TBD Meeting (4154-18)

BERLIN – Gastric banding surgery and metformin produce similar improvements in insulin sensitivity and parameters indicative of preserved beta-cell function in patients with impaired glucose tolerance (IGT) or newly diagnosed type 2 diabetes mellitus (T2DM), according to the results of a study conducted by the Restoring Insulin Secretion (RISE) Consortium.

Sara Freeman/MDedge News

“Both interventions resulted in about 50% improvements in insulin sensitivity at 1 year, which was attenuated at 2 years,” reported study investigator Thomas Buchanan, MD, of the University of Southern California, Los Angeles, at the annual meeting of the European Association for the Study of Diabetes.

“The beta-cell responses fell in a pattern that maintained relatively, but not perfectly, stable compensation for insulin resistance,” he added.

Although glucose levels improved “only slightly,” he said, “acute compensation to glucose improved significantly with gastric banding and beta-cell compensation at maximal stimulation fell significantly with metformin.”

Results of the BetaFat (Beta Cell Restoration through Fat Mitigation) study, which are now published online in Diabetes Care, also showed that greater weight loss could be achieved with surgery versus metformin, with a 8.9 kg difference between the groups at 2 years (10.6 vs. 1.7 kg, respectively, P less than .01).

HDL cholesterol levels also rose with both interventions, and gastric banding resulted in a greater effect on very low–density lipoprotein cholesterol and triglycerides, as well as serum ALT, Dr. Buchanan said.

The BetaFat study is one of three “proof-of principle” studies currently being conducted by the RISE Consortium in patients with IGT, sometimes called prediabetes, and T2DM, explained Steven E. Kahn, MB, ChB, the chair for the RISE studies.

The other two multicenter, randomized trials being conducted by the RISE Consortium are looking at the effects of medications on preserving beta-cell function in pediatric/adolescent (10-19 years) and adult (21-65 years) populations with IGT or mild, recently diagnosed T2DM. The design, and some results, of these trials can be viewed on a dedicated section of the Diabetes Care website.

Beta-cell function is being assessed using “state-of-the-art” methods; the coprimary endpoint of the surgery versus metformin study was the steady state C-peptide level and acute C-peptide response at maximal glycemia measured using a hyperglycemic “clamp.”

The goal of the RISE studies is to test different approaches to preserve beta-cell function. It is designed to answer the question of which is more effective in this setting: sustained weight loss through gastric banding such as in the BetaFat study or medication.

Patients were eligible for inclusion in the study if they were aged 21-65 years, had a body mass index of 30-40 kg/m², and had IGT or a diagnosis of T2DM within the past year for which they had received no diabetes medication at recruitment.

A total of 88 individuals were randomized with exactly half undergoing gastric banding. This consisted of a gastric band placed laparoscopically and adjusted every 2 months for the first year, and then every 3 months for the following year depending on symptoms and weight change.

Normoglycemia was observed in none of the study subjects at baseline but in 22% and 15% of those who had gastric banding or metformin, respectively, at 2 years (P = .66).

As for tolerability, five patients who underwent gastric banding experienced serious adverse events, of which two were caused by band slippage and three were caused other reasons. In the metformin arm, there were two serious adverse events, both unrelated to the medication.

“Gastric banding and metformin offered approximately equal approaches for improving insulin sensitivity in adults with mild to moderate obesity and impaired glucose tolerance or early, mild type 2 diabetes,” Dr. Buchanan concluded. “The predominant beta-cell response was a reduction in secretion to maintain a relatively constant compensation for insulin resistance, with only a small improvement in glucose. Whether these interventions will have different effects on beta-cell function over the long-term remains to be determined.”

Sara Freeman/MDedge News

Commenting on the study, Roy Taylor, MD, professor of medicine and metabolism at Newcastle University (England), noted that the changes in the lipid and liver parameters were important. Fasting plasma triglyceride levels fell from 1.3 mmol/L at baseline to 1.1 mmol/L at 2 years with surgery but stayed more or less the same with metformin (1.23 mmol/L and 1.28 mmol/L; P less than .009 comparing surgery and metformin groups at 2 years). Change in ALT levels were also significant comparing baseline values with results at 2 years, decreasing in the surgical group to a greater extent than in the metformin groups.

“There’s a really important message here, the predictors of a better response to the weight loss [i.e. changes in triglycerides and liver enzymes] are all there,” Dr. Taylor observed. “RISE has looked at 2 years of this effect, but the conversion to type 2 diabetes is probably going to happen over a longer time course.”

He added that “although the primary outcome measure of change in insulin secretion was not achieved, the writing is on the wall. These people, provided they maintain their weight loss, are likely to succeed. We see all the hallmarks of a successful outcome for the weight loss group – remove the primary driver for type 2 diabetes, and that group is on track.”

The RISE Consortium conducted the BetaFat study. The RISE Consortium is supported by grants from the National Institutes for Health. Further support came from the Department of Veterans Affairs, Kaiser Permanente Southern California, the American Diabetes Association, and Allergan. Additional donations of supplies were provided by Allergan, Apollo Endosurgery, Abbott, and Novo Nordisk. Dr. Buchanan reported receiving research funding from Allergan and Apollo Endosurgery. Dr. Taylor had no conflicts of interest.
 

SOURCES: Buchanan T et al. EASD 2018, Session S09; Xiang AH et al. Diabetes Care. 2018 Oct; dc181662.

BERLIN – Gastric banding surgery and metformin produce similar improvements in insulin sensitivity and parameters indicative of preserved beta-cell function in patients with impaired glucose tolerance (IGT) or newly diagnosed type 2 diabetes mellitus (T2DM), according to the results of a study conducted by the Restoring Insulin Secretion (RISE) Consortium.

Sara Freeman/MDedge News

“Both interventions resulted in about 50% improvements in insulin sensitivity at 1 year, which was attenuated at 2 years,” reported study investigator Thomas Buchanan, MD, of the University of Southern California, Los Angeles, at the annual meeting of the European Association for the Study of Diabetes.

“The beta-cell responses fell in a pattern that maintained relatively, but not perfectly, stable compensation for insulin resistance,” he added.

Although glucose levels improved “only slightly,” he said, “acute compensation to glucose improved significantly with gastric banding and beta-cell compensation at maximal stimulation fell significantly with metformin.”

Results of the BetaFat (Beta Cell Restoration through Fat Mitigation) study, which are now published online in Diabetes Care, also showed that greater weight loss could be achieved with surgery versus metformin, with a 8.9 kg difference between the groups at 2 years (10.6 vs. 1.7 kg, respectively, P less than .01).

HDL cholesterol levels also rose with both interventions, and gastric banding resulted in a greater effect on very low–density lipoprotein cholesterol and triglycerides, as well as serum ALT, Dr. Buchanan said.

The BetaFat study is one of three “proof-of principle” studies currently being conducted by the RISE Consortium in patients with IGT, sometimes called prediabetes, and T2DM, explained Steven E. Kahn, MB, ChB, the chair for the RISE studies.

The other two multicenter, randomized trials being conducted by the RISE Consortium are looking at the effects of medications on preserving beta-cell function in pediatric/adolescent (10-19 years) and adult (21-65 years) populations with IGT or mild, recently diagnosed T2DM. The design, and some results, of these trials can be viewed on a dedicated section of the Diabetes Care website.

Beta-cell function is being assessed using “state-of-the-art” methods; the coprimary endpoint of the surgery versus metformin study was the steady state C-peptide level and acute C-peptide response at maximal glycemia measured using a hyperglycemic “clamp.”

The goal of the RISE studies is to test different approaches to preserve beta-cell function. It is designed to answer the question of which is more effective in this setting: sustained weight loss through gastric banding such as in the BetaFat study or medication.

Patients were eligible for inclusion in the study if they were aged 21-65 years, had a body mass index of 30-40 kg/m², and had IGT or a diagnosis of T2DM within the past year for which they had received no diabetes medication at recruitment.

A total of 88 individuals were randomized with exactly half undergoing gastric banding. This consisted of a gastric band placed laparoscopically and adjusted every 2 months for the first year, and then every 3 months for the following year depending on symptoms and weight change.

Normoglycemia was observed in none of the study subjects at baseline but in 22% and 15% of those who had gastric banding or metformin, respectively, at 2 years (P = .66).

As for tolerability, five patients who underwent gastric banding experienced serious adverse events, of which two were caused by band slippage and three were caused other reasons. In the metformin arm, there were two serious adverse events, both unrelated to the medication.

“Gastric banding and metformin offered approximately equal approaches for improving insulin sensitivity in adults with mild to moderate obesity and impaired glucose tolerance or early, mild type 2 diabetes,” Dr. Buchanan concluded. “The predominant beta-cell response was a reduction in secretion to maintain a relatively constant compensation for insulin resistance, with only a small improvement in glucose. Whether these interventions will have different effects on beta-cell function over the long-term remains to be determined.”

Sara Freeman/MDedge News

Commenting on the study, Roy Taylor, MD, professor of medicine and metabolism at Newcastle University (England), noted that the changes in the lipid and liver parameters were important. Fasting plasma triglyceride levels fell from 1.3 mmol/L at baseline to 1.1 mmol/L at 2 years with surgery but stayed more or less the same with metformin (1.23 mmol/L and 1.28 mmol/L; P less than .009 comparing surgery and metformin groups at 2 years). Change in ALT levels were also significant comparing baseline values with results at 2 years, decreasing in the surgical group to a greater extent than in the metformin groups.

“There’s a really important message here, the predictors of a better response to the weight loss [i.e. changes in triglycerides and liver enzymes] are all there,” Dr. Taylor observed. “RISE has looked at 2 years of this effect, but the conversion to type 2 diabetes is probably going to happen over a longer time course.”

He added that “although the primary outcome measure of change in insulin secretion was not achieved, the writing is on the wall. These people, provided they maintain their weight loss, are likely to succeed. We see all the hallmarks of a successful outcome for the weight loss group – remove the primary driver for type 2 diabetes, and that group is on track.”

The RISE Consortium conducted the BetaFat study. The RISE Consortium is supported by grants from the National Institutes for Health. Further support came from the Department of Veterans Affairs, Kaiser Permanente Southern California, the American Diabetes Association, and Allergan. Additional donations of supplies were provided by Allergan, Apollo Endosurgery, Abbott, and Novo Nordisk. Dr. Buchanan reported receiving research funding from Allergan and Apollo Endosurgery. Dr. Taylor had no conflicts of interest.
 

SOURCES: Buchanan T et al. EASD 2018, Session S09; Xiang AH et al. Diabetes Care. 2018 Oct; dc181662.

BERLIN – Gastric banding surgery and metformin produce similar improvements in insulin sensitivity and parameters indicative of preserved beta-cell function in patients with impaired glucose tolerance (IGT) or newly diagnosed type 2 diabetes mellitus (T2DM), according to the results of a study conducted by the Restoring Insulin Secretion (RISE) Consortium.

Sara Freeman/MDedge News

“Both interventions resulted in about 50% improvements in insulin sensitivity at 1 year, which was attenuated at 2 years,” reported study investigator Thomas Buchanan, MD, of the University of Southern California, Los Angeles, at the annual meeting of the European Association for the Study of Diabetes.

“The beta-cell responses fell in a pattern that maintained relatively, but not perfectly, stable compensation for insulin resistance,” he added.

Although glucose levels improved “only slightly,” he said, “acute compensation to glucose improved significantly with gastric banding and beta-cell compensation at maximal stimulation fell significantly with metformin.”

Results of the BetaFat (Beta Cell Restoration through Fat Mitigation) study, which are now published online in Diabetes Care, also showed that greater weight loss could be achieved with surgery versus metformin, with a 8.9 kg difference between the groups at 2 years (10.6 vs. 1.7 kg, respectively, P less than .01).

HDL cholesterol levels also rose with both interventions, and gastric banding resulted in a greater effect on very low–density lipoprotein cholesterol and triglycerides, as well as serum ALT, Dr. Buchanan said.

The BetaFat study is one of three “proof-of principle” studies currently being conducted by the RISE Consortium in patients with IGT, sometimes called prediabetes, and T2DM, explained Steven E. Kahn, MB, ChB, the chair for the RISE studies.

The other two multicenter, randomized trials being conducted by the RISE Consortium are looking at the effects of medications on preserving beta-cell function in pediatric/adolescent (10-19 years) and adult (21-65 years) populations with IGT or mild, recently diagnosed T2DM. The design, and some results, of these trials can be viewed on a dedicated section of the Diabetes Care website.

Beta-cell function is being assessed using “state-of-the-art” methods; the coprimary endpoint of the surgery versus metformin study was the steady state C-peptide level and acute C-peptide response at maximal glycemia measured using a hyperglycemic “clamp.”

The goal of the RISE studies is to test different approaches to preserve beta-cell function. It is designed to answer the question of which is more effective in this setting: sustained weight loss through gastric banding such as in the BetaFat study or medication.

Patients were eligible for inclusion in the study if they were aged 21-65 years, had a body mass index of 30-40 kg/m², and had IGT or a diagnosis of T2DM within the past year for which they had received no diabetes medication at recruitment.

A total of 88 individuals were randomized with exactly half undergoing gastric banding. This consisted of a gastric band placed laparoscopically and adjusted every 2 months for the first year, and then every 3 months for the following year depending on symptoms and weight change.

Normoglycemia was observed in none of the study subjects at baseline but in 22% and 15% of those who had gastric banding or metformin, respectively, at 2 years (P = .66).

As for tolerability, five patients who underwent gastric banding experienced serious adverse events, of which two were caused by band slippage and three were caused other reasons. In the metformin arm, there were two serious adverse events, both unrelated to the medication.

“Gastric banding and metformin offered approximately equal approaches for improving insulin sensitivity in adults with mild to moderate obesity and impaired glucose tolerance or early, mild type 2 diabetes,” Dr. Buchanan concluded. “The predominant beta-cell response was a reduction in secretion to maintain a relatively constant compensation for insulin resistance, with only a small improvement in glucose. Whether these interventions will have different effects on beta-cell function over the long-term remains to be determined.”

Sara Freeman/MDedge News

Commenting on the study, Roy Taylor, MD, professor of medicine and metabolism at Newcastle University (England), noted that the changes in the lipid and liver parameters were important. Fasting plasma triglyceride levels fell from 1.3 mmol/L at baseline to 1.1 mmol/L at 2 years with surgery but stayed more or less the same with metformin (1.23 mmol/L and 1.28 mmol/L; P less than .009 comparing surgery and metformin groups at 2 years). Change in ALT levels were also significant comparing baseline values with results at 2 years, decreasing in the surgical group to a greater extent than in the metformin groups.

“There’s a really important message here, the predictors of a better response to the weight loss [i.e. changes in triglycerides and liver enzymes] are all there,” Dr. Taylor observed. “RISE has looked at 2 years of this effect, but the conversion to type 2 diabetes is probably going to happen over a longer time course.”

He added that “although the primary outcome measure of change in insulin secretion was not achieved, the writing is on the wall. These people, provided they maintain their weight loss, are likely to succeed. We see all the hallmarks of a successful outcome for the weight loss group – remove the primary driver for type 2 diabetes, and that group is on track.”

The RISE Consortium conducted the BetaFat study. The RISE Consortium is supported by grants from the National Institutes for Health. Further support came from the Department of Veterans Affairs, Kaiser Permanente Southern California, the American Diabetes Association, and Allergan. Additional donations of supplies were provided by Allergan, Apollo Endosurgery, Abbott, and Novo Nordisk. Dr. Buchanan reported receiving research funding from Allergan and Apollo Endosurgery. Dr. Taylor had no conflicts of interest.
 

SOURCES: Buchanan T et al. EASD 2018, Session S09; Xiang AH et al. Diabetes Care. 2018 Oct; dc181662.

BERLIN – Albiglutide, a glucagonlike peptide–1 (GLP-1) agonist, added on top of the standard of care reduced the incidence of major cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM) with established cardiovascular disease by a significant 22% versus placebo in the HARMONY Outcomes trial, according to results reported at the annual meeting of the European Association for the Study of Diabetes.

The trial’s findings, which were published simultaneously in the Lancet, have added “further support that evidence-based GLP-1 receptor agonists should be part of a comprehensive strategy to reduce the risk for cardiovascular events in patients with type 2 diabetes as recommended by recent cardiology and diabetes guidelines,” said study investigator Lawrence Leiter, MD.

Albiglutide was approved for the treatment of T2DM by the European Medicines Agency as Eperzan and by the Food and Drug Administration in the United States as Tanzeum in 2014. Last year, however, its manufacturer, GlaxoSmithKline, announced that it would cease further research and development, manufacturing, and sales activity for albiglutide. Nevertheless, the company remained committed to completing the HARMONY Outcomes trial, begun in 2015.

In a press release issued by GSK on Oct. 2, 2018, the same day as the trial’s findings were revealed, John Lepore, MD, the senior vice president of GSK’s R&D pipeline said, “HARMONY Outcomes was an important study for us to complete to generate new data and insights about the role of the GLP-1 receptor agonist class in the management of patients with diabetes and cardiovascular disease.”

Dr. Lepore added, “GSK continued to invest in this study… and we continue to explore opportunities to divest this medicine to a company with the right expertise and resources to realize its full potential for patients.”

During his summing up of the HARMONY Outcomes data, Dr. Leiter of the University of Toronto observed that all components of the composite primary endpoint – which included MI, cardiovascular death, and stroke – were “directionally consistent with overall benefit.” However, it was the 25% reduction in MI that drove the overall benefit seen.

With an average duration of follow-up of just 1.6 years, it was no wonder perhaps that no effect on a long-term outcome such as cardiovascular death was seen, Dr. Leiter suggested. Insufficient trial length was a fact picked up by the independent commentator for the trial David Matthews, MD, professor of diabetic medicine at the University of Oxford (England).

Courtesy EASD

“HARMONY recruited patients who were extremely near the edge of a cliff,” Dr. Matthews observed, noting that, if a trial was to be completed in such a short span of time, a very-high-risk population needed to be recruited.

Indeed, 100% of the study population in the trial had cardiovascular disease; specifically, 70% had coronary artery disease, 47% had a prior MI, 43% had undergone percutaneous coronary intervention, and 25% had peripheral arterial disease. In addition, 86% had hypertension, 20% had heart failure, and 18% had experienced a stroke. Furthermore, the average hemoglobin A_1c (HbA_1c) at baseline was 8.7%.

When you are thinking about trial design, you want to recruit patients who are near the edge so that you see lots of events, but not too near such that treatment makes no difference and not too far from the edge or the trial will go on and on, Dr. Matthews observed.

With regards to the primary composite endpoint, he noted that no adjustment of the significance level was needed to test the superiority of albiglutide over placebo. The hazard ratio was 0.78, with a P value of less than .0001 for noninferiority and P = .0006 for superiority, and event rates per 100 patient-years were 4.57 for albiglutide and 5.87 for placebo.

The mean change in HbA_1c over time was greater with albiglutide than with placebo, with a between-group difference of –0.63% at 8 months and –0.52% at 16 months. These data suggest that albiglutide seems to have weaker effects than semaglutide, Dr. Matthews noted.

“The odd thing about albiglutide was the weight didn’t change,” Dr. Matthews observed when discussing some of the secondary endpoints. The difference in body weight between albiglutide and placebo was –0.66 kg at 8 months and –0.83 kg at 16 months.

If the results on body mass index with another GLP-1 agonist, semaglutide, were considered, effects on body weight in the HARMONY Outcomes trial were negligible, Dr. Matthews added. This point was something Twitter users also commented on.

“The weight loss is really modest with albiglutide in HARMONY”, said Abd Tahrani, MD, an National Institute for Health Research clinician scientist at the University of Birmingham (U.K.) and an honorary consultant endocrinologist the Heart of England National Health Service Foundation Trust in Birmingham.

Syed Gilani, MD, a general practitioner and champion for Diabetes UK, as well as being a clinical research fellow in diabetes and senior lecturer at the University of Wolverhampton (England), agreed and tweeted: “Is there a hint of GLP-1 class effect?”

While another U.K. diabetes consultant, Partha Kar, MD, a diabetes consultant and endocrinologist at Queen Alexandria Hospital, Portsmouth, England, tweeted: “Game-changer or confirmatory of class effect with better options available?”

The lack of a weight effect could be an advantage of course, Dr. Matthews observed; differences in the GLP-1 agonists could be matched to patients’ needs, with those you do not want to lose weight being given albiglutide.

In an editorial also published in the Lancet (2018 Oct 2. doi: 10.1016/S0140-6736[18]32348-1), Marion Mafham and David Preiss, PhD, who are both from the University of Oxford, observed that “given the clear cardiovascular benefit observed with albiglutide … GlaxoSmithKline should reconsider making it available to patients.”

Ms. Mafham and Dr. Preiss also noted in their comments that, while there has been inconsistency among GLP-1 trials, the HARMONY Outcomes data now add to the evidence of a cardiovascular benefit as seen in the SUSTAIN-6 trial with semaglutide and in the LEADER trial with liraglutide.

“International guidelines should reflect the increasing weight of evidence that supports the use of GLP-1 receptor agonists in patients with type 2 diabetes and cardiovascular disease,” the editorialists wrote.

The study was sponsored by GlaxoSmithKline. Dr. Leiter was an investigator in the study and disclosed receiving research funding and honoraria from GlaxoSmithKline, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, and Sanofi Aventis, as well as honoraria from Servier. Dr. Lepore is an employee of GlaxoSmithKline. Dr. Matthews disclosed acting as an advisory board member for and receiving consulting fees or honoraria from GlaxoSmithKline, Novo Nordisk, Novartis, Eli Lilly, Sanofi Aventis, Janssen, and Servier. Ms. Mafham has no competing interests. Dr. Preiss is an investigator in a trial funded by Boehringer Ingelheim.

SOURCE: Hernandez AF et al. Lancet. 2018 Oct 2. doi: 10.1016/S0140-6736(18)32261-X.

BERLIN – Albiglutide, a glucagonlike peptide–1 (GLP-1) agonist, added on top of the standard of care reduced the incidence of major cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM) with established cardiovascular disease by a significant 22% versus placebo in the HARMONY Outcomes trial, according to results reported at the annual meeting of the European Association for the Study of Diabetes.

The trial’s findings, which were published simultaneously in the Lancet, have added “further support that evidence-based GLP-1 receptor agonists should be part of a comprehensive strategy to reduce the risk for cardiovascular events in patients with type 2 diabetes as recommended by recent cardiology and diabetes guidelines,” said study investigator Lawrence Leiter, MD.

Albiglutide was approved for the treatment of T2DM by the European Medicines Agency as Eperzan and by the Food and Drug Administration in the United States as Tanzeum in 2014. Last year, however, its manufacturer, GlaxoSmithKline, announced that it would cease further research and development, manufacturing, and sales activity for albiglutide. Nevertheless, the company remained committed to completing the HARMONY Outcomes trial, begun in 2015.

In a press release issued by GSK on Oct. 2, 2018, the same day as the trial’s findings were revealed, John Lepore, MD, the senior vice president of GSK’s R&D pipeline said, “HARMONY Outcomes was an important study for us to complete to generate new data and insights about the role of the GLP-1 receptor agonist class in the management of patients with diabetes and cardiovascular disease.”

Dr. Lepore added, “GSK continued to invest in this study… and we continue to explore opportunities to divest this medicine to a company with the right expertise and resources to realize its full potential for patients.”

During his summing up of the HARMONY Outcomes data, Dr. Leiter of the University of Toronto observed that all components of the composite primary endpoint – which included MI, cardiovascular death, and stroke – were “directionally consistent with overall benefit.” However, it was the 25% reduction in MI that drove the overall benefit seen.

With an average duration of follow-up of just 1.6 years, it was no wonder perhaps that no effect on a long-term outcome such as cardiovascular death was seen, Dr. Leiter suggested. Insufficient trial length was a fact picked up by the independent commentator for the trial David Matthews, MD, professor of diabetic medicine at the University of Oxford (England).

Courtesy EASD

“HARMONY recruited patients who were extremely near the edge of a cliff,” Dr. Matthews observed, noting that, if a trial was to be completed in such a short span of time, a very-high-risk population needed to be recruited.

Indeed, 100% of the study population in the trial had cardiovascular disease; specifically, 70% had coronary artery disease, 47% had a prior MI, 43% had undergone percutaneous coronary intervention, and 25% had peripheral arterial disease. In addition, 86% had hypertension, 20% had heart failure, and 18% had experienced a stroke. Furthermore, the average hemoglobin A_1c (HbA_1c) at baseline was 8.7%.

When you are thinking about trial design, you want to recruit patients who are near the edge so that you see lots of events, but not too near such that treatment makes no difference and not too far from the edge or the trial will go on and on, Dr. Matthews observed.

With regards to the primary composite endpoint, he noted that no adjustment of the significance level was needed to test the superiority of albiglutide over placebo. The hazard ratio was 0.78, with a P value of less than .0001 for noninferiority and P = .0006 for superiority, and event rates per 100 patient-years were 4.57 for albiglutide and 5.87 for placebo.

The mean change in HbA_1c over time was greater with albiglutide than with placebo, with a between-group difference of –0.63% at 8 months and –0.52% at 16 months. These data suggest that albiglutide seems to have weaker effects than semaglutide, Dr. Matthews noted.

“The odd thing about albiglutide was the weight didn’t change,” Dr. Matthews observed when discussing some of the secondary endpoints. The difference in body weight between albiglutide and placebo was –0.66 kg at 8 months and –0.83 kg at 16 months.

If the results on body mass index with another GLP-1 agonist, semaglutide, were considered, effects on body weight in the HARMONY Outcomes trial were negligible, Dr. Matthews added. This point was something Twitter users also commented on.

“The weight loss is really modest with albiglutide in HARMONY”, said Abd Tahrani, MD, an National Institute for Health Research clinician scientist at the University of Birmingham (U.K.) and an honorary consultant endocrinologist the Heart of England National Health Service Foundation Trust in Birmingham.

Syed Gilani, MD, a general practitioner and champion for Diabetes UK, as well as being a clinical research fellow in diabetes and senior lecturer at the University of Wolverhampton (England), agreed and tweeted: “Is there a hint of GLP-1 class effect?”

While another U.K. diabetes consultant, Partha Kar, MD, a diabetes consultant and endocrinologist at Queen Alexandria Hospital, Portsmouth, England, tweeted: “Game-changer or confirmatory of class effect with better options available?”

The lack of a weight effect could be an advantage of course, Dr. Matthews observed; differences in the GLP-1 agonists could be matched to patients’ needs, with those you do not want to lose weight being given albiglutide.

In an editorial also published in the Lancet (2018 Oct 2. doi: 10.1016/S0140-6736[18]32348-1), Marion Mafham and David Preiss, PhD, who are both from the University of Oxford, observed that “given the clear cardiovascular benefit observed with albiglutide … GlaxoSmithKline should reconsider making it available to patients.”

Ms. Mafham and Dr. Preiss also noted in their comments that, while there has been inconsistency among GLP-1 trials, the HARMONY Outcomes data now add to the evidence of a cardiovascular benefit as seen in the SUSTAIN-6 trial with semaglutide and in the LEADER trial with liraglutide.

“International guidelines should reflect the increasing weight of evidence that supports the use of GLP-1 receptor agonists in patients with type 2 diabetes and cardiovascular disease,” the editorialists wrote.

The study was sponsored by GlaxoSmithKline. Dr. Leiter was an investigator in the study and disclosed receiving research funding and honoraria from GlaxoSmithKline, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, and Sanofi Aventis, as well as honoraria from Servier. Dr. Lepore is an employee of GlaxoSmithKline. Dr. Matthews disclosed acting as an advisory board member for and receiving consulting fees or honoraria from GlaxoSmithKline, Novo Nordisk, Novartis, Eli Lilly, Sanofi Aventis, Janssen, and Servier. Ms. Mafham has no competing interests. Dr. Preiss is an investigator in a trial funded by Boehringer Ingelheim.

SOURCE: Hernandez AF et al. Lancet. 2018 Oct 2. doi: 10.1016/S0140-6736(18)32261-X.

BERLIN – Albiglutide, a glucagonlike peptide–1 (GLP-1) agonist, added on top of the standard of care reduced the incidence of major cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM) with established cardiovascular disease by a significant 22% versus placebo in the HARMONY Outcomes trial, according to results reported at the annual meeting of the European Association for the Study of Diabetes.

The trial’s findings, which were published simultaneously in the Lancet, have added “further support that evidence-based GLP-1 receptor agonists should be part of a comprehensive strategy to reduce the risk for cardiovascular events in patients with type 2 diabetes as recommended by recent cardiology and diabetes guidelines,” said study investigator Lawrence Leiter, MD.

Albiglutide was approved for the treatment of T2DM by the European Medicines Agency as Eperzan and by the Food and Drug Administration in the United States as Tanzeum in 2014. Last year, however, its manufacturer, GlaxoSmithKline, announced that it would cease further research and development, manufacturing, and sales activity for albiglutide. Nevertheless, the company remained committed to completing the HARMONY Outcomes trial, begun in 2015.

In a press release issued by GSK on Oct. 2, 2018, the same day as the trial’s findings were revealed, John Lepore, MD, the senior vice president of GSK’s R&D pipeline said, “HARMONY Outcomes was an important study for us to complete to generate new data and insights about the role of the GLP-1 receptor agonist class in the management of patients with diabetes and cardiovascular disease.”

Dr. Lepore added, “GSK continued to invest in this study… and we continue to explore opportunities to divest this medicine to a company with the right expertise and resources to realize its full potential for patients.”

During his summing up of the HARMONY Outcomes data, Dr. Leiter of the University of Toronto observed that all components of the composite primary endpoint – which included MI, cardiovascular death, and stroke – were “directionally consistent with overall benefit.” However, it was the 25% reduction in MI that drove the overall benefit seen.

With an average duration of follow-up of just 1.6 years, it was no wonder perhaps that no effect on a long-term outcome such as cardiovascular death was seen, Dr. Leiter suggested. Insufficient trial length was a fact picked up by the independent commentator for the trial David Matthews, MD, professor of diabetic medicine at the University of Oxford (England).

Courtesy EASD

“HARMONY recruited patients who were extremely near the edge of a cliff,” Dr. Matthews observed, noting that, if a trial was to be completed in such a short span of time, a very-high-risk population needed to be recruited.

Indeed, 100% of the study population in the trial had cardiovascular disease; specifically, 70% had coronary artery disease, 47% had a prior MI, 43% had undergone percutaneous coronary intervention, and 25% had peripheral arterial disease. In addition, 86% had hypertension, 20% had heart failure, and 18% had experienced a stroke. Furthermore, the average hemoglobin A_1c (HbA_1c) at baseline was 8.7%.

When you are thinking about trial design, you want to recruit patients who are near the edge so that you see lots of events, but not too near such that treatment makes no difference and not too far from the edge or the trial will go on and on, Dr. Matthews observed.

With regards to the primary composite endpoint, he noted that no adjustment of the significance level was needed to test the superiority of albiglutide over placebo. The hazard ratio was 0.78, with a P value of less than .0001 for noninferiority and P = .0006 for superiority, and event rates per 100 patient-years were 4.57 for albiglutide and 5.87 for placebo.

The mean change in HbA_1c over time was greater with albiglutide than with placebo, with a between-group difference of –0.63% at 8 months and –0.52% at 16 months. These data suggest that albiglutide seems to have weaker effects than semaglutide, Dr. Matthews noted.

“The odd thing about albiglutide was the weight didn’t change,” Dr. Matthews observed when discussing some of the secondary endpoints. The difference in body weight between albiglutide and placebo was –0.66 kg at 8 months and –0.83 kg at 16 months.

If the results on body mass index with another GLP-1 agonist, semaglutide, were considered, effects on body weight in the HARMONY Outcomes trial were negligible, Dr. Matthews added. This point was something Twitter users also commented on.

“The weight loss is really modest with albiglutide in HARMONY”, said Abd Tahrani, MD, an National Institute for Health Research clinician scientist at the University of Birmingham (U.K.) and an honorary consultant endocrinologist the Heart of England National Health Service Foundation Trust in Birmingham.

Syed Gilani, MD, a general practitioner and champion for Diabetes UK, as well as being a clinical research fellow in diabetes and senior lecturer at the University of Wolverhampton (England), agreed and tweeted: “Is there a hint of GLP-1 class effect?”

While another U.K. diabetes consultant, Partha Kar, MD, a diabetes consultant and endocrinologist at Queen Alexandria Hospital, Portsmouth, England, tweeted: “Game-changer or confirmatory of class effect with better options available?”

The lack of a weight effect could be an advantage of course, Dr. Matthews observed; differences in the GLP-1 agonists could be matched to patients’ needs, with those you do not want to lose weight being given albiglutide.

In an editorial also published in the Lancet (2018 Oct 2. doi: 10.1016/S0140-6736[18]32348-1), Marion Mafham and David Preiss, PhD, who are both from the University of Oxford, observed that “given the clear cardiovascular benefit observed with albiglutide … GlaxoSmithKline should reconsider making it available to patients.”

Ms. Mafham and Dr. Preiss also noted in their comments that, while there has been inconsistency among GLP-1 trials, the HARMONY Outcomes data now add to the evidence of a cardiovascular benefit as seen in the SUSTAIN-6 trial with semaglutide and in the LEADER trial with liraglutide.

“International guidelines should reflect the increasing weight of evidence that supports the use of GLP-1 receptor agonists in patients with type 2 diabetes and cardiovascular disease,” the editorialists wrote.

The study was sponsored by GlaxoSmithKline. Dr. Leiter was an investigator in the study and disclosed receiving research funding and honoraria from GlaxoSmithKline, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, and Sanofi Aventis, as well as honoraria from Servier. Dr. Lepore is an employee of GlaxoSmithKline. Dr. Matthews disclosed acting as an advisory board member for and receiving consulting fees or honoraria from GlaxoSmithKline, Novo Nordisk, Novartis, Eli Lilly, Sanofi Aventis, Janssen, and Servier. Ms. Mafham has no competing interests. Dr. Preiss is an investigator in a trial funded by Boehringer Ingelheim.

SOURCE: Hernandez AF et al. Lancet. 2018 Oct 2. doi: 10.1016/S0140-6736(18)32261-X.