to and received research funding from AstraZeneca. He has also received personal fees from Mundipharma and Novo Nordisk, and he has also served as consultant to several other companies with the honoraria being paid to his institution. Dr. Mathieu has had relationships with AstraZeneca and several other companies. Dr. Cherney has been a consultant to and has received research funding from AstraZeneca and several other companies. Dr. Wheeler has received personal fees from AstraZeneca and from several other companies.

[email protected]

SOURCE: Heerspink HJL et al. EASD 2020 and N Engl J Med. 2020 Sep 24. doi: 10.1056/NEJMoa2024816.

The dramatically positive safety and efficacy results from the DAPA-CKD trial, which showed that treatment with the sodium-glucose transporter 2 (SGLT2) inhibitor dapagliflozin significantly cut both chronic kidney disease progression and all-cause death in patients with or without type 2 diabetes, were also notable for broadening the population of patients eligible for this treatment to those in the upper range of stage 4 CKD.

Courtesy European Society of Cardiology

Of the 4,304 CKD patients enrolled in DAPA-CKD, 624 (14%) had an estimated glomerular filtration rate (eGFR) of 25-29 mL/min per 1.73m², an unprecedented population to receive a drug from the SGLT2 inhibitor class in a reported study. The results provided definitive evidence for efficacy and safety in this range of renal function, said Hiddo J.L. Heerspink, Ph.D., at the virtual annual meeting of the European Association for the Study of Diabetes.

Until now, the widely accepted lowest level for starting an SGLT2 inhibitor in routine practice has been an eGFR as low as 30 mL/min per 1.73 m².
 

Using SGLT2 inhibitors when eGFR is as low as 25

“It’s time to reduce the eGFR level for initiating an SGLT2 inhibitor to as low as 25,” said Dr. Heerspink, a professor of clinical pharmacology at the University of Groningen (the Netherlands).

While conceding that this is primarily a decision to be made by guideline writers and regulatory bodies, he declared what he believed was established by the DAPA-CKD findings: “We’ve shown that dapagliflozin can be safely used in these patients. It is effective across the spectrum of kidney function.”

Other experts not associated with the study agreed.

Sara Freeman/MDedge News

The trial researchers were “brave” to enroll patients with eGFRs as low as 25 mL/min per 1.73 m², and “we urgently need these agents in patients with an eGFR this low,” commented Chantal Mathieu, MD, an endocrinologist and professor of medicine at Catholic University in Leuven, Belgium, and designated discussant for the report. Overall, she called the findings “spectacular,” a “landmark trial,” and a “winner.”

The study also set an new, lower floor for the level of albuminuria that can be usefully treated with dapagliflozin (Farxiga) by enrolling patients with a urinary albumin-to-creatinine ratio as low as 200 mg/g; the previous lower limit had been 300 mg/g, noted Dr. Mathieu. The new findings pose challenges to guideline writers, regulators who approve drug labels, and payers to a quickly make changes that will bring dapagliflozin to a wider number of patients with CKD.

Once the full DAPA-CKD results are reported, “it will change practice, and push the eGFR needle down” to as low as 25. It will also lower the albuminuria threshold for using dapagliflozin or other drugs in the class, commented David Z.I. Cherney, MD, a nephrologist at the University of Toronto. “It’s just one study,” he admitted, but the consistent renal benefits seen across several studies involving all four drugs in the SGLT2 inhibitor class will help hasten this change in identifying treatable patients, as well as expand the drug class to patients with CKD but no type 2 diabetes (T2D).

“I don’t think we’ve ever had stronger evidence” for drugs that can benefit both heart and renal function, plus the drug class is “very safe, and really easy to start” and maintain in patients, Dr. Cherney said in an interview. “It’s wonderful for these patients that we now have something new for treatment,” a drug with a “very favorable benefit-to-risk ratio.”
 

Results show many dapagliflozin benefits

While this broadening of the range of patients proven to tolerate and benefit from an SGLT2 inhibitor was an important consequence of DAPA-CKD, the study’s primary finding – that dapagliflozin was as safe and effective for slowing CKD progression in patients regardless of whether they also had T2D – will have an even bigger impact on expanding the target patient population. Showing efficacy in patients with CKD but without a T2D etiology, the status of about a third of the enrolled 4,304 patients, makes this treatment an option for “millions” of additional patients worldwide, said Dr. Heerspink. “These are the most common patients nephrologists see.” A major challenge now will be to do a better job finding patients with CKD who could benefit from dapagliflozin.

DAPA-CKD enrolled CKD patients based primarily on prespecified albuminuria and eGFR levels at more than 300 centers in 34 countries, including the United States. Virtually all patients, 97%, were on the only treatment now available with proven efficacy for slowing CKD, either an ACE inhibitor or an angiotensin receptor blocker. The small number of patients not on one of these drugs was because of poor tolerance.

The study’s primary endpoint was the combined rate of cardiovascular death, renal death, end-stage renal disease, or a drop in eGFR of at least 50% from baseline. This occurred in 14.5% of patients who received placebo and in 9.2% of those who received dapagliflozin during a median follow-up of 2.4 years, a highly significant 39% relative risk reduction. Concurrently with the report at the virtual meeting the results also appeared online in the New England Journal of Medicine. This 5.3% cut in the absolute rate of the combined, primary adverse outcome converted into a number needed to treat of 19 to prevent 1 event during 2.4 years, a “much lower” number needed to treat than reported for renin-angiotensin system inhibitors in these types of patients, Dr. Heerspink said.

Notable positive secondary outcomes included a significant 31% relative cut (a 2% absolute decline) in all-cause mortality, “a major highlight” of the findings, Dr. Heerspink said. Dapagliflozin treatment also linked with a significant 29% relative cut in the incidence of cardiovascular death or hospitalization for heart failure.

“Cardiovascular disease is the most common cause of death in patients with CKD,” explained David C. Wheeler, MD, a coinvestigator on the study and professor of kidney medicine at University College London. “The heart and kidney are intertwined. This is about cardiorenal disease.”

DAPA-CKD was funded by AstraZeneca, the company that markets dapagliflozin. Dr. Heerspink has been a consultant to and received research funding from AstraZeneca. He has also received personal fees from Mundipharma and Novo Nordisk, and he has also served as consultant to several other companies with the honoraria being paid to his institution. Dr. Mathieu has had relationships with AstraZeneca and several other companies. Dr. Cherney has been a consultant to and has received research funding from AstraZeneca and several other companies. Dr. Wheeler has received personal fees from AstraZeneca and from several other companies.

[email protected]

SOURCE: Heerspink HJL et al. EASD 2020 and N Engl J Med. 2020 Sep 24. doi: 10.1056/NEJMoa2024816.

Further analyses from the cardiovascular outcome trial of the sodium-glucose transporter 2 inhibitor ertugliflozin in patients with type 2 diabetes helped better define positive effects the drug had on preserving renal function, and also gave a tantalizing hint that this drug, and hence possibly the entire SGLT2 inhibitor drug class, may benefit patients with heart failure with reduced ejection fraction.

But the underlying problem for ertugliflozin (Steglatro) – first seen when results from the VERTIS CV trial initially came out in June 2020 at the annual meeting of the American Diabetes Association – was that, while the trial met its primary endpoint of proving noninferiority to placebo for the combined endpoint of cardiovascular death, nonfatal MI, or nonfatal stroke, treatment with ertugliflozin showed no suggestion of benefit, compared with placebo for reducing this endpoint, producing a nonsignificant 3% relative cut in the combined rate of these adverse events, compared with placebo treatment.
 

‘Somewhat disappointing’ trial performance

Overall, results from VERTIS CV with ertugliflozin were “somewhat disappointing,” commented Melanie J. Davies, MD, who was not involved with the study and chaired a session at the virtual annual meeting of the European Association for the Study of Diabetes that reviewed the main results, put them into perspective, and added a few new exploratory analyses.

Although the results from 8,246-patient VERTIS CV (Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial) put ertugliflozin in the same league as other drugs from its class for safety, “we do not see the significant benefits observed in many of the previous cardiovascular outcomes trials” for other drugs in the SGLT2 inhibitor class, specifically canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance), Dr. Davies said in an interview. The upshot, for at least the time being, is that ertugliflozin “is unlikely to receive a label for any new indications,” she predicted. In contrast, the other drugs in the class have, for example, received a U.S. labeled indication to reduce cardiovascular death (empagliflozin) or major cardiovascular disease events (canagliflozin) in adults with type 2 diabetes (T2D) and cardiovascular disease, or to reduce heart failure hospitalizations (dapagliflozin).

The main results from VERTIS CV, posted online in the New England Journal of Medicine after the EASD session, showed a single significant outcome difference between treatment with ertugliflozin and placebo over a median of 3.0 years of follow-up from among 10 reported secondary outcomes: a 30% relative reduction (a 1.1% absolute reduction) in the rate of hospitalization for heart failure, the sole criterion in the report by which ertugliflozin matched the benefits of the other SGLT2 inhibitors.

But the prespecified design of VERTIS CV called for a hierarchical sequence of secondary analyses. The statistically significant noninferiority of the primary endpoint allowed calculation of the initial secondary endpoint, a reduction in the combined rate of cardiovascular death or hospitalization for heart failure. Ertugliflozin treatment cut this outcome by a relative 12%, compared with placebo, a difference that was not significant.

This neutral finding brought to a stop further statistical testing of any of the other secondary endpoints, including impact on hospitalization for heart failure by itself. It also guaranteed that no beneficial effect inferred from the trial’s data would qualify for statistical validity, making it unlikely that ertugliflozin would gain any new label indications from these results. The drug carries a U.S. label that is limited to providing glycemic control.

Choosing among the SGLT2 inhibitors

“What we can say for sure is that there is a glycemic benefit and a heart failure hospitalization benefit” across all four of the SGLT2 inhibitors. “Beyond that, the best we can say today [about using these drugs in practice] is to follow regulatory indications and guidelines recommendations,” commented Javed Butler, MD, a cardiologist and professor and chair of medicine at the University of Mississippi Medical Center, Jackson.

“These results are going to lead to some serious discussions among the research, clinical, and regulatory communities about class effects versus drug effects, and specific trial data versus the totality of evidence,” he said in an interview.

“I think it will influence prescribing ertugliflozin, particularly in patients with established cardiovascular disease, or when the goal is to improve heart failure outcomes of reduce chronic kidney disease,” added Dr. Davies, a professor of diabetes medicine at the University of Leicester (England). “We already have positive benefits [proven for these outcomes] using other agents in the class.”

Perhaps one feature potentially in ertugliflozin’s favor is its price, and whatever impact that might have for payers or patients with inadequate coverage for their drug costs. U.S. websites show a typical retail price for ertugliflozin that is roughly 40% below the three other agents in the class, a difference that can add up to an annual cost savings of about $2,500.

A major consideration for clinicians deciding which SGLT2 inhibitor to prescribe should be “what can the patient afford,” noted Darren K. McGuire, MD, a coinvestigator for VERTIS CV, during discussion of the trial at the EASD virtual meeting.
 

New analyses show more renal-effect consistency

One surprise in the initial VERTIS CV report was in the study’s key renal outcome, a composite of renal death, need for dialysis, or a doubling of the serum creatinine level, which reflects a cut of at least a 50% in estimated glomerular filtration rate (eGFR). This composite outcome trended toward a significant benefit but fell short, producing a nominal 19% relative reduction. This combined endpoint probably “set the bar too high,” said David Z.I. Cherney, MD, a nephrologist who led the renal assessments run in the trial. He presented several exploratory analyses during the virtual EASD session that provided reassuring evidence that ertugliflozin was not an outlier among the SGLT2 inhibitors when it came to kidney benefits.

Perhaps the most compelling analysis he reported was a slight tweak to the main renal composite endpoint that substituted prevention of a 40% or greater reduction in eGFR for prevention of a 50% or greater reduction. By this somewhat lower bar for efficacy, treatment with ertugliflozin in VERTIS CV linked with a 34% relative risk reduction, compared with placebo (a roughly 1% absolute reduction) that was statistically significant, and importantly came out very close to the effect for this revised endpoint that had been seen for the other three SGLT2 inhibitor drugs.

Focusing on prevention of a 40% or greater drop in eGFR “gives a much more robust measure of renal protection,” Dr. Cherney, a clinician and researcher at the University of Toronto, said in an interview. “The key message is that renal protection is much more uniform” with the rest of the drugs in the class when looked at this way or by some of the other alternative parameters he reported. But the new renal analyses do not address disparities seen among the drugs in the class for several cardiovascular disease effects.

“The overall impression from VERTIS CV is that there was less cardiovascular disease benefit,” except for prevention of heart failure hospitalization, he said.

A teaser for HFpEF

One additional notable new finding discussed during the EASD session stemmed from the investigators ability to mine the medical records of enrolled patients for information about their heart failure history and left ventricular ejection fractions, a data set that was “unique,” compared with the other cardiovascular outcome trials for the drugs in the class, noted Francesco Cosentino, MD, another VERTIS CV coinvestigator and professor of cardiology at the Karolinska Institute in Stockholm.

Roughly a quarter of the enrolled patients had a history of heart failure, and about half of these patients had heart failure with preserved ejection fraction, about 1,000 total patients. In this subgroup treatment with ertugliflozin linked with a 30% relative reduction in hospitalization for heart failure, compared with placebo, a roughly 0.5% absolute reduction. The numbers were small and underpowered for producing convincing evidence, but it provided an intriguing hint of benefit for an unmet need that is currently undergoing further testing in studies designed to specifically explore benefit in this type of heart failure patient, said Dr. Cosentino.

VERTIS CV was sponsored by Merck and Pfizer, the companies that market ertugliflozin. Dr. Davies has been a speaker on behalf of Merck and has had relationships with several other companies. Dr. Butler is a consultant to Merck and several other companies. Dr. McGuire has received honoraria from Merck, nonfinancial support from Pfizer, and has had relationships with several other companies. Dr. Cherney has received honoraria from Merck, nonfinancial research support from Pfizer, and has also had relationships with several other companies. Dr. Cosentino has received fees from Merck and Pfizer, and also from Abbott, AstraZeneca, Bayer, Bristol-Myers Squibb, and Novo Nordisk

[email protected]

Further analyses from the cardiovascular outcome trial of the sodium-glucose transporter 2 inhibitor ertugliflozin in patients with type 2 diabetes helped better define positive effects the drug had on preserving renal function, and also gave a tantalizing hint that this drug, and hence possibly the entire SGLT2 inhibitor drug class, may benefit patients with heart failure with reduced ejection fraction.

But the underlying problem for ertugliflozin (Steglatro) – first seen when results from the VERTIS CV trial initially came out in June 2020 at the annual meeting of the American Diabetes Association – was that, while the trial met its primary endpoint of proving noninferiority to placebo for the combined endpoint of cardiovascular death, nonfatal MI, or nonfatal stroke, treatment with ertugliflozin showed no suggestion of benefit, compared with placebo for reducing this endpoint, producing a nonsignificant 3% relative cut in the combined rate of these adverse events, compared with placebo treatment.
 

‘Somewhat disappointing’ trial performance

Overall, results from VERTIS CV with ertugliflozin were “somewhat disappointing,” commented Melanie J. Davies, MD, who was not involved with the study and chaired a session at the virtual annual meeting of the European Association for the Study of Diabetes that reviewed the main results, put them into perspective, and added a few new exploratory analyses.

Although the results from 8,246-patient VERTIS CV (Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial) put ertugliflozin in the same league as other drugs from its class for safety, “we do not see the significant benefits observed in many of the previous cardiovascular outcomes trials” for other drugs in the SGLT2 inhibitor class, specifically canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance), Dr. Davies said in an interview. The upshot, for at least the time being, is that ertugliflozin “is unlikely to receive a label for any new indications,” she predicted. In contrast, the other drugs in the class have, for example, received a U.S. labeled indication to reduce cardiovascular death (empagliflozin) or major cardiovascular disease events (canagliflozin) in adults with type 2 diabetes (T2D) and cardiovascular disease, or to reduce heart failure hospitalizations (dapagliflozin).

The main results from VERTIS CV, posted online in the New England Journal of Medicine after the EASD session, showed a single significant outcome difference between treatment with ertugliflozin and placebo over a median of 3.0 years of follow-up from among 10 reported secondary outcomes: a 30% relative reduction (a 1.1% absolute reduction) in the rate of hospitalization for heart failure, the sole criterion in the report by which ertugliflozin matched the benefits of the other SGLT2 inhibitors.

But the prespecified design of VERTIS CV called for a hierarchical sequence of secondary analyses. The statistically significant noninferiority of the primary endpoint allowed calculation of the initial secondary endpoint, a reduction in the combined rate of cardiovascular death or hospitalization for heart failure. Ertugliflozin treatment cut this outcome by a relative 12%, compared with placebo, a difference that was not significant.

This neutral finding brought to a stop further statistical testing of any of the other secondary endpoints, including impact on hospitalization for heart failure by itself. It also guaranteed that no beneficial effect inferred from the trial’s data would qualify for statistical validity, making it unlikely that ertugliflozin would gain any new label indications from these results. The drug carries a U.S. label that is limited to providing glycemic control.

Choosing among the SGLT2 inhibitors

“What we can say for sure is that there is a glycemic benefit and a heart failure hospitalization benefit” across all four of the SGLT2 inhibitors. “Beyond that, the best we can say today [about using these drugs in practice] is to follow regulatory indications and guidelines recommendations,” commented Javed Butler, MD, a cardiologist and professor and chair of medicine at the University of Mississippi Medical Center, Jackson.

“These results are going to lead to some serious discussions among the research, clinical, and regulatory communities about class effects versus drug effects, and specific trial data versus the totality of evidence,” he said in an interview.

“I think it will influence prescribing ertugliflozin, particularly in patients with established cardiovascular disease, or when the goal is to improve heart failure outcomes of reduce chronic kidney disease,” added Dr. Davies, a professor of diabetes medicine at the University of Leicester (England). “We already have positive benefits [proven for these outcomes] using other agents in the class.”

Perhaps one feature potentially in ertugliflozin’s favor is its price, and whatever impact that might have for payers or patients with inadequate coverage for their drug costs. U.S. websites show a typical retail price for ertugliflozin that is roughly 40% below the three other agents in the class, a difference that can add up to an annual cost savings of about $2,500.

A major consideration for clinicians deciding which SGLT2 inhibitor to prescribe should be “what can the patient afford,” noted Darren K. McGuire, MD, a coinvestigator for VERTIS CV, during discussion of the trial at the EASD virtual meeting.
 

New analyses show more renal-effect consistency

One surprise in the initial VERTIS CV report was in the study’s key renal outcome, a composite of renal death, need for dialysis, or a doubling of the serum creatinine level, which reflects a cut of at least a 50% in estimated glomerular filtration rate (eGFR). This composite outcome trended toward a significant benefit but fell short, producing a nominal 19% relative reduction. This combined endpoint probably “set the bar too high,” said David Z.I. Cherney, MD, a nephrologist who led the renal assessments run in the trial. He presented several exploratory analyses during the virtual EASD session that provided reassuring evidence that ertugliflozin was not an outlier among the SGLT2 inhibitors when it came to kidney benefits.

Perhaps the most compelling analysis he reported was a slight tweak to the main renal composite endpoint that substituted prevention of a 40% or greater reduction in eGFR for prevention of a 50% or greater reduction. By this somewhat lower bar for efficacy, treatment with ertugliflozin in VERTIS CV linked with a 34% relative risk reduction, compared with placebo (a roughly 1% absolute reduction) that was statistically significant, and importantly came out very close to the effect for this revised endpoint that had been seen for the other three SGLT2 inhibitor drugs.

Focusing on prevention of a 40% or greater drop in eGFR “gives a much more robust measure of renal protection,” Dr. Cherney, a clinician and researcher at the University of Toronto, said in an interview. “The key message is that renal protection is much more uniform” with the rest of the drugs in the class when looked at this way or by some of the other alternative parameters he reported. But the new renal analyses do not address disparities seen among the drugs in the class for several cardiovascular disease effects.

“The overall impression from VERTIS CV is that there was less cardiovascular disease benefit,” except for prevention of heart failure hospitalization, he said.

A teaser for HFpEF

One additional notable new finding discussed during the EASD session stemmed from the investigators ability to mine the medical records of enrolled patients for information about their heart failure history and left ventricular ejection fractions, a data set that was “unique,” compared with the other cardiovascular outcome trials for the drugs in the class, noted Francesco Cosentino, MD, another VERTIS CV coinvestigator and professor of cardiology at the Karolinska Institute in Stockholm.

Roughly a quarter of the enrolled patients had a history of heart failure, and about half of these patients had heart failure with preserved ejection fraction, about 1,000 total patients. In this subgroup treatment with ertugliflozin linked with a 30% relative reduction in hospitalization for heart failure, compared with placebo, a roughly 0.5% absolute reduction. The numbers were small and underpowered for producing convincing evidence, but it provided an intriguing hint of benefit for an unmet need that is currently undergoing further testing in studies designed to specifically explore benefit in this type of heart failure patient, said Dr. Cosentino.

VERTIS CV was sponsored by Merck and Pfizer, the companies that market ertugliflozin. Dr. Davies has been a speaker on behalf of Merck and has had relationships with several other companies. Dr. Butler is a consultant to Merck and several other companies. Dr. McGuire has received honoraria from Merck, nonfinancial support from Pfizer, and has had relationships with several other companies. Dr. Cherney has received honoraria from Merck, nonfinancial research support from Pfizer, and has also had relationships with several other companies. Dr. Cosentino has received fees from Merck and Pfizer, and also from Abbott, AstraZeneca, Bayer, Bristol-Myers Squibb, and Novo Nordisk

[email protected]

Further analyses from the cardiovascular outcome trial of the sodium-glucose transporter 2 inhibitor ertugliflozin in patients with type 2 diabetes helped better define positive effects the drug had on preserving renal function, and also gave a tantalizing hint that this drug, and hence possibly the entire SGLT2 inhibitor drug class, may benefit patients with heart failure with reduced ejection fraction.

But the underlying problem for ertugliflozin (Steglatro) – first seen when results from the VERTIS CV trial initially came out in June 2020 at the annual meeting of the American Diabetes Association – was that, while the trial met its primary endpoint of proving noninferiority to placebo for the combined endpoint of cardiovascular death, nonfatal MI, or nonfatal stroke, treatment with ertugliflozin showed no suggestion of benefit, compared with placebo for reducing this endpoint, producing a nonsignificant 3% relative cut in the combined rate of these adverse events, compared with placebo treatment.
 

‘Somewhat disappointing’ trial performance

Overall, results from VERTIS CV with ertugliflozin were “somewhat disappointing,” commented Melanie J. Davies, MD, who was not involved with the study and chaired a session at the virtual annual meeting of the European Association for the Study of Diabetes that reviewed the main results, put them into perspective, and added a few new exploratory analyses.

Although the results from 8,246-patient VERTIS CV (Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial) put ertugliflozin in the same league as other drugs from its class for safety, “we do not see the significant benefits observed in many of the previous cardiovascular outcomes trials” for other drugs in the SGLT2 inhibitor class, specifically canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance), Dr. Davies said in an interview. The upshot, for at least the time being, is that ertugliflozin “is unlikely to receive a label for any new indications,” she predicted. In contrast, the other drugs in the class have, for example, received a U.S. labeled indication to reduce cardiovascular death (empagliflozin) or major cardiovascular disease events (canagliflozin) in adults with type 2 diabetes (T2D) and cardiovascular disease, or to reduce heart failure hospitalizations (dapagliflozin).

The main results from VERTIS CV, posted online in the New England Journal of Medicine after the EASD session, showed a single significant outcome difference between treatment with ertugliflozin and placebo over a median of 3.0 years of follow-up from among 10 reported secondary outcomes: a 30% relative reduction (a 1.1% absolute reduction) in the rate of hospitalization for heart failure, the sole criterion in the report by which ertugliflozin matched the benefits of the other SGLT2 inhibitors.

But the prespecified design of VERTIS CV called for a hierarchical sequence of secondary analyses. The statistically significant noninferiority of the primary endpoint allowed calculation of the initial secondary endpoint, a reduction in the combined rate of cardiovascular death or hospitalization for heart failure. Ertugliflozin treatment cut this outcome by a relative 12%, compared with placebo, a difference that was not significant.

This neutral finding brought to a stop further statistical testing of any of the other secondary endpoints, including impact on hospitalization for heart failure by itself. It also guaranteed that no beneficial effect inferred from the trial’s data would qualify for statistical validity, making it unlikely that ertugliflozin would gain any new label indications from these results. The drug carries a U.S. label that is limited to providing glycemic control.

Choosing among the SGLT2 inhibitors

“What we can say for sure is that there is a glycemic benefit and a heart failure hospitalization benefit” across all four of the SGLT2 inhibitors. “Beyond that, the best we can say today [about using these drugs in practice] is to follow regulatory indications and guidelines recommendations,” commented Javed Butler, MD, a cardiologist and professor and chair of medicine at the University of Mississippi Medical Center, Jackson.

“These results are going to lead to some serious discussions among the research, clinical, and regulatory communities about class effects versus drug effects, and specific trial data versus the totality of evidence,” he said in an interview.

“I think it will influence prescribing ertugliflozin, particularly in patients with established cardiovascular disease, or when the goal is to improve heart failure outcomes of reduce chronic kidney disease,” added Dr. Davies, a professor of diabetes medicine at the University of Leicester (England). “We already have positive benefits [proven for these outcomes] using other agents in the class.”

Perhaps one feature potentially in ertugliflozin’s favor is its price, and whatever impact that might have for payers or patients with inadequate coverage for their drug costs. U.S. websites show a typical retail price for ertugliflozin that is roughly 40% below the three other agents in the class, a difference that can add up to an annual cost savings of about $2,500.

A major consideration for clinicians deciding which SGLT2 inhibitor to prescribe should be “what can the patient afford,” noted Darren K. McGuire, MD, a coinvestigator for VERTIS CV, during discussion of the trial at the EASD virtual meeting.
 

New analyses show more renal-effect consistency

One surprise in the initial VERTIS CV report was in the study’s key renal outcome, a composite of renal death, need for dialysis, or a doubling of the serum creatinine level, which reflects a cut of at least a 50% in estimated glomerular filtration rate (eGFR). This composite outcome trended toward a significant benefit but fell short, producing a nominal 19% relative reduction. This combined endpoint probably “set the bar too high,” said David Z.I. Cherney, MD, a nephrologist who led the renal assessments run in the trial. He presented several exploratory analyses during the virtual EASD session that provided reassuring evidence that ertugliflozin was not an outlier among the SGLT2 inhibitors when it came to kidney benefits.

Perhaps the most compelling analysis he reported was a slight tweak to the main renal composite endpoint that substituted prevention of a 40% or greater reduction in eGFR for prevention of a 50% or greater reduction. By this somewhat lower bar for efficacy, treatment with ertugliflozin in VERTIS CV linked with a 34% relative risk reduction, compared with placebo (a roughly 1% absolute reduction) that was statistically significant, and importantly came out very close to the effect for this revised endpoint that had been seen for the other three SGLT2 inhibitor drugs.

Focusing on prevention of a 40% or greater drop in eGFR “gives a much more robust measure of renal protection,” Dr. Cherney, a clinician and researcher at the University of Toronto, said in an interview. “The key message is that renal protection is much more uniform” with the rest of the drugs in the class when looked at this way or by some of the other alternative parameters he reported. But the new renal analyses do not address disparities seen among the drugs in the class for several cardiovascular disease effects.

“The overall impression from VERTIS CV is that there was less cardiovascular disease benefit,” except for prevention of heart failure hospitalization, he said.

A teaser for HFpEF

One additional notable new finding discussed during the EASD session stemmed from the investigators ability to mine the medical records of enrolled patients for information about their heart failure history and left ventricular ejection fractions, a data set that was “unique,” compared with the other cardiovascular outcome trials for the drugs in the class, noted Francesco Cosentino, MD, another VERTIS CV coinvestigator and professor of cardiology at the Karolinska Institute in Stockholm.

Roughly a quarter of the enrolled patients had a history of heart failure, and about half of these patients had heart failure with preserved ejection fraction, about 1,000 total patients. In this subgroup treatment with ertugliflozin linked with a 30% relative reduction in hospitalization for heart failure, compared with placebo, a roughly 0.5% absolute reduction. The numbers were small and underpowered for producing convincing evidence, but it provided an intriguing hint of benefit for an unmet need that is currently undergoing further testing in studies designed to specifically explore benefit in this type of heart failure patient, said Dr. Cosentino.

VERTIS CV was sponsored by Merck and Pfizer, the companies that market ertugliflozin. Dr. Davies has been a speaker on behalf of Merck and has had relationships with several other companies. Dr. Butler is a consultant to Merck and several other companies. Dr. McGuire has received honoraria from Merck, nonfinancial support from Pfizer, and has had relationships with several other companies. Dr. Cherney has received honoraria from Merck, nonfinancial research support from Pfizer, and has also had relationships with several other companies. Dr. Cosentino has received fees from Merck and Pfizer, and also from Abbott, AstraZeneca, Bayer, Bristol-Myers Squibb, and Novo Nordisk

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